www.CovidReference.

com

Bernd Sebastian Kamps

Christian Hoffmann

COVID
reference
eng | 2020.5
covidreference.com
 Bernd Sebastian Kamps
Christian Hoffmann
COVID Reference
www.CovidReference.com
Fifth Edition 2020.5

CR 2020.5.04, uploaded on
7 November 2020

Editors, authors, publishing house and translators

have received no support from third parties to realize this textbook.
 Bernd Sebastian Kamps
Christian Hoffmann

COVID Reference
www.CovidReference.com
Edition 2020.5

Steinhäuser Verlag
4 |

Bernd Sebastian Kamps, M.D.

www.Amedeo.com

Christian Hoffmann, M.D.

Infektionsmedizinisches Centrum
Hamburg MVZ PartG (ICH)
ICH Stadtmitte
Glockengiesserwall 1
20095 Hamburg
researchgate.net/profile/Christian_Hoffmann8

Disclaimer
COVID medicine is a new and fast-changing field. The editors and authors of CovidReference.com
have made every effort to provide information that is accurate and complete as of the date of
publication. However, in view of the rapid changes occurring in medical science, COVID preven-
tion and policy, as well as the possibility of human error, this text may contain technical inaccu-
racies, typographical or other errors. Readers are advised to check the trials databases (fda.gov,
etc) as well as the product information currently provided by the manufacturer of each drug to
be administered to verify the recommended dose, the method and duration of administration,
and contraindications. It is the responsibility of the treating physician (and last-year students!)
who relies on experience and knowledge about the patient to determine the best treatment and
dosages for the patient. The information contained herein is provided “as is” and without war-
ranty of any kind. The contributors to this site, including Steinhäuser Verlag, disclaim responsi-
bility for any errors or omissions or for results obtained from the use of information contained
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© 2020 by Steinhäuser Verlag
ISBN: 978-3-942687-46-1
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 | 5

PREFACE
Second waves, third waves, never ending waves – as the world is about to en-
ter the second year of the SARS-CoV-2 pandemic, people realize that they are
just at the beginning of a global health and economic crisis. In the Northern
Hemisphere, the 6 dark autumn and winter months have begun and the world
is holding its breath: will the new coronavirus follow the track of the 1918 flu
epidemic, relatively mild in spring and devastating in autumn and winter?
There is no doubt that the immense resources of medicine and biotechnology
will soon produce a safe and effective vaccine; however, only fools expect
mass vaccinations before the middle of 2021 and a measurable impact on the
pandemic before 2022.
In the meantime, people around the globe will reduce their contacts with
other people and perfect their skills of social distancing. They will continue to
wear face masks next year, the year after and maybe beyond. It isn’t fun but it
must be done.

Bernd Sebastian Kamps & Christian Hoffmann

1 November 2020
6 | CovidReference.com

PREFACE TO THE FIRST EDITION

Seventeen years ago, in the middle of the outbreak, we decided to write a
short medical text about the ongoing SARS drama, presenting the scientific
data and providing real-time updates. After publishing three editions in
6 months, a scientific magazine concluded that our SARS Reference
(www.SARSReference.com) was “not fancy”, but presented “plenty of infor-
mation”. When we became aware of the new coronavirus epidemic in mid-
January 2020, we immediately felt that time had come to repeat our milleni-
um exercise.
While SARS-CoV-2 seems under control in China, the epidemic is moving west
briskly. What only weeks ago seemed an impossible feat – imposing and en-
forcing strict quarantine measures and isolating millions of people – is now a
reality in many countries. People all over the world will have to adapt and
invent new lifestyles in what is the most disruptive event since World War II.
We believe that the current situation needs a new type of textbook. Humanity
is confronting an unknown and threatening disease which is often severe and
fatal. Health care systems are overwhelmed. There is no proven treatment
and vaccines will not be available soon. Such a situation has not existed since
the flu pandemic in 1918.
We believe a clear head is crucial in times of over-information, with dozens of
scientific papers published every day, news about hundreds of studies being
planned or already on the way and social media blending hard data with ru-
mors and fake news. The tedious work of screening the scientific literature
and the scientific data has to be done – regularly & constantly, like a Swiss
watch.
Over the coming months, COVID Reference will be presenting updates on a
weekly basis and narrating the scientific data as coherently as possible.
Remember Science Magazine. It isn’t fancy.
Bernd Sebastian Kamps & Christian Hoffmann
29th March 2020
 | 7

CONTRIBUTING AUTHORS
Thomas Kamradt, M.D.
Professor of Immunology
President, German Society of Immunology
Institute of Immunology
University Hospital Jena
Leutragraben 3
D – 07743 Jena
linkedin.com/in/thomas-kamradt-93816ba5

Stefano Lazzari, M.D.

Specialist in Public Health and Preventive Medicine
International Consultant in Global Health
Former WHO Director
linkedin.com/in/stefano-lazzari-79a933a

Jennifer Neubert, M.D.

Department of Pediatric Oncology,
Hematology and Clinical Immunology
Center for Child and Adolescent Health
Medical Faculty
Heinrich-Heine-University Düsseldorf

Tim Niehues, M.D.

Centre for Child and Adolescent Health
Helios Klinikum Krefeld
Lutherplatz 40
D – 47805 Krefeld
https://www.researchgate.net/profile/Tim_Niehues

Wolfgang Preiser, M.D.

University of Stellenbosch
Division of Medical Virology
Tygerberg Campus
PO Box 19063, Tygerberg 7505, South Africa
8 | CovidReference.com

Matthias Richl, M.D., MBA

Consultant
InnKlinikum Mühldorf
Department of Anaesthesiology and Intensive Care Medicine
Krankenhausstraße 1
84453 Mühldorf am Inn

Peter Rupp M.D., MHA

Consultant and Head of Department
InnKlinikum Mühldorf
Department of Emergency Medicine
Krankenhausstraße 1
84453 Mühldorf am Inn

Markus Unnewehr, M.D

Consultant and Head of Department
St. Barbara-Klinik Hamm
Department of Respiratory Medicine and Infectious Diseases
Am Heessener Wald 1
59073 Hamm
http://linkedin.com/in/markus-unnewehr-36a3161b9

Emilia Wilson, M.D.

University of Stellenbosch
Division of Medical Virology
Tygerberg Campus
PO Box 19063, Tygerberg 7505, South Africa
 | 9

COVID REFERENCE INTERNATIONAL

All collaborators are volunteers

Español
Anisha Gualani Gualani
Medical student, Universidad de Sevilla-US
Jesús García-Rosales Delgado
Medical student, Universidad de Sevilla-US

Italiano
Alberto Desogus
Emeritus oncologist, Oncological Hospital, Cagliari
Stefano Lazzari
M.D., Specialist in Public Health and Preventive Medicine
International Consultant in Global Health
Former WHO Director
Grazia Kiesner (Italian)
Medical Student, Università degli Studi di Firenze

Português
Joana Catarina Ferreira Da Silva
Medical student, University of Lisbon
Sara Mateus Mahomed
Medical student, University of Lisbon

Français
Bruno Giroux
M. D., Paris
Georges Mion
Professor, M.D., Service d’anesthésie réanimation, Hôpital Cochin Paris
10 | CovidReference.com

Türkçe
Zekeriya Temircan
Ph.D. in Health/Clinic Psychology
Neuropsychology Department
Turkey
Füsun Ferda Erdoğan
Professor, Erciyes University Neurology Department/
Pediatric Neurology
Gevher Nesibe Genom and Stem Cell Institute Neuroscience Department
Turkey
Dilara Güngör
İstanbul University/Çapa Medical School Student
Turkey
Türev Demirtas
M.D., Erciyes University Faculty of Medicine
History of Medicine and Ethics Department
Kayseri / Turkey.

Tiếng Việt
Khanh Phan Nguyen Quoc
M.D., Oxford University Clinical Research Unit
Nam Ha Xuan
Medical student, Hue University of Medicine and Pharmacy
Kim Le Thi Anh (Vietnamese)
Medical student, School of Medicine and Pharmacy, Vietnam National University
Hanoi

Deutsch
Ulf Lüdeke
www.Sardinienintim.com
 | 11

Copy-Editor

Rob Camp

Art

Attilio Baghino
Cover

Félix Prudhomme
YouTube: IYENSS

Thomas Splettstösser
SciStyle (Figures)

IT Support
Stephan K.
 | 13

CONTENT
0. Top 10 17

1. Epidemiology 19
Hotspots of SARS-CoV-2 Transmission 23
Special Aspects of the Pandemic 35
The SARS-CoV-2 pandemic: Past and Future 43
Outlook 49
New References (5th Edition) 51
References (all) 78

2. Transmission 93
Introduction 93
The Virus 94
Person-to-person transmission 96
Routes of Transmission 97
Transmission Event 105
Outlook 116
New References (5th Edition) 118
References (all) 134

3. Prevention 149
Introduction 149
Containment or mitigation of COVID-19? 166
Conclusion 167
References 168
14 | CovidReference.com

4. Virology 185
Introduction 185
References 186

5. Vaccines 203
Advanced SARS-CoV-2 Candidates 203
The Future of SARS-CoV-2 vaccines 205
Immunization Fundamentals 211
Questions for the Future 217
Outlook 220
Weekend Reference 221
New References (5th Edition) 221
References (All) 241

6. Diagnostic Tests and Procedures 251

Diagnosis 251
Radiology 268
References 271

7. Clinical Presentation 279

Incubation period 279
Asymptomatic cases 280
Symptoms 282
Laboratory findings 292
Clinical classification 296
Outcome 297
Reactivations, reinfections 310
Long-term sequelae 311

Kamps – Hoffmann
 | 15

Outlook 313
References 314

8. Treatment 329
1. Inhibitors of the viral RNA synthesis 331
2. Various antiviral agents 337
3. Monoclonal Antibodies and Convalescent Plasma 340
4. Immunomodulators 346
Other treatments for COVID-19 (with unknown or unproven
mechanisms of action) 355
Outlook and Recommendations 357
References 358

9. Severe COVID-19 369

Definition and classification 369
Features, course and outcome 369
Spotlight: The situation in a German COVID-19 hospital 371
Special situations in severe COVID-19 373
References 375

10. Comorbidities 379

Hypertension and cardiovascular comorbidities 380
Diabetes mellitus 386
COPD and smoking 388
HIV infection 389
Immunosuppression (other than HIV) 392
Cancer 394
Transplantation 397
Other comorbidities 399
16 | CovidReference.com

11. Pediatrics 401

SARS-CoV-2 infection in children 401
Epidemiology of COVID-19 in children 402
Natural course and risk factors for complications 403
Pathophysiology and immunopathology 404
Transmission 406
Diagnosis and classification 408
Management 415
References 421

12. The First Eight Months 429

Dezember - March 429
April 445
May 454
June 460
July 471

Kamps – Hoffmann
 Top 10 | 17

0. Top 10
Please bookmark www.CovidReference.com/Top10 and come back every day
for the Daily Top 10 Papers on COVID-19. Each citation comes with a short
comment and a link to the full-text article.

COVID Reference ENG 005

18 | CovidReference.com

Kamps – Hoffmann
 Epidemiology | 19

1. Epidemiology
Bernd Sebastian Kamps
Stefano Lazzari

In December 2019, several patients from Wuhan, People’s Republic of China,

developed pneumonia and respiratory failure reminiscent of the SARS epi-
demic in 2003 (WMHC 2019, www.SARSReference.com). In early January 2020,
a new virus, later denominated SARS-CoV-2, was isolated from bronchoalveo-
lar lavage fluid samples and found to be a betacoronavirus (Zhou 2020). The
virus spread first within China (Yu X 2020) and to several countries in Asia
before reaching Iran and Italy where it caused major outbreaks. During the
first 11 weeks of the pandemic, almost two-thirds of first cases in affected
countries were in people reported to have recently travelled from only three
affected countries (China, Iran, or Italy), showing how international travel
from a few countries with substantial SARS-CoV-2 transmission might have
seeded additional outbreaks around the world (Dawood 2020).
Despite some early successes in containment, SARS-CoV-2 eventually took
hold in both Europe and North America during the first two months of 2020:
in Italy around the end of January, in Washington State around the beginning
of February, followed by New York City later that month (Worobey 2020 - see
also Figure 6, Deng X 2020, McNeil Jr DG). In Brazil, it was found that there
had been more than 100 international virus introductions, with 76% of Brazil-
ian strains falling into three clades that were introduced from Europe be-
tween 22 February and 11 March 2020 (Candido 2020).
Between then and the time of this writing (31 October), SARS-CoV-2 has
spread to every corner of the world. More than 40 million people have been
diagnosed with SARS-CoV-2 infection and more than a million people have
died of COVID-19, the disease caused by SARS-CoV-2. Not all cases, in particu-
lar if asymptomatic, have been diagnosed and the true number of infections
and deaths is probably much higher. Relatively few large scale seroprevalence
studies have been completed but the available seroprevalence data show that
only a few places, like Mumbai and Manaus, have reached a high prevalence
in the population, close to the level required for some kind of herd immunity
(see Table 1). [Herd immunity is defined as the proportion of a population
that must be immune to an infectious disease, either by natural infection or
vaccination, to provide indirect protection (herd protection) to those who are
not immune to the disease (D’Souza 2020, Adam 2020).

COVID Reference ENG 005

20 | CovidReference.com

Table 1 shows that countries hit hardest by the COVID-19 pandemic have
higher seroprevalence rates but, without an effective vaccine, no country can
count on any kind of herd immunity in the near future.

Table 1. Seroprevalence data 2020

Sample
collection
Italy* Nationwide May 25-July 15 2.5% Sabbadini 2020
Italy Lodi (red zone) 23% Percivalle 2020
Spain Nationwide 5.0% Pollán 2020
Madrid >10%
Spain Madrid 11% Soriano 2020
Switzerland Geneva 5.0- Stringhini 2020
11%
Denmark Faroe Islands 0.6% Petersen 2020
UK UK 6% Ward 2020
London 13%
South West 3%
China Wuhan March 9-April 10 3.2- Xu X 2020
3.8%
US New York City March 23-April 1 6.9% Havers 2020
San Francisco Bay April 23-27 1.0%
area
US New York State 14% Rosenberg 2020
US NYC, Health care 13.7% Moscola 2020
personnel
US Nationwide in July 2020 8.3% Anand 2020
patients receiving
dialysis
India Mumbai July 57% Kolthur-Seetharam
2020
Brazil Manaus March-August 66% Buss 2020
Not peer-reviewed.
Results have
recently been
questioned.
* Note that Italy’s national survey results are preliminary and probably an underestimation.
The country only managed to collect 40% of the planned samples, with many people
refusing to be tested. Insiders never believed these figures and favored a seropositivity rate
of 5-10% like in Spain or in France. Now we have a new estimate of COVID-19 prevalence
in Italy by Francesca Bassi and colleagues: 9%, corresponding to almost 6 million Italians
(Bassi 2020).
.

Kamps – Hoffmann
 Epidemiology | 21

The articles cited in Table 1 report some interesting findings:

• Wuhan – Seropositivity for IgM and IgG antibodies was low (3.2%-
3.8%) even in a highly affected city like Wuhan (Xu X 2020).
• New York City – In New York, the prevalence of SARS-CoV-2 among
health care personnel was 13.7% (5523 of 40,329 individuals tested)
(Moscola 2020) which was similar to that among adults randomly
tested in New York State (14.0%) (Rosenberg 2020).
• UK – Black, Asian and minority ethnic (BAME) individuals were be-
tween two and three times as likely to have had SARS-CoV-2 infec-
tion compared to white people. An interesting trend: young people
aged 18-24 had the highest rates (8%), while older adults aged 65 to
74 were least likely to have been infected (3%).
• Mumbai – In a cross-sectional survey the prevalence of past SARS-
CoV-2 infection in three areas in Mumbai was around 57% in the
slum areas of Chembur, Matunga and Dahisar, and 16% in neighbor-
ing non-slums (Kolthur-Seetharam 2020). In some places of the world
herd immunity may be within reach.
• Geneva – Young children (5–9 years) and older people (≥ 65 years)
had significantly lower seroprevalence rates than other age groups
(Stringhini 2020).

• Faroe Islands – At the beginning of the pandemic, small islands

tended to have low seropositivity rates.
It is worth noting that we still have few nationwide population-based sero-
prevalance studies, that the sensitivity and specificity of serological tests be-
ing used can vary from place to place, and that some people might have been
infected without showing detectable levels of antibodies. Based on all availa-
ble serological studies, WHO has estimated that around 10% of the world pop-
ulation, or 760 million people, might have been infected as of October 2020.
https://www.euronews.com/2020/10/05/around-10-of-the-world-s-
population-may-have-had-covid-19-according-to-who
The mean incubation period of SARS-CoV-2 infection is around 5 days (Li
2020, Lauer 2020, Nie X 2020). The serial interval – defined as the duration of
time between a primary case-patient having symptom onset and a secondary
case-patient having symptom onset – has been estimated to be between 5 and
7.5 days (Cereda 2020). SARS-CoV-2 is highly contagious, with an estimated
basic reproduction number R0 of around 2.5-3.0 (Chan 2020, Tang B 2020, Zhao
2020). [R0 indicates the average number of infections one case can generate
over the course of the infectious period in a naïve, uninfected population.

COVID Reference ENG 005

22 | CovidReference.com

Read the guide by David Adam (Adam 2020) for more precious information on
R0.]

Prevention
SARS-CoV-2 is easily transmissible both by symptomatic and asymptomatic
individuals, thrives in closed and densely inhabited environments, and is
amplified by so-called ‘superspreader’ events.
The five golden rules to minimize the risk of SARS-CoV-2 infection
1. Wear face masks in public spaces.
2. Keep a distance of 2 (two!) meters to other people.
3. Avoid crowded places (more than 5-10 people).
4. Avoid in particular crowded and closed spaces (even worse: air-
conditioned closed places where air is being moved around).
5. Avoid in all circumstances - crowded, closed and noisy spaces
where people must shout to communicate. These are SARS-CoV-2’s
preferred playgrounds.
Find below a detailed discussion of SARS-CoV-2 transmission (pages 93) and
its prevention (page 149).

As with the earlier SARS and MERS outbreaks (Shen Z 2004, Cho SY 2016), the
spread of SARS-CoV-2 is characterized by the occurrence of so-called “super-
spreaders events” where one source of infections seems responsible for a
large number of secondary infections. (Wang L 2020) This phenomenon is well
described by a recent study of SARS-CoV-2 transmission in Hong-Kong (Adam
DC 2020). The authors analyzed all clusters of infection in 1038 cases that oc-
curred between January and April 2020 and concluded that 19% of cases were
responsible for causing 80% of the additional community cases, with large
clusters originating from bars, weddings, and religious ceremonies. Interest-
ingly, decreased delays in confirmation of symptomatic cases did not influ-
ence the rate of transmission (suggesting higher rate of transmission at or
before symptom onset), whereas rapid contact tracing and quarantine of con-
tacts was very effective in terminating the transmission chain. Other authors
(Endo 2020) have estimated a k of 0.1 outside China, meaning that only 10% of
infected individuals transmit the virus (k or dispersion factor describes, in
mathematical models, how much the disease tends to cluster).

Kamps – Hoffmann
 Epidemiology | 23

A relatively low dispersion factor with few infected people causing most
transmissions could explain some puzzling aspects of the beginning of the
COVID-19 pandemic. For example, why the early introductions in Europe of
SARS-Cov-2 in December 2019 (France) and in January 2020 (France, Germa-
ny) did not result in earlier outbreaks. Or why the large outbreak in Northern
Italy in February 2020 did not lead to a similar rapid spread of the virus in the
rest of the country.
Understanding the reasons underlining superspreader events can be key to
the success of preventive measures, so the big question is, “Why do some
COVID-19 patients infect many others, whereas most don’t spread the virus at
all?” (Kupferschmidt 2020). It is possible that some individuals simply shed
more virus that others, or that there is much more shedding at a specific
moment of higher contagiousness in the natural history of the infection, pos-
sibly when viral load is at its peak. Environmental conditions also clearly play
a role, with crowded, closed places where people talk loudly, shout, sing or
exercise being at higher risk, possibly because of the higher production and
diffusion of small particles like aerosols. A “superspreader individual“ in a
“superspreading setting“ may result in a very large number of infections, as
seen in the Shincheonji church cluster in South Korea where, in March 2020,
one single person was estimated to have generated more than 6000 cases.
A better understanding of superspreader events may help in defining the
most effective measures to reduce SARS-CoV-2 transmission by reducing the
likelihood of superspreading events. We will explore below the most common
“hotspots” of SARS-CoV-2 infection, where the likelihood of single or multiple
infections is higher.

In this chapter, we will discuss:

1. Hotspots of SARS-CoV-2 infection
2. Special aspects of the pandemic in selected places
3. The Pandemic: Past and Future

Hotspots of SARS-CoV-2 Transmission

The following settings were, are or can be catalyzers of outbreaks:
• Hospitals
• Nursing facilities
• Homes (also including intense social life with friends and colleagues)

COVID Reference ENG 005

24 | CovidReference.com

• Leisure facilities such as bars, clubs, choirs, discos, sports facilities and
restaurants
• Workplaces
• Schools
• Mass gatherings
o Marriages
o Funerals
o Religious gatherings
• Closed and densely populated spaces
o Prisons
o Homeless shelters
o Ships (closed spaces)
o Cruise ships
o Aircraft carriers and other military vessels

Hospitals
During the first months of the SARS-CoV-2 pandemic, when suspicion of the
disease was low, transmission in hospitals and other health care centers (in-
cluding doctors offices) played a prominent role in the origin and spread of
local epidemics. This was reminiscent of SARS and of the largest MERS out-
break outside of the Arabian peninsula which occurred in the Republic of Ko-
rea in 2015, where 184 of 186 cases were infected nosocomially (Korea Centers
for Disease Control and Prevention 2015). Hospitals, as many other places
where strangers meet, can be a favorable environment for the propagation of
SARS-CoV-2 (Wison 2020). Within the first 6 weeks of the epidemic in China,
1716 cases and at least 5 deaths (0.3%) were confirmed among health care
workers by nucleic acid testing (Wu 2020). In some instances, hospitals could
have been even the main COVID-19 hub, facilitating transmission between
health workers and uninfected patients (Nacoti 2020).
One hospital environment study reports that the virus was widely present in
the air and on object surfaces in both the intensive care units and general
wards, implying a potentially high infection risk for medical staff. Contamina-
tion was greater in ICUs (Self 2020). Virus RNA has been found on floors,
computer mice, trash cans, sickbed handrails, and was detected in the air up
to approximately 4 m from patients (Guo 2020). The virus was also isolated
from toilet bowl and sink samples, suggesting that viral shedding in stool
could be a potential route of transmission (Young 2020, Tang 2020). However,

Kamps – Hoffmann
 Epidemiology | 25

most of these studies have evaluated only the presence of viral RNA, not its
infectivity.
Although nosocomial spread of the virus is well documented, appropriate
hospital infection control measures can prevent nosocomial transmission of
SARS-CoV-2 (Chen 2020, Nagano 2020, Callaghan 2020). This was nicely
demonstrated by the case of a person in her 60s who travelled to Wuhan on
Dec 25, 2019, returned to the US on Jan 13, 2020, and transmitted SARS-CoV-2
to her husband. Although both were hospitalized in the same facility and
shared hundreds (n = 348) of contacts with HCWs, nobody else became infect-
ed (Ghinai 2020).
However, working in a high-risk department, longer duty hours, and sub-
optimal hand hygiene after coming into contact with patients are all associat-
ed with an increased risk of infection in health care workers (Ran 2020). At
one time, during the early epidemic in March 2020, around half of 200 cases
in Sardinia were among hospital staff and other health care workers. On 14
April, the US CDC reported that 9282 Health Care Personnel had been infected
with SARS-COV-2 in the US. Health care workers from COVID-19 have a high-
er risk of being SARS-CoV-2 infected (5.4%) than those from non–COVID units
(0.6%) (Vahidy 2020). In a prospective cohort study in London, 25% of HCWs
were already seropositive at enrolment (26 March to 8 April) and a further
20% became seropositive within the first month of follow-up (Houlihan 2020).
However, a Chinese study of 9684 healthcare workers (HCW) in Tongji Hospi-
tal showed a higher rate of infection in non-first-line HCW (93/6.574, 1.4%)
when compared to those who worked in fever clinics or wards (17/3110, 0.5%)
(Lai X 2020). Interpretation: those who worked in clinical departments other
than fever clinics and wards may have had less access to, or have neglected to
adopt, adequate protective measures.
The risk factors for SARS-CoV-2 infection in health care workers have been
summarized in a recent review (Chou 2020). There is evidence that more con-
sistent and full use of recommended PPE measures was associated with de-
creased risk for infection. Association was most consistent for masks but was
also observed for gloves, gowns, and eye protection, as well as hand hygiene.
Some evidence was found that N95 respirators might be associated with high-
er reduction of risk for infection than surgical masks. Evidence also indicated
an association with certain exposures (such as involvement in intubations,
direct contact with infected patients, or contact with bodily fluids).
SARS-CoV-2 outbreaks have also been documented in dialysis units
(Schwierzeck 2020, Rincón 2020). The prevalence of SARS-CoV-2 antibodies
was lower among personnel who reported always wearing a face covering

COVID Reference ENG 005

26 | CovidReference.com

while caring for patients (6%), compared with those who did not (9%) (Self
2020).

Long-term care facilities

Long-term care facilities (LTC) are high-risk settings for infectious respirato-
ry diseases. The first important study published in May 2020 reported an out-
break in a skilled nursing facility in King County, Washington, US, where 167
cases of COVID-19 (101 residents, 50 health care personnel and 16 visitors)
were diagnosed within less than three weeks from the identification of the
first case: (McMichael 2020) (Table 2).
Table 2. COVID outbreak in a long-term care facility

Residents Healthcare Visitors

(N = 101) personnel (N = 16)
(N = 50)
Median age (range) 83 (51-100) 43.5 (21-79) 62.5 (52-88)
Female (%) 68.3 76 31.2
Hospitalized (%) 54.5 6.0 50.0
Died (%) 33.7 0 6.2
Chronic underlying
conditions (%)
Hypertension 67.3 8.0 12.5
Cardiac disease 60.4 8.0 18.8
Renal disease 40.6 0 12.5
Diabetes mellitus 31.7 10.0 6.2
Obesity 30.7 6.0 18.8
Pulmonary disease 31.7 4.0 12.5

Among residents (median age: 83 years), the case fatality rate was 33.7%.
Chronic underling conditions included hypertension, cardiac disease, renal
disease, diabetes mellitus, obesity, and pulmonary disease. The study demon-
strated that once introduced in a long-term care facility, often by a care
worker or a visitor, SARS-CoV-2 has the potential to spread rapidly and wide-
ly, with devastating consequences.
By mid-April 2020, more than 1300 LTC facilities in the US had identified in-
fected patients (Cenziper 2020, CDC 200311). As most residents had one or
more chronic underling conditions such as hypertension, cardiac disease,
renal disease, diabetes mellitus, obesity and pulmonary disease, COVID-19 put
them at very high risk for premature death.
Later studies found a high percentage of asymptomatic residents (43%) dur-
ing the two weeks prior to testing (Graham 2020b); extraordinarily high sero-

Kamps – Hoffmann
 Epidemiology | 27

positivity rates (72%; Graham 2020a); and a higher infection rate in residents
(9.0%) than in staff (4.7%) (Marossy 2020).
A national survey covering 96% of all long-term care facilities in Italy found
that in Lombardy, the epicenter of the epidemic, 53.4% of the 3045 residents
who died between 1 February and 14 April were either diagnosed with COVID-
19 or presented flu-like symptoms. Among the 661 residents who were hospi-
talized during the same period, 199 (30%) were found positive by a PCR test.
As soon as a single case is detected among residents of a nursing facility, it is
recommended to test all residents, as many of them may still be asymptomat-
ic. After an outbreak at a long-term care nursing facility, all residents, re-
gardless of symptoms, underwent serial (approximately weekly) nasopharyn-
geal SARS-CoV-2 RT-PCR testing. Nineteen of 99 (19%) residents had positive
test results for SARS-CoV-2 (Dora 2020). Fourteen of the 19 residents with
COVID-19 were asymptomatic at the time of testing. Among these, eight de-
veloped symptoms 1-5 days after specimen collection and were later classified
as pre-symptomatic.
Mortality in LTCs is almost always high. In a study from Ontario, Canada, the
incidence of mortality was more than 13 times higher than the one seen in
community-living adults older than 69 years during a similar period (Fisman
2020). In one UK investigation involving 394 residents and 70 staff in 4 nurs-
ing homes in central London, 26% of residents died over a two-month period
(Graham 2020). It is estimated that residents in long-term care facilities con-
tributed 30–60% of all COVID-19 deaths in many European countries (ECDC
2020; see also the statement to the press by Hans Henri P. Kluge, WHO Re-
gional Director for Europe). Excess mortality data suggests that in several
countries many deaths in long-term care facilities might have occurred in
patients not tested for COVID-19, which are often not included in the official
national COVID-19 mortality statistics.

Homes
Infection rates at home varied widely (between 11% and 19%) in three studies.
One group noted that household contacts and those travelling with a COVID-
19 case had a 6 to 7 times higher risk of infection than other close contacts,
and that children were as likely to be infected as adults (Bi Q 2020). Another
group found that the odds of infection among children and young people (<
20 years old) was only 0.26 times that among the elderly (≥ 60 years old) (Jing
QL 2020). A third group calculated that the secondary attack rate in children
was 4% compared to 17.1% in adults, and that the secondary attack rate in
contacts who were spouses of index cases was 27.8% compared to 17.3% in
other adult members in the households (Li W 2020). It has been objected that

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these transmission rates may be an underestimate if index cases were isolated

outside of the home (Sun 2020). In yet another study, 32.4% (48 of 148) of
household contacts of 35 index cases were infected (Wu J 2020).
In Spain, during the summer of 2020, social settings such as family gatherings
or private parties accounted for 14% of cases (854/6208) in an analysis of 551
outbreaks. SARS-CoV-2 positive cases linked to leisure venues such as bars,
restaurants, or clubs were even more frequent (NCOMG 2020) (see next para-
graph).

Leisure venues (bars, clubs, choirs, karaoke, discos, etc.)

In Spain, an analysis of 551 outbreaks from mid-June to 2 August linked 1230
of 6208 cases (20%) to leisure venues such as bars, restaurants, or clubs
(NCOMG 2020). Data from Japan showed that of a total of 61 COVID-19 clus-
ters, 10 (16%) were in restaurants or bars; 7 (11%) in music-related events,
such as live music concerts, chorus group rehearsals, and karaoke parties; 5
(8%) in gymnasiums; 2 (3%) in ceremonial functions (Furuse 2020). In South
Korea, superspreading events in nightclubs in downtown Seoul were shown
to have the potential to spark a local resurgence of cases (Kang 2020). In Hong
Kong, an explosive summer outbreak was best explained by the sudden in-
crease in social gatherings after the easing of public health control measures,
especially gatherings at eateries (To 2020). College trips and summer camps
represent another environment for efficient SARS-CoV-2 transmission. In one
case, a spring break trip from Austin to Mexico resulted in 14 asymptomatic
and 50 symptomatic cases (Lewis 2020). CDC reported an outbreak with 260
(44%) out of 597 attendees of an overnight summer camp in Georgia becoming
infected in June 2020 (Szablewski 2020). The camp adopted most of CDC’s sug-
gested preventive measures for Youth and Summer Camps but wearing cloth
masks and opening windows and doors for increased ventilation in buildings
were not implemented .
Choirs, too, are places of efficient SARS-CoV-2 transmission. On 8 March 2020,
the Amsterdam Mixed Choir gave a performance of Bach’s St John Passion in
the city’s Concertgebouw Auditorium. Days later, the first singers developed
symptoms and in the end 102 of 130 choristers were confirmed to have
COVID-19. One 78-year-old choir member died, as did three partners of choir
members; some singers required intensive care (The Guardian, 17 May). On 9
March, members of the Berlin Cathedral Choir met for their weekly rehearsal.
Three weeks later, 32 out of 74 choir members were positive for SARS-CoV-2
(NDR 2020). All recovered. On 10 March 2020, 61 members of a Skagit County
choir in Washington met for a 2,5-hour practice. A few weeks later, research-
ers reported that 32 confirmed and 20 probable secondary COVID-19 cases

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 Epidemiology | 29

had occurred (attack rate = 53.3% to 86.7%); three patients were hospitalized,
and two died. The authors conclude that transmission was likely facilitated by
close proximity (within 6 feet) during practice and increased viral diffusion
by the act of singing (Hamner 2020).
In an unintentional experiment, the German national team of amateur boxers
proved that even 100% transmission rates can be achieved within days. In a
training camp, some of the 18 athletes and 7 coaches and supervisors started
having cold symptoms. Four days later, all 25 persons tested positive for
SARS-CoV-2 (Anonymous 2020).
These data suggest that any noisy, closed and stagnant air environments (e.g.,
discos, pubs, birthday parties, restaurants, meat processing facilities, etc.)
where people stand, sit or lie close together are ideal conditions for generat-
ing large SARS-CoV-2 outbreaks. If they need to shout for communication, the
situation may become explosive.

Workplaces
As early as January 2020, SARS-CoV-2 was found to spread during workshops
and company meetings (Böhmer 2020). A few weeks later, an outbreak of
SARS-CoV-2 infection was reported from a call center where 94 out of 216
employees working on the same floor were infected, translating to an attack
rate of 43.5% (Park SY 2020). Particularly instructive is the case of a scientific
advisory board meeting held in Munich, Germany, at the end of February.
Eight dermatologists and 6 scientists (among them the index patient) met in a
conference room of about 70 m2 with a U-shaped set-up of tables separated by
a central aisle > 1 meter wide. During the meeting that lasted 9,5 hours, re-
freshments were served in the room 4 times. In the evening, the participants
had dinner in a nearby restaurant and shook hands for farewell, with a few
short hugs (no kisses!). Finally, the index patient shared a taxi with three col-
leagues for about 45 min. Outcome: the index patient infected at least 11 of
the 13 other participants. When isolated either in a hospital or at home these
individuals infected an additional 14 persons (Hijnen 2020). In the presence of
an infected individual, workplaces can be important amplifiers of local
transmission.
In May 2020, outbreaks with hundreds of infected individuals were reported
from meat-packing plants in Germany (DER SPIEGEL), the US (The Guardian)
and France (Le Monde). Outbreaks in meat processing facilities were also re-
ported from other countries. In March and April, 25.6% (929) of employees
and 8.7% (210) of their contacts were diagnosed with COVID-19 in South Da-
kota, USA; two employees died (Steinberg 2020). The highest attack rates oc-
curred among employees who worked < 6 feet (2 meters) from one another at

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the production line. Another study reported 16,233 COVID-19 cases and 86
COVID-19–related deaths among workers in 239 facilities (Waltenburg 2020).
The percentage of workers with COVID-19 ranged from 3.1% to over 20% per
facility (Waltenburg 2020). Promiscuity, noise, cold and humid conditions are
currently favored as explanations for these unusual outbreaks. In Spain, the
above-mentioned analysis of 551 outbreaks from mid-June to 2 August linked
around 500 of 6208 cases (8%) to occupational settings, in particular, workers
in the fruit and vegetable sector and workers at slaughterhouses or meat pro-
cessing plants (360/6208 cases) (NCOMG 2020).

Schools
Schoolchildren usually play a major role in the spread of respiratory viruses,
including influenza. However, while the SARS-CoV-2 virus has been detected
in many children, they generally experience milder symptoms than adults,
need intensive care less frequently and have a low death rate. An analysis of
data from Canada, China, Italy, Japan, Singapore and South Korea found that
susceptibility to infection in individuals under 20 years of age was approxi-
mately half that of adults aged over 20 years, and that clinical symptoms are
manifest in 21% of infections in 10-to-19-year-olds, rising to 69% of infections
in people aged over 70 years (Davis 2020).
The role of children in SARS-COV-2 transmission is still unclear. Several stud-
ies have suggested that children rarely transmit the infection. In a small
COVID-19 cluster detected in the French Alps at the end of January, one per-
son returning from China infected eleven other people, including a nine-year-
old schoolboy. The researchers closely tracked and tested all contacts (Danis
2020). The boy had gone to school after showing COVID-19 symptoms and was
estimated to have had more than sixty high-risk close contacts. No one was
found positive to the coronavirus, though many had other respiratory infec-
tions. Also, no virus was found in the boy’s two siblings who were on the same
Alpine vacation.
A study by the Institut Pasteur in April 2020 (before school closure) that in-
cluded 510 primary school children concluded that “it appears that the chil-
dren did not spread the infection to other students or to teachers or other
staff at the schools”. Another study in 40 patients less that 16 years old in
Geneva, Switzerland (Posfay-Barbe 2020) also concluded that unlike with oth-
er viral respiratory infections, children do not seem to be a major vector of
SARS-CoV-2 transmission, with most pediatric cases described inside familial
clusters and no documentation of child-to-child or child-to-adult transmis-
sion.“

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 Epidemiology | 31

However, a review of 14 published studies (Rajmil 2020) was less categorical,

simply concluding that children are not transmitters to a greater extent than
adults. A more recent metanalysis of published evidence (Viner 2020) states
that there is insufficient evidence to conclude whether transmission of SARS-
CoV-2 by children is lower than by adults.
CDC reported in September on twelve children who acquired COVID-19 in
three different child-care facilities in Utah. It documented transmission from
these children to at least 12 (26%) of 46 non-facility contacts and that trans-
mission was observed from two of three children with confirmed, asympto-
matic COVID-19. In addition, several studies have found that both sympto-
matic and asymptomatic children can shed the SARS-CoV-2 virus for several
days or weeks after infection (Liu 2020, Han 2020). However, qualitative posi-
tive or negative findings for molecular detection of virus may not necessarily
correlate with infectivity (DeBiasi 2020).
In the early autumn of 2020, how to re-open schools was a hot debate. In Tai-
wan authorities established general guidelines, including a combination of
strategies such as active campus-based screening and access control; school-
based screening and quarantine protocols; student and faculty quarantine
when warranted; mobilization of administrative and health center staff; regu-
lation of dormitories and cafeterias; and reinforcement of personal hygiene,
environmental sanitation, and indoor air ventilation practices (Cheng SY
2020). Most European countries have decided to reopen schools, considering
the possible increase in infections as being less damaging than the loss of ed-
ucation in schoolchildren. At the time of this writing (31 October), the reo-
pening of schools in European countries does not seem to have contributed
substantially to the national epidemics. It can indeed be difficult to determine
if children were infected at home, at school (by their peers or by their teach-
ers) or outside during social or sport gatherings. In some school clusters, the
index cases identified were teachers and/or parents (Torres 2020), so school
prevention should focus on enforcing preventive measures and avoiding new
cases among teachers. In any case, close monitoring of school clusters will
provide much needed additional data that might help clarify the role of chil-
dren of different ages in the spread of the virus, and whether schools can be
considered hotspots or not of SARS-CoV-2 transmission.

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Mass gatherings

Sports events
A football match played in Milan, Italy on 19 February 2020 has been de-
scribed as “Game zero” or “a biological bomb”. The match was attended by
40,000 fans from Bergamo and 2500 from Valencia and was played just two
days before the first positive case of COVID-19 was confirmed in Lombardy.
Thirty-five percent of Valencia’s team members tested positive for the coro-
navirus a few weeks later, as did several Valencia fans. By mid-March, there
were nearly 7,000 people in Bergamo who had tested positive for the corona-
virus with more that 1,000 deaths, making Bergamo the most heavily hit
province during the initial COVID-19 outbreak in Italy.
Other sport events have been implicated in the COVID-19 spread, including
the match between Liverpool and Atletico Madrid, held at Anfield stadium on
11th March and attended by 3,000 supporters from Madrid, the center of the
pandemic in Spain, and the Cheltenham horseracing festival, with races at-
tracting crowds of over 60,000 people (Sassano 2020). Most national and in-
ternational large sport events, cancelled or postponed in the first half of 2020,
have resumed during the summer months, though with closed doors or major
limitations in the number of spectators. Large sports events including tens of
thousands of spectators might not take place for several years.

Religious gatherings
Several mass gathering religious events have been associated with explosive
outbreaks of COVID-19. As mentioned above, in April 2020, a total of 5212
coronavirus cases were related to an outbreak at the Shincheonji Church in
South Korea, accounting for about 48.7% of all infections in the country at
that time.
The annual gathering of the Christian Open Door Church held between 17 and
24 February in Mulhouse, France, was attended by about 2500 people and be-
came the first significant cluster in France. After a parishioner and 18 family
members tested positive on 1 March, a flurry of reported cases brought the
existence of a cluster to light. According to an investigative report by France
Info, more than 1,000 infected members from the rally in Mulhouse contrib-
uted to the start of the COVID-19 epidemic in France. Many diagnosed cases
and deaths in France as well as Switzerland, Belgium and Germany were
linked to this gathering.
Another report described 35 confirmed COVID-19 cases among 92 attendees
at church events in Arkansas during March 6–11. The estimated attack rates

Kamps – Hoffmann
 Epidemiology | 33

ranged from 38% to 78% (James 2020). In Frankfurt, Germany, one of the first
post-lockdown clusters started during a religious ceremony held on 10 May.
As of 26 May, 112 individuals were confirmed to be infected with SARS-CoV-2
(Frankfurter Rundschau). May we suggest that going to church does not pro-
tect you from SARS-CoV-2?
Huge religious mass gatherings should probably be postponed. Gatherings
that attract millions of pilgrims from many countries (with pilgrims typically
> 50 years old and often suffering from chronic disease such as diabetes or
cardiovascular disease [Mubarak 2020]) have clearly the potential to create
giga-spreading events, saturating designated wards and ICU capacity within
days. Reducing the number of pilgrims and excluding foreign pilgrims is
therefore a wise decision (Khan 2020). Events attended by even more people,
such as the Sabarimala annual 41-day long Hindu pilgrimage (average attend-
ance: 25 million people) would need even more careful planning (Nayar 2020).

Closed and densely populated spaces

Prisons
According to WHO, people deprived of their liberty, such as people in prisons
and other places of detention, are more vulnerable to COVID-19 outbreaks
(WHO 200315). People in prison are forced to live in close proximity and thus
may act as a source of infection, amplification and spread of infectious dis-
eases within and beyond prisons. The global prison population is estimated at
11 million and prisons are in no way “equipped” to deal with COVID-19 (Burki
2020).
In US prisons, COVID-19 attack rates are high. By June 6, 2020, there had been
42,107 cases and 510 deaths among 1.3 million prisoners (Saloner 2020, Wal-
lace 2020). Among 98 incarcerated and detained persons in Louisiana who
were quarantined because of virus exposure, 71 (72%) had SARS-CoV-2 infec-
tion identified through serial testing, among them 45% without any symp-
toms at the time of testing (Njuguna 2020). In July 2020, more than one-third
of the inmates and staff (1600 people) in San Quentin Prison tested positive
(Maxmen 2020). Six had died. Still in July 2020, the rate of COVID-19 among
incarcerated individuals in Massachusetts was nearly 3 times that of the gen-
eral population and 5 times the US rate (Jiménez 2020).

Homeless shelters
Testing in 1192 residents and 313 staff members in 19 homeless shelters from
4 US cities (see table online), initially triggered by the identification of a
COVID-19 cluster, found infection rates of up to 66% (Mosites 2020).

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In another report from Boston, Massachusetts, 147/408 (36%) homeless shel-

ter residents were positive. Of note, 88% had no fever or other symptoms at
the time of diagnosis (Baggett 2020).
In yet another study of 14 homeless shelters in King County, Washington, re-
searchers divided the number of positive cases by the total number of partic-
ipant encounters, regardless of symptoms. Among 1434 encounters, 29 (2%)
cases of SARS-CoV-2 infection were detected across 5 shelters. Eighty-six per-
cent of persons with positive test results slept in a communal space rather
than in a private or shared room (Rogers 2020).

Cruise ships, aircraft carriers etc.

Cruise ships carry many people in confined spaces. On 3 February 2020, 10
cases of COVID-19 were reported on the Diamond Princess cruise ship. Within
24 hours, all sick passengers were isolated and removed from the ship and the
rest of the passengers quarantined on board. Over time, more than 700 of the
3,700 passengers and crew tested positive (around 20%). One study suggested
that without any intervention 2920 individuals out of the 3700 (79%) would
have been infected (Rocklov 2020). The study also showed that an early evac-
uation of all passengers on 3 February would have been associated with only
76 infected. For cruise ships, SARS-CoV-2 may spell disaster – carrying vil-
lage-loads of people from one place to another may not be a viable business
model for years to come.
Big navy vessels such as aircraft carriers can become floating petri dishes for
emerging viral respiratory diseases. Already in 1996, an outbreak of influenza
A (H3N2) occurred aboard a navy ship. At least 42% of the crew became ill
within few days, although 95% had been appropriately vaccinated (Earhart
2001). Since the beginning of the year, several outbreaks of COVID-19 on mili-
tary ships have been reported, facilitated by the small enclosed areas of work
and the lack of private quarters for the crew. The largest outbreaks have been
reported on the USS Theodore Roosevelt and the French aircraft carrier Charles
de Gaulle. During the Theodore Roosevelt outbreak in late March, around 600
sailors out of a crew of 4800 were infected with SARS-CoV-2 (see also the
March 30 entry of the Timeline); around 20% reported no symptoms and one
sailor died. (USNI News). Preventive measures, such as using face-coverings
and observing social distancing, reduced risk of infection: among 382 service
members, those who reported taking preventive measures had a lower infec-
tion rate than did those who did not report taking these measures (e.g., wear-
ing a face-covering, 56% versus 81%; avoiding common areas, 54% versus 68%;
and observing social distancing, 55% versus 70%, respectively) (Payne 2020).

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 Epidemiology | 35

On the French aircraft carrier Charles-de-Gaulle, a massive epidemic was con-

firmed on 17 April. Among the 1760 sailors, 1046 (59%) were positive for
SARS-CoV-2, 500 (28%) presented symptoms, 24 (1.3%) sailors were hospital-
ized, 8 required oxygen therapy and one was admitted in intensive care.
Smaller clusters have also been reported on 5 other US military vessels, and
in one each from France, Taiwan, and Holland. However, given usual security
policies and communication restrictions of national armies and navies, it is
possible that other unreported cluster of cases and even deaths might have
occurred.

Special Aspects of the Pandemic

The COVID-19 pandemic has highlighted a number of specific aspects and
lessons learned from different countries that should be kept in mind during
the management of future pandemics (by coronaviruses, influenza viruses or
by as yet unknown viruses):
• First outbreak (China)
• Surprise or unpreparedness (Italy)
• Unwillingness to prepare (UK, USA, Brazil)
• Partial preparedness (France)
• Preparedness (Germany)
• Herd immunity? (Sweden)
• Deferred beginning (South America)
• Splendid isolation (New Zealand, Australia)
• Unknown (?) outcome (Africa)

First outbreak (China)

China was caught by surprise by the COVID-19 outbreak – as any other nation
would have been – but “thanks” to the SARS outbreak in 2003 (Kamps-
Hoffmann 2003), was prepared for it. At first, the epidemic spread within Wu-
han and Hubei Province (December 2019, Li Q 2020) and then nationwide to
all provinces in January 2020, favored by travelers departing from Wuhan
before the Chinese Spring Festival (Zhong 2020, Jia JS 2020). However, within
3 weeks from the identification of the new virus, the government ordered the
lockdown of more than 50 million people in Wuhan and the surrounding
province of Hubei, as well as travel restrictions for hundreds of millions of
Chinese citizens. This astonishing first in human history achieved what even

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specialists didn’t dare dream: curbing an epidemic caused by a highly conta-

gious virus (Lau 2020).
As early as four weeks after the Wuhan lockdown, there was evidence that
strict containment measures were capable of curbing a SARS-CoV-2 epidemic
as shown in Figure 1 (page 35). The lesson from China: it is possible to lock-
down entire provinces or countries and lockdown works. Some authorities in
the Western Hemisphere followed the example of China (Italy, for example,
ordered a lockdown as early as 18 days after the diagnosis of the first autoch-
thonous case), other governments did not. It cannot be overemphasized that
China has basically managed to control the spread of SARS-CoV-2 since
March. How was that possible (Burki 2020)?

Preparedness (Taiwan, Vietnam, Japan)

On 7 June, Taiwan (24 million people with a population density of 650/km2)
had reported only 443 cases and 7 deaths. Most SARS-CoV-2 infections were
not autochthonous. As of 6 April 2020, 321 cases were imported by Taiwanese
citizens who had travelled once or more to 37 countries for tourism, business,
work, or study (Liu JY 2020). From the beginning, Taiwan drew on its SARS
experience to focus on protecting health care workers’ safety and strengthen-
ing pandemic response (Schwartz 2020 + The Guardian, 13 March 2020). An
early study suggested that identifying and isolating symptomatic patients
alone might not suffice to contain the epidemic and recommended more gen-
eralized measures such as social distancing (Cheng HY 2020). Big data analyt-
ics were used in containing the epidemic. On one occasion, authorities offered
self-monitoring and self-quarantine to 627,386 persons who potentially had
contact with the more than 3,000 passengers of a cruise ship. These passen-
gers had disembarked at Keelung Harbor in Taiwan for a 1-day tour five days
before the COVID-19 outbreak on the Diamond Princess cruise ship on Febru-
ary 5, 2020 (Chen CM 2020).
Vietnam, too, did remarkably well. One hundred days after the first SARS-
CoV-2 case was reported in Vietnam on January 23rd, 270 cases were con-
firmed, with no deaths. Although there was a high proportion of asympto-
matic and imported cases as well as evidence for substantial pre-symptomatic
transmission, Vietnam controlled SARS-CoV-2 spread through the early in-
troduction of mass communication, meticulous contact-tracing with strict
quarantine, and international travel restrictions (Pham QT 2020).
Finally, in Japan, public adherence to the rules, along with cluster tracing
and a ban on mass gatherings, seem to have helped in bringing the outbreak

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 Epidemiology | 37

under control. Where widespread mask use and hygiene is a normal part of
etiquette, combatting SARS-CoV-2 is easier (Looi 2020).
Experiences from these countries show that effective testing and contact
tracing, combined with physical distancing measures, can keep the pandemic
at bay and an economy open. Health is the key to wealth.

Surprise or unpreparedness (Italy)

In Italy and France, SARS-CoV-2 was circulating as early as January among
asymptomatic or pauci-symptomatic people (Cereda 2020, Gámbaro 2020).
Italy was the first European country struck by the pandemic. Complete ge-
nome analysis of SARS-CoV-2 isolates suggests that the virus was introduced
on multiple occasions (Giovanetti 2020). Although the first local case was di-
agnosed only on 20 February, the force of the outbreak suggests that the virus
had been circulating for weeks, possibly as early as 1 January (Cereda 2020).
However, it was not straightforward to decipher the subtle signs of coming
events, in Italy as elsewhere. During the yearly flu season, COVID-19 deaths in
elderly people could easily be interpreted as flu deaths. And the rapid spread
of SARS-CoV-2 among the most active social age group – young people crowd-
ed in bars, restaurants and discos –would not have caused visible life-
threatening symptoms. Before being detected, the epidemic had plenty of
time (at least a month) to grow.
One additional possible reason for the delay in recognizing the encroaching
epidemic in Italy might have been the Italian ‘suspected case definition for
COVID-19’. It included (like the suspected case definitions recommended at
that time by WHO) the mandatory epidemiological criteria of ‘history of trav-
el to China or in contact with a person from China’ before requesting a PCR
test. A strict application of this case definition discouraged testing suspected
pneumonia cases where the link with China was not clear (which would even-
tually happen everywhere after the first asymptomatic infections). The anes-
thesiologist who eventually requested the PCR test for Mattia, the Italian pa-
tient #1, did it “under her own responsibility since not in line with MOH
guidelines”.
It is as yet unclear why the epidemic took such a dramatic turn in the north-
ern part of Italy, especially in Lombardy (Gedi Visual 2020), while other areas,
especially the southern provinces, were relative spared. Overdispersion might
be an explanation (see above). Of note, healthcare in Italy is run regionally
and for a long time, the Lombardy Region has favored the development of a
mostly private and hospital-centered system, with great facilities but poor
community-based services. This meant that COVID-19 patients were quickly

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run to the hospital, even with minor symptoms, resulting in overcrowded

emergency services and major nosocomial spread. A more decentralized and
community-based system like in the Veneto Region (plus maybe a bit of luck)
could have greatly reduced the mortality from COVID-19 in Lombardy. In ad-
dition, Italy had not updated nor implemented the 2006 national pandemic
preparedness plan (https://www.saluteinternazionale.info/2020/04/cera-
una-volta-il-piano-pandemico). The lack of preparedness and the overlap of
responsibilities hampered considerably the initial coordination of the nation-
al response between the regions and the central government.

Unwillingness to prepare, or denial (UK, Iran, USA, Brazil)

In the UK, clumsy political maneuvering delayed the start of effective lock-
down measures by a week or more. As the epidemic doubles in size about eve-
ry 7 days (Li 2020), around 50% and 75% of all deaths might have been pre-
vented had lockdown or social distancing measures been ordered one or two
weeks earlier, respectively. Early data from Ireland and the United Kingdom
seem to confirm this assumption. Each day of delay increased mortality risk
by 5 to 6% (Yehya 2020). The consequences were dramatic (Stoke 2020, Max-
men 2020).
Like in Iran, where the regime covered up news of the coronavirus for three
days to avoid impacting on the turnout at parliamentary elections on 21 Feb-
ruary, domestic politics (or paranoia; BMJ, 6 March 2020) influenced the epi-
demic response in the US. Scientific advice from CDC and other national pub-
lic health institutions was ignored (The Lancet 2020). The US is the country
with the highest number of cases and deaths. Without this unprecedented
vacuum in leadership (NEJM Editors 2020), most of these deaths would have
been prevented.
Brazil, which is also not an example of good governance performance, has
become the country with the second highest number of deaths in the world.

Partial preparedness (France)

France was partially prepared. During the first national outbreak near Mul-
house, hospitals were overwhelmed. Despite the updated and well-structured
pandemic plan (https://www.gouvernement.fr/risques/plan-pandemie-
grippale), all over the country protective equipment was in short supply; in
particular, face masks were sorely lacking after a decision by the Hollande
government to greatly reduce the stocks of 1.7 billion protective masks (sur-
gical and FFP2) available in 2009 and considered too expensive to only 145
million surgical masks in 2020 (“We are not going to manage mask stocks, it is

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 Epidemiology | 39

expensive, because we have to destroy them every five years. Nous n’allons pas
gérer des stocks de masques, c’est coûteux, parce qu’il faut les détruire tous les cinq
ans.”) (Le Monde 200506).
However, France, thanks to Italy, had an important advantage: time. It had
several weeks to learn from the events in Lombardy. When, on the weekend
of 21 March, virtually from one day to the next, patients started pouring into
the hospitals of the Greater Paris Region, the number of available intensive
care unit beds had already increased from 1400 to 2,000 during the preceding
week. Furthermore, two years before, in a simulation of a major terrorist at-
tack, France had tested the use of a high-speed TGV train for transporting
casualties. At the height of the COVID epidemic, more than 500 patients were
evacuated from epidemic hotspots like Alsace and the Greater Paris area to
regions with fewer COVID-19 cases. Specially adapted high-speed trains as
well as aircraft were employed, transporting patients as far away as Brittany
and the Bordeaux area in the South-West, 600 km from Paris and 1000 km
from Mulhouse. The French management of ICU beds was a huge logistical
success.

Good virologists, huge lab network, family doctors (Germany)

Germany’s fatality rate is lower than in other countries. It is assumed that the
main reason for this difference is simply testing. While other countries were
conducting a limited number of tests in older patients with severe disease,
Germany was doing many more tests that included milder cases in younger
people (Stafford 2020). The more people with no or mild symptoms you test
and isolate, the lower the fatality rate and the spread of infection.
Furthermore, in Germany’s public health system, SARS-CoV-2 testing is not
restricted to a central laboratory as in many other nations but can be con-
ducted at quality-controlled laboratories throughout the country. Thanks to
reliable PCR methods that had been developed by the end of January from the
Drosten group at Berlin’s Charité (Corman 2020), within a few weeks the
overall capacity reached half a million PCR tests a week. The same low fatality
rate is seen in South Korea, another country with high testing rates.
Finally, another important reason for the low mortality in Germany might be
the age distribution. During the first weeks of the epidemic, most people be-
came infected during carnival sessions or ski holidays. The majority were
younger than 50 years of age. Mortality in this age group is markedly lower
than in older people.
As a result of these first-wave distinctive features, the case-fatality rate (CFR)
of COVID was 0,7% in Germany, compared with CFRs as high as 9,3% and 7,4%

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in Italy and the Netherlands, respectively (Sudharsanan 2020, Fisman 2020).

Age distribution of cases may explain as much as 66% of the variation of
SARS-CoV-2 cases across countries (Sudharsanan 2020).

Herd immunity? Not yet! (Sweden)

Sweden has never really imposed a lockdown, counting on the population to
adopt individual social distancing and other protective measures to curb the
transmission of SARS-CoV-2. The price was high (Habib 2020). In October
2020, Sweden had a death rate 10 times higher than Norway and five times
higher than Denmark, with most deaths occurring in care homes and immi-
grant communities. Still worse, Sweden didn’t benefit economically of its no-
lockdown approach as its economic performance contracted at a similar rate
as countries in the rest of Europe (Financial Times, 10 May 2020).
Will the autumn and winter reduce the mortality gap between Sweden and
Norway and Denmark? Will Sweden, after accepting many deaths in spring,
see fewer of them in the future? Will those who died early reduce the number
of deaths seen later? Will a (still low!) level of community immunity help slow
down the epidemic in winter? In any case, evaluations of cell phone data
show that Swedes traveled much less during the summer than, for example,
Norwegians or Danes, so they may have imported less infections from sum-
mer vacation hotspots. For a detailed discussion of herd immunity, see Ran-
dolph 2020.

Deferred beginning, then major impact (South America)

The first case of COVID-19 in Latin America was reported on 26 February in
Brazil and by early April all countries had reported at least one imported
case. However, in the initial months of 2020, the number of cases was com-
paratively low in South America compared to Europe or Asia (Haider 2020). As
a matter of fact, the local epidemics took off roughly 4 weeks later than in
Europe (see www.worldometers.info/coronavirus).
However, the epidemic accelerated during the month of May when South
America become the epicenter of the coronavirus pandemic according to
WHO. In September, Latin America, home to around 8% of the world’s popula-
tion, accounted for over a quarter of all confirmed COVID-19 cases and nearly
a third of all related deaths. There is, however, wide variation between coun-
tries, with Brazil and Mexico having some of the worst epidemics in the
world, while Uruguay infection rates are comparable to the best performing
countries in Asia or Europe (Taylor 2020).

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 Epidemiology | 41

According to Marcos Espinal and colleagues from WHO, there are several fac-
tors in Latin America that make this pandemic more difficult to manage: ine-
quality, belts of poverty surrounding big cities, informal economies, and diffi-
cult areas of access. Here, as elsewhere, leadership and sound public health
policies made a difference. Both Brazil’s and Mexico’s presidents have been
widely criticized for playing down the threat of COVID-19, not taking action
to slow its spread, and suggesting alternative ineffective ways of protection
(for example, the use of traditional scarves (?) instead of face masks).
However, other countries have performed much better, managing to keep
infections low. For example, Cuba and Costa Rica have enforced strict testing,
isolation and quarantine measures. The most successful country so far has
been Uruguay that managed, though a mix of effective testing, contact trac-
ing, isolation and quarantine, to keep infection rates very low without gener-
alized lockdowns. The President simply asked, rather than ordered, people to
stay home for their own well-being and that of fellow citizens (Taylor 2020).

Splendid isolation (New Zealand, Australia)

Australia, New Zealand, French Polynesia, Fiji, New Caledonia and Papua New
Guinea and Oceania are among the least hit areas in the world. Geographically
isolated islands or island states should be the ideal candidates for elimination
trials. However, even New Zealand, which viewed itself in the post-
elimination stage and where public life had returned to near normal (Baker
2020), was suddenly called back into COVID-19 reality when new cases were
discovered in August 2020.
In Australia, transmission was initially driven by multiple SARS-CoV-2 impor-
tations by returned international travelers which accounted for over half of
locally acquired cases (Seemann 2020). However, on 20 June, the State of Vic-
toria reported a spike in community transmitted cases, apparently following
lax implementation of quarantine measures, that resulted in a large outbreak
with more than 20,000 cases and 800 deaths and the imposition of strict lock-
down measures in the State and a night curfew in Melbourne. An easing of
restrictions only started mid-September, following a major decrease in the
number of new cases.
Both Australia and New Zealand have considered a strategy of COVID-19 elim-
ination, i.e. the absence of sustained endemic community transmission in the
country. The recent outbreaks have raised the question of whether elimina-
tion is a reasonable goal (Hewyood 2020). The elimination of any infectious
disease is an ambitious objective, requiring strong public health measures
and substantial resources. In principle, a zero-case scenario of not less than
three months would be the condition for declaring a state or country SARS-

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CoV-2-free. Then, strict travel and border restrictions and quarantine

measures must be implemented over a prolonged period, since the virus con-
tinues to spread around the world. It looks like international travel to New
Zealand and Australia may continue to be banned for quite some time.

Africa: The unknown (?) outcome

The transmissibility of SARS-CoV-2, combined with the scarcity of crucial
health equipment and facilities and the challenges of implementing wide-
spread case isolation (Wells 2020), was supposed to result in a devastating
impact of COVID-19 on African countries. These predictions have not materi-
alized. (To put the area into focus, remember that Europe without Russia has
a surface of roughly 6 million km2, Africa has 30 million km2. That should ex-
plain by itself that the burden and outcomes associated with COVID-19 in Af-
rica shows substantial variations across African countries [Twahirwa 2020].
There is no ‘one’ Africa.)
Some official figures are certainly underestimates, voluntary or not, due to
regional difficulties in reporting. In some cities, such as Kano, Nigeria, major
outbreaks may already be underway. The New York Times reported on 17
May, “so many doctors and nurses have been infected with SARS-CoV-2 that
few hospitals are now accepting patients”. Gravediggers are working over-
time. In Mogadishu, Somalia, officials say burials had tripled, according to the
same report. In Tanzania, the US embassy has warned of the risk of “expo-
nential growth” of COVID-19 cases in the country, adding that hospitals were
“overwhelmed” (The Guardian, 19 May).
However, there has been no COVID-19 explosion in Africa. Has time come to
hypothesize an “African exception”? It is probably too early to say but de-
mographics might explain in part the difference. In the Democratic Republic
of the Congo and Malawi, for instance, only 2-3% of the population is older
than 65 years (Kalk 2020), in sharp contrast to Europe at 20,5% or Lombardy
at 26%. If 65-year-old SARS-CoV-2 infected individuals are 100 times more
likely to die from COVID-19 than a 25-year-old, we should expect two differ-
ent epidemics. Simply, the age pyramid might make the difference.

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 Epidemiology | 43

The SARS-CoV-2 pandemic: Past and Future

Natural course of a pandemic
The COVID-19 epidemic started in Wuhan, in Hubei province, China, and
spread within 30 days from Hubei to the rest of mainland China, to neighbor-
ing countries (in particular, South Korea, Hong Kong and Singapore) and west
to Iran, Europe and the Americas. The first huge outbreaks occurred in re-
gions with cold winters (Wuhan, Iran, Northern Italy, the Alsace region in
France).
Fifty years ago, the course of the COVID-19 pandemic would have been differ-
ent, with slower global spread but high burden due to limited diagnostic and
therapeutic capacities and no option of nation-wide lockdowns (see also a
report of the influenza pandemics in 1957 and 1968: Honigsbaum 2020). Ac-
cording to one (controversial) simulation, in the absence of interventions and
with a mortality rate of around 0.5%, without interventions COVID-19 would
have resulted in 7.0 billion infections and 40 million deaths globally during
the first year (Patrick 2020). The peak in mortality (daily deaths) would have
been observed approximately 3 months after the beginning of local epidem-
ics. Another model predicted that 80% of the US population (around 260 mil-
lion people) would have contracted the disease. Of those, 2.2 million Ameri-
cans would have died, including 4% to 8% of those over age 70 (Ferguson
2020). In Germany alone, the SARS-CoV-2 pandemic could have resulted in
730,000 deaths (Barbarossa 2020) and in 500,000 deaths each in France, Italy,
Spain and the UK.

The 2020 Lockdowns

Fortunately, for now, the world has been spared from a freely circulating
SARS-CoV-2. If humanity can change the climate, why shouldn’t we be able to
change the course of a pandemic? Although economists warned that unem-
ployment could surpass the levels reached during the Great Depression in the
1930s, at first, almost all governments considered saving hundreds of thou-
sands lives more important than avoiding a massive economic recession. First
in China, six weeks later in Italy and another a week later in most Western
European countries, more recently in the US and in many other countries in
the world, unprecedented experiments of gigantic dimensions were started:
ordering entire regions or the whole nation to lockdown. By the first week of
April, 4 billion people worldwide were under some form of lockdown — more
than half of the world’s population. Lockdowns in Europe were generally less
strict than in China, allowing the continuation of essential services and indus-
tries and the circulation of people when justified.

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People were generally compliant to mandatory stay-at-home orders, even in

the US. Based on location data from mobile devices, in 97.6% of US counties
these orders were associated with decreased median population movement
(Moreland 2020). Lockdowns were generally also well accepted. During the
week of May 5–12, 2020, a survey among 2402 adults In New York City and Los
Angeles found widespread support of stay-at-home orders and non-essential
business closures and a high degree of adherence to COVID-19 mitigation
guidelines (Czeisler 2020). In New York City, SARS-CoV-2 prevalence varied
substantially between boroughs between 22 March and 3 May 2020 (for ex-
ample, Manhattan: 11,3%; South Queens: 26,0%). These differences in preva-
lence correlate with antecedent reductions in commuting-style mobility be-
tween the boroughs. Prevalence was lowest in boroughs with the greatest
reductions in morning movements out of and evening movements into the
borough (Kissler 2020).
Lockdowns were also successful in slowing down the pandemic. According to
one study, between 12 and 15 million individuals in Europe had been infected
with SARS-CoV-2 by May 4th, representing between 3.2% and 4.0% of the
population (Flaxman June 2020). Projected percentages of the total popula-
tion infected were for Austria 0,76%, Belgium 8,0%, Denmark 1,0%, France
3,4%, Germany 0,85%, Italy 4,6%, Norway 0,46%, Spain 5,5%, Sweden 3,7%,
Switzerland 1,9% and the UK 5,1%. In South America, lockdowns were suc-
cessful, too, although they worked best among the wealthy and less well
among the less wealthy who had to choose between the risk of dying from
COVID or dying from hunger.
There is no real pandemic in Africa, a never-ending wave in the Americas,
and now a second wave in Europe. The worst may be yet to come (The Lancet
2020) with more people dying and every death leaving 10 more people
mourning a grandparent, parent, sibling, spouse, or child (Verdery 2020). Will
the winter SARS-CoV-2 pandemic follow the scenario of the 1918 influenza
pandemic (Horton 2020)?
In the French Bouches-du-Rhône department which includes Marseille, the
first signs of the second wave were detected in wastewater on July 131. Three
weeks later, the first post-lockdown rise in new SARS-CoV-2 infections was
seen in young adults 20 to 29 years old, and again a few weeks later, infection

1
SARS-CoV-2 can be detected in wastewater using RT-qPCR. In one study, the
total load of gene equivalents in wastewater correlated with the cumulative
and the acute number of COVID-19 cases reported in the respective catch-
ment areas [Westhaus 2020]. Note that wastewater is no route for SARS-CoV-2
transmission to humans! All replication tests were negative tests.

Kamps – Hoffmann
 Epidemiology | 45

rates increased in older age groups. In Spain (NCOMG 2020), Switzerland (see
Figure 1) and other European countries, the second wave looked equally trig-
gered mostly by transmission among young adults in leisure venues such as
bars, restaurants, discos or clubs during the summer 2020.

Figure 1. Weekly positive SARS-CoV-2 tests in Switzerland by age group (August 3 through
October 5).Source: SRF, So entwickeln sich die Corona-Zahlen in der Schweiz
(https://www.srf.ch/news/schweiz/coronavirus-so-entwickeln-sich-die-corona-zahlen-in-der-
schweiz; accessed 12 October 2020).

Let’s briefly discuss

• Measuring the epidemic
• Herd immunity: Not yet
• Vaccines: Be patient
• ‘Variolation’ – Finding of the year?
• Protection: People at risk
• Prevention: Testing, tracing, isolating
• Curfews

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Measuring the epidemic

In the current second European wave, the number of newly diagnosed SARS-
CoV-2 cases and the positive rate of PCR tests are certainly useful markers for
the evolution of national epidemics; however, the number of hospitalizations
and, most importantly, the number of new admissions to intensive care units
(ICU) and deaths are the crucial figures in terms of disease burden (Figure 2
and 3).
Note that all these markers have limitations. For example, the number of pos-
itive cases identified are related to the number of tests performed and testing
strategies. Hospital admissions also have limitations (hospital admission cri-
teria may change from place to place and be modified over time) and can be
influenced by, for example, the availability of quality home-based care or the
collapse of an overburdened health system. In addition, many governments
are not publicly providing numbers of daily hospital admissions and dis-
charges (Garcia-Basteiro 2020).
In anticipating local epidemics, politicians should prepare for the worst, at
least until spring 2021. An important feature of this second wave of infections
is its widespread nature, as opposed to earlier, more localized outbreaks (e.g.
northern Italy, Madrid, Spain or Mulhouse, France.) More populated and bet-
ter-connected municipalities were generally affected earlier by the SARS-
CoV-2 epidemic, and less populated municipalities at a later stage of the epi-
demic (de Souza 2020). However, relaxation of mitigation measures leading to
a resumption of “normal” diffusion may initially appear to have few negative
effects, only to lead to deadly outbreaks weeks or months later (Thomas
2020). Public health messaging may need to stress that apparent lulls in dis-
ease progress are not necessarily indicators that the threat has subsided, and
that areas “passed over” by past outbreaks could be impacted at any time.

Herd immunity: Not yet

Herd immunity, the notion introduced to a wider public by a foolish politi-
cian, may not be on the agenda for a long time. Herd immunity, also known as
indirect protection, community immunity, or community protection, refers to the
protection of susceptible individuals against an infection when a sufficiently
large proportion of immune individuals exist in a population (Omer 2020). As
for now, not a single country is anywhere close to reaching herd immunity.
Even in past hotspots like Wuhan, the prevalence of SARS-CoV-2 IgG positivi-
ty was 9.6% among 1021 people applying for a permission (the SARS‐CoV‐2
nucleic acid test needed to be negative) (Wu X 2020). A French study project-
ed 2.8 million or 4.4% (range: 2.8–7.2) prevalence of infections in France. In
Los Angeles, the prevalence of antibodies was 4.65% (Sood 2020). (And even

Kamps – Hoffmann
 Epidemiology | 47

this low number may be biased because symptomatic persons may have been
more likely to participate.) A nationwide coronavirus antibody study in Spain
showed that about 5% of the population had contracted the virus. These in-
fection rates are clearly insufficient to avoid a second wave of a SARS-CoV-2
epidemic (Salje 2020). Achieving herd immunity without overwhelming hos-
pital capacity would require an unlikely balancing of multiple poorly defined
forces (Brett 2020).

Vaccines: Be patient
Some fools – politicians and experts alike – announced efficient and safe vac-
cines two months before Christmas 2020. Reality will see such thoroughly
tested vaccines delivered to the first groups of vaccinees (i.e., health care
workers) way into 2021, and nobody should expect vaccines to have a notice-
able impact on the SARS-CoV-2 pandemic before the end of next year. In the
meantime, people will need to be patient and look for alternative ways of pro-
tection.

‘Variolation’ – Finding of the year?

Reducing the viral SARS-CoV-2 inoculum might not only reduce the probabil-
ity of infection but also favor an asymptomatic infection while still generat-
ing immunity. This suggestion (Bielecki 2020) was later further developed
(Ghandi 2020; see also the comments to the paper by Rasmussen 2020,
Brosseau 2020): if facial masking may help in reducing the size of the viral
inoculum, universal facial masking might ensure that a greater proportion of
new infections are asymptomatic. If universal masking could be proved to be
a form of ‘variolation’ (inoculation), it would be an additional argument in
favor of strict mask wearing.

Protecting people at risk

Protecting those at higher risk of SARS-CoV-2 infection, for example the el-
derly and healthcare workers (Nguyen 2020), will continue to be the highest
priority over the coming months. Specific population groups might be at
higher risk too. In the UK and the US, Black, Asian, and minority ethnic
health care workers are at especially high risk of SARS-CoV-2 infection, with
at least a fivefold (!) increased risk of COVID-19 compared with the non-
Hispanic white general community. The infection rate is also higher in the
most poor and vulnerable areas, thus emphasizing existing inequalities
(Grasso 2020: COVID of the rich, COVID of the poor).
In a cross-sectional study of 396 pregnant New York City residents, large
household membership, household crowding, and low socioeconomic status

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were associated with a 2-3 fold higher risk of infection (Emeruwa 2020).
American Indian and Alaska Native (AI/AN) persons, too, appear to be dispro-
portionately affected by the COVID-19 pandemic. In one study, the overall
COVID-19 incidence among AI/AN persons was 3.5 times that among white
persons (594 per 100,000 AI/AN population compared with 169 per 100,000
white population) (Hatcher 2020).

Prevention: Testing, tracing, isolating

Screening, case investigation, contact tracing, and isolation of infected per-
sons is paramount during periods of community transmission. In a random
sample of 350 adults aged ≥ 18 years who had positive RT-PCR in outpatient
and inpatient settings at 11 US academic medical centers, only 46% were
aware of recent close contact with someone with COVID-19, most commonly a
family member (45%) or a work colleague (34%) (Tenforde 2020).
Testing presents numerous challenges (Clapham 2020), but the more people
you test for SARS-CoV-2, the better. In a worldwide cross-sectional study
(Liang LL 2020), COVID-19 mortality was
• Negatively associated with
o Test number per 100 people
o Government effectiveness score
o Number of hospital beds
• Positively associated with
o Proportion of population aged 65 or older
o Transport infrastructure low quality score
Testing was a major limiting factor in assessing the extent of SARS-CoV-2
transmission during its initial spread into the US (Perkins 2020). After a na-
tional emergency was declared, fewer than 10% of locally acquired, sympto-
matic infections in the US were detected over a period of a month. This gap in
surveillance during a critical phase of the epidemic resulted in a large, unde-
tected reservoir of infections by early March. Other countries did better.
Citywide mass nucleic acid testing of SARS-CoV-2 for all citizens is possible as
shown in Wuhan city (14 May to 1 June 2020). The results are sometimes mea-
ger, revealing just 6 persons who test positive for SARS-CoV-2 (0,006% of
107,662 residents around the Huanan Seafood Market), but are able to suffo-
cate a nascent epidemic (Jingwen L 2020).
It is important to recognize that despite aggressive efforts by health depart-
ments, many COVID-19 patients do not report contacts, and many contacts
cannot be reached (Lash 2020). Staff members in North Carolina, US have in-

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 Epidemiology | 49

vestigated 5514 (77%) persons with COVID-19 in Mecklenburg County and 584
(99%) in Randolph Counties: during periods of high COVID-19 incidence, 48%
and 35% of patients reported no contacts, and 25% and 48% of contacts were
not reached. Median interval from index patient specimen collection to con-
tact notification was 6 days. Some countries are obviously better prepared for
mass testing than others and capable of performing 9 million tests in 5 days
after the detection of 12 cases in a previously COVID-free area (Vidal Liy 2020
+ BBC).

Curfews
Lockdowns are effective but frighteningly costly. The spring lockdown cost
most countries around 10% of their PIB with unforeseeable economic, politi-
cal and also health consequences; in exchange, they can “flatten the curve”
and did succeed in keeping seroprevalence rates low, somewhere between 1%
and 10%. General lockdowns are clearly not a viable model for the future.
Might curfews be a less costly alternative, both economically and socially? In
French Guiana, an overseas départment, a combination of curfews and target-
ed lockdowns in June and July 2020 was sufficient to avoid saturation of hos-
pitals. On weekdays, residents were first ordered to stay at home at 11 p.m.,
then at 9 p.m., later at 7 p.m., and finally at 5 p.m. On weekends, everyone
had to stay at home from 1 p.m. on Saturday (Andronico 2020). Whether cur-
fews can be successfully adapted to other areas than French Guiana, is not
known. French Guiana is a young territory with a median age of 25 years and
the risk of hospitalization following infection was only 30% that of France.
About 20% of the population had been infected with SARS-CoV-2 by July 2020
(Andronico 2020). Following Belgium and Germany, France has just imple-
mented now its night curfew in Paris and a few other major cities. Be pre-
pared to see more curfews orders over the coming six months.

Outlook
How long will SARS-CoV-2 stay with us? How long will it be before we return
to pre-COVID-19 ‘normalcy’? For how long will a combination of physical dis-
tancing, enhanced testing, quarantine, and contact tracing be needed? Histor-
ical evidence from prior influenza pandemics indicates that pandemics tend
to come in waves over the first 2–5 years as population immunity builds-up
(naturally or through vaccination) and that this is the most likely trajectory
for SARS-CoV-2 (Petersen 2020). Even vaccines are not expected to have a
substantial impact on the pandemic before 2022, if ever. In the meantime,
classical infection control measures are the only way to reduce the number of
infections and avoid healthcare systems from breaking down, leaving patients

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with other morbidities – common emergencies and surgery, cancer treat-

ment, management of patients with chronic diseases – stranded and aban-
doned in a medical no-man’s land.
Summer of 2020 has shown that the post-lockdown epidemic dynamic was
driven by younger adults with gradual ‘spill-over’ into older age groups.
However, the formula ‘young adults -> parents -> grandparents -> death’ shall
not be used as a simplistic model for the European second wave. SARS-CoV-2
is introduced and spread in communities via all conceivable routes. It is
therefore important to define the behaviors than can minimize the risk of
local lockdowns and economic hardship.
In situations of intense SARS-CoV-2 community transmission, the prevention
triad is simple:
1. Stop people from meeting each other in large gatherings.
2. If they MUST meet, have them wear face masks.
3. In any case reduce the time infected or suspected infectious people
meet any other people at all: test as much as possible, isolate cases
quickly and track the close contacts.
In transmission hotspots, restrictive social-distancing measures will need to
be combined with widespread testing and contact tracing to slow down the
ongoing pandemic (Giordano 2020 + less realistic, Peto 2020). People should
concentrate on the essential activities of providing food and shelter as well as
continuing their job, school and university activities. All ‘après-work’ and
‘après-school’ activities should be reduced to a minimum (no evening bars, no
night life). In such social slowdowns, people will need to avoid prolonged
meetings with people from outside their inner-core “friends-and-family-
bubble”, in particular social events which bring people from many different
families together (marriages, funerals, religious events). Even inside the in-
ner-core “friends-and-family-bubble”, meetings should be restricted to a
handful of people. Economically, a social slowdown implies the temporary
closure of places where foreigners, strangers or simply unacquainted people
meet: discos, amusement parks, bars, restaurants, brothels and many more.
In a situation of intense SARS-CoV-2 community transmission, strangers must
not come into contact.
Coronaviruses have come a long way (Weiss 2020) and will stay with us for a
long time. Questions abound: When will we move freely around the world as
we did before? Will air traffic return to pre-COVID-19 levels by 2024 or only
later? Will we be inclined to plan vacations nearer to home rather than on the
other side of the globe? Will we wear face masks for years? Will there be any
nightlife event with densely packed people dancing and shouting and drink-

Kamps – Hoffmann
 Epidemiology | 51

ing in any city in the world anytime soon? Nobody knows. We only know that
old and obese countries are hard hit and young and slim countries are rela-
tively spared.
The French have an exquisitely precise formula to express unwillingness for
living in a world you do not recognize: “Un monde de con!” Fortunately, we
will be able to walk out of this monde de con thanks to a scientific community
which is larger, stronger, and faster than at any time in history. (BTW, should
politicians who are skeptical of science be ousted out of office? Yes, please! It
is about time!) As of today, we do not know how long-lasting, how intense,
and how deadly this pandemic will be. We are walking on moving ground and,
in the coming months and years, we will need to be flexible, resilient, and
inventive, looking for and finding solutions nobody would have imagined just
months ago. Sure enough though, science will lead the way out. If we could
leap five years into the future and read the story of COVID-19, we would not
believe our eyes.

New References (5th Edition)

The following pages add short comments to the papers published since the
previous edition (June-October). The comments are from
https://covidreference.com/daily-science. After a selection of the best arti-
cles, find the new articles of the 5th edition grouped according to the outline
of the chapter (page 55). The complete list of references starts at page 78.

Top Articles
Leadership vacuum
NEJM Editors. Dying in a Leadership Vacuum. N Engl J Med 2020; 383:1479-
1480. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMe2029812
SARS-CoV-2 and the COVID-19 pandemic became a test of leadership. With no
good options to combat a novel pathogen, countries were forced to make
hard choices about how to respond. In the United States, the leaders have
failed that test.

“Variolation”?
Bielecki M, Züst R, Siegrist D, et al. Social distancing alters the clinical
course of COVID-19 in young adults: A comparative cohort study. Clin Inf
Dis, June 29, 2020. Full-text: https://doi.org/10.1093/cid/ciaa889

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52 | CovidReference.com

Gandhi M, Rutherford GW. Facial Masking for Covid-19 — Potential for

“Variolation” as We Await a Vaccine. NEJM September 8, 2020. Full-text:
https://doi.org/10.1056/NEJMp2026913
Reducing the viral SARS-CoV-2 inoculum might not only reduce the probabil-
ity of infection but also favor an asymptomatic infection while still generat-
ing immunity. This suggestion by Michel Bielecki et al. in June 2020 (Bielecki
2020) was later developed by Monica Gandhi and George W. Rutherford
(Ghandi 2020). If facial masking may help reducing the size of the viral inocu-
lum, universal facial masking might ensure that a greater proportion of new
infections are asymptomatic. If universal masking could be proved to be a
form of “variolation” (inoculation), it would be a giant leap to pandemic con-
trol.

SARS-CoV-2 Emergence in Europe and North America

Worobey M, Pekar J, Larsen BB, et al. The emergence of SARS-CoV-2 in Eu-
rope and North America. Science 2020, published 10 September. Full-text:
https://doi.org/10.1126/science.abc8169
Despite the early successes in containment, SARS-CoV-2 eventually took hold
in both Europe and North America during the first two months of 2020: first
in Italy around the end of January, then in Washington State around the be-
ginning of February, and followed by New York City later that month
(Worobey 2020; see also Figure 6).

Brazil
Candido DS, Claro M, de Jesus JG, et al. Evolution and epidemic spread of
SARS-CoV-2 in Brazil. Science 23 Jul 2020:eabd2161. Full-text:
https://doi.org/10.1126/science.abd2161
Sequencing of hundreds of genomes showed that more than 100 international
virus introductions in Brazil with 76% of Brazilian strains falling into three
clades that were introduced from Europe between 22 February and 11 March
2020 (Candido 2020).

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 Epidemiology | 53

Mumbai, India
Kolthur-Seetharam U, Shah D, Shastri J, Juneja S, Kang G, Malani A, Mohanan
M, Lobo GN, Velhal G, Gomare M. SARS-CoV2 Serological Survey in Mumbai
by NITI-BMC-TIFR. Tata Institute of Fundamental Research (TIFR) 2020,
published 29 June. Full-text: https://www.tifr.res.in/TSN/article/Mumbai-
Serosurvey%20Technical%20report-NITI.pdf
In a cross-sectional survey in Mumbai, India, the prevalence of SARS-CoV-2
infection in three areas in Mumbai (called ‘wards’) was around 57% in the
slum areas of Chembur, Matunga and Dahisar, and 16% in neighboring non-
slums (Kolthur-Seetharam 2020). If these data are confirmed, some Mumbai
areas would soon reach herd immunity and could return to a pre-COVID way
of life. For many countries in the world, this would be the best piece of news
since the beginning of the pandemic.

Frontline healthcare workers: US

Self WH, Tenforde MW, Stubblefield WB, et al. Seroprevalence of SARS-CoV-
2 Among Frontline Health Care Personnel in a Multistate Hospital Net-
work — 13 Academic Medical Centers, April–June 2020. MMWR. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6935e2
Many cases appear to go undetected: among 3,248 HCWs who routinely cared
for COVID-19 patients in 13 US academic medical centers from February 1,
2020, 194 (6%) had evidence of previous SARS-CoV-2 infection, with consider-
able variation by location that generally correlated with community cumula-
tive incidence. Among 194 participants who had SARS-CoV-2 antibodies, 56
(29%) did not recall any symptoms consistent with an acute viral illness in the
preceding months and 133 (69%) did not have a previous positive test result
demonstrating an acute SARS-CoV-2 infection. Prevalence of SARS-CoV-2 an-
tibodies was lower among personnel who reported always wearing a face cov-
ering while caring for patients (6%), compared with those who did not (9%).

Frontline healthcare workers: London

Houlihan CF, Vora N, Byrne T, et al. Pandemic peak SARS-CoV-2 infection
and seroconversion rates in London frontline health-care workers. Lan-
cet July 09, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31484-7
High-risk frontline healthcare workers (HCV) are really at high risk. In a pro-
spective cohort study in an acute National Health Service hospital trust in
London, 25% of HCWs were already seropositive at enrolment (26 March to 8
April) and a further 20% became seropositive within the first month of follow-

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up (Houlihan 2020). Most infections occurred between March 30 and April 5,

the week with the highest number of new cases in London.

School Openings
Cheng SY, Wang J, Shen AC, et al. How to Safely Reopen Colleges and Uni-
versities During COVID-19: Experiences From Taiwan. Ann Int Med 2020,
Jul 2. Full-text: https://doi.org/10.7326/M20-2927
Taiwan is one of the few countries where schools are functioning normally.
To secure the safety of students and staff, the Ministry of Education in Taiwan
established general guidelines, including a combination of strategies such as –
our future? - active campus-based screening and access control; school-based
screening and quarantine protocols; student and faculty quarantine when
warranted; mobilization of administrative and health center staff; regulation
of dormitories and cafeterias; and reinforcement of personal hygiene, envi-
ronmental sanitation, and indoor air ventilation practices (Cheng SY 2020).
Depressing (“un monde de con”), but probably necessary.

Second Wave
NCOMG. The national COVID-19 outbreak monitoring group. COVID-19 out-
breaks in a transmission control scenario: challenges posed by social
and leisure activities, and for workers in vulnerable conditions, Spain,
early summer 2020. Eurosurveillance Volume 25, Issue 35, 03/Sep/2020.
Full-text: https://www.eurosurveillance.org/content/10.2807/1560-
7917.ES.2020.25.35.2001545
From mid-June to 2 August, excluding single household outbreaks, 673 out-
breaks were notified in Spain (NCOMG 2020). There were two main settings
where over 55% of active outbreaks (303/551) and over 60% (3,815/6,208) of
active outbreak cases originated: First, social settings such as family gather-
ings or private parties (112 outbreaks, 854 cases), followed by those linked to
leisure venues such as bars, restaurants, or clubs (34 outbreaks, over 1,230
cases). Second, occupational settings (representing 20% of all active out-
breaks), mainly among workers in the fruit and vegetable sector (31 out-
breaks and around 500 cases) and workers at slaughterhouses or meat pro-
cessing plants (12 outbreaks and around 360 cases).

Rigorous wildlife disease surveillance

Watsa M. Rigorous wildlife disease surveillance. Science 10 Jul 2020, 369:
145-147. Full-text: https://doi.org/10.1126/science.abc0017

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 Epidemiology | 55

Emerging infectious diseases (EID) associated with the wildlife trade remain
the largest unmet challenge of current disease surveillance efforts. Interna-
tional or national conventions on pathogen screening associated with ani-
mals, animal products or their movements are urgently needed (Watsa 2020).
Internationally recognized standard for managing wildlife trade on the basis
of known disease risks should be established.

More Articles
Introduction
McNeil Jr DG. A Viral Epidemic Splintering Into Deadly Pieces. The New York
Times, 29 July 2020. Full-text:
https://www.nytimes.com/2020/07/29/health/coronavirus-future-america.html
Some articles in the lay press are outstanding documents, and a few are better than
two thirds of published and pre-published scientific articles about COVID-19. Read
these 4,000 words thoughtfully put down by Donald G. McNeil Jr. If you don’t read it
now, read it on the weekend.

Adam D. A guide to R — the pandemic’s misunderstood metric. Nature News. 03

July 2020. Full-text: https://www.nature.com/articles/d41586-020-02009-w
Nice article about what R, the reproduction number, can and can’t tell us about man-
aging COVID-19 (Adam 2020). Politicians seem to have embraced R with enthusiasm
but it’s far more important to watch for clusters of cases and to set up comprehensive
systems to test people, trace their contacts and isolate those infected, than to look at
R.

Yu X, Wei D, Chen Y, et al. Retrospective detection of SARS-CoV-2 in hospitalized

patients with influenza-like illness. Emerging Microbes & Infections 2020, Full-text:
https://doi.org/10.1080/22221751.2020.1785952
There was no ‘stealthy’ SARS-CoV-2 transmission before the outbreak in Wuhan, Chi-
na. In a retrospective screening for SARS-CoV-2 RNA in 1,271 nasopharyngeal swab
samples, as well as the prevalence of IgM, IgG, and total antibodies against SARS-CoV-2
in 357 matched serum samples collected from hospitalized patients with influenza-like
illness between December 1, 2018 and March 31, 2020 in Shanghai Ruijin Hospital, the
onset date of the earliest COVID-19 case was January 25 (Yu X 2020).

Worobey M, Pekar J, Larsen BB, et al. The emergence of SARS-CoV-2 in Europe and
North America. Science 2020, published 10 September. Full-text:
https://doi.org/10.1126/science.abc8169
Despite the early successes in containment, SARS-CoV-2 eventually took hold in both
Europe and North America during the first two months of 2020: first in Italy around

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the end of January, then in Washington State around the beginning of February, and
followed by New York City later that month (Worobey 2020; see also Figure 6).

Dawood FS, Ricks P, Njie GJ, et al. Observations of the global epidemiology of
COVID-19 from the prepandemic period using web-based surveillance: a cross-
sectional analysis. Lancet Infect Dis 2020, published 29 July. Full-text:
https://doi.org/10.1016/S1473-3099(20)30581-8
Fatimah Dawood and colleagues describe the global spread of SARS-CoV-2 and charac-
teristics of COVID-19 cases and clusters before WHO declared COVID-19 as a pandemic
on 11 March 2020 (i.e., pre-pandemic). They identified cases of COVID-19 from official
websites, press releases, press conference transcripts, and social media feeds of na-
tional ministries of health or other government agencies. Cases with travel links to
China, Italy, or Iran accounted for almost two-thirds of the first reported COVID-19
cases from affected countries (Dawood 2020). There were many clusters of household
transmission among early cases; however, clusters in occupational or community set-
tings tended to be larger.

Deng X, Gu W,Federman S, et al. Genomic surveillance reveals multiple introduc-

tions of SARS-CoV-2 into Northern California. Science 08 Jun 2020. Full-text:
https://doi.org/10.1126/science.abb9263
Early genomic surveillance revealed the cryptic introduction of at least 7 different
SARS-CoV-2 lineages into California (Deng X 2020).

Candido DS, Claro M, de Jesus JG, et al. Evolution and epidemic spread of SARS-CoV-
2 in Brazil. Science 23 Jul 2020:eabd2161. Full-text:
https://doi.org/10.1126/science.abd2161
Sequencing of hundreds of genomes showed that more than 100 international virus
introductions in Brazil with 76% of Brazilian strains falling into three clades that were
introduced from Europe between 22 February and 11 March 2020 (Candido 2020).

Seroprevalence
ITALY

Sabbadini LL, Romano MC, et al. [First results of the seroprevalence survey about
SARS-CoV-2] (Primi risultati dell’indagine di sieroprevalenza sul SARS-CoV-2). Italian
Health Ministery and National Statistics Institute 2020, published 3 August. Full-text
(Italian):
https://www.istat.it/it/files//2020/08/ReportPrimiRisultatiIndagineSiero.pdf
According to a representative study by the Italian Ministry of Health (64,000 partici-
pants), 1.5 million people (2.5% of the population) had SARS-CoV-2 antibodies during
the study period from May 25 to July 15 (Sabbadini 2020). This figure is higher than
the currently reported 250,000 cases. If these figures are true, the infection fatality rate
(IFR, the proportion of deaths among all the infected individuals) in Italy would be

Kamps – Hoffmann
 Epidemiology | 57

2.3% (35,000 deaths/1,500,000 infections). This is higher than in other European coun-
tries and needs to be addressed in future studies.

Bassi F, Arbia G, Falorsi PD. Observed and estimated prevalence of Covid-19 in Ita-
ly: How to estimate the total cases from medical swabs data. Sci Total Environ.
2020 Oct 8:142799. PubMed: https://pubmed.gov/33066965. Full-text:
https://doi.org/10.1016/j.scitotenv.2020.142799
A national survey in Italy from May to July 2020 (see previous article) found a nation-
wide seropositivity rate of 2.5% (Sabbadini 2020). Insiders never believed these figures
and favored a seropositivity rate of 5-10% like in Spain or in France. Now we have a
new estimate of COVID-19 prevalence in Italy by Francesca Bassi and colleagues: 9%,
corresponding to almost 6 million Italians.

Percivalle E, Cambiè G, Cassaniti I, et al. Prevalence of SARS-CoV-2 specific neutral-

ising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at
06 April 2020. Euro Surveill. 2020 Jun;25(24):2001031. PubMed:
https://pubmed.gov/32583766. Full-text: https://doi.org/10.2807/1560-
7917.ES.2020.25.24.2001031
In the highly affected “Lodi Red Zone” in Italy (an area of 169 km2, including 10 munic-
ipalities and 51,500 inhabitants, which went into lockdown in February 2020), 91 of
390 blood donors (23%) aged 19–70 years were antibody positive (Percivalle 2020).

SPAIN

Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al. Prevalence of SARS-CoV-2 in

Spain (ENE-COVID): a nationwide, population-based seroepidemiological study.
The Lancet 2020, July 06, 2020. Full-text: https://doi.org/10.1016/S0140-
6736(20)31483-5
The vast majority (95%) of the Spanish population is seronegative, even in hotspot
areas. In a nationwide, representative study, 61,075 participants were tested. Sero-
prevalence was 5.0% (95% CI 4.7–5.4) by the point-of-care test and 4.6% (4.3–5.0) by
immunoassay, with a lower seroprevalence in children younger than 10 years (< 3.1%
by the point-of-care test) (Pollán 2020). There was high geographical variability, with
higher prevalence around Madrid (> 10%) and lower in coastal areas (< 3%).
Soriano V, Meiriño R, Corral O, Guallar MP. SARS-CoV-2 antibodies in adults in Ma-
drid, Spain. Clin Infect Dis. 2020 Jun 16:ciaa769. PubMed:
https://pubmed.gov/32544951. Full-text: https://doi.org/10.1093/cid/ciaa769
Even in regions that were hard hit by the first SARS-CoV-2 wave (like the Madrid area
with with 65,000 confirmed cases and 9,000 deaths up to May 10th), only roughly 11%
of adults had SARS-CoV-2 antibodies at the time of lockdown release on May 10th
(Soriano 2020).

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US

Ng DL, Goldgof GM, Shy BR, et al. SARS-CoV-2 seroprevalence and neutralizing ac-
tivity in donor and patient blood. Nat Commun. 2020 Sep 17;11(1):4698. PubMed:
https://pubmed.gov/32943630. Full-text: https://doi.org/10.1038/s41467-020-18468-8
In April 2020, SARS-CoV-2 seroprevalence was low in the San Francisco Bay Area
(0.26% in 387 hospitalized patients; 0.1% in 1,000 blood donors) (Ng DL 2020).
Charles Y. Chiu, Dianna Ng and colleagues also describe the longitudinal dynamics of
immunoglobulin-G (IgG), immunoglobulin-M (IgM), and in vitro neutralizing antibody
titers in COVID-19 patients. The median time to seroconversion ranged from 10.3–11.0
days for these 3 assays. The authors provide evidence that seropositive results using
SARS-CoV-2 anti-nucleocapsid protein IgG and anti-spike IgM assays are generally
predictive of in vitro neutralizing capacity.

Havers FP, Reed C, Lim T, et al. Seroprevalence of Antibodies to SARS-CoV-2 in 10

Sites in the United States, March 23-May 12, 2020. JAMA Intern Med. 2020 Jul 21.
PubMed: https://pubmed.gov/32692365. Full-text:
https://doi.org/10.1001/jamainternmed.2020.4130
In a cross-sectional study, the proportion of seropositive persons ranged from 1.0% in
the San Francisco Bay area (collected April 23-27) to 6.9% of persons in New York City
(collected March 23-April 1) (Havers 2020). The estimated number of SARS-CoV-2 in-
fections is around 10 times the number of reported cases.

Moscola J, Sembajwe G, Jarrett M, et al. Prevalence of SARS-CoV-2 Antibodies in

Health Care Personnel in the New York City Area. JAMA 2020, published 6 August.
https://doi.org/10.1001/jama.2020.14765
Health care personnel (HCP) have a high exposure risk for SARS-CoV-2 infection. In
New York, the prevalence of SARS-CoV-2 was 13.7 (5523 of 40,329 HCWs tested) which
was similar to that among adults randomly tested in New York State (14.0%). (Moscola
2020).

INDIA

Kolthur-Seetharam U, Shah D, Shastri J, Juneja S, Kang G, Malani A, Mohanan M, Lobo

GN, Velhal G, Gomare M. SARS-CoV2 Serological Survey in Mumbai by NITI-BMC-
TIFR. Tata Institute of Fundamental Research (TIFR) 2020, published 29 June. Full-
text: https://www.tifr.res.in/TSN/article/Mumbai-
Serosurvey%20Technical%20report-NITI.pdf
In a cross-sectional survey in Mumbai, India, the prevalence of SARS-CoV-2 infection
in three areas in Mumbai (called ‘wards’) was around 57% in the slum areas of Chem-
bur, Matunga and Dahisar, and 16% in neighboring non-slums (Kolthur-Seetharam
2020). If these data are confirmed, some Mumbai areas would soon reach herd immun-

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ity and could return to a pre-COVID way of life. For many countries in the world, this
would be the best piece of news since the beginning of the pandemic.

FAROE ISLANDS

Petersen MS, Strøm M, Christiansen DH, Fjallsbak JP, Eliasen EH, Johansen M, et al.
Seroprevalence of SARS-CoV-2–specific antibodies, Faroe Islands. Emerg Infect Dis
2020 Nov. Published August 2020. Full-text: https://doi.org/10.3201/eid2611.202736
In the Faroe Islands, an autonomous territory within the Kingdom of Denmark with a
population of around 50,000, only 6 out of 1,075 randomly selected participants (0.6%)
tested seropositive for antibodies to SARS-CoV-2 (Petersen 2020). At present, small
islands tend to have low seropositivity rates.

UK

Ward H, Atchison C, Whitaker M, et al. Antibody prevalence for SARS-CoV-2 follow-

ing the peak of the pandemic in England: REACT2 study in 100,000 adults. Impe-
rial College London 2020. Pre-print: https://www.imperial.ac.uk/media/imperial-
college/institute-of-global-health-innovation/Ward-et-al-120820.pdf
By the end of June 2020, an estimated 3.4 million people, or slightly under 6% of the
UK population, had antibodies to the virus and had likely had COVID-19. London had
the highest numbers (13%), while the South West had the lowest (3%) (Ward 2020).
Black, Asian and minority ethnic (BAME) individuals were between two and three
times as likely to have had SARS-CoV-2 infection compared to white people. An inter-
esting trend: young people aged 18-24 had the highest rates (8%), while older adults
aged 65 to 74 were least likely to have been infected (3%).

CHINA

Xu X, Sun J, Nie S, et al. Seroprevalence of immunoglobulin M and G antibodies

against SARS-CoV-2 in China. Nat Med. 2020 Jun 5. PubMed:
https://pubmed.gov/32504052. Full-text: https://doi.org/10.1038/s41591-020-0949-6
At the end of the 2020 winter epidemic, the seropositivity (IgM and IgG antibodies ) in
Wuhan was low, varying between 3.2% and 3.8% in different sub-cohorts (Xu X 2020).

SWITZERLAND

Stringhini S, Wisniak A, Piumatti G, et al. The Lancet, June 11, 2020. Seroprevalence
of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a
population-based study. Full-text: https://doi.org/10.1016/S0140-6736(20)31304-0
Geneva was a COVID-19 hot spot in Switzerland (5000 cases over < 2.5 months in half a
million people). The seroprevalence increased from about 5% to about 11% over five

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consecutive weekly sero-surveys among 2,766 randomly selected participants from a

previous population-representative survey, and 1,339 household members aged 5
years and older (Stringhini 2020). Of note, young children (5–9 years) and older people
(≥ 65 years) had significantly lower seroprevalence than the other age groups. Authors
estimated that there were 11 infections for every COVID-19 confirmed case.

Hotspots of SARS-CoV-2 Transmission

HOSPITALS

Nagano T, Arii J, Nishimura M, et al. Diligent medical activities of a publicly desig-

nated medical institution for infectious diseases pave the way for overcoming
COVID-19: A positive message to people working at the cutting edge. Clin Infect
Dis. 2020 May 31. PubMed: https://pubmed.gov/32474577. Full-text:
https://doi.org/10.1093/cid/ciaa694
Standard preventive measures against infectious diseases can prevent SARS-CoV-2
exposure in medical staff. Of 509 medical staff members working to treat COVID-19
patients at the Hyogo Prefectural Kakogawa Medical Center, a large medical institu-
tion for infectious diseases in Japan (mean number of hospitalized COVID-19 patients
was 20), none had IgG antibodies for SARS-CoV-2 on May 1-8 (Nagano 2020).

Callaghan AW, Chard AN, Arnold P, et al. Screening for SARS-CoV-2 Infection With-
in a Psychiatric Hospital and Considerations for Limiting Transmission Within
Residential Psychiatric Facilities - Wyoming, 2020. MMWR Morb Mortal Wkly Rep.
2020 Jul 3;69(26):825-829. PubMed: https://pubmed.gov/32614815. Full-text:
https://doi.org/10.15585/mmwr.mm6926a4
Implementing expanded admission screening and infection prevention and control
procedures is effective even within a psychiatric ward (Callaghan 2020).

Rincón A, Moreso F, López-Herradón A. The keys to control a coronavirus disease

2019 outbreak in a haemodialysis unit. Clinical Kidney Journal, 13 July 2020. Full-
text: https://doi.org/10.1093/ckj/sfaa119
In an hemodialysis unit in Barcelona, 18% of patients receiving treatment became
infected (Rincón 2020). The main risk factors for SARS-CoV-2 infection were sharing
health-care transportation, living in a nursing home and having been admitted to the
reference hospital within the previous 2 weeks.

Vahidy FS, Bernard DW, Boom ML, et al. Prevalence of SARS-CoV-2 Infection Among
Asymptomatic Health Care Workers in the Greater Houston, Texas, Area. JAMA
Netw Open. 2020 Jul 1;3(7):e2016451. PubMed: https://pubmed.gov/32716512. Full-
text: https://doi.org/10.1001/jamanetworkopen.2020.16451

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 Epidemiology | 61

Among clinical HCWs, 5.4% from COVID-19 units and 0.6% from non–COVID units had
RT-PCR test results positive for SARS-CoV-2 (Vahidy 2020).

LONG-TERM CARE FACILITIES

Marossy A, Rakowicz S, Bhan A, et al. A study of universal SARS-CoV-2 RNA testing

of residents and staff in a large group of care homes in South London. J Infect Dis.
2020 Sep 5:jiaa565. PubMed: https://pubmed.gov/32889532. Full-text:
https://doi.org/10.1093/infdis/jiaa565
In one of the largest studies of care homes in Europe which involved 2,455 individuals,
residents and staff from 37 care homes in the London Borough of Bromley were tested
irrespective of symptoms. Overall, the point prevalence of SARS-CoV-2 infection was
6.5% with a higher rate in residents (9.0%) than in staff (4.7%) (Marossy 2020).

Fisman DN, Bogoch I, Lapointe-Shaw L, et al. Risk Factors Associated With Mortality
Among Residents With Coronavirus Disease 2019 (COVID-19) in Long-term Care
Facilities in Ontario, Canada. JAMA, published July 22, Full-text:
https://doi.org/10.1001/jamanetworkopen.2020.15957
Hotspot LTCF. In a study from Ontario, Canada, the incidence of mortality was more
than 13 times greater than that seen in community-living adults older than 69 years
during a similar period (Fisman 2020).

Graham NSN, Junghans C, McLaren R, et al. High rates of SARS-CoV-2 seropositivity

in nursing home residents. J Infection August 26, 2020a. Full-text:
https://doi.org/10.1016/j.jinf.2020.08.040
Some nursing homes in the UK achieved fairly high seropositivity rates. In one study,
72% percent of nursing home residents were anti-SARS-CoV-2 IgG antibody positive
(Graham 2020). Seropositivity was not associated with the presence of comorbidities.

ECDC Public Health Emergency Team, Danis K, Fonteneau L, et al. High impact of
COVID-19 in long-term care facilities, suggestion for monitoring in the EU/EEA.
May 2020. Eurosurveillance, Volume 25, Issue 22, 04/Jun/2020 Article. Full-text:
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.22.2000956
Residents in long-term care facilities contribute 30–60% of all COVID-19 deaths in
many European countries (ECDC 2020). Surveillance and infection prevention and
control measures are paramount: identify clusters early, decrease the spread within
and between facilities and reduce the size and severity of outbreaks.

Graham N, Junghans C, Downes R, et al. SARS-CoV-2 infection, clinical features and

outcome of COVID-19 in United Kingdom nursing homes. J Infect 2020b, Jun
3:S0163-4453(20)30348-0. PubMed: https://pubmed.gov/32504743. Full-text:
https://doi.org/10.1016/j.jinf.2020.05.073

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Hotspot nursing home. In one UK investigation involving 394 residents and 70 staff in
4 nursing homes in central London, 26% of residents died over a two-month period
(Graham 2020). Systematic testing identified 40% of residents as positive for SARS-
CoV-2 and of these, 43% were asymptomatic and 18% had only atypical symptoms
during the two weeks prior to testing. Of note, this was also true of many residents in
the days leading up to death indicating that even in severe COVID-19, fever and cough
were commonly absent. 4% of asymptomatic staff also tested positive.

Dora AV, Winnett A, Jatt LP, et al. Universal and Serial Laboratory Testing for
SARS-CoV-2 at a Long-Term Care Skilled Nursing Facility for Veterans - Los An-
geles, California, 2020. MMWR Morb Mortal Wkly Rep. 2020 May 29;69(21):651-655.
PubMed: https://pubmed.gov/32463809. Full-text:
https://doi.org/10.15585/mmwr.mm6921e1
Again and again: Test them all, immediately. After an outbreak at a long-term care
nursing facility, all residents, regardless of symptoms, underwent serial (approximate-
ly weekly) nasopharyngeal SARS-CoV-2 RT-PCR testing. Nineteen of 99 (19%) residents
had positive test results for SARS-CoV-2 (Dora 2020). Fourteen of the 19 residents with
COVID-19 were asymptomatic at the time of testing. Among these, eight developed
symptoms 1-5 days after specimen collection and were later classified as presympto-
matic.

LEISURE VENUES (BARS, CLUBS, CHOIRS, KARAOKE, DISCOS, ETC.)

NCOMG. The national COVID-19 outbreak monitoring group. COVID-19 outbreaks in

a transmission control scenario: challenges posed by social and leisure activities,
and for workers in vulnerable conditions, Spain, early summer 2020. Eurosurveil-
lance Volume 25, Issue 35, 03/Sep/2020. Full-text:
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.35.2001545
Hotspot Movida. From mid-June to 2 August, excluding single household outbreaks,
673 outbreaks were notified in Spain (NCOMG 2020). There were two main settings
where over 55% of active outbreaks (303/551) and over 60% (3,815/6,208) of active
outbreak cases originated: First, social settings such as family gatherings or private
parties (112 outbreaks, 854 cases), followed by those linked to leisure venues such as
bars, restaurants, or clubs (34 outbreaks, over 1,230 cases). Second, occupational set-
tings (representing 20% of all active outbreaks), mainly among workers in the fruit
and vegetable sector (31 outbreaks and around 500 cases) and workers at slaughter-
houses or meat processing plants (12 outbreaks and around 360 cases).

Data from Japan showed that of a total of 61 COVID-19 clusters, 18 (30%) were in
healthcare facilities; 10 (16%) in care facilities of other types, such as nursing homes
and day care centers; 10 (16%) in restaurants or bars; 8 (13%) in workplaces; 7 (11%) in
music-related events, such as live music concerts, chorus group rehearsals, and karao-

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 Epidemiology | 63

ke parties; 5 (8%) in gymnasiums; 2 (3%) in ceremonial functions; and 1 (2%) in trans-

portation-related incident in an airplane (Furuse 2020). Of note, 41% of probable pri-
mary case-patients were pre-symptomatic or asymptomatic at the time of transmis-
sion. 45% had cough. Many clusters were associated with heavy breathing in close
proximity.

Kang CR, Lee JY, Park Y, Huh IS, Ham HJ, Han JK, et al. Coronavirus disease exposure
and spread from nightclubs, South Korea. Emerg Infect Dis. 2020 Sep. Full-text:
https://doi.org/10.3201/eid2610.202573
Superspreading events in nightclubs have the potential to spark local resurgence of
cases. Large-scale testing (41,612 total tests!) for active case-finding among persons
who visited 5 Itaewon nightclubs in downtown Seoul found positive results in 0.19%
(67/35,827) of nightclub visitors, 0.88% (51/5,785) of their contacts, and 0.06%
(1/1,627) of anonymously tested persons (Kang 2020). In total, 246 COVID-19 cases
were associated with the reopening of nightclubs in Seoul.

Lewis M, Sanchez R, Auerbach S, et al. COVID-19 Outbreak Among College Students

After a Spring Break Trip to Mexico — Austin, Texas, March 26–April 5, 2020.
MMWR Morb Mortal Wkly Rep. ePub: 24 June 2020. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6926e1
Asymptomatic persons or those with mild symptoms likely played an important role
in sustaining transmission. A college trip is an ideal environment for SARS-CoV-2
transmission (64 cases on one trip, 14 asymptomatic and 50 symptomatic; Lewis 2020).

WORKPLACES

Waltenburg MA, Victoroff T, Rose CE, et al. Update: COVID-19 Among Workers in
Meat and Poultry Processing Facilities – United States, April–May 2020. MMWR
Morb Mortal Wkly Rep. ePub: 7 July 2020. Full-text:
https://www.cdc.gov/mmwr/volumes/69/wr/mm6927e2.htm
Meat and poutry processing facilities are SARS-CoV-2 hotspots. One study reported
16,233 COVID-19 cases and 86 COVID-19–related deaths among workers in 239 facilities
(Waltenburg 2020). The percentage of workers with COVID-19 ranged from 3.1% to
24.5% per facility.
Among seven facilities that implemented facility-wide testing, the crude prevalence of
asymptomatic or presymptomatic infections among 5,572 workers who had positive
SARS-CoV-2 test results was 14.4% (Waltenburg 2020).

Steinberg J, Kennedy ED, Basler C, et al. COVID-19 Outbreak Among Employees at a

Meat Processing Facility — South Dakota, March–April 2020. MMWR Morb Mortal
Wkly Rep 2020;69:1015–1019. Full-text: http://dx.doi.org/10.15585/mmwr.mm6931a2

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Early outbreak in a meat processing facility in the US. From March 16 to April 25,
25.6% (929) of employees and 8.7% (210) of their contacts were diagnosed with COVID-
19; two employees died (Steinberg 2020). The highest attack rates occurred among
employees who worked < 6 feet (2 meters) from one another on the production line.

SCHOOLS

Davies NG, Klepac P, Liu Y et al. Age-dependent effects in the transmission and
control of COVID-19 epidemics. Nat Med 2020, June 16.
https://doi.org/10.1038/s41591-020-0962-9
Children have a lower susceptibility to infection. Using epidemic data from Canada,
China, Italy, Japan, Singapore, and South Korea, one group found that susceptibility to
infection in individuals under 20 years of age was approximately half that of adults
aged over 20 years, and clinical symptoms manifest in 21% of infections in 10- to-19-
year-olds, rising to 69% of infections in people aged over 70 years (Davis 2020).

Panovska-Griffiths J, Kerr CC, Stuart RM, et al. Determining the optimal strategy for
reopening schools, the impact of test and trace interventions, and the risk of
occurrence of a second COVID-19 epidemic wave in the UK: a modelling study.
Lancet Child Adolesc Health 2020, August 03, 2020. Full-text:
https://doi.org/10.1016/S2352-4642(20)30250-9
Reopening of schools must be accompanied by large-scale, population-wide testing of
symptomatic individuals and effective tracing of their contacts, followed by isolation
of diagnosed individuals. Without these levels of testing and contact tracing, reopen-
ing of schools together with gradual relaxing of the lockdown measures are likely to
induce a second wave that would peak in December 2020 (Panovska-Griffiths).

Brown NE, Bryant-Genevier J, Bandy U, Browning CA, Berns AL, Dott M, et al. Anti-
body responses after classroom exposure to teacher with coronavirus disease,
March 2020. Emerg Infect Dis. 2020 Sep [date cited].
https://doi.org/10.3201/eid2609.201802
No big surprise: classroom interaction between an infected teacher and students
might result in virus transmission. After returning from Europe to the United States
on March 1, 2020, a symptomatic teacher received positive test results. In total 2/21
students exposed to the teacher in the classroom had positive serologic results.

Cheng SY, Wang J, Shen AC, et al. How to Safely Reopen Colleges and Universities
During COVID-19: Experiences From Taiwan. Ann Int Med 2020, Jul 2. Full-text:
https://doi.org/10.7326/M20-2927
Taiwan is one of the few countries where schools are functioning normally. To secure
the safety of students and staff, the Ministry of Education in Taiwan established gen-
eral guidelines, including a combination of strategies such as – our future? - active

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 Epidemiology | 65

campus-based screening and access control; school-based screening and quarantine

protocols; student and faculty quarantine when warranted; mobilization of adminis-
trative and health center staff; regulation of dormitories and cafeterias; and rein-
forcement of personal hygiene, environmental sanitation, and indoor air ventilation
practices (Cheng SY 2020). Depressing (un monde de con), but probably necessary.
Torres JP, Piñera C, De La Maza V, et al. SARS-CoV-2 antibody prevalence in blood in
a large school community subject to a Covid-19 outbreak: a cross-sectional study.
Clin Infect Dis. 2020 Jul 10:ciaa955. PubMed: https://pubmed.gov/32649743. Full-text:
https://doi.org/10.1093/cid/ciaa955
School-based outbreak are common with cases among teachers, children and parents.
In some situations, the index cases were teachers and/or parents (Torres 2020). Reo-
pening schools should focus on avoiding new cases among teachers

MASS GATHERINGS

Anonymous. Deutsche Box-Olympiamannschaft mit Coronavirus infiziert. Die Zeit

2020, published 12 September. Full-text: https://www.zeit.de/sport/2020-
09/trainingslager-oesterreich-deutsche-box-olympiamannschaft-coronavirus-
infektion-quarantaene
In an unintentional experiment, the German national team of amateur boxers has
proved that you can achieve a 100% transmission rate in a small group within days. In
a training camp, some of the 18 athletes and 7 coaches and supervisors had cold symp-
toms four days ago. Now all 25 persons have tested positive for SARS-CoV-2. So far, no
serious cases.

Mubarak N, Zin CS. Religious tourism and mass religious gatherings - The
potential link in the spread of COVID-19. Current perspective and future
implications. Travel Med Infect Dis. 2020 Jun 9;36:101786. PubMed:
https://pubmed.gov/32531422. Full-text: https://doi.org/10.1016/j.tmaid.2020.101786
Religious mass gatherings should probably postponed. Of particular concern are
pilgrims returning to home countries with inadequate quarantine and diagnostic
infrastructure, especially those over 50 years old or suffering from chronic disease
such as diabetes or cardiovascular disease (Mubarak 2020).

Khan A, Bieh KL, El-Ganainy A, et al. Estimating the COVID-19 Risk during the Hajj
Pilgrimage. Journal of Travel Medicine, 05 September 2020. Full-text:
https://doi.org/10.1093/jtm/taaa157
A religious gathering that attracts 2.5 million pilgrims from over 150 countries has
clearly the potential to create a giga-spreading event. Designated ward and ICU beds
could be saturated within days. Reducing the number of pilgrims and excluding for-
eign pilgrims is a wise decision (Khan 2020)

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Nayar KR, Koya SF, Ramakrishnan V, et al. Call to avert acceleration of COVID-19
from India’s Sabarimala pilgrimage of 25 million devotees. Journal of Travel Medi-
cine, 05 September 2020, taaa153. Full-text: https://doi.org/10.1093/jtm/taaa153
Hajj or the Sabarimala annual 41-day long Hindu pilgrimage attended by an average of
25 million pilgrims (Nayar 2020). How would proceed to require a negative SARS-CoV-
2 antigen test from all pilgrims?

CLOSED AND DENSELY POPULATED SPACES

Njuguna H, Wallace M, Simonson S, et al. Serial Laboratory Testing for SARS-CoV-2

Infection Among Incarcerated and Detained Persons in a Correctional and Deten-
tion Facility — Louisiana, April–May 2020. MMWR Morb Mortal Wkly Rep. ePub: 29
June 2020. Full-text: http://dx.doi.org/10.15585/mmwr.mm6926e2
High COVID-19 attack rates in prisons. Among 98 incarcerated and detained persons in
Louisiana who were quarantined because of virus exposure, 71 (72%) had lab-
confirmed SARS-CoV-2 infection identified through serial testing, among them 45%
without any symptoms at the time of testing (Njuguna 2020). Serial testing of contacts
of persons with COVID-19 in correctional and detention facilities can identify asymp-
tomatic and presymptomatic persons who would be missed through symptom screen-
ing alone.

Jiménez MC, Cowger TL, Simon LE, Behn M, Cassarino N, Bassett MT. Epidemiology of
COVID-19 Among Incarcerated Individuals and Staff in Massachusetts Jails and
Prisons. JAMA Netw Open 2020;3(8). Full-text:
https://doi.org/10.1001/jamanetworkopen.2020.18851
In July 2020, the rate of COVID-19 among incarcerated individuals was nearly 3 times
that of the Massachusetts general population and 5 times the US rate (Jiménez 2020).
Of 14,987 individuals incarcerated across Massachusetts prison facilities, 1032 con-
firmed cases of COVID-19 were reported among incarcerated individuals (n = 664) and
staff (n = 368).

Saloner B, Parish K, Ward JA. COVID-19 Cases and Deaths in Federal and State Pris-
ons. JAMA July 8, 2020. Full-text: https://doi.org/10.1001/jama.2020.12528
By June 6, 2020, there had been 42,107 cases of COVID-19 and 510 deaths among 1.3
million prisoners in the US (Saloner 2020).

Maxmen A. California's San Quentin prison declined free coronavirus tests and
urgent advice — now it has a massive outbreak. Nature NEWS 07 July 2020. Full-
text: https://doi.org/10.1038/d41586-020-02042-9
In July 2020, more than one-third of the inmates and staff (1,600 people) in San
Quentin Prison tested positive (Maxmen 2020). Six had died.

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 Epidemiology | 67

Rogers JH, Link AC, McCulloch D, et al. Characteristics of COVID-19 in Homeless

Shelters : A Community-Based Surveillance Study. Ann Intern Med. 2020 Sep 15.
PubMed: https://pubmed.gov/32931328. Full-text: https://doi.org/10.7326/M20-3799
In this cross-sectional, community-based surveillance study of 14 homeless shelters in
King County, Washington, Helen Chu, Julia Rogers and colleagues divided the number
of positive cases by the total number of participant encounters, regardless of symp-
toms. Among 1434 encounters, 29 (2%) cases of SARS-CoV-2 infection were detected
across 5 shelters. Eighty-six percent of persons with positive test results slept in a
communal space rather than in a private or shared room (Rogers 2020).

Payne DC, Smith-Jeffcoat SE, Nowak G, et al. SARS-CoV-2 Infections and Serologic
Responses from a Sample of U.S. Navy Service Members — USS Theodore Roose-
velt, April 2020. MMWR Morb Mortal Wkly Rep. ePub: 9 June 2020. Full-text:
https://www.cdc.gov/mmwr/volumes/69/wr/mm6923e4.htm
In late March 2020, a large outbreak on the aircraft carrier USS Theodore Roosevelt
was characterized by widespread transmission with relatively mild symptoms and
asymptomatic infection among mostly young, healthy adults with close, congregate
exposures. One fifth of infected participants reported no symptoms. Preventive
measures, such as using face-coverings and observing social distancing, reduced risk
for infection: among 382 service members, those who reported taking preventive
measures had a lower infection rate than did those who did not report taking these
measures (e.g., wearing a face-covering, 56% versus 81%; avoiding common areas, 54%
versus 68%; and observing social distancing, 55% versus 70%, respectively) (Payne
2020).

Special Aspects of the Pandemic

PREPAREDNESS

Pham QT, Rabaa MA, Duong HL, et al. The first 100 days of SARS-CoV-2 control in
Vietnam. Clin Infect Dis 2020, published 1 August. Full-text:
https://doi.org/10.1093/cid/ciaa1130
Vietnam did remarkably well. One hundred days after the first SARS-CoV-2 case was
reported in Vietnam on January 23rd, 270 cases were confirmed, with no deaths. Alt-
hough there was a high proportion of asymptomatic and imported cases as well as
evidence for substantial pre-symptomatic transmission, Vietnam controlled SARS-
CoV-2 spread through the early introduction of mass communication, meticulous con-
tact-tracing with strict quarantine, and international travel restrictions (Pham QT
2020). A lesson for the world?

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Looi MK. Covid-19: Japan ends state of emergency but warns of "new normal".
BMJ. 2020 May 26;369:m2100. PubMed: https://pubmed.gov/32457055. Full-text:
https://doi.org/10.1136/bmj.m2100
Japan has done a good job. Public adherence to the rules, along with cluster tracing
and a ban on mass gatherings, seems to have achieved success in bringing the out-
break under control,
If, as in Japan, widespread mask use and hygiene is a normal part of etiquette, combat-
ting SARS-CoV-2 is easier (Looi 2020).

Stoke EK, Zambrano LD, Anderson KN. Coronavirus Disease 2019 Case Surveillance
— United States, January 22–May 30, 2020. MMWR June 15, 2020. Full-text:
https://www.cdc.gov/mmwr/volumes/69/wr/mm6924e2.htm
In June, the CDC reported data on 1,320,488 laboratory-confirmed COVID-19 cases.
Overall, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an
intensive care unit (ICU), and 71,116 (5%) died. Hospitalizations were six times higher
among patients with a reported underlying condition (45.4%) than those without
reported underlying conditions (7.6%). Deaths were 12 times higher among patients
with reported underlying conditions (19.5%) compared with those without reported
underlying conditions (1.6%) (Stoke 2020).

UNWILLINGNESS TO PREPARE/DENIAL (UK, USA, BRAZIL)

NEJM Editors. Dying in a Leadership Vacuum. N Engl J Med 2020; 383:1479-1480.

Full-text: https://www.nejm.org/doi/full/10.1056/NEJMe2029812
SARS-CoV-2 and the COVID-19 pandemic became a test of leadership. With no good
options to combat a novel pathogen, countries were forced to make hard choices
about how to respond. In the United States, the leaders have failed that test.

Yehya N, Venkataramani A, Harhay MO. Statewide Interventions and Covid-19 Mor-

tality in the United States: An Observational Study. Clin Infect Dis. 2020 Jul 8. Pub-
Med: https://pubmed.gov/32634828. Full-text: https://doi.org/10.1093/cid/ciaa923
Every day counts. In this large, nationwide study, later statewide emergency declara-
tions and school closures were associated with higher COVID-19 mortality. Each day of
delay increased mortality risk by 5 to 6% (Yehya 2020).

Maxmen A. Why the United States is having a coronavirus data crisis. Nature 2020,
published 25 August. Full-text: https://www.nature.com/articles/d41586-020-02478-z
To respond to a pandemic, you need reliable information on who is infected, why and
where. Unfortunately, many countries suffered from a dearth of data (Maxmen 2020).

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 Epidemiology | 69

SPLENDID ISOLATION (NEW ZEALAND, AUSTRALIA)

Baker MG, Anglemyer A. Successful Elimination of Covid-19 Transmission in New

Zealand. N Engl J Med 2020, published 7 August. Full-text:
https://www.nejm.org/doi/full/10.1056/NEJMc2025203
Heywood AE, Macintyre CR. Elimination of COVID-19: what would it look like and
is it possible? Lancet 2020, published 6 August. Full-text:
https://doi.org/10.1016/S1473-3099(20)30633-2
Is elimination of SARS-CoV-2 possible (Hewyood 2020)? Geographical isolated islands
or island states should be the identical candidates for elimination trials. However,
even New Zealand which viewd itself in the post-elimination stage and where public
life had returned to near normal (Baker 2020), was suddenly called back into COVID-19
reality when new cases were discovered in early August. The elimination of any infec-
tious disease is ambitious, requiring substantial resources. They suggest a zero-case
scenario of not less than three months before declaring an area SARS-CoV-2-free. For
obvious reasons, islands or island states have the best chances to achieve this goal
(Hewyood 2020).

Seemann T, Lance CR, Sherry NL, et al. Tracking the COVID-19 pandemic in Austral-
ia using genomics. Nat Commun 11, 4376 (2020). Full-text:
https://doi.org/10.1038/s41467-020-18314-x
Multiple SARS-CoV-2 importations by returned international travelers drove trans-
mission in Australia, with travel-related cases responsible for establishing ongoing
transmission lineages (each with 3–9 cases) accounting for over half of locally ac-
quired cases (Seemann 2020).

THE UNKNOWN (?) OUTCOME

Kalk A, Schultz A. SARS-CoV-2 epidemic in African countries—are we losing per-

spective? Lancet, August 07, 2020. Full-text: https://doi.org/10.1016/S1473-
3099(20)30563-6
Lockdown for everybody? Maybe not. In the Democratic Republic of the Congo and
Malawi, for instance, only 2-3% of the population is older than 65 years. Under these
circumstances, full lockdown measures might cause more harm than SARS-CoV-2 it-
self (Kalk 2020).
Twahirwa Rwema JO, Diouf D, Phaswana-Mafuya N, et al. COVID-19 Across Africa:
Epidemiologic Heterogeneity and Necessity of Contextually Relevant Transmis-
sion Models and Intervention Strategies. Ann Intern Med. 2020 Jun 18. PubMed:
https://pubmed.gov/32551812. Full-text: https://doi.org/10.7326/M20-2628
Europe without Russia has a surface of roughly 6 million km2, Africa has 30 million
km2. That should explain by itself that the burden and outcomes associated with
COVID-19 in Africa shows substantial variations across African countries (Twahirwa
2020).

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Walker PG, Whittaker C, Watson OJ, et al. The impact of COVID-19 and strategies for
mitigation and suppression in low- and middle-income countries. Science 12 Jun
2020. Full-text: https://DOI.ORG/10.1126/science.abc0035
The impact of the SARS-CoV-2 pandemic in low- and middle-income countries (LMIC)
is still unknown. On one hand, we have an overall younger population, on the other
hand, there is a higher burden of infectious diseases such as AIDS and TB already, and
of poverty-related determinants of poorer health outcomes such as malnutrition
(Walker 2020). There is also a more persistent spread to older age categories (higher
levels of household-based transmissions) and poorer quality health care and lack of
health care capacity.

The SARS-CoV-2 pandemic: Past and Future

NATURAL COURSE OF A PANDEMIC

Barbarossa MV, Fuhrmann J, Meinke JH, et al. Modeling the spread of COVID-19 in
Germany: Early assessment and possible scenarios. PLoS One. 2020 Sep
4;15(9):e0238559. PubMed: https://pubmed.gov/32886696. Full-text:
https://doi.org/10.1371/journal.pone.0238559
Without restrictive measures, about 32 million total infections and 730,000 deaths
could result in Germany alone over the course of the epidemic (Barbarossa 2020).

THE 2020 LOCKDOWNS

Sudharsanan N, Didzun O, Bärnighausen T Geldsetzer P. The Contribution of the Age

Distribution of Cases to COVID-19 Case Fatality Across Countries - A 9-Country
Demographic Study. Ann Intern Med 2020, published 22 July. Full-text:
https://doi.org/10.7326/M20-2973
The overall observed case-fatality rates (CFR) vary widely, with the highest rates in
Italy (9.3%) and the Netherlands (7.4%) and the lowest rates in South Korea (1.6%) and
Germany (0.7%). This cross-sectional study of population-based data from China,
France, Germany, Italy, the Netherlands, South Korea, Spain, Switzerland, and the US
finds that age distribution of cases explains 66% of the variation of across countries,
with a resulting age-standardized median CFR of 1.9%. See also the editorial by David
N. Fisman, Amy L. Greer, and Ashleigh R. Tuite: Age Is Just a Number: A Critically
Important Number for COVID-19 Case Fatality; full-text:
https://doi.org/10.7326/M20-4048.

David N. Fisman, Amy L. Greer, and Ashleigh R. Tuite: Age Is Just a Number: A Criti-
cally Important Number for COVID-19 Case Fatality; full-text:
https://doi.org/10.7326/M20-4048.

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 Epidemiology | 71

During the first European wave of the SARS-CoV-2 pandemic, case-fatality rates (CFR)
varied widely, with the highest rates in Italy (9.3%) and the Netherlands (7.4%) and the
lowest rates in South Korea (1.6%) and Germany (0.7%) (Sudharsanan 2020, Fisman
2020). The study also found that age distribution of cases explains 66% of the variation
of across countries.

Kissler SM, Kishore N, Prabhu M, et al. Reductions in commuting mobility correlate

with geographic differences in SARS-CoV-2 prevalence in New York City. Nat
Commun. 2020 Sep 16;11(1):4674. PubMed: https://pubmed.gov/32938924. Full-text:
https://doi.org/10.1038/s41467-020-18271-5
SARS-CoV-2 prevalence varied substantially between New York City boroughs between
22 March and 3 May 2020 (for example, Manhattan: 11.3%; South Queens: 26.0%).
These differences in prevalence correlate with antecedent reductions in commuting-
style mobility between the boroughs. Prevalence was lowest in boroughs with the
greatest reductions in morning movements out of and evening movements into the
borough (Kissler 2020).

Czeisler MÉ, Tynan MA, Howard ME, et al. Public Attitudes, Behaviors, and Beliefs
Related to COVID-19, Stay-at-Home Orders, Nonessential Business Closures, and
Public Health Guidance - United States, New York City, and Los Angeles, May 5-
12, 2020. MMWR Morb Mortal Wkly Rep. 2020 Jun 19;69(24):751-758. PubMed:
https://pubmed.gov/32555138. Full-text: https://doi.org/10.15585/mmwr.mm6924e1
Most people agreed: during the week of May 5–12, 2020, a survey among 2,402 adults
in New York City and Los Angeles and broadly across the United States found wide-
spread support of stay-at-home orders and nonessential business closures and high
degree of adherence to COVID-19 mitigation guidelines (Czeisler 2020). 74-82% report-
ed they would not feel safe if these restrictions were lifted nationwide at the time the
survey was conducted. In addition, among those who reported that they would not
feel safe, some indicated that they would nonetheless want community mitigation
strategies lifted and would accept associated risks (13-17%, respectively).

Moreland A, Herlihy C, Tynan MA, et al. Timing of State and Territorial COVID-19
Stay-at-Home Orders and Changes in Population Movement - United States,
March 1-May 31, 2020. MMWR Morb Mortal Wkly Rep. 2020 Sep 4;69(35):1198-1203.
PubMed: https://pubmed.gov/32881851 . Full-text:
https://doi.org/10.15585/mmwr.mm6935a2
US Americans were compliant to mandatory stay-at-home orders. Based on location
data from mobile devices, in 97.6% of counties these orders were associated with de-
creased median population movement (Moreland 2020).

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Flaxman S, Mishra S, Gandy A, et al. Estimating the effects of non-pharmaceutical

interventions on COVID-19 in Europe. Nature. 6/2020 Jun 8. PubMed:
https://pubmed.gov/32512579. Full-text: https://doi.org/10.1038/s41586-020-2405-7
According to one study, between 12 and 15 million individuals in Europe had been
infected with SARS-CoV-2 by May 4th, representing between 3.2% and 4.0% of the
population (Flaxman 2020). Percentages of total population infected were for Austria
0.76% (0.59% - 0.98%), Belgium 8.0 % (6.1% - 11%), Denmark 1.0% (0.81% - 1.4%), France
3.4% (2.7% - 4.3%), Germany 0.85% (0.66% - 1.1%), Italy 4.6% (3.6% - 5.8%), Norway
0.46% (0.34% - 0.61%), Spain 5.5% (4.4% - 7.0%), Sweden 3.7% (2.8% - 5.1%), Switzerland
1.9% (1.5% - 2.4%) and United Kingdom 5.1% (4.0% - 6.5%).

Habib H. Has Sweden's controversial covid-19 strategy been successful? BMJ. 2020
Jun 12;369:m2376. PubMed: https://pubmed.gov/32532807. Full-text:
https://doi.org/10.1136/bmj.m2376
Has Sweden’s controversial covid-19 strategy been successful? After a negative press
at the beginning of the 2020 summer (Habib 2020) which stressed that the country was
still far away from herd immunity and the death toll 5 to 10 times higher than in
neighboring Denmark and Finland, the evaluation in October has changed…

FIRST AUTUMN, FIRST WINTER

Verdery AM, Smith-Greenaway E, Margolis R, Daw J. Tracking the reach of COVID-19

kin loss with a bereavement multiplier applied to the United States. Proc Natl
Acad Sci U S A. 2020 Jul 10:202007476. PubMed: https://pubmed.gov/32651279. Full-
text: https://doi.org/10.1073/pnas.2007476117
In the US, every death from COVID-19 will leave approximately nine bereaved, i.e.,
people who lost a grandparent, parent, sibling, spouse, or child (Verdery 2020).

MEASURING THE EPIDEMIC

Westhaus S, Weber FA, Schiwy S, et al. Detection of SARS-CoV-2 in raw and treated
wastewater in Germany - Suitability for COVID-19 surveillance and potential
transmission risks. Sci Total Environ 2020 August 18;751:141750. PubMed:
https://pubmed.gov/32861187. Full-text:
https://doi.org/10.1016/j.scitotenv.2020.141750
SARS-CoV-2 can be detected in wastewater in Germany using RT-qPCR. The total load
of gene equivalents in wastewater correlated with the cumulative and the acute num-
ber of COVID-19 cases reported in the respective catchment areas. Thus, wastewater-
based epidemiology can be regarded as a complementary measure to survey the out-
break (Westhaus 2020). (Important note: wastewater is no route for SARS-CoV-2
transmission to humans! All replication tests were negative tests for replication.)

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 Epidemiology | 73

Thomas LJ, Hunag O, Yin F, et al. Spatial heterogeneity can lead to substantial local
variations in COVID-19 timing and severity. PNAS September 10, 2020. Full-text:
https://doi.org/10.1073/pnas.2011656117
Relaxation of mitigation measures leading to a resumption of “normal” diffusion may
initially appear to have few negative effects, only to lead to deadly outbreaks weeks or
months later (Thomas 2020). Public health messaging may need to stress that appar-
ent lulls in disease progress are not necessarily indicators that the threat has subsid-
ed, and that areas “passed over” by past outbreaks could be impacted at any time.

HERD IMMUNITY: NOT YET

Brett TS, Rohani P. Transmission dynamics reveal the impracticality of COVID-19

herd immunity strategies. Proc Natl Acad Sci U S A. 2020 Sep 22:202008087. PubMed:
https://pubmed.gov/32963094. Full-text: https://doi.org/10.1073/pnas.2008087117
Achieving herd immunity without overwhelming hospital capacity leaves little room
for error, as the author of one paper put it (Brett 2020). In other words: their modeling
did not support achieving herd immunity as a practical objective, requiring an unlike-
ly balancing of multiple poorly defined forces.

Eckerle I, Meyer B. SARS-CoV-2 seroprevalence in COVID-19 hotspots. The Lancet

July 06, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31482-3
Comment on these findings. Most of the population appears to have remained unex-
posed to SARS-CoV-2, even in areas with widespread virus circulation. Any proposed
approach to achieve herd immunity through natural infection is not only highly un-
ethical, but also unachievable (Eckerle 2020). With a large majority of the population
being infection-naïve, virus circulation can quickly return to early pandemic dimen-
sions in a second wave once measures are lifted.

Buss LF, Prete Jr CA, Abrahim CMM, et al. COVID-19 herd immunity in the Brazilian
Amazon. medRxiv 2020, posted 21 September. Full-text:
https://doi.org/10.1101/2020.09.16.20194787
As much as 66% of the population of Manaus (two million people), Brazil, could have
been infected with SARS-CoV-2. Ester Sabino, Lewis Buss and colleagues show that the
transmission of SARS-CoV-2 in Manaus increased quickly during March and April and
declined more slowly from May to September. In June, one month following the epi-
demic peak, 44% of the population was seropositive for SARS-CoV-2. After correcting
for confounding factors, the authors estimate the epidemic size to be 66% by early
August 2020. Note that these findings have not yet been peer reviewed and that the
results have recently been questioned.
Remember: herd immunity is defined as the proportion of a population that must be
immune to an infectious disease, either by natural infection or vaccination, such that

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new cases decline and R0 falls below 1 (see also

https://www.nature.com/articles/d41586-020-02009-w).

“VARIOLATION” – FINDING OF THE YEAR?

Bielecki M, Züst R, Siegrist D, et al. Social distancing alters the clinical course of
COVID-19 in young adults: A comparative cohort study. Clin Inf Dis, June 29, 2020.
Full-text: https://doi.org/10.1093/cid/ciaa889
Important finding that was long suspected: viral inoculum during infection or mode of
transmission may be key factors determining the clinical course of COVID-19. The
authors prospectively studied an outbreak in Switzerland among a population of 508
predominantly male soldiers with a median age of 21 years. Infections were followed
in two spatially separated cohorts with almost identical baseline characteristics - be-
fore and after implementation of stringent social distancing. Results: of 354 soldiers
infected prior to the implementation of social distancing, 30% fell ill. In contrast, none
out of 154 soldiers in which infections (confirmed by NP swabs or serology) appeared
after implementation of social distancing developed COVID-19.

PROTECTING PEOPLE AT RISK

Nguyen LH, Drew DA, Graham MS, et al. Risk of COVID-19 among front-line health-
care workers and the general community: a prospective cohort study. Lancet
Public Health. 2020 Sep;5(9):e475-e483. PubMed: https://pubmed.gov/32745512. Full-
text: https://doi.org/10.1016/S2468-2667(20)30164-X
Front-line health care workers are at increased risk of SARS-CoV-2 infection. In a pro-
spective, observational cohort study in the UK and the USA, front-line health care
workers were at increased risk for reporting a positive COVID-19 test (adjusted HR
11.6) (Nguyen 2020). An increased risk (HR 3.4) was even found after accounting for
differences in testing frequency between front-line health care workers and the gen-
eral community. Post-hoc analyses showed that Black, Asian, and minority ethnic
health care workers are at especially high risk of SARS-CoV-2 infection, with at least a
fivefold (!) increased risk of COVID-19 compared with the non-Hispanic white general
community.

Emeruwa UN, Ona S, Shaman JL, et al. Associations Between Built Environment,
Neighborhood Socioeconomic Status, and SARS-CoV-2 Infection Among Pregnant
Women in New York City. JAMA 2020, June 18, 2020. Full-text:
https://doi.org/10.1001/jama.2020.11370
In a cross-sectional study of 396 pregnant New York City residents, large household
membership, household crowding, and low socioeconomic status were associated with
a 2-3 fold higher risk of infection (Emeruwa 2020).

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 Epidemiology | 75

Hatcher SM, Agnew-Brune C, Anderson M, et al. COVID-19 Among American Indian

and Alaska Native Persons — 23 States, January 31–July 3, 2020. MMWR Morb
Mortal Wkly Rep 2020, published 19 August 2020. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6934e1
American Indian and Alaska Native (AI/AN) persons appear to be disproportionately
affected by the COVID-19 pandemic. In one study, the overall COVID-19 incidence
among AI/AN persons was 3.5 times that among white persons (594 per 100,000 AI/AN
population compared with 169 per 100,000 white population) (Hatcher 2020).

Grasso D, Zafra M, Ferrero B, et al. Covid de ricos, covid de pobres: las restricciones
de la segunda ola exponen las desigualdades de Madrid. El País 2020, published 17
September. Full-text: https://elpais.com/espana/madrid/2020-09-16/covid-de-ricos-
covid-de-pobres-las-restricciones-de-la-segunda-ola-exponen-las-desigualdades-de-
madrid.html
The authors explain that the number of infections is higher in the most vulnerable
areas, where possible limitations will weigh the most.

PREVENTION: TESTING, TRACING, ISOLATING

Lash RR, Donovan CV, Fleischauer AT, et al. COVID-19 Contact Tracing in Two Coun-
ties - North Carolina, June-July 2020. MMWR Morb Mortal Wkly Rep. 2020 Sep
25;69(38):1360-1363. PubMed: https://pubmed.gov/32970654. Full-text:
https://doi.org/10.15585/mmwr.mm6938e3
Despite aggressive efforts by health departments, many COVID-19 patients do not
report contacts, and many contacts cannot be reached (Lash 2020). Staff members in
North Carolina/US have investigated 5,514 (77%) persons with COVID-19 in Mecklen-
burg County and 584 (99%) in Randolph Counties: during periods of high COVID-19
incidence, 48% and 35% of patients reported no contacts, and 25% and 48 % of contacts
were not reached. Median interval from index patient specimen collection to contact
notification was 6 days. Improved timeliness of contact tracing, community engage-
ment, and community-wide mitigation are needed to reduce SARS-CoV-2 transmis-
sion.

Clapham H, Hay J, Routledge I, et al. Seroepidemiologic Study Designs for Deter-

mining SARS-COV-2 Transmission and Immunity. Emerg Infect Dis. 2020 Jun
16;26(9). PubMed: https://pubmed.gov/32544053. Full-text:
https://doi.org/10.3201/eid2609.201840
Test, test, test… but how accurate are the tests? Numerous challenges exist in terms of
sample collection, what the presence of antibodies actually means, and appropriate
analysis and interpretation to account for test accuracy and sampling biases (Clapham
2020). The authors review strengths and limitations of different assay types and study
designs

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Liang LL, Tseng CH, Ho HJ, Wu CY. Covid-19 mortality is negatively associated with
test number and government effectiveness. Sci Rep. 2020 Jul 24;10(1):12567. Pub-
Med: https://pubmed.gov/32709854. Full-text: https://doi.org/10.1038/s41598-020-
68862-x
In a worldwide cross-sectional study (Liang LL 2020), the authors find that COVID-19
mortality is
• Negatively associated with
o Test number per 100 people
o Government effectiveness score
o Number of hospital beds
• Positively associated with
o Proportion of population aged 65 or older
o Transport infrastructure quality score
Remember: Government effectiveness!

Jingwen Li, Chengbi Wu, Xing Zhang, Lan Chen, Xinyi Wang, Xiuli Guan, Jinghong Li,
Zhicheng Lin, Nian Xiong. Post-pandemic testing of SARS-CoV-2 in Huanan Sea-
food Market area in Wuhan, China. Clinical Infectious Diseases 2020, published 25
July 2020. Full-text: https://doi.org/10.1093/cid/ciaa1043
Citywide mass nucleic acid testing of SARS-CoV-2 for all citizens is possible as shown
in Wuhan city (14 May to 1 June 2020). The results are sometimes meager, revealing
just 6 persons who test positive for SARS-CoV-2 (0.006% of 107,662 residents around
the Huanan Seafood Market), but are able to suffocate a nascent epidemic (Jingwen L
2020).

Perkins TA, Cavany SM, Moore SM, et al. Estimating unobserved SARS-CoV-2 infec-
tions in the United States. PNAS August 21, 2020. Full-text:
https://doi.org/10.1073/pnas.2005476117
Testing was a major limiting factor in assessing the extent of SARS-CoV-2 transmission
during its initial invasion into the US (Perkins 2020). After a national emergency was
declared, fewer than 10% of locally acquired, symptomatic infections in the US may
were detected over a period of a month. This gap in surveillance during a critical
phase of the epidemic resulted in a large, unobserved reservoir by early March.

CURFEWS

Andronico A, Kiem CT, Paireaux J, et al. Evaluating the impact of curfews and other
measures on SARS-CoV-2 transmission in French Guiana. medRxiv 2020, posted 12
October. Full-text: https://doi.org/10.1101/2020.10.07.20208314

Kamps – Hoffmann
 Epidemiology | 77

Might curfews be a less costly alternative, both economically and socially? In French
Guiana, an overseas départment, a combination of curfews and targeted lockdowns in
June and July 2020 was sufficient to avoid saturation of hospitals. On weekdays, resi-
dents were first ordered to stay at home 11 p.m., then at 9 p.m., later again at 7 p.m.,
and finally at 5 p.m. On weekends, everyone had to stay at home from 1 p.m. on Satur-
day (Andronico 2020). Whether curfews can be successfully adapted to other areas
than French Guaiana, is not known. French Guaiana is a young territory with a median
age is 25 years and the risk of hospitalisation following infection was only 30% that of
France. About 20% of the population had been infected with SARS-CoV- by July 2020
(Andronico 2020). Be prepared though to see some curfews orders over the coming six
months.

Outlook
Horton R. Offline: The second wave. Lancet 2020, June 27, 395, ISSUE 10242, P1960.
Full-text: https://doi.org/10.1016/S0140-6736(20)31451-3
In June, scientists predicted a second SARS-CoV-2 wave in Europe. They were right. We
should now hope that the current epidemic doesn’t follow the scenario of the 1918
influenza pandemic (Horton 2020).

Petersen E, Koopmans M, Go U, et al. Comparing SARS-CoV-2 with SARS-CoV and

influenza pandemics. Lancet Inf Dis 2020, July 03, 2020. Full-text:
https://doi.org/10.1016/S1473-3099(20)30484-9
How long will a combination of physical distancing, enhanced testing, quarantine, and
contact tracing be needed? Historical evidence from prior influenza pandemics indi-
cates that pandemics tend to come in waves over the first 2–5 years as population
immunity builds-up (naturally or through vaccination) and that this is the most likely
trajectory for SARS-CoV-2 (Petersen 2020).

Watsa M. Rigorous wildlife disease surveillance. Science 10 Jul 2020, 369: 145-147.
Full-text: https://doi.org/10.1126/science.abc0017
Emerging infectious diseases (EID) associated with the wildlife trade remain the larg-
est unmet challenge of current disease surveillance efforts. International or national
conventions on pathogen screening associated with animals, animal products or their
movements are urgently needed (Watsa 2020). Internationally recognized standard for
managing wildlife trade on the basis of known disease risks should be established.

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 Transmission | 93

2. Transmission
Bernd Sebastian Kamps
Christian Hoffmann

Figure 1. Transmission of SARS-CoV-2. 1) After coughing, sneezing, shouting and even

after speaking – particularly loud speaking–, large droplets (green) drop to the ground
around the young man. 2) In addition, some droplets, small and lightweight enough (red),
are transported by air currents over longer distances (WHO 20200709). The second – aero-
sol – transmission is now recognized as a possibly relevant transmission route in the SARS-
CoV-2. Adapted from Morawska 2020. Art work: Félix Prudhomme – IYENSS.

Introduction
Viruses have substantially influenced human health, interactions with the
ecosphere, and societal history and structures (Chappell 2019). In a highly
connected world, microbial evolution is boosted and pathogens exploit hu-
man behaviors to their own benefit (Morens 2013). This was critically shown
during the SARS epidemic in 2003 (Kamps-Hoffmann 2003), the outbreak of
Middle East Respiratory Syndrome coronavirus (MERS-CoV) (Zaki 2012), the
last great Ebola epidemic in West Africa (Arwady 2015, Heymann 2015) and
the Zika epidemic in 2015-2017 (Fauci 2016). Over the same time period, more
virulent strains of known respiratory pathogens – H5N1 influenza virus, tu-
berculosis, avian H7N9 influenza virus – have emerged (Kamps-Hoffmann
2006, Jassal 2009, Gao 2013).

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The Virus
SARS-CoV-2, Severe Acute Respiratory Syndrome coronavirus 2, is a highly
transmissible ‘complex killer’ (Cyranoski 2020) that forced half of humanity, 4
billion people, to bunker down in their homes in the early spring of 2020. The
respiratory disease rapidly evolved into a pandemic (Google 2020). In most
cases, the illness is asymptomatic or paucisymptomatic and self-limited. A
subset of infected individuals has severe symptoms and sometimes prolonged
courses (Garner 2020). Around 10% of infected people need hospitalization
and around one third of them treatment in intensive care units. The overall
mortality rate of SARS-CoV-2 infection seems to be less than 1%.
Coronaviruses are tiny spheres of about 70 to 80 nanometers (a millionth of a
millimeter) on thin-section electron microscopy (Perlman 2019). Compared to
the size of a human, SARS-CoV-2 is as small as a big chicken compared to the
planet Earth (El País). The raison d’être of SARS-CoV-2 is to proliferate, like
that of other species, for example H. sapiens sapiens who has been successful in
populating almost every corner of the world, sometimes at the expense of
other species. SARS-CoV-2, for now, seems to be on a similarly successful
track. By 7 June, only a handful of countries can claim to have been spared by
the pandemic.
SARS-CoV-2’s global success has multiple reasons. The new coronavirus hi-
jacks the human respiratory system to pass from one individual to another
when people sneeze, cough, shout and speak. It is at ease both in cold and in
warm climates; and, most importantly and unlike the two other deadly coro-
naviruses SARS-CoV and MERS-CoV, it manages to get transmitted to the next
individual before it develops symptoms in the first one (see below, Asympto-
matic Infection, page 107). There is no doubt that SARS-CoV-2 has a bright
future – at least until the scientific community develops a safe vaccine (see
the chapter Vaccines, page 203) and efficient drugs.

SARS-CoV-2 and its kin

SARS-CoV-2 is a coronavirus like
• SARS-CoV (cousin from the 2002/2003 epidemic),
• MERS-CoV (Middle East Respiratory Syndrome coronavirus),
• and a group of so-called CAR coronoviruses (for Community-Acquired
Respiratory CoVs: 229E, OC43, NL63, HKU1).
The CAR group of viruses are highly transmissible and produce about 15 to
30% of common colds, typically in the winter months. On the contrary, SARS-
CoV and MERS-CoV have case fatality rates of 10% and 34%, respectively, but

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they never achieved pandemic spread. SARS-CoV-2, from a strictly viral point
of view, is the shooting star in the coronavirus family: it combines high
transmissibility with high morbidity and mortality.
SARS-CoV-2 is a virus like other commonly known viruses that cause human
disease such as hepatitis C, hepatitic B, Ebola, influenza and human immuno-
deficiency viruses. (Note that the differences between them are bigger than
those between humans and amebas.) With the exception of influenza, these
viruses have a harder time infecting humans than SARS-CoV-2. Hepatitis C
virus (HCV), a major cause of chronic and often fatal liver disease, is mainly
transmitted by percutaneous exposure to blood, by unsafe medical practices
and, less frequently, sexually. The human immunodeficiency virus (HIV), in
addition to exposure to blood and perinatal transmission, also exploits sexual
contact as a potent transmission route. Hepatitis B virus (HBV) is an even
more versatile spreader than HCV and HIV as it can be found in high titers in
blood, cervical secretions, semen, saliva, and tears; even tiny amounts of
blood or contaminated secretions can transmit the virus. Ideal infection envi-
ronments for HBV include, for example, schools, institutions and hospitals
where individuals are in close and prolonged contact.
Of note, apart from HIV and hepatitis B and C, most viral diseases have no
treatment. For example, there is no treatment for measles, polio, or smallpox.
For influenza, decades of research have produced two specific drugs which
have not been able to demonstrate reduced mortality – despite tests on thou-
sands of patients. After 35 years of research, there is still no vaccine to pre-
vent HIV infection.

Ecology of SARS-CoV-2
SARS-CoV-2 is present at high concentrations in the upper and lower respira-
tory tract (Zhu N 2020, Wang 2020, Huang 2020). The virus has also been
found, albeit at low levels, in the kidney, liver, heart, brain, and blood (Puelles
2020). Outside the human body, the virus is more stable at low temperature
and low humidity conditions, whereas warmer temperatures and higher hu-
midity shorten the half-life (Matson 2020). It has also been shown to be de-
tectable as an aerosol (in the air) for up to three hours, up to 24 hours on
cardboard and up to two to three days on plastic and stainless steel (van
Doremalen 2020). As expected, viral RNA was more likely to be found in areas
immediately occupied by COVID-19 patients than in other hospital areas
(Zhou J 2020). Another study documented contamination of toilets (toilet
bowl, sink, and door handle) and air outlet fans (Ong SWX 2020). This is in
line with the experience from MERS where many environmental surfaces of

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patients’ rooms, including points frequently touched by patients or

healthcare workers, were contaminated by MERS-CoV (Bin 2016).

Person-to-person transmission
Person-to-person transmission of SARS-CoV-2 was established within weeks
of identification of the first cases (Chan JF 2020, Rothe 2020). Shortly after, it
was suggested that asymptomatic individuals would probably account for a
substantial proportion of all SARS-CoV-2 transmissions (Nishiura 2020, Li
2020). Viral load can be high 2-3 days before the onset of symptoms and al-
most half of all secondary infections are supposed to be caused by pre-
symptomatic patients (He 2020).
A key factor in the transmissibility of SARS-CoV-2 is the high level of viral
shedding in the upper respiratory tract (Wolfel 2020), even among pauci-
symptomatic patients. Pharyngeal virus shedding is very high during the first
week of symptoms, with a peak at > 7 x 108 RNA copies per throat swab on
day 4. Infectious virus was readily isolated from samples derived from the
throat or lung. That distinguishes it from SARS-CoV, where replication oc-
cured mainly in the lower respiratory tract (Gandhi 2020); SARS-CoV and
MERS-CoV infect intrapulmonary epithelial cells more than cells of the upper
airways (Cheng PK 2004, Hui 2018).
The shedding of viral RNA from sputum appears to outlast the end of symp-
toms and seroconversion is not always followed by a rapid decline in viral
load (Wolfel 2020). This contrasts with influenza where persons with asymp-
tomatic disease generally have lower quantitative viral loads in secretions
from the upper respiratory tract than from the lower respiratory tract and a
shorter duration of viral shedding than persons with symptoms (Ip 2017).
A recently published review summarized the evidence of human SARS-CoV-2
transmission (Meyerowitz 2020). Their key points:
1. Respiratory transmission is the dominant mode of transmission.
2. Vertical transmission occurs rarely; transplacental transmission has
been documented.
3. Direct contact and fomite transmission are presumed but are likely
only an unusual mode of transmission.
4. Although live virus has been isolated from saliva and stool and viral
RNA has been isolated from semen and blood donations, there are no
reported cases of SARS-CoV-2 transmission via fecal–oral, sexual, or
bloodborne routes. To date, there is 1 cluster of possible fecal–
respiratory transmission.

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5. Cats and ferrets can be infected and transmit to each other, but there
are no reported cases to date of transmission to humans; minks
transmit to each other and to humans.

Routes of Transmission
SARS-CoV-2 is spread predominantly via virus-containing droplets through
sneezing, coughing, or when people interact with each other for some time in
close proximity (usually less than one metre) (ECDC 2020, Chan JF 2020, Li Q
2020, Liu Y 2020). These droplets can then be inhaled or land on surfaces
where they can be detectable for up to four hours on copper, up to 24 hours
on cardboard and up to two to three days on plastic and stainless steel (van
Doremalen 2020, Aboubakr 2020). Other people may come into contact with
these droplets and get infected when they touch their nose, mouth or eyes
(Wang Y 2020, Deng W 2020). SARS-CoV-2 environmental contamination
around COVID-19 patients is extensive, and hospital IPC procedures should
account for the risk of fomite, and potentially airborne, transmission of the
virus (Santarpia 2020).

Respiratory transmission
SARS-CoV-2 is transmitted via (macro-)droplets greater than 5-10 μm in di-
ameter, commonly referred to as respiratory droplets, and via smaller par-
ticles, < 5μm in diameter, which are referred to as droplet nuclei or aerosols.
The almost century-old dichotomy (Wells 1934) “droplets vs. aerosol trans-
mission” has been challenged by SARS-CoV-2. It is now accepted that there is
no real evidence that SARS-CoV-2 pathogens should be carried only in large
droplets (Fennelly 2020). At the beginning of the current pandemic, aerosol
transmission of SARS-CoV-2 was generally not accepted; however, over the
months, it became evident that some COVID-19 clusters, for example in choirs
(Hamner 2020, Miller 2020), shopping malls (Cai J 2020), restaurants (Li Y 2020
+ Lu J 2020), meat processing plants (Günter 2020, The Guardian) or vertically
aligned flats connected by drainage pipes in the master bathrooms (Kang M
2020, Gormley 2020), were best explained by aerosol transmission.
On July 9 2020, WHO updated its information about SARS-CoV-2 transmission
(WHO 20200709), “There have been reported outbreaks of COVID-19 in some
closed settings, such as restaurants, nightclubs, places of worship or places of
work where people may be shouting, talking, or singing. In these outbreaks,
aerosol transmission, particularly in these indoor locations where there are
crowded and inadequately ventilated spaces where infected persons spend
long periods of time with others, cannot be ruled out.” In the preceding days,

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a group of more than 200 scientists led by Lidia Morawska and Donald K. Mil-
ton had published a three-page warning: It is Time to Address Airborne Trans-
mission of COVID-19 (see also LM’s first alert on 10 April and the overviews by
Prather, Wang and Schooley as well as Jayaweera 2020 et al.). As always, dis-
cordant views have been voiced, arguing that long-range aerosol-based
transmission is not the dominant mode of SARS-CoV-2 transmission (Klompas
2020) and that the main mode of transmission of SARS-CoV-2 is short range
through droplets and close contact (Chagla 2020). Today, aerosol transmission
of SARS-CoV-2 is an accepted notion.
Viruses are released during exhalation, talking, and coughing in micro-
droplets small enough to remain aloft in the air and pose a risk of exposure at
distances beyond 1 to 2 m from an infected individual (Morawska 2020b).
Morawska, Milton et al. suggested the following measures to mitigate air-
borne transmission of SARS-CoV-2:
• Provide sufficient and effective ventilation (supply clean outdoor air,
minimize recirculating air) particularly in public buildings, work-
place environments, schools, hospitals, and retirement care homes.
• Supplement general ventilation with airborne infection controls
such as local exhaust, high efficiency air filtration, and germicidal ul-
traviolet lights.
• Avoid overcrowding, particularly in public transport and public
buildings.
A precautionary approach to COVID-19 prevention is shown in Table 1.
The evidence for aerosol transmission and resulting recommendations for
prevention have been sublimely summarized by Prather et al. in five sentenc-
es: “Respiratory infections occur through the transmission of virus-
containing droplets (>5 to 10 μm) and aerosols (≤5 μm) exhaled from infected
individuals during breathing, speaking, coughing, and sneezing. Traditional
respiratory disease control measures are designed to reduce transmission by
droplets produced in the sneezes and coughs of infected individuals. Howev-
er, a large proportion of the spread of coronavirus disease 2019 (COVID-19)
appears to be occurring through airborne transmission of aerosols produced
by asymptomatic individuals during breathing and speaking (Morawska 2020,
Anderson 2020, Asadi 2019). Aerosols can accumulate, remain infectious in
indoor air for hours, and be easily inhaled deep into the lungs. For society to
resume, measures designed to reduce aerosol transmission must be imple-
mented, including universal masking and regular, widespread testing to iden-
tify and isolate infected asymptomatic individuals (Prather 2020).”

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Table 1. Reducing the transmission of SARS-CoV-2

Transmission route Prevention

1. (Macro-)Droplets (> 5 µm) Face masks + social distancing

2. Aerosol (micro-droplets, ≤ • Face masks
5µm) • Improved ventilation
(open doors and windows; upgrade ventilation
systems)
• Improved air filtering
• Avoidance of crowded and closed spaces
3. Fomites Handwashing
For mechanical systems, organizations such as ASHRAE (the American Society of Heating,
Ventilating, and Air Conditioning Engineers) and REHVA (the Federation of European
Heating, Ventilation and Air Conditioning Associations) have provided guidelines based on
the existing evidence of airborne transmission (Morawska 2020b).

A recent demonstration of aerosol production visualizes speech-generated

oral fluid droplets and underlines that even normal speaking may be an im-
portant mode of transmission (Bax 2020). The authors provide videos showing
speech droplets emitted by four people, when speaking the phrase “spit hap-
pens” with the face positioned about 10–15 cm behind a thin sheet of intense
green laser light (video: https://www.youtube.com/watch?v=ooVjNth4ut8).
Previously, experimental support for aerosol transmission of SARS-CoV-2
came from studies that visualized droplet formation at the exit of the mouth
during violent expiratory events such as sneezing and coughing (Scharfman
2016, Bourouiba 2020; see also the video). These studies showed that the life-
time of a droplet could be considerably longer than previously assumed.
When analyzed with highly sensitive laser light scattering, loud speech was
found to be able to emit thousands of oral fluid droplets per second which
could linger in the air for minutes (Anfinrud 2020, Stadnytskyi 2020; see also
the movies showing the experimental setup and the critical comment by Ab-
bas 2020). Loud and persistent shouting as would be usual in noisy, closed and
stagnant air environments (meat packing facilities, discos, pubs, etc.) is now
believed to produce the same number of droplets as produced by coughing
(Chao 2020). Speech and other vocal activities such as singing have also been
shown to generate air particles, with the rate of emission corresponding to
voice loudness (Asadi 2019).
Of note, during the 2003 SARS epidemic, an airborne route
of transmission also appeared to be a plausible explanation for the so-called
Amoy Garden outbreak. On that occasion, the virus was aerosolized within
the confines of very small bathrooms and may have been inhaled, ingested or

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transmitted indirectly by contact with fomites as the aerosol settled (WHO

2003).
Recognizing that SARS-CoV-2 is transmitted via aerosol has even more far-
reaching consequences – personal, professional, societal and economic – in
situations of community COVID-19 outbreaks. At the personal level (remind-
er: 20% of infected individuals are thought to transmit 80% of SARS-CoV-2
cases, so minimizing the probability of coming close to such super-spreader
invidivuals is imperative), people might wish to avoid prolonged meetings
with people from outside their inner-core “friends-and-family-bubble”; in-
side the bubble, meetings should be restricted to a handful of people. For eve-
ryday life, the following five rules of thumb are helpful:
6. Wear face masks in public spaces.
7. Keep a distance of 2 (two!) meters to other people.
8. Avoid crowded places (more than 5-10 people).
9. Avoid in particular crowded and closed spaces (even worse: air-
conditioned closed places where air is being moved around).
10. Avoid in any circumstances crowded, closed and noisy spaces where
people must shout to communicate. These are SARS-CoV-2’s pre-
ferred playgrounds.
At the professional level, healthcare workers will require nothing short of
optimal protection. As N95 respirators achieve better filtration of airborne
particles than medical masks, they should be recommended for all inpatient
care of patients with COVID-19, not only during aerosol generating proce-
dures (Dau 2020). Guideline recommendations that do not support N95 use for
all inpatient COVID-19 management should consider reevaluating the existing
data.
At the societal level, the attendance of important biographic events such as
weddings, baptisms, circumcisions and funerals may need to be limited to a
handful of intimate friends and family (probably less than 10). Religious ser-
vices and recreational activities such as team sport and choir singing may not
be possible.
At the economic level, all activities which bring numerous people from out-
side the “friends-and-family-bubbles” together may be banned during new
community outbreaks. Instead of complete lockdowns like those enacted dur-
ing the spring of 2020 – and which are not economically sustainable – partial
lockdowns would target places where strangers or simply unacquainted peo-
ple meet: discos, amusement parks, bars, restaurants, brothels and many
more. Other activities such as meat processing plants might need major re-

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structuring before resuming work. Re-opening schools in September has been

and remains a world-wide challenge.
If SARS-CoV-2 is transmitted airborne for several meters, previous prevention
recommendations of frequent hand-washing and maintaining a distance of at
least one meter (arm’s length) (WHO 20200329) are insufficient. Instead, ade-
quate control measures would include wearing suitable masks whenever in-
fected persons may be nearby and providing adequate ventilation of enclosed
spaces where such persons are known to be or may recently have been
(Morawska 2020, Somsen 2020, Meselson 2020). Infrastructure may have to be
adjusted, for example, Heating, Ventilation and Air Conditioning Systems
(HVAC) in buildings and on ships (Correia 2020, Gormley 2020). Most of all,
tighter prevention recommendations will have unforeseeable consequences
for all places where foreigners, strangers or simply unacquainted people
meet. SARS-CoV-2 will thus continue to impact cultural and economic life –
theaters, cinemas, bars, restaurants, shops, etc – for some time to come.
In the meantime, the discussion about SARS-CoV-2 and aerosols continues.
Even the droplet/aerosol terminology has now been questioned by advocates
of a new distinction between aerosols and droplets using a size threshold of
100 μm, not the historical 5 μm (Prather 2020). The authors argue that this
size more effectively separates their aerodynamic behavior, ability to be in-
haled, and efficacy of interventions. Viruses in droplets (larger than 100 μm)
typically fall to the ground in seconds within 2 m of the source and can be
sprayed like tiny cannonballs onto nearby individuals. Recently, a fourth
transmission route has been hypothesized: aerosolized fomites. In this case,
virus would remain viable in the environment, on materials like paper tissues
and on the bodies of living animals, long enough to be aerosolized on non-
respiratory dust particles that can transmit infection through the air to new
mammalian hosts (Asadi 2020). In retrospective, we will one day understand
that transmission of viruses is not the only conceptual framework upset by
the SARS-CoV-2 virus.

Fomites
It is still unclear to which extent transmission via fomites (e.g., elevator but-
tons, hand rails, restroom taps) is epidemiologically relevant (Cai J 2020). [A
fomite is any inanimate object that, when contaminated with or exposed to
infectious agents such as a virus, can transfer a disease to another person.]
SARS-CoV-2 seems omnipresent in the spaces inhabited by infected individu-
als. A protein-rich medium like airway secretions could protect the virus
when it is expelled and may enhance its persistence and transmission by con-
taminated fomites (Pastorino 2020). For example, SARS-CoV-2 RNA was de-

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tected from 58 out of 601 samples (10%) from case cabins 1-17 days after the
cabins were vacated, but not from non-case cabins (Yamagishi 2020). There
was no difference in the detection proportion between cabins for symptomat-
ic (15%, 28/189) and asymptomatic cases (21%, 28/131). However, no SARS-
CoV-2 virus was isolated from any of the samples. Potential drivers of the
SARS-CoV-2 surface adsorption and stability in various environmental condi-
tions have been recently discussed (Joonaki 2020).
Recently, the role of fomites in SARS-CoV-2 transmission has been ques-
tioned. Some authors find that the chance transmission through inanimate
surfaces might be less frequent than hitherto assumed (Mondelli 2020) and
less likely to occur in real-life conditions, provided that standard cleaning
procedures and precautions are enforced. Transmission through fomites
would occur only in instances where an infected person coughs or sneezes on
the surface, and someone else touches that surface soon after the cough or
sneeze (within 1–2 h) (Goldman 2020). In any case, even face coverings may
protect indirectly against fomite transmission. After analyzing mask-wearing
and face-touching behavior in public areas, one group found that mask wear-
ing was associated with reduced face-touching behavior, especially touching
of the eyes, nose, and mouth (Chen Y 2020). They conclude that the reduction
of face-touching behaviors by mask wearing could contribute to curbing the
COVID-19 pandemic.

Mother-to-child
Mother-to-child transmission doesn’t seem to be a prominent route of SARS-
CoV-2 transmission. There is one report of a newborn with elevated SARS-
CoV-2 IgM antibodies who was exposed for 23 days from the time of the
mother’s diagnosis of COVID-19 to delivery (Dong L 2020). However, there was
no evidence for intrauterine vertical transmission among another group of
nine women with COVID-19 pneumonia in late pregnancy (Chen H 2020).
Vaginal (n=24) versus elective cesarean (n=16) was addressed in a study from
Northern Italy. In one case a newborn had a positive test after a vaginal oper-
ative delivery (Ferrazzi 2020). Two women with COVID-19 breastfed without a
mask because infection was diagnosed in the post-partum period; their new-
borns tested positive for SARS-CoV-2 infection. The authors conclude that
although post-partum infection cannot be excluded with 100% certainty, vag-
inal delivery seems to be associated with a low risk of intrapartum SARS-CoV-
2 transmission. There is also a case report of transplacental transmission
where a 23-year-old COVID-19 patient who gave birth by cesarean section to a
baby found to have the infection (Vivanti 2020). The viral load was much
higher in the placental tissue than in the amniotic fluid or maternal blood:

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this suggests the presence of the virus in placental cells, which is consistent
with findings of inflammation seen at histological examination (the baby was
fine).
SARS-CoV-2 has been found in breast milk (Wu Y 2020, Groß 2020, Bastug
2020). In one study, SARS-CoV-2 RNA was detected in one milk sample, but
the viral culture for that sample was negative. These data suggest that SARS-
CoV-2 RNA does not represent replication-competent virus and that breast
milk may not be a source of infection for the infant (Chambers 2020). As of
May 2020, the Italian Society on Neonatology (SIN), endorsed by the Union of
European Neonatal & Perinatal Societies (UENPS), recommended breastfeed-
ing as advisable if a mother previously identified as COVID-19-positive or un-
der investigation for COVID-19 was asymptomatic or paucisymptomatic at
delivery. On the contrary, when a mother with COVID-19 is too sick to care
for the newborn, the neonate should be managed separately and fed freshly
expressed breast milk (Davanzo 2020, Davanzo 2020b [Italian]). This guidance
may be subject to change in the coming months.

Stool, urine
Although no cases of fecal-oral transmission of SARS-CoV-2 have been re-
ported thus far, a study from Zhuhai reports prolonged presence of SARS-
CoV-2 viral RNA in fecal samples. Of the 41 (55%) of 74 patients with fecal
samples that were positive for SARS-CoV-2 RNA, respiratory samples re-
mained positive for SARS-CoV-2 RNA for a mean of 17 days and fecal samples
remained positive for a mean of 28 days after first symptom onset (Wu Y
2020). In another study, 22/133 patients, SARS-CoV-2 was still detected in the
sputum or feces (up to 39 and 13 days, respectively) after pharyngeal swabs
became negative (Chen 2020). In still another study, seven out of ten children
contained SARS-CoV-2 virus RNA in their fecal specimens, despite all patients
showing negative results in respiratory tract specimens and the median time
from onset to having negative results in respiratory tract and fecal specimens
was 9 days and 34.43 days, respectively (Du W 2020).
Until proof of the contrary, the possibility of fecal-oral transmission should
not be excluded. Strict precautions must be observed when handling the
stools of patients infected with coronavirus. Sewage from hospitals should
also be properly disinfected (Yeo 2020). Fortunately, antiseptics and disin-
fectants such as ethanol or bleach have good activity on human coronaviruses
(Geller 2012). During the SARS-CoV outbreak in 2003, where SARS-CoV was
shown to survive in sewage for 14 days at 4°C and for 2 days at 20°C (Wang
XW 2005), environmental conditions could have facilitated this route of
transmission.

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Blood products
SARS-CoV-2 is rarely detected in blood (Wang W 2020, Wolfel 2020). After
screening of 2430 donations in real-time (1656 platelet and 774 whole blood),
authors from Wuhan found plasma samples positive for viral RNA from 4
asymptomatic donors (Chang 2020). It remains unclear whether detectable
RNA signifies infectivity.
In a Korean study, seven asymptomatic blood donors were later identified as
COVID-19 cases. None of 9 recipients of platelets or red blood cell transfusions
tested positive for SARS-CoV-2 RNA (Kwon 2020). More data are needed be-
fore transmission through transfusion can be declared safe.

Sexual transmission
It is unknown whether purely sexual transmission is possible. Scrupulously
eluding infection via fomites and respiratory droplets during sexual inter-
course would suppose remarkable acrobatics many people might not be will-
ing to perform. Reassuringly, SARS-CoV-2 doesn’t seem to be present in se-
men (Guo L 2020).
Cats and dogs et al.
SARS-CoV-2 can be transmitted to cats and dogs (Newman 2020, Garigliany
2020). When inoculated with SARS-CoV-2, cats can transmit the virus to other
cats (Halfmann 2020) and although none of the cats showed symptoms, all
shedded virus for 4 to 5 days and developed antibody titers by day 24. In an-
other report, two out of fifteen dogs from households with confirmed human
cases of COVID-19 in Hong Kong were found to be infected. The genetic se-
quences of viruses from the two dogs were identical to the virus detected in
the respective human cases (Sit 2020). In still another paper, 817 companion
animals in northern Italy at the height of the spring 2020 epidemic were test-
ed for SARS-CoV-2. Although no animals tested PCR positive, 3.4% of dogs and
3.9% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with
dogs from COVID-19 positive households being significantly more likely to
test positive than those from COVID-19 negative households (Patterson 2020).
Evidence of infection of animals with SARS-CoV-2 has been shown experi-
mentally both in vivo and in vitro for monkeys, cats, ferrets, rabbits, foxes, and
hamsters (Edwards 2020). While computational models also predicted infec-
tivity of pigs and wild boar (Santini 2020), a recent study suggested that pigs
and chickens could not be infected intranasally or oculo-oronasally by SARS-
CoV-2 (Schlottau 2020).

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At present, it seems unlikely that animals are potential intermediate hosts in

the chain of human–pet–human transmission. Only special circumstances,
such as the high animal population densities encountered on infected mink
farms, might put humans at risk of animal-to-human transmission. In any
case, persons with COVID-19 should be advised to avoid contact with animals.
Companion animals that test positive for SARS-CoV-2 should be monitored
and separated from persons and other animals until they recover (Newman
2020).

Transmission Event
Transmission of a virus from one person to another depends on four varia-
bles:
1. The nature of the virus;
2. The nature of the transmitter;
3. The nature of the transmittee (the person who will become infected);
4. The transmission setting.

Virus
In order to stay in the evolutionary game, all viruses have to overcome a se-
ries of challenges. They must attach to cells; fuse with their membranes; re-
lease their nucleic acid into the cell; manage to make copies of themselves;
and have the copies exit the cell to infect other cells. In addition, respiratory
viruses must make their host cough and sneeze to get back into the environ-
ment again. Ideally, this happens before the hosts realize that they are sick.
This is all the more amazing as SARS-CoV-2 is more like a piece of computer
code than a living creature in sensu strictu (its 30,000 DNA base pairs are a
mere 100,000th of the human genetic code). That doesn’t prevent the virus
from being ferociously successful:
• It attaches to the human angiotensin converting enzyme 2 (ACE2) recep-
tor (Zhou 2020) which is present not only in nasopharyngeal and oropha-
ryngeal mucosa, but also in lung cells, such as in type II pneumocytes.
SARS-CoV-2 thus combines the high transmission rates of the common
coronavirus NL63 (infection of the upper respiratory tract) with the sever-
ity of SARS in 2003 (lower respiratory tract);
• It has a relatively long incubation time of around 5 days (influenza: 1-2
days), thus giving it more time to spread;
• It is transmitted by asymptomatic individuals.

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As mentioned above, SARS-CoV-2 can be viable for days (van Doremalen

2020). Environmental factors that might influence survival of the virus out-
side the human body will be discussed below (page 115).
The virologic determinants of more or less successful SARS-CoV-2 transmis-
sion are not yet fully understood.

Transmittor
The mean incubation of SARS-CoV-2 infection is around 5 days (Lauer 2020, Li
2020, Zhang J 2020, Pung 2020), comparable to that of the coronaviruses caus-
ing SARS or MERS (Virlogeux 2016). Almost all symptomatic individuals will
develop symptoms within 14 days of infection (Bai Y 2020). Infectiousness
seems to peak on or before symptom onset (He X 2020).
It is currently unknown if SARS-CoV-2 transmission correlates with the fol-
lowing characteristics of the index case (transmittor):
• Symptom severity;
• Large concentrations of virus in the upper and lower respiratory tract;
• SARS-CoV-2 RNA in plasma;
• In the future: reduced viral load due to drug treatment (like in people
treated for HIV infection) [Cohen 2011, Cohen 2016, LeMessurier 2018])
There are some first hints that symptom severity of the index case has an
impact on transmission probability. In one study of 3410 close contacts of 391
SARS-CoV-2 infected index cases, the secondary attack rate increased with
the severity of index cases, from 0.3% for asymptomatic to 3.3% for mild, 5.6%
for moderate, and 6.2% for severe or critical cases (Luo L 2020). Index cases
with expectoration were associated with higher risk for secondary infection
(13.6% vs. 3.0% for index cases without expectoration).
SARS-CoV-2 transmission certainly correlates with a still ill-defined “super-
spreader status” of the infected individual. For unknown reasons, some indi-
viduals are remarkably contageous, capable of infecting dozens or hundreds
of people, possibly because they breathe out many more particles than others
when they talk (Asadi 2019), shout, cough or sneeze. Transmission of SARS-
CoV and MERS-CoV as well occurred to a large extent by means of super-
spreading events (Peiris 2004, Hui 2018). Super-spreading has been recog-
nized for years to be a normal feature of disease spread (Lloyd-Smith 2005).
One group suggested that 80% of secondary transmissions could be caused by
around 20% of infectious individuals (Adam 2020). A value called the disper-
sion factor (k) describes this phenomenon. The lower the k is, the more
transmission comes from a small number of people (Kupferschmidt 2020,

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Tufekci 2020; if you like the FT, read also To beat Covid-19, find today’s super-
spreading ‘Typhoid Marys’). While SARS was estimated to have a k of 0.16
(Lloyd-Smith 2005) and MERS of 0.25, in the flu pandemic of 1918, in contrast,
the value was about one, indicating that clusters played less of a role (Endo
2020). For the SARS-CoV-2 pandemic, the dispersion factor (k) is currently
thought to be higher than for SARS and lower than for the 1918 influenza
(Endo 2020, Miller 2020, On Kwok 2020, Wang L 2020).
Transmission is more likely when the infected individual has few or no symp-
toms because no one will take notice and maintain precautions. Around half
of secondary cases are supposed to be transmitted during the pre-
symptomatic stage of the index case (He X 2020). Asymptomatic transmis-
sion of SARS-CoV-2 – proven a few weeks after the beginning of the pandemic
(Bai Y 2020) – has justly been called the Achilles’ heel of the COVID-19 pan-
demic (Gandhi 2020). As shown during an outbreak in a skilled nursing facili-
ty, the percentage of asymptomatic individuals can be as high as 50% early
(Arons 2020; most of these individuals would later develop some symptoms).
Importantly, SARS-CoV-2 viral load was comparable in individuals with typi-
cal and atypical symptoms, and in those who were pre-symptomatic or
asymptomatic. Seventeen of 24 specimens (71%) from pre-symptomatic per-
sons had viable virus by culture 1 to 6 days before the development of symp-
toms (Arons 2020), suggesting that SARS-CoV-2 may be shed at high concen-
trations before symptom development.
Note that although SARS-CoV-2 is highly transmissible, given the right cir-
cumstances and the right prevention precautions, zero transmission is pos-
sible. In one case report, there was no evidence of transmission to 16 close
contacts, among them 10 high-risk contacts, from a patient with mild illness
and positive tests for up to 18 days after diagnosis (Scott 2020).
To what extent children contribute to the spread of SARS-CoV-2 infection in
a community is unknown. Infants and young children are normally at high
risk for respiratory tract infections. The immaturity of the infant immune
system may alter the outcome of viral infection and is thought to contribute
to the severe episodes of influenza or respiratory syncytial virus infection in
this age group (Tregoning 2010). Until now, however, there is a surprising
absence of pediatric patients with COVID-19, something that has perplexed
clinicians, epidemiologists, and scientists (Kelvin 2020).
Although a retrospective study among individuals hospitalized in Milan
showed that only about 1% of children and 9% of adults without any symp-
toms or signs of SARS-CoV-2 infection tested positive for SARS-CoV-2 (Milani
2020) – suggesting a minor role of children in transmission –, children can be
the source for important outbreaks. Twelve children who acquired SARS-CoV-

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2 infection in child-care facilities – all with mild or no symptoms – transmit-

ted the virus to at least 12 (26%) of 46 non-facility contacts (Lopez 2020). Fam-
ily gatherings are well-known settings for widespread SARS-CoV-2 transmis-
sion. In an outbreak that occurred during a 3-week family gathering of five
households, an adolescent aged 13 years was the suspected primary patient.
Among the 14 persons who stayed in the same house, 12 experienced symp-
toms (Schwartz 2020). Of note, none of the additional six family members who
maintained outdoor physical distance without face masks during two longer
visits (10 and 3 hours) to the family gathering developed symptoms.
Health authorities should know that SARS-CoV-2 infected individuals do not
need to be quarantined for weeks. Persistently positive RT-PCRs generally do
not reflect replication-competent virus. SARS-CoV-2 infectivity rapidly de-
creases to near-zero after about 10 days in mild-to-moderately-ill patients
and 15 days in severely-to-critically-ill and immunocompromised patients
(Rhee 2020). Of note, RT-PCR cycle threshold (Ct) values (a measure for viral
load) correlated strongly with cultivable virus. In one study, the probability
of culturing virus declined to 8% in samples with Ct > 35 and to 6% (95% CI:
0.9–31.2%) 10 days after onset; it was similar in asymptomatic and sympto-
matic persons (Singanayagam 2020).
In any potential transmission setting, face coverings reduce the transmission
of SARS-CoV-2. Among 139 clients exposed to two symptomatic hair stylists
with confirmed COVID-19 while both the stylists and the clients wore face
masks, not a single symptomatic secondary case was observed; among 67 cli-
ents tested for SARS-CoV-2, all tests were negative (Hendrix 2020). At least
one hair stylist was infectious: all four close household contacts (presumably
without masks) became ill. Unfortunately, face masks don’t work everywhere
– and not for everyone. In some countries, infected individuals claimed the
right to not wear face coverings in the name of liberty (they forgot that an
individual’s liberty ends where it infringes on the liberties of others). Inter-
estingly, social distancing compliance can be predicted by individual differ-
ences in working memory (WM) capacity. WM retains a limited amount of
information over a short period of time at the service of other ongoing men-
tal activities. Limited WM capacity constrains mental functions while extend-
ed capacities are often associated with better cognitive and affective out-
comes. The hidden message in the paper by Weizhen Xie et al: if the guy sit-
ting next to you in the bus does not wear a mask, don’t insist. His working
memory capacity is poor (Xie W 2020). Change seats.

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Transmittee
Upon exposure to SARS-CoV-2, the virus may come in contact with cells of the
upper or lower respiratory tract of an individual. After inhalation, larger res-
piratory droplets are filtered by the nose or deposited in the oropharynx,
whereas smaller droplet nuclei are carried by the airstream into the lungs
where their site of deposition depends on their mass, size and shape and is
governed by various mechanisms (Dhand 2020).
Numerous cell entry mechanisms of SARS-CoV-2 have been identified that
potentially contribute to the immune evasion, cell infectivity, and wide
spread of SARS-CoV-2 (Shang J 2020). Susceptibility to SARS-CoV-2 infection
is probably influenced by the host genotype. This would explain the higher
percentage of severe COVID-19 in men (Piccininni 2020) and possibly the
similar disease course in some twins in the UK (The Guardian, 5 May 2020).
A high percentage of SARS-CoV-2 seronegative individuals have SARS-CoV-2
reactive T cells. This is explained by previous exposure to other coronavirus-
es (“common cold” coronaviruses) which have proteins that are highly simi-
lar to those of SARS-CoV-2. It is still unclear whether these cross-reactive T
cells confer some degree of protection, are inconsequential or even potential-
ly harmful if someone who possesses these cells becomes infected with SARS-
CoV-2 (Braun 2020, Grifoni 2020).
The “right” genotype may not be sufficient in the presence of massive expo-
sure, for example by numerous infected people and on multiple occassions as
might happen, for example, in health care institutions being overwhelmed
during the beginning of an epidemic. It is known from other infectious dis-
eases that viral load can influence the incidence and severity of disease. Alt-
hough the evidence is limited, high infection rates among health workers
have been attributed to more frequent contact with infected patients, and
frequent exposure to excretia with high viral load (Little 2020).
Recently, it has been shown that rigorous social distancing not only slowed
the spread of SARS-CoV-2 in a cohort of young, healthy adults but also pre-
vented symptomatic COVID-19 while still inducing an immune response
(Bielecki 2020). After an outbreak in two Swiss army companies (company 2
and 3, see Table 2), 62% of tested soldiers were found to have been exposed to
SARS-CoV-2 and almost 30% had COVID-19 symptoms. In company 1 where
strict distancing and hygiene measures (SDHMs) had been implemented after
the outbreak in companies 2 and 3, only 15% had exposure to SARS-CoV-2, but
none of them had COVID-19 symptoms. (The Swiss army SDHMs: keep a dis-
tance of at least 2 m from each other at all times; wear a surgical face mask in
situations where this can not be avoided [e.g., military training]; enforce a

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distance of 2 m between beds and during meals; clear and disinfect all sani-
tary facilities twice daily; separate symptomatic soldiers immediately.)

Table 2: Baseline characteristics of the study population on March 31, 2020

Company 1 Company 2 Company 3 Company 2+3
Soldiers 154 200 154 354
Tested* 88 130 51 181
Exposed to 13/88 (15%) 83/130 (64%) 30/51 (59%) 113/181 (62%)
SARS-CoV-2**
COVID-19*** 0 (0%) 54/200 (27%) 48/154 (31%) 102/354 (29%)
* More than 50% of the soldiers of all companies were sampled on
April 14.
** On April 14, detection of SARS-CoV-2 in nasopharyngeal swabs
or by positive serology test for immunoglobulin A, G or M.
*** Symptomatic patients between March 11 and May 3, 2020.

The authors cautiously suggested that quantitatively reducing the viral in-
oculum received by SARS-CoV-2 virgin recipients not only reduced the prob-
ability of infection but also could have caused asymptomatic infections in
others while still being able to induce an immunological response (Bielecki
2020), and idea that was later echoed by Monica Gandhi and George W. Ruth-
erford (Ghandi 2020).
If genes offer no protection, behavior may do so. In the coming autumn and
winter months 2020/2021, face covering is paramount. It reduces, for exam-
ple, the number of infections among hospital personnel. In March 2020, the
Mass General Brigham, the largest health care system in Massachusetts (12
hospitals, > 75,000 employees), implemented universal masking of all HCWs
and patients with surgical masks. During the pre-intervention period, the
SARS-CoV-2 positivity rate increased exponentially, with a case doubling time
of 3.6 days. During the intervention period, the positivity rate decreased line-
arly from 14.65% to 11.46% (Wang X 2020). In Paris, in a 1500-bed adult and a
600-bed pediatric setting of a university hospital, the total number of HCW
cases peaked on March 23rd, then decreased slowly, concomitantly with a
continuous increase in preventive measures (including universal medical
masking and PPE) (Contejean 2020). In Chennai, India, before the introduction
of face shields, 12/62 workers were infected while visiting 5880 homes with
31,164 persons (222 positive for SARS-CoV-2). After the introduction of
shields among 50 workers (previously uninfected) who continued to provide
counseling, visiting 18,228 homes with 118,428 persons (2682 positive), no
infection occurred (Bhaskar 2020). The preventive measures are not new to

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medicine – surgeons have been using personal protective equipment (PPE) for
more than a century (Stewart 2020). The wearing of masks by adults also re-
mains critical to reducing transmission in child-care settings (Link-Gelles
2020).
Masks work even with super-emittors. By measuring outward emissions of
micron-scale aerosol particles by healthy humans performing various expira-
tory activities, William D. Ristenpart, Sima Asadi and colleagues found that
both surgical masks and unvented KN95 respirators reduced the outward par-
ticle emission rates by 90% and 74% on average during speaking and cough-
ing. These masks similarly decreased the outward particle emission of a
coughing super-emitter, who for unclear reasons emitted up to two orders of
magnitude more expiratory particles via coughing than average (Asadi 2020).
An interesting collateral finding is that people speak more loudly, but do not
cough more loudly, when wearing a mask.
After visualizing the flow fields of coughs under various mouth covering sce-
narios, a recently published study (Simha 2020) found that
1. N95 masks are the most effective at reducing the horizontal spread
of a cough (spread: 0.1 and 0.25 meters).
2. A simple disposable mask can reduce the spread to 0.5 meters, while
an uncovered cough can travel up to 3 meters.
3. Coughing into the elbow is not very effective. Unless covered by a
sleeve, a bare arm cannot form the proper seal against the nose nec-
essary to obstruct airflow and a cough is able to leak through any
openings and propagate in many directions.
Although the data regarding the effectivity of face masks is now clear, will
everyone understand, i.e., even individuals with a still functioning working
memory? If some individuals continue to put themselves at risk of SARS-CoV-
2 infection (as well as their friends and relatives in case of infection), what
are the drivers of behaviors that might influence risk for COVID-19 exposure
among young adults? In a remote US county, the drivers were low severity of
disease outcome; peer pressure; and exposure to misinformation, conflicting
messages, or opposing views regarding masks (Wilson 2020). A scientifically
inspired national prevention policy will be needed to counter misinformation
and – let’s speak frankly for just two seconds! – address human stupidity.
First, public health officials need to ensure that the public understands clear-
ly when and how to wear cloth face coverings properly. Second, innovation is
needed to extend physical comfort and ease of use. Third, the public needs
consistent, clear, and appealing messaging that normalizes community mask-

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ing (Brooks 2020). A small adaption in our daily lives relies on a highly effec-
tive low-tech solution that can help turn the tide.

Transmission setting
The transmission setting, i.e., the actual place where the transmission of
SARS-CoV-2 occurs, is the final element in the succession of events that leads
to the infection of an individual. High population density which facilitates
super-spreading events (see also chapter Epidemiology, Transmission Hotspots,
page 23) is key to widespread transmission of SARS-CoV-2.
In the early phase of the pandemic, hospitals and other health care centers
have sometimes been hotspots of SARS-CoV-2 transmission, either because of
ignorance or missing protective equipment. In a major London teaching hos-
pital, 66/435 (15%) of COVID-19 inpatient cases between 2 March and 12 April
2020 were definitely or probably hospital-acquired through varied transmis-
sion routes (case fatality: 36%) (Rickman 2020).
In a prospective international multicentre cohort study of 1718 healthcare
workers participating in 5148 at-risk tracheal intubation episodes, the overall
incidence of the primary endpoint (lab‐confirmed COVID‐19 diagnosis or new
symptoms requiring self‐isolation or hospitalisation) was 10.7% over a medi-
an of 32 days (El-Boghdadly 2020).
In Greece, healthcare personnel represented approximately 10% of all noti-
fied COVID-19 cases. Those with high-risk occupational exposure to COVID-19
had increased probability of serious morbidity, healthcare seeking, hospitali-
zation and absenteeism (Maltezou 2020).
In the University of Washington medical system and its affiliated organiza-
tions, between March 12 and April 23, a total of 3477 symptomatic employees
were tested; 185 (5.3%) employees tested positive for COVID-19. The preva-
lence of SARS-CoV-2 was similar when comparing frontline HCWs (5.2%) to
non-frontline staff (5.5%) (Mani 2020).
Awaiting results from (difficult) randomised trials, the currently best availa-
ble evidence suggests for all public and healthcare settings (Chu DK 2020) the
FPE protection triad of

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• Physical distancing of at least 1 m, even better 2 m.

• Face mask, ideally N95 or similar.
• Eye protection (mandatory in health care settings and similar).
Find a helpful video, demonstrating the complex procedure for putting on
and removing PPE as recommended by the CDC (Ortega 2020). It is safe and
cheap to assume that SARS-CoV-2 is everywhere (Lednicky 2020).

Indoor environments
Indoor environments are SARS-CoV-2’s preferred playgrounds. In one model-
ing study, the authors estimated that viral load concentrations in a room with
an individual who was coughing frequently were very high, with a maximum
of 7.44 million copies/m3 from an individual who was a high emitter (Riediker
2020). However, regular breathing from an individual who was a high emitter
was modeled to result in lower room concentrations of up to 1248 copies/m3.
They conclude that the estimated infectious risk posed by a person with typi-
cal viral load who breathes normally was low and that only a few people with
very high viral load posed an infection risk in the poorly ventilated closed
environment simulated in this study.
Clusters of cases have been reported in many, predominantly indoor, settings.
Viable virus from air samples was isolated from samples collected 2 to 4.8
meters away from two COVID-19 patients (Lednicky 2020). The genome se-
quence of the SARS-CoV-2 strain isolated was identical to that isolated from
the NP swab from the patient with an active infection. Estimates of viable
viral concentrations ranged from 6 to 74 TCID50 units/L of air. During the
first months of the pandemic, most clusters were found to involve fewer than
100 cases, with the exceptions being in healthcare (hospitals and elderly
care), large religious gatherings and large co-habitation settings (worker
dormitories and ships). Other settings with examples of clusters between 50–
100 cases in size were schools, sports, bars, shopping centers and a confer-
ence (Leclerc 2020).
Transportation in closed spaces – by bus, train or aircraft – has been shown to
transmit SARS-CoV-2 at various degrees, depending on face mask use and
time of travel. One paper describes a bus ride in a vehicle 11,3 meters long
and 2,5 meters wide with 49 seats, fully occupied with all windows closed and
the ventilation system on during the 2,5-hour trip. Among the 49 passengers
(including the driver) who shared the ride with the index person, eight tested
positive and eight developed symptoms. The index person sat in the second-
to-last row, and the infected passengers were distributed over the middle and
rear rows (Luo K 2020). An even more informative paper describes 68 individ-

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uals (including the source patient) taking a bus on a 100-minute round trip to
attend a worship event. In total, 24 individuals (35%) received a diagnosis of
COVID-19 after the event. The authors were able to identify seats for each
passenger and divided bus seats into high-risk and low-risk zones (Shen Y
2020). Passengers in the high-risk zones had moderately but non-significantly
higher risk of getting COVID-19 than those in the low-risk zones. On the 3-
seat side of the bus, except for the passenger sitting next to the index patient,
none of the passengers sitting in seats close to the bus window developed
infection. In addition, the driver and passengers sitting close to the bus door
also did not develop infection, and only 1 passenger sitting by an operable
window developed infection. The absence of a significantly increased risk in
the part of the bus closer to the index case suggested that airborne spread of
the virus may at least partially explain the markedly high attack rate ob-
served. Lesson learned for the future? If you take the bus, choose seats near a
window – and open it!
To answer the question how risky train traveling is in the COVID-19 era, one
group analyzed passengers in Chinese high-speed trains. They quantified the
transmission risk using data from 2334 index patients and 72,093 close con-
tacts who had co-travel times of 0–8 hours from 19 December 2019 through 6
March 2020. Unsurprisingly, travelers adjacent to an index patient had the
highest attack rate (3.5%) and the attack rate decreased with increasing dis-
tance but increased with increasing co-travel time. The overall attack rate of
passengers with close contact with index patients was 0.32% (Hu M 2020).
A recently published review about in-flight transmission of SARS-CoV-2 finds
that the absence of large numbers of confirmed and published in-flight
transmissions of SARS-CoV is encouraging but not definitive evidence that
fliers are safe (Freedman 2020). At present, based on circumstantial data,
strict use of masks appears to be protective. In previous studies, SARS-CoV-2
transmission has been described onboard aircrafts (Chen J 2020, Hoehl 2020).
Note that if you don’t wear a mask, business class will not protect you from
infection. A Vietnamese group report on a cluster among passengers on VN54
(Vietnam Airlines), a 10-hour commercial flight from London to Hanoi on
March 2, 2020 (at that time, the use of face masks was not mandatory on air-
planes or at airports) (Khanh 2020). Affected persons were passengers, crew,
and their close contacts. The authors traced 217 passengers and crew to their
final destinations and interviewed, tested, and quarantined them. Among the
16 persons in whom SARS-CoV-2 infection was detected, 12 (75%) were pas-
sengers seated in business class along with the only symptomatic person (at-
tack rate 62%). Seating proximity was strongly associated with increased in-
fection risk (risk ratio 7.3, 95% CI 1.2–46.2).

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Transmission clusters, partly linked to super-spreader events, have been re-

ported since the very beginning of the SARS-CoV-2 pandemic:
• Business meeting, Southern Germany, 20-21 January (Rothe 2020)
• Cruise Ship, Yokohoma, Japan, 4 February (Rocklov 2020)
• Church meeting, Daegu, Korea, 9 and 16 February (Kim 2020)
• Religious gathering, Mulhouse, France, 17-24 February (Kuteifan 2020)
• Medical advisory board meeting, Munich, Germany, 20-21 (Hijnen 2020)
• Nursing facility, King County, Washington, 28 February (McMichael 2020)
• Aircraft carriers: Theodore Roosevelt (Payne 2020) + Charles-de-Gaulle,
March (Le Monde)
• Choir (Hamner 2020)
• Concert (Plautz 2020)
• Homeless shelter, Boston, 28 March (Baggett 2020)
A study of 1407 transmission pairs that formed 643 transmission clusters in
mainland China identified 34 super-spreaders, with 29 super-spreading
events occurring outside households (Xu XK 2020).

Temperature and climate

Another variable still poorly understood is ambient temperature and humidi-
ty.
SARS-CoV-1 (2003): The transmission of coronaviruses can be affected by
several factors, including the climate (Hemmes 1962). Looking back to the
2003 SARS epidemic, we find that the stability of the first SARS virus, SARS-
CoV, depended on temperature and relative humidity. A study from Hong
Kong, Guangzhou, Beijing, and Taiyuan suggested that the SARS outbreak in
2002/2003 was significantly associated with environmental temperature. The
study provided some evidence that there was a higher possibility for SARS to
reoccur in spring than in autumn and winter (Tan 2005). It was shown that
SARS-CoV remained viable for more than 5 days at temperatures of 22–25°C
and relative humidity of 40–50%, that is, typical air-conditioned environ-
ments (Chan KH 2011). However, viability decreased after 24 h at 38°C and 80–
90% relative humidity. The better stability of SARS coronavirus in an envi-
ronment of low temperature and low humidity could have facilitated its
transmission in subtropical areas (such as Hong Kong) during the spring and
in air-conditioned environments. It might also explain why some Asian coun-
tries in the tropics (such as Malaysia, Indonesia or Thailand) with high tem-

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perature and high relative humidity environment did not have major com-
munity SARS outbreaks (Chan KH 2011).
SARS-CoV-2 (2020): It is as yet unclear as to whether and to what extent cli-
matic factors influence virus survival outside the human body and might in-
fluence local epidemics. SARS-CoV-2 is not readily inactivated at room tem-
perature and by drying like other viruses, for example herpes simplex virus.
One study mentioned above showed that SARS-CoV-2 can be detectable as an
aerosol (in the air) for up to three hours, up to four hours on copper, up to 24
hours on cardboard and up to two to three days on plastic and stainless steel
(van Doremalen 2020).
A few studies suggest that low temperature might enhance the transmissibil-
ity of SARS-CoV-2 (Wang 2020b, Tobías 2020) and that the arrival of summer
in the northern hemisphere could reduce the transmission of the COVID-19. A
possible association of the incidence of COVID-19 and both reduced solar ir-
radiance and increased population density has been discussed (Guasp 2020). It
was reported that simulated sunlight rapidly inactivated SARS-CoV-2 sus-
pended in either simulated saliva or culture media and dried on stainless
steel plates while no significant decay was observed in darkness over 60
minutes (Ratnesar-Shumate 2020). However, another study concluded that
transmission was likely to remain high even at warmer temperatures (Sehra
2020). In particular the current epidemics in Brazil and India and the south-
ern US – areas with high temperatures – should temper hopes that COVID
“simply disappears like a miracle”. Warm and humid summer conditions
alone might be unlikely to limit substantially new important outbreaks (Luo
2020, Baker 2020, Collins 2020).

Outlook
Almost a year after the first SARS-CoV-2 outbreak in China, the transmission
dynamics driving the pandemic are coming into focus. It now appears that a
high percentage (as high as 80%?) of secondary transmissions could be caused
by a small fraction of infectious individuals (10 to 20%?; Adam 2020); if this is
the case, then the more people are grouped together, the higher the probabil-
ity that a superspreader is part of the group.
It is now acknowledged that aerosol transmission plays an important role in
SARS-CoV-2 transmission (Morawska 2020b, WHO 20200709, Prather 2020); if
this is the case, then building a wall around this same group of people and
putting a ceiling above them further enhances the probability of SARS-CoV-2
infection.

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 Transmission | 117

It finally appears that shouting and speaking loudly emits thousands of oral
fluid droplets per second which could linger in the air for minutes (Anfinrud
2020, Stadnytskyi 2020, Chao 2020, Asadi 2019, Bax 2020); if this is the case,
then creating noise (machines, music) around people grouped in a closed en-
vironment would create the perfect setting for a superspreader event.
Over the coming months, the scientific community will try and
• define more precisely the role of fomites in the transmission of SARS-CoV-
2;
• unravel the secrets of super-spreading;
• advance our understanding of host factors involved in the successful
“seeding” of SARS-CoV-2 infection;
• elucidate the role of children in the transmission of the virus at the com-
munity level;
• explicate the role of young adults in the genesis of the second European
SARS-CoV-2 wave;
• continue to describe the conditions under which people should be allowed
to gather in larger groups;
Without a coronavirus vaccine, nobody will return to a “normal” pre-2020
way of life. The most promising exit strategy for the coronavirus crisis is an
efficient vaccine that can be rolled out safely and affordably to billions of
people. Thousands of researchers are working around the clock, motivated by
fame (becoming the next Dr. Salk?) and money (becoming the next Scrooge
McDuck?). Until the worldwide availability of a vaccine, the only feasable
prevention scheme is a potpourri of physical distancing (Kissler 2020), inten-
sive testing, case isolation, contact tracing, quarantine (Ferretti 2020) and, as
a last (but not impossible) resort, local lockdowns and curfews.

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New References (5th Edition)

The following pages add short comments to the papers published since the
previous edition (June-October). The comments are from
https://covidreference.com/daily-science. The complete list of references
starts at page 134.

The Virus
Zhou J, Otter JA, Price JR, et al. Investigating SARS-CoV-2 surface and air contami-
nation in an acute healthcare setting during the peak of the COVID-19 pandemic
in London. Clin Infect Dis. 2020 Jul 8:ciaa905. PubMed: https://pubmed.gov/32634826.
Full-text: https://doi.org/10.1093/cid/ciaa905
In a cross-sectional observational study in a London hospital, SARS-CoV-2 was detect-
ed on 114/218 (52.3%) of surfaces and 14/31 (38.7%) air samples but no virus was cul-
tured. As expected, viral RNA was more likely to be found in areas immediately occu-
pied by COVID-19 patients than in other areas (Zhou J 2020).
Schlottau K, Rissmann M, Graaf A, et al. SARS-CoV-2 in fruit bats, ferrets, pigs, and
chickens: an experimental transmission study. Lancet Microbe July 07, 2020. Full-
text: https://doi.org/10.1016/S2666-5247(20)30089-6
When intranasally inoculated with TCID50 of a SARS-CoV-2 isolate, twelve fruit bats
(Rousettus aegyptiacus) showed characteristics of a reservoir host and 12 ferrets
(Mustela putorius) mimicked subclinical human infection with efficient spread. Pigs
(Sus scrofa domesticus) and 20 chickens (Gallus gallus domesticus could not be infect-
ed by SARS-CoV-2 (Schlottau 2020).

Routes of Transmission
Meyerowitz EA, Richterman A, Gandhi RT, Sax PE. Transmission of SARS-CoV-2: A
Review of Viral, Host, and Environmental Factors. Ann Intern Med 2020, published
17 September. Full-text: https://doi.org/10.7326/M20-5008
Eric Meyerowitz et al. present a comprehensive review of the evidence of human
SARS-CoV-2 transmission (Meyerowitz 2020). Their key points:
1. Respiratory transmission is the dominant mode of transmission.
2. Vertical transmission occurs rarely; transplacental transmission has been
documented.
3. Cats and ferrets can be infected and transmit to each other, but there are no
reported cases to date of transmission to humans; minks transmit to each
other and to humans.
4. Direct contact and fomite transmission are presumed but are likely only an
unusual mode of transmission.
5. Although live virus has been isolated from saliva and stool and viral RNA has
been isolated from semen and blood donations, there are no reported cases
of SARS-CoV-2 transmission via fecal–oral, sexual, or bloodborne routes. To
date, there is 1 cluster of possible fecal–respiratory transmission.

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 Transmission | 119

AEROSOL, DROPLETS

Prather KA, Marr LC, Schooley RT, et al. Airborne transmission of SARS-CoV-2. Sci-
ence 05 Oct 2020: eabf0521. Full-text: https://doi.org/10.1126/science.abf0521
According to Kimberly Prather and colleagues, we should clarify the terminology to
distinguish between aerosols and droplets using a size threshold of 100 μm, not the
historical 5 μm (Prather 2020). This size more effectively separates their aerodynamic
behavior, ability to be inhaled, and efficacy of interventions. Viruses in droplets (larg-
er than 100 μm) typically fall to the ground in seconds within 2 m of the source and
can be sprayed like tiny cannonballs onto nearby individuals.

Bax A, Bax CE, Stadnytskyi V, Anfinrud P. SARS-CoV-2 transmission via speech-

generated respiratory droplets. Lancet Inf Dis September 11, 2020. Full-text:
https://doi.org/10.1016/S1473-3099(20)30726-X
Spit happens. This group published the impressive NEJM video, visualizing speech-
generated oral fluid droplets and suggesting that normal speaking might be an im-
portant mode of transmission (Bax 2020). Here, the four authors vigorously resist the
criticism of other authors who argued that the video experiments were unrealistic.
They also provide nice new videos showing speech droplets emitted by four people,
when speaking the phrase “spit happens” with the face positioned about 10–15 cm
behind a thin sheet of intense green laser light.
Anfinrud P, Stadnytskyi V, Bax CE, Bax A. Visualizing Speech-Generated Oral Fluid
Droplets with Laser Light Scattering. N Engl J Med. 2020 May 21;382(21):2061-2063.
PubMed: https://pubmed.gov/32294341. Full-text:
https://doi.org/10.1056/NEJMc2007800
New video: https://www.youtube.com/watch?v=ooVjNth4ut8

Fennelly KP. Particle sizes of infectious aerosols: implications for infection con-
trol. Lancet Respir Med, July 24, 2020. Full-text: https://doi.org/10.1016/S2213-
2600(20)30323-4
Is there really evidence that some pathogens are carried only in large droplets?
(Fennelly 2020) Or would cough aerosols and exhaled breath from patients with vari-
ous respiratory infections show striking similarities in aerosol size distributions? In
case of doubt, how would you protect your family and yourself?
Santarpia JL, Rivera DN, Herrera VL et al. Aerosol and surface contamination of
SARS-CoV-2 observed in quarantine and isolation care. Sci Rep 10, 12732 (2020).
Full-text: https://doi.org/10.1038/s41598-020-69286-3
After evacuation from the Diamond Princess cruise ship in March 2020, 11 were admit-
ted to a hospital in Nebraska, two in a biocontainment unit and 9 in a quarantine unit.
Key features of both units included: (1) individual rooms with private bathrooms; (2)
negative-pressure rooms (> 12 ACH) and negative-pressure hallways; (3) key-card ac-
cess control; (4) unit-specific infection prevention and control (IPC) protocols includ-
ing hand hygiene and changing of gloves between rooms; and (5) personal protective

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equipment (PPE) for staff that included contact and aerosol protection. Joshua San-
tarpia and colleagues collected air and surface samples to examine viral shedding
from isolated individuals and detected viral contamination among all samples. Their
data suggest that SARS-CoV-2 environmental contamination around COVID-19
patients is extensive, and hospital IPC procedures should account for the risk of fom-
ite, and potentially airborne, transmission of the virus (Santarpia 2020).

Klompas M, Baker MA, Rhee C. Airborne Transmission of SARS-CoV-2: Theoretical

Considerations and Available Evidence. JAMA. 2020 Aug 4;324(5):441-442. PubMed:
https://pubmed.gov/32749495 . Full-text: https://doi.org/10.1001/jama.2020.12458
Brief review. It is impossible to conclude that aerosol-based transmission never oc-
curs, write Michael Klompas and colleagues, but the balance of currently available
evidence suggests that long-range aerosol-based transmission is not the dominant
mode of SARS-CoV-2 transmission (Klompas 2020).

Chagla Z, Hota S, Khan S, Mertz D; International Hospital and Community Epidemiolo-

gy Group. Airborne Transmission of COVID-19. Clin Infect Dis. 2020 Aug 11:ciaa1118.
PubMed: https://pubmed.gov/32780799. Full-text:
https://doi.org/10.1093/cid/ciaa1118
Zain Chagla and colleagues discuss the paper by Morawska L, Milton DK, It is Time to
Address Airborne Transmission of COVID-19 (Clin Infect Dis 2020, 6 July). They agree that
there is potential for the transmission by aerosols, especially in poorly ventilated in-
door crowded environments. However, they argue that the main mode of transmis-
sion of SARS-CoV-2 is short range through droplets and close contact. Explore
this one-page comment to see how the debate continues (Chagla 2020).

Asadi S, Gaaloul ben Hnia N, Barre RS, et al. Influenza A virus is transmissible via
aerosolized fomites. Nat Commun 11, 4062 (2020). Full-text:
https://doi.org/10.1038/s41467-020-17888-w
SARS-CoV-2 can be transmitted via droplets, fomites and possibly aerosol. Will we
need to get accustomed to a fourth transmission route, aerosolized fomites? That’s
what Nicole Bouvier and colleagues suggest, although for now only for influenza A
virus. They show that dried influenza virus remains viable in the environment, on
materials like paper tissues and on the bodies of living animals, long enough to be
aerosolized on non-respiratory dust particles that can transmit infection through the
air to new mammalian hosts (Asadi 2020). Will we soon see a paper about SARS-CoV-2
transmission via aerosolized fomites?

Kang M, Wi J, Yuan J, et al. Probable Evidence of Fecal Aerosol Transmission of

SARS-CoV-2 in a High-Rise Building. Ann Intern Med 2020, published 1 September.
Full-text: https://doi.org/10.7326/M20-0928

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 Transmission | 121

Nanshan Zhong, Min Kang and colleagues report 9 infected patients in 3 families.
While the first family had a history of travel to the coronavirus disease 2019 (COVID-
19) epicenter Wuhan, the other 2 families had no travel history and a later onset of
symptoms. The families lived in 3 vertically aligned flats connected by drainage pipes
in the master bathrooms. The authors suggest that virus-containing fecal aerosols
may have been produced in the associated vertical stack during toilet flushing after
use by the index patients (Kang M 2020). This report reminds us of a SARS-1 outbreak
in March 2003 among residents of Amoy Gardens, Hong Kong, with a total of 320 SARS
cases in less than three weeks (see www.SARSReference.com, page 65).
See also the comment by Michael Gormley [Gormley M. SARS-CoV-2: The Growing
Case for Potential Transmission in a Building via Wastewater Plumbing Systems.
Ann Intern Med 2020, published 1 September. Full-text: https://doi.org/10.7326/M20-
6134] concludes that that wastewater plumbing systems, particularly those in high-
rise buildings, deserve closer investigation, both immediately in the context of SARS-
CoV-2 and in the long term, because they may be a reservoir for other harmful patho-
gens.

FOMITES

Mondelli MU, Colaneri M, Seminari E, et al. Low risk of SARS-CoV-2 transmission by

fomites in real-life conditions. Lancet Infect Dis September 29, 2020. Full-text:
https://doi.org/10.1016/S1473-3099(20)30678-2
Some arguments that environmental contamination leading to SARS-CoV-2 transmis-
sion is unlikely to occur in real-life conditions, provided that standard cleaning proce-
dures and precautions are enforced. The chance of transmission through inanimate
surfaces is likely less frequent than hitherto recognized (Mondelli 2020).

Yamagishi T, Ohnishi M, Matsunaga N, et al. Environmental sampling for severe

acute respiratory syndrome coronavirus 2 during COVID-19 outbreak in the Di-
amond Princess cruise ship. J Infect Dis. 2020 Jul 21:jiaa437. PubMed:
https://pubmed.gov/32691828. Full-text: https://doi.org/10.1093/infdis/jiaa437
In the early epidemic in Japan, many infections occurred among the passengers and
crew members on board the Diamond Princess cruise ship in February, 2020. By March
1, 2020, there were approximately 700 individuals with laboratory-detected SARS-
CoV-2 infection (see the previous articles by Russell et al., Yamagishi et al. and Tabata
et al.). The authors performed environmental sampling on the Diamond Princess
cruise ship on 22-23 February 2020 (prior to disinfection of the vessel and while some
passengers and crew members remained aboard) and obtained specimens from cabins
in which confirmed COVID-19 cases stayed (case cabins), cabins with no confirmed
case at any point (non-case cabins), and common areas. SARS-CoV-2 RNA was detected
from 58 out of 601 samples (10%) from case cabins 1-17 days after the cabins were
vacated, but not from non-case cabins (Yamagishi 2020). There was no difference in
the detection proportion between cabins for symptomatic (15%, 28/189) and asymp-

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tomatic cases (21%, 28/131). No SARS-CoV-2 virus was isolated from any of the sam-
ples. The authors conclude that transmission risk of SARS-CoV-2 from symptomatic
and asymptomatic patients may be similar and environmental surfaces could be in-
volved in viral transmission.

Chen Y, Qin G, Chen J, et al. Comparison of Face-Touching Behaviors Before and

During the Coronavirus Disease 2019 Pandemic. JAMA Netw Open
2020;3(7):e2016924. https://doi.org/10.1001/jamanetworkopen.2020.16924
Is wearing face masks really associated with reduced face-touching behaviors? To
answer the question, Xing Li and colleagues from Sun Yat-sen University, Guangzhou,
China, used videos recorded in public transportation stations, streets, and parks
among the general population in China, Japan, South Korea, Western Europe (ie, Eng-
land, France, Germany, Spain, and Italy), and the US to analyze mask-wearing and
face-touching behavior in public areas. The authors found that mask wearing was
associated with reduced face-touching behavior, especially touching of the eyes, nose,
and mouth (Chen Y 2020). They conclude that the reduction of face-touching behav-
iors by mask wearing could contribute to curbing the COVID-19 pandemic. Excellent
news for the coming months.

Joonaki E, Hassanpouryouzband A, Heldt Cl, et al. Surface Chemistry Can Unlock

Drivers of Surface Stability of SARS-CoV-2 in Variety of Environmental Condi-
tions. Chem, August 06, 2020. Full-text: https://doi.org/10.1016/j.chempr.2020.08.001
Nice overview of existing knowledge concerning viral spread, molecular structure of
SARS-CoV-2, and the stability of the virus surface. Edris Joonaki and colleagues discuss
potential drivers of the SARS-CoV-2 surface adsorption and stability in various envi-
ronmental conditions (Joonaki 2020).

Deng W, Bao L, Gao H, et al. Ocular conjunctival inoculation of SARS-CoV-2 can

cause mild COVID-19 in rhesus macaques. Nat Commun 11, 4400 (2020). Full-text:
https://doi.org/10.1038/s41467-020-18149-6
If you are exploring extra-respiratory routes of SARS-CoV-2 transmission, read the
article by Chuan Qin, Wei Deng and colleagues. The authors inoculated five rhesus
macaques with SARS-CoV-2 conjunctivally, intratracheally, and intragastrically. The
conjunctivally infected animal had a higher viral load in the nasolacrimal system than
the intratracheally infected animal but also showed mild interstitial pneumonia, sug-
gesting distinct viral distributions (Deng W 2020).

MOTHER-TO-CHILD

Vivanti AJ, Vauloup-Fellous C, Prevot S, et al. Transplacental transmission of SARS-

CoV-2 infection. Nat Commun2020. Full-text: https://doi.org/10.1038/s41467-020-
17436-6

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Maybe the first documented case of transplacental transmission. French doctors re-
port on a 23-year-old COVID-19 patient who gave birth by cesarean section to a baby
found to have the infection (Vivanti 2020). The viral load was much higher in the pla-
cental tissue than in the amniotic fluid or maternal blood: this suggests the presence
of the virus in placental cells, which is consistent with findings of inflammation seen
at histological examination. Good news: baby is fine.

Chambers C, Krogstad P, Betrand K, et al. Evaluation for SARS-CoV-2 in Breast Milk

From 18 Infected Women. JAMA August 19, 2020. Full-text:
https://doi.org/10.1001/jama.2020.15580
There are some case reports on the detection of SARS-CoV-2 in breast milk. Christina
Chambers and colleagues examined 64 breast milk samples from 18 infected women.
Although SARS-CoV-2 RNA was detected in one milk sample, the viral culture for that
sample was negative. These data suggest that SARS-CoV-2 RNA does not represent
replication-competent virus and that breast milk may not be a source of infection for
the infant (Chambers 2020).

CATS AND DOGS

Patterson EI, Elia G, Grassi A, et al. Evidence of exposure to SARS-CoV-2 in cats and
dogs from households in Italy. bioRxiv 23 July 2020. Full-text:
https://doi.org/10.1101/2020.07.21.214346
Nicola Decaro and colleagues assess SARS-CoV-2 infection in 817 companion animals
in northern Italy at the height of the spring 2020 epidemic. Although no animals test-
ed PCR positive, 3.4% of dogs and 3.9% of cats had measurable SARS-CoV-2 neutraliz-
ing antibody titers, with dogs from COVID-19 positive households being significantly
more likely to test positive than those from COVID-19 negative households (Patterson
2020). From their experience, the authors conclude that it is unlikely that infected
pets play an active role in SARS-CoV-2 transmission to humans. Only under special
circumstances, such as the high animal population densities encountered on infected
mink farms, animal-to-human transmission might be likely.

Garigliany M, Van Laere AS, Clercx C, et al. SARS-CoV-2 Natural Transmission from
Human to Cat, Belgium, March 2020. Emerg Infect Dis. 2020 Aug 12;26(12). PubMed:
https://pubmed.gov/32788033. Full-text: https://doi.org/10.3201/eid2612.202223
Mutien Garigliany from Liège, Belgium, and colleagues report a human-to-cat trans-
mission. A household cat was productively infected with the SARS-CoV-2 virus excret-
ed by its owner, and the infection caused a non-fatal but nevertheless severe disease
(Garigliany 2020).

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Transmission Event
TRANSMITTOR

Rockett RJ, Arnott A, Lam C, et al. Revealing COVID-19 transmission in Australia by

SARS-CoV-2 genome sequencing and agent-based modeling. Nat Med 2020 Jul 9.
PubMed: https://pubmed.gov/32647358. Full-text: https://doi.org/10.1038/s41591-
020-1000-7
These researchers examined the added value of near real-time genome sequencing of
SARS-CoV-2 in a subpopulation of infected patients during the first 10 weeks of
COVID-19 containment in Australia. Genomic evidence was used to cluster 38.7%
(81 out of 209) of cases for which the available epidemiological data could not
identify direct links (Rockett 2020). This included clustering 12.4% (26 out of 209) of
cases with a history of recent arrival from overseas with other cases without a travel
history and 5.3% (11/209) of locally acquired cases with unknown epidemiological
links. Twenty-two (10.5%) of the 209 cases were epidemiologically classified as ‘locally
acquired—contact not identified’.

Park YJ, Choe YJ, Park O, et al. Contact Tracing during Coronavirus Disease Out-
break, South Korea, 2020. Emerg Infect Dis October 2020. Full-text:
https://wwwnc.cdc.gov/eid/article/26/10/20-1315_article
The authors analyzed 59,073 contacts of 5,706 COVID-19 index patients. Of 10,592
household contacts, 11.8% had COVID-19; rates were higher for contacts of children
than adults. Of 48,481 non-household contacts, 1.9% had COVID-19. Interestingly, the
highest COVID-19 rate (18.6%) was found for household contacts of school-aged chil-
dren (Park YJ 2020) and the lowest (5.3%) for household contacts of children 0–9 years
in the middle of school closure.

Milani GP, Bottino I, Rocchi A, et al. Frequency of Children vs Adults Carrying Se-
vere Acute Respiratory Syndrome Coronavirus 2 Asymptomatically. JAMA Pediatr.
Published online September 14, 2020. Full-text:
https://doi.org/10.1001/jamapediatrics.2020.3595
Early reports suggested that children, often asymptomatic, might be facilitators of
SARS-CoV-2 transmission and amplify local outbreaks. Here, Carlo Agostini, Gregorio
Milani and colleagues conducted a study among individuals hospitalized in Milan.
About 1% of children and 9% of adults without any symptoms or signs of SARS-CoV-2
infection tested positive for SARS-CoV-2. The authors conclude that their data do not
support the hypothesis that children are at higher risk of carrying SARS-CoV-2 asymp-
tomatically than adults (Milani 2020). Attention: a retrospective analysis.

Luo L, Liu D, Liao X, et al. Contact Settings and Risk for Transmission in 3410 Close
Contacts of Patients With COVID-19 in Guangzhou, China: A Prospective Cohort
Study. Ann Intern Med. 2020 Aug 13. PubMed: https://pubmed.gov/32790510. Full-
text: https://doi.org/10.7326/M20-2671

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Chen Mao and colleagues traced 3410 close contacts of 391 SARS-CoV-2 infected index
cases between 13 January and 6 March 2020. 127 contacts (3.7%) were secondarily in-
fected. Compared with the household setting (10.3%), the secondary attack rate was
lower for exposures in healthcare settings (1.0%) and on public transportation (0.1%).
Interestingly, although not unexpectedly, the secondary attack rate increased
with the severity of index cases, from 0.3% for asymptomatic to 3.3% for mild,
5.6% for moderate, and 6.2% for severe or critical cases (Luo L 2020). Index cases
with expectoration were associated with higher risk for secondary infection (13.6% vs.
3.0% for index cases without expectoration).

Xie W, Campbell S, Zhang W. Working memory capacity predicts individual differ-

ences in social-distancing compliance during the COVID-19 pandemic in the
United States. Proc Natl Acad Sci U S A. 2020 Jul 10:202008868. PubMed:
https://pubmed.gov/32651280. Full-text: https://doi.org/10.1073/pnas.2008868117
Among 850 US residents participating in a survey, the authors found that social dis-
tancing compliance could be predicted by individual differences in working memory
(WM) capacity. WM retains a limited amount of information over a short period of
time at the service of other ongoing mental activities. Its limited capacity constrains
our mental functions, such that higher WM capacity is often associated with better
cognitive and affective outcomes. Of note, the unique contribution of WM capacity to
the individual differences in social distancing compliance could not be explained by
other psychological and socioeconomic factors (e.g., moods, personality, education,
and income levels). The message that the authors hide using scientific language can be
said more clearly: if you see a guy sitting in the bus not wearing a mask: poor idiot,
don’t get closer. His WM capacity is poor (Xie W 2020).

Rhee C, Kanjilal S, Baker M, et al. Duration of SARS-CoV-2 Infectivity: When is it

Safe to Discontinue Isolation? Clinical Infectious Diseases, 25 August 2020, ciaa1249.
Full-text: https://doi.org/10.1093/cid/ciaa1249
Persistently positive RT-PCRs generally do not reflect replication-competent virus.
SARS-CoV-2 infectivity rapidly decreases thereafter to near-zero after about 10 days in
mild-to-moderately-ill patients and 15 days in severely-to-critically-ill and immuno-
compromised patients (Rhee 2020). This review summarizes evidence-to-date on the
duration of infectivity of SARS-CoV-2.

Singanayagam A, Patel M, Charlett A. Duration of infectiousness and correlation

with RT-PCR cycle threshold values in cases of COVID-19, England, January to
May 2020. Euro Surveill. 2020;25(32). Full-text: https://doi.org/10.2807/1560-
7917.ES.2020.25.32.2001483
More on “viral load” and infectivity. Virus culture was attempted from 324 samples
(from 253 cases) that tested positive for SARS-CoV-2 by RT-PCR. RT-PCR cycle thresh-
old (Ct) values correlated strongly with cultivable virus. Probability of culturing virus

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declined to 8% in samples with Ct > 35 and to 6% (95% CI: 0.9–31.2%) 10 days after on-
set; it was similar in asymptomatic and symptomatic persons (Singanayagam 2020).

Lesho E, Reno L, Newhart D, et al. Temporal, Spatial, and Epidemiologic Relation-

ships of SARS-CoV-2 Gene Cycle Thresholds: A Pragmatic Ambi-directional Ob-
servation. Clinical Infectious Diseases, 25 August 2020, ciaa1248. Full-text:
https://doi.org/10.1093/cid/ciaa1248
Same direction. This prospective serial sampling of 70 patients revealed clinically rel-
evant cycle thresholds (Ct, “viral load”), namely a Ct of 24 (“high viral load”), 34,
and > 40 (“negative”) that occurred 9, 26, and 36 days after symptom onset. Of
note, race, gender, or corticosteroids did not appear to influence RNA-positivity. A
retrospective analysis of 180 patients revealed that initial Ct did not correlate with
requirement for admission or intensive care (Lesho 2020).

Lopez AS, Hill M, Antezano J, et al. Transmission Dynamics of COVID-19 Outbreaks

Associated with Child Care Facilities — Salt Lake City, Utah, April–July 2020.
MMWR Morb Mortal Wkly Rep. ePub: 11 September 2020. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6937e3
Cuc Tran, Adriana Lopez and colleagues describe 12 children who acquired SARS-CoV-
2 infection in child-care facilities. All had mild or no symptoms. They transmitted the
virus to at least 12 (26%) of 46 non-facility contacts (Lopez 2020). The authors conclude
that testing children who might not have symptoms could improve control of trans-
mission from child-care attendees to family members.

Schwartz NG, Moorman AC, Makaretz A, et al. Adolescent with COVID-19 as the
Source of an Outbreak at a 3-Week Family Gathering — Four States, June–July
2020. MMWR Morb Mortal Wkly Rep. ePub: 5 October 2020. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6940e2
Children can serve as the source for COVID-19 outbreaks, even when their symptoms
are mild (Schwartz 2020). In this outbreak that occurred during a 3-week family gath-
ering of five households, an adolescent aged 13 years was the suspected primary pa-
tient. Among the 14 persons who stayed in the same house, 12 experienced symptoms.
Of note, none of the additional six family members who maintained outdoor physical
distance without face masks during two longer visits (10 and 3 hours) to the family
gathering developed symptoms.

TRANSMITTEE

Lewis NM, Chu VT, Ye D, et al. Household Transmission of SARS-CoV-2 in the Unit-
ed States. Clinical Infectious Diseases, 16 August 2020. Full-text:
https://doi.org/10.1093/cid/ciaa1166

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Nathaniel M Lewis and colleagues sought to estimate the household secondary infec-
tion rate (SIR) of SARS-CoV-2 and evaluate potential risk factors for secondary infec-
tion among 58 households in Utah and Wisconsin. Fifty-two of 188 household contacts
acquired secondary infections (SIR: 28%, 95% CI: 22–34%). Of note, household contacts
to COVID-19 patients with immunocompromised conditions had increased odds of
infection (OR: 15.9, 95% CI: 2.4–106.9) as well as household contacts who themselves
had diabetes mellitus (OR: 7.1, 95% CI: 1.2–42.5) (Lewis 2020).

Wilson RF, Sharma AJ, Schluechtermann S, et al. Factors Influencing Risk for COVID-
19 Exposure Among Young Adults Aged 18–23 Years — Winnebago County, Wis-
consin, March–July 2020. MMWR Morb Mortal Wkly Rep. ePub: 9 October 2020. DOI:
http://dx.doi.org/10.15585/mmwr.mm6941e2
Still in the US: Which are the drivers of behaviors that might influence risk for COVID-
19 exposure among young adults? In a remote US County, these were low severity of
disease outcome; peer pressure; and exposure to misinformation, conflicting messag-
es, or opposing views regarding masks (Wilson 2020). A scientifically inspired national
prevention policy would have been helpful.

Asadi S, Cappa CD, Barreda S, et al. Efficacy of masks and face coverings in control-
ling outward aerosol particle emission from expiratory activities. Sci Rep 10,
15665 (2020). Full-text: https://doi.org/10.1038/s41598-020-72798-7
Masks work with super-emittors! William D. Ristenpart, Sima Asadi and colleagues
measured outward emissions of micron-scale aerosol particles by healthy humans
performing various expiratory activities while wearing different types of medical-
grade or homemade masks. Both surgical masks and unvented KN95 respirators re-
duced the outward particle emission rates by 90% and 74% on average during speaking
and coughing. These masks similarly decreased the outward particle emission of a
coughing super-emitter, who for unclear reasons emitted up to two orders of magni-
tude more expiratory particles via coughing than average (Asadi 2020). An interesting
collateral finding: people speak more loudly, but do not cough more loudly, when
wearing a mask.

Hendrix MJ, Walde C, Findley K, Trotman R. Absence of Apparent Transmission of

SARS-CoV-2 from Two Stylists After Exposure at a Hair Salon with a Universal
Face Covering Policy — Springfield, Missouri, May 2020. MMWR Morb Mortal Wkly
Rep. 14 July 2020. Full-text: http://dx.doi.org/10.15585/mmwr.mm6928e2
Have we ever mentioned masks? Among 139 clients exposed to two symptomatic hair
stylists with confirmed COVID-19 while both the stylists and the clients wore face
masks, not a single symptomatic secondary case was observed; among 67 clients tested
for SARS-CoV-2, all tests were negative (Hendrix 2020). At least one hair stylist was
infectious: all four close household contacts (presumably without masks) became ill.

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Wang X, Ferro EG, Zhou G, Hashimoto D, Bhatt DL. Association Between Universal
Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care
Workers. JAMA. 2020 Jul 14. PubMed: https://pubmed.gov/32663246. Full-text:
https://doi.org/10.1001/jama.2020.12897

Again, universal masking: in March 2020, the Mass General Brigham, the largest health
care system in Massachusetts (12 hospitals, > 75,000 employees), implemented univer-
sal masking of all HCWs and patients with surgical masks. During the preinterven-
tion period, the SARS-CoV-2 positivity rate increased exponentially, with a case dou-
bling time of 3.6 days. During the intervention period, the positivity rate decreased
linearly from 14.65% to 11.46%, with a weighted mean decline of 0.49% per day and a
net slope change of 1.65% additional decline per day compared with the preinterven-
tion period (Wang X 2020).
Contejean A, Leporrier J, Canouï E, et al. Comparing dynamics and determinants of
SARS-CoV-2 transmissions among health care workers of adult and pediatric
settings in central Paris. Clin Infect Dis. 2020 Jul 15:ciaa977. PubMed:
https://pubmed.gov/32663849. Full-text: https://doi.org/10.1093/cid/ciaa977
This prospective study compared a 1,500-bed adult and a 600-bed pediatric setting of a
university hospital located in central Paris. From February 24th until April 10th, 2020,
all symptomatic HCW were screened. Attack rates were of 3.2% and 2.3% in the adult
and pediatric setting, respectively (p = 0.0022). In the adult setting, HCW more fre-
quently reported exposure to COVID-19 patients without PPE (25% versus 15%, p =
0.046) (Contejean 2020). The total number of HCW cases peaked on March 23rd, then
decreased slowly, concomitantly with a continuous increase in preventive measures
(including universal medical masking and PPE). Residual transmissions were related to
exposures with undiagnosed patients or colleagues but not to contacts with children
attending out-of-home care facilities.

Brooks JT, Butler JC, Redfield RR. Universal Masking to Prevent SARS-CoV-2
Transmission—The Time Is Now. JAMA July 14, 2020. Full-text:
https://doi.org/10.1001/jama.2020.13107
Data is clear now. First, public health officials need to ensure that the public under-
stands clearly when and how to wear cloth face coverings properly. Second, innova-
tion is needed to extend physical comfort and ease of use. Third, the public needs con-
sistent, clear, and appealing messaging that normalizes community masking (Brooks
2020). According to the authors, broad adoption of cloth face coverings is a civic
duty, a small adaption in our daily lives reliant on a highly effective low-tech solution
that can help turn the tide.

Stewart CL, Thornblade LW, Diamond DJ, Fong Y, Melstrom LG. Personal Protective
Equipment and COVID-19: A Review for Surgeons. Ann Surg. 2020 Aug;272(2):e132-
e138. PubMed: https://pubmed.gov/32675516. Full-text:
https://doi.org/10.1097/SLA.0000000000003991

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Are you a surgeon? Then your particular medical association has been using personal
protective equipment (PPE) for more than a century (Stewart 2020). This review
addresses both the mechanism of SARS-CoV-2 transmission and the capabilities of PPE
in the perioperative COVID-19 setting.

Bhaskar ME, Arun S. SARS-CoV-2 Infection Among Community Health Workers in

India Before and After Use of Face Shields. JAMA August 17, 2020. Full-text:
https://doi.org/10.1001/jama.2020.15586
This observational study describes transmission before and after the use of face
shields (made of polyethylene terephthalate) in health workers in Chennai, India. Be-
fore the introduction of face shields, 12/62 workers were infected, while visiting 5,880
homes with 31,164 persons (222 positive for SARS-CoV-2). After the introduction,
among 50 workers (previously uninfected) who continued to provide counseling, visit-
ing 18,228 homes with 118,428 persons (2682 positive), no infection occurred (Bhaskar
2020).

Link-Gelles R, DellaGrotta AL, Molina C, et al. Limited Secondary Transmission of

SARS-CoV-2 in Child Care Programs — Rhode Island, June 1–July 31, 2020. MMWR
Morb Mortal Wkly Rep. ePub: 21 August 2020. Full-text:
http://dx.doi.org/10.15585/mmwr.mm6934e2
Ruth Link-Gelles et al. report a possible secondary transmission in four of the 666
child-care programs in Rhode Island that were allowed to reopen. The apparent ab-
sence of secondary transmission within the other 662 child-care programs was likely
the result of efforts to contain SARS-CoV-2 transmission, in particular maximum class
sizes and use of face masks for adults (Link-Gelles 2020). The authors conclude that
adherence to current CDC recommendations remains critical to reducing transmission
in child-care settings, including wearing of masks by adults, limiting mixing be-
tween established student-teacher groups, staying home when ill, and cleaning and
disinfecting frequently touched surfaces.

Simha PP, Rao PSM. Universal trends in human cough airflows at large distances
featured. Physics of Fluids 32, 081905 (2020). Published 25 August. Full-text:
https://doi.org/10.1063/5.0021666
Fine droplets can pass through layers of masks and are carried away by the exhaled
airflow unlike larger droplets that settle down due to gravity. Now Padmanabha
Prasanna Simha and Prasanna Simha Mohan Rao visualize the flow fields of coughs
under various mouth covering scenarios. The results:
1. N95 masks are the most effective at reducing the horizontal spread of a
cough (spread: 0.1 and 0.25 meters).
2. A simple disposable mask can reduce the spread to 0.5 meters, while an un-
covered cough can travel up to 3 meters.

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3. Coughing into the elbow? Not very effective! Unless covered by a sleeve, a
bare arm cannot form the proper seal against the nose necessary to obstruct
airflow and a cough is able to leak through any openings and propagate in
many directions (Prasanna Simha 2020).

TRANSMISSION SETTING

Gebrekidan S, Bennhold K, Apuzzo M, Kirkpatrick DD. Ski, Party, Seed a Pandemic:

The Travel Rules That Let Covid-19 Take Flight. The New York Times 2020 pub-
lished 1 October. Full-text: https://www.nytimes.com/2020/09/30/world/europe/ski-
party-pandemic-travel-coronavirus.html
ISCHGL, Austria — They came from across the world to ski in the most famous resorts
of the Austrian alps... (Gebrekidan 2020).

Lednicky JA, Lauzardo M, Hugh Fan Z, et al. Viable SARS-CoV-2 in the air of a hospi-
tal room with COVID-19 patients. Int J Infect Dis. 2020 Sep 16:S1201-9712(20)30739-6.
PubMed: https://pubmed.gov/32949774. Full-text:
https://doi.org/10.1016/j.ijid.2020.09.025
John A. Lednicky and colleagues isolated viable virus from air samples collected 2 to
4.8 meters away from two COVID-19 patients (Lednicky 2020). The genome sequence of
the SARS-CoV-2 strain isolated was identical to that isolated from the NP swab from
the patient with an active infection. Estimates of viable viral concentrations ranged
from 6 to 74 TCID50 units/L of air.

Freedman DO, Wilder-Smith A. In-flight Transmission of SARS-CoV-2: a review of

the attack rates and available data on the efficacy of face masks. Journal of Travel
Medicine September 25. Full-text: https://doi.org/10.1093/jtm/taaa178.
Review of outbreaks during flights. According to the authors, the absence of large
numbers of confirmed and published in-flight transmissions of SARS-CoV is encourag-
ing but not definitive evidence that fliers are safe. At present, based on circumstantial
data, strict use of masks appears to be protective (Freedman 2020). Structured pro-
spective studies to quantitate transmission risk on flight with rigid masking protocols
are now most pressing.

Khanh NC, Thai PQ, Quach H-L, Thi NA-H, Dinh PC, Duong TN, et al. Transmission of
severe acute respiratory syndrome coronavirus 2 during long flight. Emerg Infect
Dis 2020, published 18 September. Full-text: https://doi.org/10.3201/eid2611.203299
The authors report a cluster of cases among passengers on VN54 (Vietnam Airlines), a
10-hour commercial flight from London to Hanoi on March 2, 2020. Among the 16 per-
sons in whom SARS-CoV-2 infection was detected, 12 (75%) were passengers seated in
business class along with the only symptomatic person (attack rate 62%) (Khanh 2020).
The authors find that blocking middle seats, currently recommended by the airline

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industry, may in theory prevent some in-flight transmission events but seems to be
insufficient to prevent superspreading events. They conclude that the risk for on-
board transmission of SARS-CoV-2 during long flights is real and has the potential to
cause COVID-19 clusters of substantial size, even in business class–like settings with
spacious seating arrangements well beyond the established distance used to define
close contact on airplanes. (Note that at the time, March 2, the use of face masks was
not mandatory on airplanes or at airports, and there was no social distancing on the
aircraft.)

Chen J, He H, Cheng W, et al. Potential transmission of SARS-CoV-2 on a flight from

Singapore to Hanghzou, China: An epidemiological investigation. J Trav Med 2020,
Jul 6, 2020. Full-text: https://doi.org/10.1016/j.tmaid.2020.101816
Among 335 passengers on a flight from Singapore to Hangzhou in China (a Boeing 787,
5-hour flight, seat occupancy 89%), a total of 16 COVID-19 patients were diagnosed
among all passengers, yielding an attack rate of 4.8%. However, after careful investiga-
tion, only one case was identified who appears to have become infected during the
flight (Chen J 2020). He was seated near four infected passengers from Wuhan for ap-
proximately an hour (he had moved a seat) and did not wear his facemask correctly
during the flight. The sources of infection in the other 15 passengers were complex
and the passengers could have acquired their infections in Wuhan before the tour, or
during the group tour before boarding.

Hoehl S, Karaca O, Kohmer M, et al. Assessment of SARS-CoV-2 Transmission on an

International
Flight and Among a Tourist Group. JAMA Netw Open August 18, 2020, 3(8). Full-text:
https://doi.org/10.1001/jamanetworkopen.2020.18044
Two likely SARS-CoV-2 transmissions on a 4.5-hour flight from Tel Aviv to Frankfurt,
with 7 index cases. Both passengers were seated within two rows of an index case
(Hoehl 2020). According to the authors, it could be speculated that the rate may have
been reduced further had the passengers worn masks.

Plautz J. Is it safe to strike up the band in a time of coronavirus? Science, 17 July

2020. Full-text: https://www.sciencemag.org/news/2020/07/it-safe-strike-band-time-
coronavirus
Is keeping 2 meters away enough to stay safe from a trumpet at full blast? Try it, find
out! Introduce five student musicians – a soprano singer and clarinet, flute, French
horn, and trumpet players — in a clean room one at a time and let them perform a
short solo piece (Plautz 2020).

Hu M, Lin H, Wang J, et al. The risk of COVID-19 transmission in train passengers:

an epidemiological and modelling study. Clin Infect Dis 2020, published 29 July.
Full-text: https://doi.org/10.1093/cid/ciaa1057

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How risky is train traveling in the COVID-19 era? To answer this question, analyze
passengers in Chinese high-speed trains. Jinfeng Wang and colleagues quantified the
transmission risk using data from 2,334 index patients and 72,093 close contacts who
had co-travel times of 0–8 hours from 19 December 2019 through 6 March 2020. Un-
surprisingly, travelers adjacent to an index patient had the highest attack rate (3.5%)
and the attack rate decreased with increasing distance, but increased with increasing
co-travel time. The overall attack rate of passengers with close contact with index
patients was 0.32% (Hu M 2020). The author’s conclusion: during COVID outbreaks,
when travelling on public transportation in confined spaces such as trains, increase
seat distance and reduce passenger density.

Shen Y, Li C, Dong H. Community Outbreak Investigation of SARS-CoV-2 Transmis-

sion Among Bus Riders in Eastern China. JAMA Intern Med, September 1, 2020. Full-
text: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2770172
If you take the bus, choose seats near a window (and open it). On January 19, 2020, 68
individuals (including the source patient) took a bus on a 100-minute round trip to
attend a worship event. In total, 24 (35%) received a diagnosis of COVID-19 after the
event. The authors were able to identify seats for each passenger and divided bus seats
into high-risk and low-risk zones (Shen Y 2020). Passengers in the high-risk zones had
moderately but non-significantly higher risk of getting COVID-19 than those in the
low-risk zones. On the 3-seat side of the bus, except for the passenger sitting next to
the index patient, none of the passengers sitting in seats close to the bus window de-
veloped infection. In addition, the driver and passengers sitting close to the bus door
also did not develop infection, and only 1 passenger sitting by an operable window
developed infection. The absence of a significantly increased risk in the part of the bus
closer to the index case suggested that airborne spread of the virus may at least par-
tially explain the markedly high attack rate observed.
Luo K, Lei Z, Hai Z, et al. Transmission of SARS-CoV-2 in Public Transportation
Vehicles: A Case Study in Hunan Province, China. Open Forum Infectious Diseases
13 September 2020, ofaa430. Full-text: https://doi.org/10.1093/ofid/ofaa430
Transmission in a bus. The tour coach was 11.3 meters long and 2.5 meters wide with
49 seats, fully occupied with all windows closed and the ventilation system on during
the 2.5-hour trip. Among the 49 passengers (including the driver) who shared the ride
with the index person, eight tested positive and eight developed symptoms (Luo K
2020). The index person sat in the second-to-last row, and the infected passengers
were distributed over the middle and rear rows.

Fisher KA, Tenforde MW, Feldstein LR, et al. Community and Close Contact Expo-
sures Associated with COVID-19 Among Symptomatic Adults ≥18 Years in 11 Out-
patient Health Care Facilities — United States, July 2020. MMWR Morb Mortal
Wkly Rep 2020;69:1258–1264. Full-text: http://dx.doi.org/10.15585/mmwr.mm6936a5
Eating and drinking and socializing? Everything may well return to normal in about
two years. In the meantime, note that adults with a positive SARS-CoV-2 test result

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 Transmission | 133

were found to be twice as likely to have had dinner at a restaurant than those with
negative test results (Fisher 2020). Kiva Fisher and colleagues conclude that eating and
drinking on-site at locations that offer such options might be important risk factors
associated with SARS-CoV-2 infection. Bars and restaurants are in for a rough autumn
and winter season.

Riediker M, Tsai D. Estimation of Viral Aerosol Emissions From Simulated Individ-

uals With Asymptomatic to Moderate Coronavirus Disease 2019. JAMA Netw Open
2020;3(7):e2013807. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.13807
In this modeling study, Michael Riediker from the Swiss Centre for Occupational and
Environmental Health in Winterthur and Dai-Hua Tsai from the University Hospital of
Psychiatry in Zurich, Switzerland, it is estimated that viral load concentrations in a
room with an individual who was coughing frequently were very high, with a maxi-
mum of 7.44 million copies/m3 from an individual who was a high emitter (Riediker
2020). However, regular breathing from an individual who was a high emitter was
modeled to result in lower room concentrations of up to 1248 copies/m3. They con-
clude that the estimated infectious risk posed by a person with typical viral load who
breathes normally was low and that only a few people with very high viral load posed
an infection risk in the poorly ventilated closed environment simulated in this study.
In late March 2020, a large outbreak on the aircraft carrier USS Theodore Roosevelt
was characterized by widespread transmission with relatively mild symptoms and
asymptomatic infection among mostly young, healthy adults with close, congregate
exposures. One fifth of infected participants reported no symptoms. Preventive
measures, such as using face-coverings and observing social distancing, reduced risk
for infection: among 382 service members, those who reported taking preventive
measures had a lower infection rate than did those who did not report taking these
measures (e.g., wearing a face-covering, 56% versus 81%; avoiding common areas, 54%
versus 68%; and observing social distancing, 55% versus 70%, respectively) (Payne
2020).

Adam DC, Wu P, Wong JY, et al. Clustering and superspreading potential of SARS-
CoV-2 infections in Hong Kong. Nat Med (2020). Full-text:
https://doi.org/10.1038/s41591-020-1092-0
Dillon Adam, Peng Wu and colleagues identified 4–7 superspreading events (SSEs)
across 51 clusters (n = 309 cases) and estimate that 19% (95% confidence interval, 15–
24%) of cases seeded 80% of all local transmissions (Adam 2020). After controlling for
age, transmission in social settings was associated with more secondary cases than
households when controlling for age. Social settings are likely to become major battle
grounds of coming SARS-CoV-2 waves.

Wang L, Didelot X, Yang J, et al. Inference of person-to-person transmission of

COVID-19 reveals hidden super-spreading events during the early outbreak

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phase. Nat Commun 11, 5006 (2020). Full-text: https://doi.org/10.1038/s41467-020-

18836-4
Super-spreading events are an important phenomenon in the transmission of many
diseases (such as SARS-CoV-1, MERS-CoV, Ebola virus, etc.), in which certain individu-
als infect a disproportionately large number of people. Here Yuhai Bi, Liang Wang and
colleagues show that super-spreading events played an important role in the early
stage of the COVID-19 outbreak. They estimated the dispersion parameter to be 0.23
(95% CI: 0.13–0.39) (Wang L 2020). (What is the dispersion parameter? Check this FT
article: To beat Covid-19, find today’s superspreading ‘Typhoid Marys’)

Tufekci Z. This Overlooked Variable Is the Key to the Pandemic. The Atlantic 2020,
published 30 September. Full-text:
https://www.theatlantic.com/health/archive/2020/09/k-overlooked-variable-
driving-pandemic/616548/
Even non-scientists have heard about R0 (pronounced as “r-naught”)—the basic re-
productive number of a pathogen, a measure of its contagiousness on average. But
even some scientists may have not yet encountered k, the measure of its dispersion. If
you haven’t done it before, do it now: explore k. It’s simply a way of asking whether a
virus spreads in a steady manner or in big bursts, whereby one person infects many,
all at once (Tufekci 2020).

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 Prevention | 149

3. Prevention
Stefano Lazzari

Introduction
In the absence of an effective vaccine or antiviral treatment, prevention
through public health measures remains the mainstay of SARS-COV-2 infec-
tion control and pandemic impact mitigation. Effective preventive measures
for respiratory infections have been standard practices for many years. How-
ever, uncertainties still exist about the role and importance of different
transmission routes in the spread of SARS-COV-2 (see chapter Transmission).
This complicates the choices in terms of the most efficient and effective mix
of personal and public health measures to be implemented and the preven-
tion messages to be communicated to the public.
The basic COVID-19 preventive strategies include: the identification and isola-
tion of infectious cases and quarantine for suspected cases and close contacts;
changes in individual behaviors including physical and social distancing, use
of face masks and hand hygiene; public health measures like travel re-
strictions, bans on mass gatherings and localized or nationwide lockdowns
when the other measures prove ineffective in halting the spread of the virus.
Specific prevention measures can be simple recommendations left to the de-
cision of the individual, or mandatory measures to be implemented under
control by the public health authorities. Preventive measures can therefore
be applied at the personal, community and societal level.
In this chapter we will review the available scientific evidence on the effec-
tiveness of these measures in reducing the spread of SARS-COV-2.

Prevention at the personal level

Good respiratory hygiene/cough etiquette.

Good respiratory hygiene refers to measures aimed at containing respiratory
secretions and reducing their spread in the environment or to other people.
(Chavis, 2019) Traditionally, they include:
• Covering your mouth and nose with a tissue or with your elbow when
coughing or sneezing; and safe disposal of the tissue once used.
• Use of a surgical or tissue face mask.
• Perform hand hygiene often, and always after contact with potentially
contaminated objects/materials.

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Good respiratory hygiene and cough etiquette are usually recommended for
individuals with signs and symptoms of a respiratory infection. However, giv-
en the established risk of SARS-COV-2 infection from asymptomatic individu-
als, public health authorities all over the world have recommended these
measures for everybody when in public places. This is not without controver-
sy, in particular on the use of masks in the absence of symptoms.

Face masks
The use of face masks to reduce the risk of infection is an established medical
and nursing procedure. It is therefore surprising that it has created such a
debate in the context of COVID-19. The initial recommendation by WHO and
other health authorities that masks should only be used by health workers
and symptomatic patients resulted in controversy among the experts and
widespread confusion among the public. This advice was contradictory with
the images of people wearing masks in all settings from countries in Asia that
successfully managed to contain the pandemic. In addition, the existence of
different types of masks greatly complicated communication efforts.
Face masks can prevent transmission of respiratory viruses in two ways:
1. when worn by healthy individuals they are protecting them from in-
fection by reducing the exposure of the mouth and nose to viral par-
ticles present in the air or on contaminated hands;
2. when worn by an infected person they perform source control, by
reducing the amount of virus dispersed in the environment while
coughing, sneezing or talking.
Different types of masks perform these tasks differently, which also dictates
the situations in which they should be used. Type of masks most currently
used include:
• N95 (or FFP2) masks, designed to block 95% of very small particles.
They reduce the wearer’s exposure to particles including aerosols
and large droplets. They also reduce the patient or other bystanders’
exposure to particles emitted by the wearer (unless they are
equipped with a one-way valve to facilitate breathing).
• Surgical masks only filter effectively large particles. Being loose fit-
ted, they will reduce only marginally the exposure of the wearer to
droplets and aerosols. They do, however, limit considerably the
emission of saliva or droplets by the wearer, reducing the risk of in-
fecting other people.

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• Cloth masks will stop droplets that are released when the wearer
talks, sneezes, or coughs. As recommended by WHO, they should in-
clude multi-layers of fabric. When surgical or N95 masks are not
available, cloth masks can still reduce the risk of SARS-COV-2 trans-
mission in public places.
If masks are protective, why they were not widely recommended at the be-
ginning of the pandemic? Whether due to poor communication, fear of short-
age of essential medical supplies, or under-appreciation of the role of asymp-
tomatic carriers in spreading the virus, the initial reluctance in promoting
mask use and the resulting controversy was clearly not helpful in combating
the pandemic and contributed to a general undermining of the credibility of
public health authorities.
It was only on 5 June, months into the pandemic, that WHO released updated
guidance on the use of masks, recognizing the role that face masks can play in
reducing transmission from asymptomatic carriers in particular settings. This
was a few days after the publication of a comprehensive review and meta-
analysis of observational studies showing a significant reduction in risk of
infection with all types of masks (Chu 2020). Surgical masks were also shown
to work in a hamster model (Chan JF 2020). Other authors, based on reviews
or modelling, recommend wearing suitable masks whenever an infected per-
sons may be nearby (Meselson 2020, Prather 2020, Zhang 2020). (See also the
discussion on droplets and aerosol, page 97.)
While there is now a general acceptance, some controversy on the use of
masks continues, including on the potential negative effects of wearing masks
on health, for example on cardiopulmonary capacity (Fikenzer, 2020). Regard-
less of the controversy and the mounting “No-Mask” movements, face masks
are clearly “here to stay”. The view of people wearing face masks in public,
which in the past surprised and at times amused Western travelers to Asian
countries, will be a common sight worldwide for months and maybe for years
to come.
Hand Hygiene
The role of fomites in transmission of SARS-CoV-2 remains unclear but can-
not be excluded. (Although objects can be easily contaminated by infected
droplets and contaminate hands, it is extremely challenging to prove such
transmission.) In any case, frequent handwashing is known to disrupt the
transmission of respiratory diseases since people routinely make finger-to-
nose or finger-to-eye contact (Kwok, 2015). Handwashing for 30 seconds with
ordinary soap is always recommended when there is a contact with a poten-
tially infected item and regularly whenever possible (ex. when returning

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home). If water and soap are not available (ex. in public places), use of hy-
droalcoholic solutions or gel is recommended. These solutions have been
shown to efficiently inactivate the SARS-COV-2 virus in 30 seconds (Kratzel,
2020) and can be home-made using a WHO recommended formulation. Hand-
hygiene has the added advantage of preventing infections from many other
respiratory pathogens. Unfortunately, both water for handwashing and hy-
droalcoholic solutions are often not available in resource-poor settings
(Schmidt, 2020)

Physical/Social distancing and avoiding crowded conditions

Physical distancing means keeping a safe distance from others. The term is
often confused with the more common “social distancing”, usually imposed
during lockdowns, that means reducing social contacts as much as possible by
staying home and keeping away from others to prevent the spread of COVID-
19.
Social distancing has been unequivocally shown to contribute to reducing the
spread of SARS-CoV-2. In Wuhan and Shanghai, daily contacts were reduced
7-8-fold during the social distancing period, with most interactions restricted
to the household (Zhang J 2020b, Du Z 2020). Social distancing can be an indi-
vidual choice, but it is usually imposed by health authorities during “Lock-
downs” or “stay-at-home orders”. We will expand on the issues related to
lockdowns and social distancing in the sections below.
With the end of lockdowns and the restart of economic and social activities,
physical distancing in public places should become an important behavioural
aspect of everyday life and an essential measure to reduce the spread of
SARS-COV-2. Keeping a safe distance from others seems like a straightforward
recommendation but defining what can be considered a “safe distance” is in
fact quite complex. In a published meta-analysis (Chu, 2020), the authors es-
timated that the risk of being infected with SARS-COV-2 is reduced to 13% for
those standing at 1 m and further reduced to only 3% beyond that distance.
Based on this evidence, the WHO and ECDC recommend a minimum inter-
personal distance of 1 m, although other agencies and countries suggest 1.5 m
(Australia, Italy, Germany), 1.8 m (US CDC), or even 2 meters (Canada, China,
UK). (BBC News, 2020)
Some authors suggest that even 2 meters might not be sufficient and that
being “safe” would depend on multiple factors related to both the individual
and the environment. These could include infecting viral load, duration of
exposure, number of individuals present, indoor versus outdoor settings, lev-
el of ventilation, and whether face coverings are worn or not. (Qureshi, 2020,
Jones 2020). In crowded conditions, including public transport (e.g. trains,

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buses, metros), physical distancing is often impossible and the use of a pro-
tective mask is usually mandatory.

Figure 1. Jones NR,et al. Two metres or one: what is the evidence for physical distancing in
covid-19? BMJ. 2020 Aug 25;370:m3223. Reproduced with permission.

Speak quietly, don’t shout (or sing)!

Traditionally, visible droplets produced during coughing and sneezing are
considered the main carriers of respiratory viruses. It has only recently
emerged that normal speech also yields large quantities of particles that are
too small to be visible but are large enough to carry a variety of communica-
ble respiratory pathogens and can remain airborne for longer periods. The
rate of particle emission during normal human speech is positively correlated
with the loudness (amplitude) of vocalization, ranging from approximately 1
to 50 particles per second (0.06 to 3 particles per cm3), regardless of the lan-
guage spoken (English, Spanish, Mandarin, or Arabic) (Asadi 2019). However,
a small fraction of individuals behaves as “speech superemitters,” consistent-
ly releasing many more particles than their peers.
These data may help explain the occurrence of some super-spreaders events
(e.g. choirs, parties and festivals, slaughterhouses, sport events, religious cel-
ebrations, family gatherings, etc.) that are disproportionately responsible for
outbreaks of COVID-19 (See Epidemiology section). While research will con-

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tinue to study super-spreaders events, people should abide to a very simple

rule: Regardless of physical distance, speak quietly, don’t shout!

Household hygiene
Several studies suggest the possibility of aerosol and fomite transmission of
SARS-CoV-2, since the virus can remain viable and infectious in aerosols for
hours and on surfaces up to several days (Doremalen 2020, Chin 2020).
Though transmission of SARS-COV-2 from contaminated surfaces has not
been clearly documented, traditional good home hygiene measures like
cleaning floors and furniture, keeping good ventilation and the general disin-
fection of frequently used objects (e.g. door and window handles, kitchen and
food preparation areas, bathroom surfaces, toilets and taps, touchscreen
personal devices, computer keyboards, and work surfaces) are recommend-
ed to prevent transmission, particularly where confirmed or suspected
COVID-19 cases are present (CDC 2020, WHO 20200515).
SARS-COV-2 is sensitive to ultraviolet rays and heat (Chin 2020). Sustained
heat at 56°C for 30 minutes, 75% alcohol, chlorine-containing disinfectants,
hydrogen peroxide disinfectants and chloroform can effectively inactivate
the virus. Common detergents and sodium hypochlorite (bleach) can also be
used effectively (Kampf 2020). To avoid poisoning, disinfectants should al-
ways be used at the recommended concentrations, wearing appropriate PPE
and should never be mixed. US CDC reported a substantial increase in calls to
the poison centers in March 2020 associated with improper use of cleaners
and disinfectants; many cases were in children <5 years old (MMWR 2020).

Chemoprophylaxis (not there yet!)

In the future, antiviral drugs may be used to reduce viral shedding in sus-
pected cases and as a prophylactic treatment of contacts. As for now, unfor-
tunately, no such drugs are available.

Prevention at the community/societal levels

Widespread testing, quarantine, and intensive contact tracing
Tedros Adhanom Ghebreyesus didn’t get everything right in the SARS-CoV-2
pandemic, but he was right when he recommended: “Test! Test! test!” (WHO,
16 March 2020). Indeed, identification, and testing of suspected cases, isola-
tion and care for those confirmed, and tracing, testing and quarantine of
close contacts are critical activities to try to break the chain of transmission
in any epidemic. They worked well, for example, in responding to the 2003
SARS outbreak and many countries in Asia successfully applied them to

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COVID-19 (Li 2020, Lam 2020, Park 2020). The South Korea experience has
been nicely summarized in an article in The Guardian.
However, despite the early availability of sensitive PCR tests (Sheridan
2020), many countries in Europe and elsewhere were initially caught by sur-
prise. Unprepared, they struggled at first to provide sufficient testing, isola-
tion and contact tracing capacities to keep up with the pace of spread of
SARS-COV-2. In Italy, the lack of laboratory capacities led to limiting PCR
tests to symptomatic patients only, missing many asymptomatic cases. Other
countries, like Germany, fared better in diagnostics but implementing contact
tracing proved difficult everywhere when the epidemic reached its peak, due
to the large number of potential contacts of asymptomatic cases and their
relatively long incubation period.
Ensuring sufficient testing capacities paired with the development of new
rapid diagnostic tests (see section on Diagnosis) will continue to be an essen-
tial measure in facing COVID-19 clusters or the “second wave” of infections.
Advanced pooled testing strategies (Mallapaty, 2020) and the use of saliva
samples could facilitate the task by allowing the rapid testing of large number
of people, as China has done by testing all the population of large urban areas
like Wuhan (more than 10 million people) in less than 2 weeks.
Isolation (separation of ill or infected persons from others) and quarantine
(the restriction of activities or separation of persons who are not ill, but who
may be exposed to an infectious agent or disease) are essential measures to
reduce the spread of COVID-19. Unless a patient is hospitalized, quarantine
and isolation are usually done at home or in dedicated facilities like hotels,
dormitories, or group isolation facilities. (CDC 2020) Given the uncertainty
about the infectivity of the suspected individual, preventive measures are
similar for both isolation of confirmed cases and quarantine of contacts. Basi-
cally, you are required to stay at home or in the facility and avoid non-
essential contacts with others, including household members, for a set period
to avoid spreading the infection.
The long incubation and high pre-symptomatic infectivity of COVID-19 puts
family members of infected individuals at particular risk (Little 2020). The
infection rate found for household members varies between 11% and 32% (Bi
Q 2020, Wu J 2020). These differences are probably due to different isolation
measures implemented inside the family homes. Ideally, people in isolation
should have access to a separate bedroom (and bathroom), personal protec-
tion equipment (PPE) and should not have contacts with people at high risk of
serious COVID-19 disease.

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The period of isolation and quarantine required before suspected or con-

firmed cases can be considered no more infectious is still being debated. Ini-
tially, the requirement for a confirmed case was to have clinically recovered
and to have two negative RT-PCR results on sequential samples taken at least
24 hours apart. (WHO 2020) This second criteria proved challenging in coun-
tries with limited testing capacities and even when tests are available, some
patients can continue to have positive PCR results for weeks or months after
the cessation of symptoms, leading to prolonged, probably unnecessary isola-
tion periods.
Updated WHO criteria were published in June (WHO 20200617). Based on data
showing the rarity of the presence of vital virus after 9 days from symptom
onset (Cevic 2020), the new recommendation is to limit the isolation period
to:
• 10 days after symptom onset, plus at least 3 additional days without
symptoms for symptomatic patients.
• 10 days after positive test for SARS-CoV-2 for asymptomatic cases.
However, several countries, (e.g. Italy), continue to apply the earlier testing
criteria including a negative PCR test, which can result in individual being
kept in isolation for a longer period.
Recommended quarantine period for contacts and for travelers has not
changed and remains set at 14 days, though several countries have reduced it
to 10 days (e.g. Switzerland).
Contact tracing can be effective in reducing the risk of spread of the virus
(Keeling 2020) but it is a complex and resource intensive exercise. It is most
effective when implemented early in the outbreak, before there is sustained
community transmission. Once cases are soaring, identifying and monitoring
all the potential contacts using only the public health resources becomes
close to impossible and additional measures like physical distancing, face
masks and localized lockdowns become necessary (Cheng 2020). WHO has
published detailed guidance on contact tracing for COVID-19 and alternative
approaches to contact tracing that results in resource-saving measures have
recently been suggested. (ECDC, April 2020)
As stated by several authors, (Steinbrook, 2020, Salathé 2020) in countries
that have managed to bring the pandemic under control a necessary step in
“reopening” society was to have sufficient testing and contact tracing capaci-
ties to successfully contain the outbreaks that will inevitably occur as social
restrictions are removed or relaxed. The coming winter months will show
which countries will have learned this important lesson.

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Tracking apps
Mobile phone data reveal astonishing details about population movements.
According to an analysis by Orange, a French phone operator, data from its
telephone subscribers revealed that 17% of the inhabitants of Grand Paris
(Métropole du Grand Paris, 7 million people) left the region between March
13 and 20 – just before and after the implementation of the French lockdown
measures (Le Monde, 4 April 2020). Again, mobile phone data from individuals
leaving or transiting through the prefecture of Wuhan between 1 January and
24 January 2020 showed that the distribution of population outflow from Wu-
han accurately predicted the relative frequency and geographical distribution
of SARS-CoV-2 infections throughout China until 19 February 2020 (Jia JS
2020).
Numerous countries have tried to harness the power of the smartphone to
design and target measures to contain the spread of the pandemic (Oliver
2020). In addition to the dissemination of COVID-19 information and preven-
tion messages, the use of smartphones in support to contact tracing has been
promoted widely. This contact tracing system (better named “exposure noti-
fication”) would basically use an application to detect if the phone has come
in close distance for a set period of time from another phone of a person di-
agnosed with SARS-COV-2 and therefore potentially infectious. It will then
give a warning message prompting the owner to seek medical assistance, self-
isolation, and testing.
The deployment of these tracking applications has faced several hurdles, in-
cluding the need for inter-operability across platforms (Google, Apple) and
across countries (unfortunately, each European country has developed its
own app); the possibility of false-positive alerts; and the need for a majority
of the population to download and regularly activate the app to be truly ef-
fective. The need to preserve the privacy of the users forced less performing
technical solutions (e.g. decentralized data systems with data only stored in
each phone vs centralized database; preference for less-accurate Bluetooth
connection over GPS geo-localization; voluntary decision required on the
sharing of data; ensuring time-limited storage of collected data, etc.) For ex-
ample, in June, Norway's health authority had to delete all data gathered via
its Covid-19 contact-tracing app and suspend its further use following a rul-
ing by the Norwegian Data Protection Authority.
A few months into their introductions, most COVID-19 tracking apps have
failed to deliver as expected. In almost all countries only a small proportion
of the population have downloaded the app (only Qatar, Israel, Australia,
Switzerland, and Turkey have seen downloads above the minimum threshold
of 15% of the population) and probably even less people are regularly activat-

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ing it. More importantly, the success of a tracking application should not be
measured by the number of downloads but by the number of contacts detect-
ed, which so far have been relatively few (due to privacy concerns, the total
number of contacts is not available in countries where information is decen-
tralized).
Several countries, including France and Germany, have started to provide
additional services with the app, including for accessing laboratory services
and receiving test results. Maybe, with these improvements, these tracking
applications will become more efficient and their use will increase in future,
though they will probably only be only a support rather that a replacement
for a traditional “manual” contact tracing system.

Mandatory use of face masks

Wearing a face mask to protect self and others from SARS-COV-2 infection
may be an individual choice (see above). However, as of 6 May 2020, more
than 150 countries have made wearing a mask in some settings a mandatory
requirement as a collective preventive public health measure. Mandatory
settings range from “everywhere in public” to all indoor public places, public
transportation, shops, workplaces, schools, etc. Children and people with
breathing difficulties are often exempted from the mandatory use of face
masks. (US CDC 2020, WHO 2020, ECDC 2020) As a result, the global number of
people regularly wearing masks in public has soared, reaching the peak of 80-
90% of the population in most countries in Asia but also in Italy, France, and
Spain. Surprisingly, mask acceptance has increased to the point of being
branded as a fashion items.
As shown in the chart, authorities in Asia have mandated the use of face
masks in public at the early stages of the pandemic, which contributed to re-
duced spread and the sharp drops in infections. As mentioned earlier, in
many other parts of the world, conflicting advice with misleading or incom-
plete information about the usefulness of masks has caused confusion among
the population and a late adoption of this preventive measure. In addition, a
growing “no-Masks” movement has gathered momentum, staging rallies in
several countries. Regardless, as new infections have started to increase
again following the summer reopening, mandatory mask requirements have
been introduced again in most European countries and is becoming a norm in
most public places.

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Figure 2. Source: YouGov.com. Reproduced with permission.

Ban on mass gatherings

Recognizing their potential role in generating explosive clusters of SARS-
COV-2 infections, (McCloskey 2020, Ebrahim 2020) most countries have im-
plemented nationwide bans of mass gathering like sporting and cultural
events, concerts, religious celebrations, rallies and political demonstrations,
etc. Several important international mass gatherings events have been can-
celled or postponed in 2020, including the Tokyo Olympic Games, Euro foot-
ball championship, Formula 1 Grand Prix races, the Eurovision Song Con-
test, Geneva Motor Show, Christian Holy Week events in Rome, Umrah pil-
grimage to Mecca, and many others.
It is currently uncertain under which conditions cultural events that require
closeness of spectators (e.g. cinema, theatre, opera, etc.), religious ceremo-
nies, political rallies, and other social events that require the contemporane-
ous presence of large numbers of clients in a restricted, closed space (discos,
bar, etc.) can be resumed without the risk of resulting in a super spreader
event. The limited reopening of these premises during the summer holidays
has recently been associated with a resurgence of the spread of the virus ob-
served in Greece, Spain, France, and Italy. Most sport events have resumed,

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but without public. WHO has recently published key recommendations for
mass gatherings in the context of COVID-19. Unless the risk of SARS-COV-2
spread is reduced significantly, postponing or cancelling of planned large
event is likely to continue in the months to come.

Localized and nationwide Lockdowns

Lockdowns (or “stay-at-home orders”) are restrictions of movements of the
whole population, ordered by a government authority to suppress or mitigate
an epidemic or pandemic. They differ from quarantine in that all residents
are supposed to stay at home, except for those involved in essential tasks,
while quarantine is usually limited to people suspected to be infected.
Lockdowns and social distancing have been used for centuries in the fight
against epidemics, as famously illustrated in the Decameron, a book by Bocac-
cio, an Italian writer, which contains tales told by a group of young people
sheltering in a villa outside Florence to escape the Black Death of 1348. How-
ever, the 2020 nationwide lockdowns which ordered almost 4 billion people in
90 countries to stay at home were unprecedented in human history. (see also
Chronology) For the first time, lockdowns were imposed initially in a whole
city of 10 million people (Wuhan), then to 60 million people in the whole
province of Hubei, finally to a whole country (Italy, followed by most other
European countries.) Though countries opted for more (China) or less (Eu-
rope) strict confinement measures, lockdowns were clearly effective in de-
creasing a hypothesized infection rate of 60% to 70% to less than 10%.
(Cowling 2020)
How strict such measures can be has been shown in Hong Kong (Normile
2020). The recipe: hospitalize all those who test positive, regardless of wheth-
er they have symptoms, order two weeks of self-quarantine to all close con-
tacts, introduce electronic wristbands, etc. A website even displays the loca-
tion of infected people in Hong Kong at all times: https://chp-
dashboard.geodata.gov.hk/covid-19/en.html. Such strict measures can be
very effective but would not be acceptable or feasible in most countries. In-
deed, one of the limitations of lockdowns is that they can never be 100% com-
plete. People occupied in essential services (e.g. health, security, transport,
communication, food production and delivery, etc.) will need to be allowed to
move and work, and sick people will need to continue to access health ser-
vices.
Generalized lockdowns are blunt prevention tools, affecting the whole
healthy population to reduce the risk of transmission from the relatively few
potentially infectious individuals. (Hsiang 2020) They impose a major eco-

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nomic and social burden on the affected populations, while also preventing at
times access to prevention and treatment for other health conditions
(Charlesworth 2020). They have been described as a type of “induced coma”
for the whole society and economy, though few benefits are also noted, for
xample on pollution levels. (UNDP 2020) Various authors (Marshall 2020,
Pierce 2020, Williams 2020, Galea 2020) have also emphasized the combined
impact of the pandemic, social distancing and closures on the mental health
of the population. In addition, implementing generalized lockdowns in low-
income countries is particularly difficult. People in the informal economy
without social net benefits may be forced to choose between the risk of infec-
tion and risking of falling into poverty and hunger. (ILO, 2020)
In fact, widespread testing, isolation and quarantine, combined with popula-
tion behavioral changes (physical distancing, use of masks, hand hygiene) –
that have a less disruptive social and economic impact – have been shown to
succesfullly contain COVID-19 if applied widely and consistently (Cowling
2020). A key metric for their success is whether critical care capacities are
exceeded. To avoid this, prolonged or intermittent social distancing may be
necessary into 2022 (Kissler 2020).
In summary, the tighter you control the infected individuals and trace and
isolate the close contacts, the less restriction you will have to impose on the
uninfected. The hope is for countries to learn this lesson and, being better
prepared, to be able to avoid in future the need for generalized lockdowns to
respond to COVID-19 (and other epidemics). However, the resurgence of
COVID-19 in Europe is showing how difficult it is to balance health and eco-
nomic/social imperatives. Until an effective vaccine becomes available, local-
ized or even generalized temporary lockdowns might continue to be required
in the fight against this pandemic.

Travel bans/border closures

It has long been recognized that both land, sea and air travel can be efficient
and rapid routes for the international spread of a pandemic virus. (Hufnagel
2004, Hollingsworth 2007) The conditions for restricting movements of people
and goods between countries in case of a public health emergency are there-
fore described in the WHO International Health Regulations adopted by all
WHO member states in 2005 (IHR 2005).
As of 18 June 2020, almost all (191) countries have taken some measures that
restrict people’s movement since the COVID-19 pandemic began. Measures
range from control of entry onto the territory of a State to control of move-
ment within a territory, comprising of partial or total border closures (125
countries) and international flight suspensions (122 countries).

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As pointed out by some authors (Habibi 2020), these measures may be in

breach of the IHR 2005, as they do not seem grounded on “scientific princi-
ples, scientific evidence, or advice from WHO” as required by IHR. (WHO 2005)
This position is based on several scientific studies that have shown how the
imposition of travel bans and border closures can be only partially effective
in slowing down the introduction and spread of an epidemic or pandemic
virus (like influenza or Ebola) while being potentially damaging and even
counterproductive (Brownstein 2006, Mateus 2014, Poletto 2014).
In fact, widespread travel restrictions and border closures have not prevent-
ed SARS-COV-2 from reaching quickly just about every country on the planet
(see section on Epidemiology). Though Italy was the first in Europe to impose
a travel ban on China, it was also the first European country to experience a
major COVID-19 outbreak. Australia has imposed a total travel ban since 24
March that contributed initially to stop the spread of the virus but did not
prevent returning citizens and poorly-trained quarantine guards to break the
rules and cause the ongoing major outbreak in Melbourne. One reason why
travel bans are usually ineffective is that you cannot prevent everybody from
entering a country. Some people (e.g. Citizens, long-term residents, diplo-
mats, air or ship crews, health personnel, sometimes businessmen, etc.) are
often exempted and able to travel under national or international agree-
ments. Others (e.g. illegal migrants) can cross borders unofficially.
Some authors have also pointed out how the travel bans and border closures
can restrict the movement of vital health equipment and supplies (e.g. medi-
cines, PPEs, testing reagents and equipment) and also essential personnel,
particularly needed in countries with limited resources (Devi 2020). Others
suggest that early detection, hand washing, self-isolation, and household
quarantine will likely be more effective than travel restrictions at mitigating
this pandemic. (Chinazzi 2020)
On the other hand, the economic damage of travel bans has been substantial.
The activities of airlines, airports, travel agents, hotels and resorts has basi-
cally come to a halt at the peak of the pandemic. Eurocontrol has recorded a
90% drop in air passenger in Europe at the end of April; the figure has im-
proved with the reopening of borders but is still at -50% compared to 2019 as
of mid-July. In May, the UN World Tourism Organization (UNWTO) projected
the potential economic loss for the tourist industry worldwide at US$ 910
billion to US$ 1.2 trillion, with 100-120 million jobs at risk.
Generalized travel bans and border closures can effectively reduce the spread
of a pandemic virus but, like generalized lockdowns, are blunt tools, affect a
large number of uninfected individuals and can result in an erroneous and
dangerous false sense of security in the population and in the authorities. In

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most cases, they will eventually end up being breached one way or the other.
Their impact on the life of many people, the economy and the trade is sub-
stantial and strict screening and quarantine measures for travellers can be as
effective in avoiding transmission of the virus by imported cases. Hopefully,
as countries will increasingly learn how to deal with the risk of COVID-19 in
more efficient and effective ways, international travel will finally be allowed
to resume in a safe environment.

Vaccinate for seasonal influenza and (hopefully soon) for COVID-19

Several authors (Richmond 2020, Jaklevic 2020, Singer 2020, Rubin 2020,
Maltezoua 2020) and public health agencies are recommending expanding
seasonal flu vaccination in the context of the COVID-19 pandemic. This fol-
lows concerns about the potential “double epidemic” of COVID-19 and sea-
sonal flu during the winter months (Balakrishnan 2020, Gostin 2020). There
are indeed many similarities (but also a few important differences) between
the two diseases (Solomon 2020, Zayet 2020, Faury 2020) which may compli-
cate the differential diagnosis for symptomatic patients, e.g. similar transmis-
sion routes, similar symptoms for mild cases (except for signs of neurological
involvement like anosmia), similar high-risk groups for severe complications
and mortality. A “double epidemic” could overburden both primary care ser-
vices and hospitals, require a major increase in diagnostic capacities, lead to
unnecessary isolation and quarantine of influenza cases and even increase
stigma and discrimination of anyone presenting with symptoms of a respira-
tory infection (Rubin 2020). The possibility of COVID-19 and flu co-infection
should also not be ruled out (Kim 2020). Combined SARS-CoV-2 and flu diag-
nostic tests, as recently approved by the FDA and being evaluated in some
countries in Europe, could be useful in quickly identifying the pathogen(s)
involved from a single sample.
Increasing coverage of seasonal influenza vaccination among high-risk
groups is a good public health measure on its own, as influenza is estimated
to cause close to 10 million hospitalizations and between 294,000 and 518,000
deaths every year (Paget 2019, CDC-US). It is also an essential measure in the
response to COVID-19 to avoid a potential breakdown of health care systems
and the related increase in mortality and morbidity. Unfortunately, the nor-
mal uptake of flu vaccination in high-risk groups (> 65 years of age) has been
largely insufficient, averaging around 50% in OECD countries. Along with ef-
forts to increase coverage in the recommended risk groups, additional
measures being suggested include reducing the recommended age for vac-
cination from 65 to 60 years, universal vaccination of children aged 6 months

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to 17 years, mandatory vaccination for all health-care workers, including all

workers and visitors of long-term care facilities (Balakrishnan 2020, Gostin
2020, CDC).
However, widespread implementation of these additional measures will not
be simple. The usual misguided concerns about the safety of vaccines and
more recent social media fake news reports about the possibility of flu vac-
cine causing COVID-19 will need to be addressed. Reduced healthcare seeking
behaviors due to fear of SARS-CoV-2 infection could also be a challenge. In
addition, despite efforts by vaccine manufacturers and a major increase in flu
vaccine production capacities in the last decade, due in part to preparation
for a possible flu pandemic (Rockman 2020), vaccine availability is unlikely to
be sufficient to meet such an increase in demand, at least for the coming
northern hemisphere flu season in 2020-21.
The definition of the composition of the seasonal flu vaccine is agreed by a
WHO advisory group of flu experts based on an analysis of the data generated
by the WHO Global Influenza Surveillance and Response System (GISRS). The
group reviews the results of flu surveillance, laboratory and clinical studies
and makes recommendations on the composition of the influenza vaccine
based on the best match with available vaccine viruses. The advisory group
meetings are held in February (for the northern hemisphere’s seasonal influ-
enza vaccine) and in September (for the southern hemisphere’s vaccine) to
allow sufficient time (7-9 months) for the production of the required doses of
vaccine. (Dunning 2020).
Influenza vaccine effectiveness can vary from season to season depending on
the similarity or “match” between the flu vaccine and the flu viruses spread-
ing in the community. During those years when the flu vaccine is not well
matched to circulating influenza viruses, effectiveness can be as low as 20%,
rising to 60% for the years when there is a good match. However, even less
effective influenza vaccines have been shown to reduce considerably the bur-
den of severe cases of influenza, admission to ICUs, and flu-related deaths
(Thompson 2018, Ferdinands 2019).
Several recent studies have reported that indicators of influenza activity have
been declining substantially in 2020 in both the northern (e.g. in Asia and the
US) and the southern hemispheres, including in countries that implemented
limited lockdown measures (Soo 2020, Olsen 2020, Itaya 2020). The decreased
influenza activity was closely associated with the introduction of interven-
tions to reduce SARS-CoV-2 transmission. (Choe 2020). This is really good
news, as the evidence on the effectiveness of public health interventions in
slowing the spread of a pandemic virus has been otherwise limited (Fong
2020, Xiao 2020, Ryu 2020). If these findings are confirmed during the coming

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 Prevention | 165

winter season in the northern hemisphere, not only this would avoid the
danger of a “dual epidemic” but it will also confirm that non-pharmaceutical
interventions are essential in the response to future pandemics and could
become standard interventions, in addition to vaccination, for reducing the
health burden of seasonal influenza and other respiratory infections in high
risk groups.
On the down side, the limited detection and isolation of flu viruses by the
WHO surveillance system will reduce the availability of updated and robust
data for the decision on the composition of the flu vaccine for 2021, raising
the danger of a poor match between future influenza vaccines and circulating
flu viruses.

Figure 3. The southern hemisphere skipped flu season in 2020 – Efforts to stop covid-19
have had at least one welcome side-effect. The Economist 2020, published 12 September.
Full-text: https://www.economist.com/graphic-detail/2020/09/12/the-southern-hemisphere-
skipped-flu-season-in-2020. Reproduced with permission.

Additional potential good news could come from research on the effects of
influenza vaccination on the severity of SARS-CoV-2 infection. Among the few
studies available, a recently pre-published paper (Fink 2020) reports on the
analysis of data from 92,664 confirmed COVID-19 cases in Brazil showing that
patients who received a trivalent influenza vaccine during the last campaign
(March 2020) experienced on average 8% lower odds of needing intensive care
treatment (95% CIs [0.86, 0.99]), 18% lower odds of requiring invasive respira-

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tory support (0.74, 0.88) and 17% lower odds of death (0.75, 0.89). Similar con-
clusions were reached in another pre-print paper modelling COVID-19 mor-
tality data and recent influenza vaccination coverage in the US (Zanettini
2020).
More studies are clearly required before reaching conclusions, but the availa-
ble evidence does suggest that increasing coverage of influenza vaccination
would result in both direct and indirect benefits in terms of reduced morbidi-
ty and mortality from both COVID-19 and influenza. These efforts could also
have long-term benefits in expanding influenza vaccine production and up-
take, both for seasonal influenza and in preparation for future flu pandemics.
Experience and lessons learned from these efforts will be of great value once
a COVID-19 vaccine becomes available, since production, distribution and
promotion of uptake for the new vaccine will face similar challenges and will
need to prioritize the same vulnerable populations (Jaklevic 2020, Mendelson
2020).

Containment or mitigation of COVID-19?

Public health interventions to control an outbreak or an epidemic aim at
achieving two separate but linked objectives (Zhang 2020, OECD 2020):
• To contain the spread by minimizing the risk of transmission from in-
fected to non-infected individuals, eventually suppressing transmission
and ending the outbreak.
• To mitigate the impact by slowing the spread of the disease while pro-
tecting those at higher risk. While not halting the outbreak, this would
“flatten the epidemic curve”, reduce disease burden and avoid a peak in
health care demand. In case of new emerging pathogens, it would also
buy time to develop effective treatments or vaccines. (Djidjou-Demasse
2020)
Containment strategies rely heavily on case detection and contract tracing,
isolation, and quarantine. They are usually applied most successfully in the
early stages of an outbreak or epidemic, when the number of cases is still
manageable by the public health system. (Hellewell 2020) When containment
measures are insufficient or applied too late, mitigation becomes the only
option, usually through the imposition of generalized preventive measures
like closing of non-essential activities, social distancing, mandatory mask use,
or lockdowns. (Parodi 2020, Walker 2020)
During the first months of the COVID-19 pandemic, several countries (China,
Vietnam, South Korea, Australia, New Zealand) have shown how the imple-

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mentation of a well-timed, comprehensive package of aggressive containment

and mitigation policies can be effective in suppressing the COVID-19 epidem-
ic, at least in the short-term. Other countries (most countries in Europe) have
not been able to suppress transmission but have managed to mitigate the im-
pact and bring the spread of SARS-COV-2 down to acceptable levels during
the summer months. In others the pandemic is still raging with no end in
sight (e.g., US, Brazil, most of Latin America) and a second wave of infections
is now becoming evident in several European countries. In any case, as long
as the virus is actively spreading anywhere in the world, no country can feel
safe (as shown by the recent outbreaks in Victoria, Australia and in New Zea-
land). The fight against SARS-CoV-2 is far from over.

Conclusion
While the quest for an effective vaccine or antiviral treatment continues,
countries are still struggling to find the right mix of preventive measures
(and the right balance between health and socio-economic priorities) to build
an effective response to the COVID-19 pandemic.
Finding the right prevention mix means identifying what are the most cost-
effective measures that can be widely implemented to reduce or halt the
transmission of the virus. For this, we need a better understanding of how
this virus spreads and how effective the different preventive measures are.
Only more research and better science will provide this information.
However, finding the right balance also means recognizing that some
measures can be effective, but carry very high social, economic, political, ed-
ucational, and even health costs. These are political decisions. For example,
many European countries have tried very hard to avoid imposing again strict
generalized lockdowns, border closures or travel bans. These measures are
simply too costly for society to be acceptable.
The best scenario is to be able to respond to new cluster of cases or the accel-
eration of the spread of the virus, due to “superspreaders” events or a relaxa-
tion of individual preventive measures, through localized time-limited public
health measures, their effectiveness being judged by better and timely moni-
toring of the spread of the virus. Even in the absence of COVID-19 vaccines or
treatments and comprehensive knowledge of the immune response to SARS-
CoV-2, countries can navigate pathways to reduced transmission, decreased
severe illness and mortality, and less economic disruption in the short and
longer term (Bedford 2020). It is not ideal, it is not being “back to normal”,
but in the absence of a “silver bullet” it is probably the best option we have
right now to contain this pandemic.

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• Disinfection of environments in healthcare and non-healthcare
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Hospitals and other health care settings

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• Infection prevention and control andpreparedness for COVID-19
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Nursing facilities
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Long-term Care Institutions

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Workplaces
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Schools
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Prisons
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Homeless shelters
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 Virology | 185

4. Virology
Emilia Wilson
Wolfgang Preiser

Introduction
In January 2020, a novel virus later named severe acute respiratory syndrome
coronavirus (SARS-CoV-2) was isolated from the broncho-alveolar fluid of a
patient in Wuhan, People’s Republic of China, suffering from what became
known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 is highly trans-
missible and pathogenic. Until present (October 2020), it has infected tens of
millions of individuals, causing more than a million deaths and debilitating
the economy.
Coronaviruses (CoV) are large, spherical, enveloped RNA viruses with distinct
protruding spike glycoproteins visible on the viral surface. The name is de-
rived from the Latin “corona”, which means crown or halo, referencing the
characteristic morphology when viewed under an electron microscope (Zuck-
erman 2009, Perlman 2020). Structural proteins include envelope (E), matrix
(M), and nucleocapsid (N).CoV contain a single strand of positive-sense RNA.
Their genome size ranges from c. 26 to 32 kilobases, placing them among the
known RNA viruses with the largest genomes.
The family Coronaviridae belongs to the order Nidovirales, suborder
Cornidovirineae. Subfamily Orthocoronavirinae includes four genera: alpha-,
beta-, delta- and gammacoronavirus. Genera alpha- and betacoronavirus con-
tain several human-pathogenic subgenera and species. SARS-CoV-2 is a previ-
ously unknown betacoronavirus in subgenus Sarbecovirus, like its close rela-
tive, severe acute respiratory syndrome-related coronavirus (SARS-CoV).
Other notable beta-CoV are Middle East respiratory syndrome-related CoV
(MERS-CoV) in subgenus Merbecovirus as well as human CoV HKU1 and hu-
man CoV OC43, species Betacoronavirus 1, both in subgenus Embecovirus.
Species in of the family Coronaviridae infect various species of animals – hu-
mans, other mammals, and birds - causing a broad spectrum of different dis-
eases. Human CoV are primarily respiratory pathogens but may cause enteric
disease. Respiratory illness caused by human CoV HCoV-OC43, HCoV-HKU1,
HCoV-229E, and HCoV-NL63 is usually mild and “common cold”-like and thus
not of major public health concern (Korsman 2012). The highly pathogenic
CoV affecting humans cause severe acute respiratory infections often result-
ing in serious disease and death is was caused by the novel SARS-CoV and

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MERS-CoV. There is strong evidence that these viruses emerged recently

from animal reservoirs, originating in bats and transmitted to man via inter-
mediate host species. Intra- and inter-species transmission of CoVs, and ge-
netic recombination events contribute to the emergence of new CoV strains.
The following sections will review coronaviruses in general with a more de-
tailed appraisal of the origin, evolution, virological structure and pathogene-
sis of SARS-CoV-2 to expand knowledge pertaining to COVID-19 and prospec-
tive anti-viral and vaccine therapies.

***

The complete chapter will be available soon.

***

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Genomic variation
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This in-depth molecular analysis reconstructs key genomic features that
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A SARS-CoV-2 variant carrying the Spike protein amino acid change
D614G (caused by an A-to-G nucleotide mutation at position 23,403 in the
Wuhan reference strain) has become the most prevalent form in the
global pandemic within a month, indicating a fitness advantage (better
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D614G is more infectious than the ancestral form on human lung cells,
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Origin and hosts

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Review on notable genomic features of SARS-CoV-2, compared to alpha-
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virus is not a laboratory construct or a purposefully manipulated virus.

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SARS-CoV and MERS-CoV likely originated in bats, both jumping species
to infect humans through different intermediate hosts.

Lam TT, Shum MH, Zhu HC, et al. Identifying SARS-CoV-2 related coronaviruses in Malayan
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Do Malayan pangolins act as intermediate hosts? Metagenomic sequenc-
ing identified pangolin-associated coronaviruses, including one with
strong similarity to SARS-CoV-2 in the receptor-binding domain.

Xiao K, Zhai J, Feng Y, et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pan-
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In a wildlife rescue center, authors found a coronavirus in 25 Malayan
pangolins (some of them were very sick), showing 90-100% amino acid
identity with SARS-CoV-2 in different genes. Comparative genomic anal-
ysis suggested that SARS-CoV-2 might have originated from the recom-
bination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus.
As the RBD of Pangolin-CoV is virtually identical to that of SARS-CoV-2,
the virus in pangolins presents a potential future threat to public health.
Pangolins and bats are both nocturnal animals, eat insects, and share
overlapping ecological niches, which make pangolins the ideal interme-
diate host. Stop the illegal pangolin trade!

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19 Outbreak. Curr Biol. 2020 Mar 13. PubMed: https://pubmed.gov/32197085. Fulltext:
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 Virology | 189

This study suggests that pangolin species are a natural reservoir of SARS-
CoV-2-like CoVs. Pangolin-CoV was 91.0% and 90.6% identical to SARS-
CoV-2 and Bat-CoV RaTG13, respectively.

Zhou H, Chen X, Hu T, et al. A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains
Natural Insertions at the S1/S2 Cleavage Site of the Spike Protein. Curr Biol. 2020 May
11. PubMed: https://pubmed.gov/32416074. Full-text:
https://doi.org/10.1016/j.cub.2020.05.023
A novel bat-derived coronavirus was identified from a metagenomics
analysis of samples from 227 bats collected from Yunnan Province in
2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-
2 at the scale of the complete genome and 97.2% identity in the lab gene,
in which it is the closest relative of SARS-CoV-2 reported to date. Howev-
er, RmYN02 showed low sequence identity (61.3%) in the receptor bind-
ing domain and might not bind to ACE2.

Stability and transmission of the virus

Chin AW, Chu JT, Perera MR, et al. Stability of SARS-CoV-2 in different environmental condi-
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SARS-CoV-2 was highly stable at 4°C (almost no reduction on day 14) but
sensitive to heat (70°C: inactivation 5 min, 56°: 30 min, 37°: 2 days). It al-
so depends on the surface: No infectious virus could be recovered from
print and tissue paper after 3 hours, from treated wood and cloth on day
2, from glass and banknotes on day 4, stainless steel and plastic on day 7.
Strikingly, a detectable level of infectious virus (<0·1% of the original in-
oculum) was still present on the outer layer of a surgical mask on day 7.

Kim YI, Kim SG, Kim SM, et al. Infection and Rapid Transmission of SARS-CoV-2 in Ferrets.
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Ferrets shed the virus in nasal washes, saliva, urine, and feces up to 8
days post-infection. They may represent an infection and transmission
animal model of COVID-19 that may facilitate development of SARS-CoV-
2 therapeutics and vaccines.

Leung NH, Chu Dk, Shiu EY. Respiratory virus shedding in exhaled breath and efficacy of face
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This study from Hong Kong (performed 2013-16) quantified virus in res-
piratory droplets and aerosols in exhaled breath. In total, 111 partici-
pants (infected with seasonal coronavirus, influenza or rhinovirus) were
randomized to wear or not to wear a simple surgical face mask. Results
suggested that masks could be used by ill people to reduce onward

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transmission. In respiratory droplets, seasonal coronavirus was detected

in 3/10 (aerosols: 4/10) samples collected without face masks, but in 0/11
(0/11) from participants wearing face masks. Influenza viruses were de-
tected in 6/23 (8/23) without masks, compared to 1/27 (aerosol 6/27!)
with masks. For rhinovirus, there were no significant differences at all.
Of note, authors also identified virus in some participants who did not
cough at all during the 30 min exhaled breath collection, suggesting
droplet and aerosol routes of transmission from individuals with no ob-
vious signs or symptoms.

Shi J, Wen Z, Zhong G, et al. Susceptibility of ferrets, cats, dogs, and other domesticated ani-
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SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks. Howev-
er, ferrets and cats are permissive to infection and cats were susceptible
to airborne infection. But cat owners can relax. Experiments were done
in a small number of cats exposed to high doses of the virus, probably
more than found in real-life. It also remains unclear if cats secrete
enough coronavirus to pass it on to humans.

van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2
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Stability of SARS-CoV-2 was similar to that of SARS-CoV-1, indicating
that differences in the epidemics probably arise from other factors and
that aerosol and fomite transmission of SARS-CoV-2 is plausible. The vi-
rus can remain viable and infectious in aerosols for hours and on surfac-
es up to days (depending on the inoculum shed).

Chan KH, Sridhar S, Zhang RR, et al. Factors affecting stability and infectivity of SARS-CoV-2.
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Dry heat is bad, damp cold is good (for the virus). Dried SARS-CoV-2 virus
on glass retained viability for over 3-4 days at room temperature and for
14 days at 4°C, but lost viability rapidly at 37°C. SARS-CoV-2 in solution
remained viable for much longer under the same different temperature
conditions.

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 Virology | 191

Cell tropism, ACE expression

Chu H, Chan JF, Yuen TT, et al. Comparative tropism, replication kinetics, and cell damage
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An elegant study, explaining distinct clinical features of COVID-19 and
SARS. Investigation of cell susceptibility, species tropism, replication ki-
netics, and virus-induced cell damage from both SARS-CoVs, using live
infectious virus particles. SARS-CoV-2 replicated more efficiently in hu-
man pulmonary cells, indicating that SARS-CoV-2 has most likely
adapted better to humans. SARS-CoV-2 replicated significantly less in in-
testinal cells (might explain lower diarrhea frequency compared to
SARS) but better in neuronal cells, highlighting the potential for neuro-
logical manifestations.

Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection
Gradient in the Respiratory Tract. Cell, May 26, 2020. Full-text:
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This study quantitated differences in ACE2 receptor expression and
SARS-CoV-2 infectivity in the nose (high) vs the peripheral lung (low). If
the nasal cavity is the initial site mediating seeding of the lung via aspi-
ration, these studies argue for the widespread use of masks to prevent
aerosol, large droplet, and/or mechanical exposure to the nasal passages.

Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, replication competence, and innate im-
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junctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med. 2020 May 7.
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2600(20)30193-4
More insights into the transmissibility and pathogenesis. Using ex vivo
cultures, the authors evaluated tissue and cellular tropism of SARS-CoV-
2 in human respiratory tract and conjunctiva in comparison with other
coronaviruses. In the bronchus and in the conjunctiva, SARS-CoV-2 rep-
lication competence was higher than SARS-CoV. In the lung, it was simi-
lar to SARS-CoV but lower than MERS-CoV.

Shang J, Ye G, Shi K. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020,

March 30. Full-text: https://doi.org/10.1038/s41586-020-2179-y.
How well does SARS-CoV-2 recognize hACE2? Better than other corona-
viruses. Compared to SARS-CoV and RaTG13 (isolated from bats), ACE2-
binding affinity is higher. Functionally important epitopes in SARS-CoV-
2 RBM are described that can potentially be targeted by neutralizing an-
tibody drugs.

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Sungnak W, Huang N, Bécavin C,et al. SARS-CoV-2 entry factors are highly expressed in nasal
epithelial cells together with innate immune genes. Nature Medicine, Published: 23
April 2020. Full-text: https://www.nature.com/articles/s41591-020-0868-6
Another elegant paper, confirming the expression of ACE2 in multiple
tissues shown in previous studies, with added information on tissues not
previously investigated, including nasal epithelium and cornea and its
co-expression with TMPRSS2. Potential tropism was analyzed by survey-
ing expression of viral entry-associated genes in single-cell RNA-
sequencing data from multiple tissues from healthy human donors.
These transcripts were found in specific respiratory, corneal and intesti-
nal epithelial cells, potentially explaining the high efficiency of SARS-
CoV-2 transmission.

Spike protein
Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of
the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of
the same clade. Antiviral Res. 2020 Apr;176:104742. PubMed:
https://pubmed.gov/32057769. Fulltext: https://doi.org/10.1016/j.antiviral.2020.104742
Identification of a peculiar furin-like cleavage site in the Spike protein of
SARS-CoV-2, lacking in other SARS-like CoVs. Potential implication for
the development of antivirals.

Watanabe Y, Allen JD, Wrapp D, McLellan JS, Crispin M. Site-specific glycan analysis of the
SARS-CoV-2 spike. Science. 2020 May 4. PubMed: https://pubmed.gov/32366695. Full-text:
https://doi.org/10.1126/science.abb9983
The surface of the envelope spike is dominated by host-derived glycans.
These glycans facilitate immune evasion by shielding specific epitopes
from antibody neutralization. SARS-CoV-2 S gene encodes 22 N-linked
glycan sequons per protomer. Using a site-specific mass spectrometric
approach, the authors reveal these glycan structures on a recombinant
SARS-CoV-2 S immunogen.
Cai Y, Zhang J, Xiao T, et al. Distinct conformational states of SARS-CoV-2 spike protein.
Science 21 Jul 2020. Full-text: https://doi.org/10.1126/science.abd4251
The authors report two cryo-EM structures, derived from a preparation
of the full-length S protein, representing its pre-fusion (2.9Å resolution)
and post-fusion (3.0Å resolution) conformations, respectively, and iden-
tify a structure near the fusion peptide – the fusion peptide proximal re-
gion (FPPR), which may play a critical role in the fusogenic structural re-
arrangements of S protein.

Ke Z, Oton J, Qu K, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact

virions. Nature 2020, published 17 August. Full-text: https://doi.org/10.1038/s41586-020-
2665-2

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More on how SARS-CoV-2 Spike (S) proteins function and how they in-
teract with the immune system. This work extends the knowledge of the
structures, conformations and distributions of S trimers within virions.

Toelzer C, Gupta K, Yadav SK, et al. Free fatty acid binding pocket in the locked structure of
SARS-CoV-2 spike protein. Science 21 Sep 2020. Full-text:
https://doi.org/10.1126/science.abd3255
The structure of the SARS-CoV-2 S glycoprotein. The RBDs tightly bind
the essential free fatty acid (FFA) linoleic acid (LA) in three composite
binding pockets. The LA-binding pocket presents a promising target for
future development of small molecule inhibitors that, for example, could
irreversibly lock S in the closed conformation and interfere with recep-
tor interactions.

Turoňová B, Sikora M, Schürmann C, et al. In situ structural analysis of SARS-CoV-2 spike

reveals flexibility mediated by three hinges. Science 2020, published 18 August. Full-
text: https://science.sciencemag.org/content/early/2020/08/17/science.abd5223
This work shows that the stalk domain of S contains three hinges, allow-
ing S to scan the host cell surface, shielded from antibodies by an exten-
sive glycan coat.

Binding to ACE
Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to
the ACE2 receptor. Nature. Published: 30 March 2020. Full-text:
https://www.nature.com/articles/s41586-020-2180-5
To elucidate the SARS-CoV-2 RBD and ACE2 interaction at a higher reso-
lution/atomic level, authors used X-ray crystallography. Binding mode
was very similar to SARS-CoV, arguing for a convergent evolution of
both viruses. The epitopes of two SARS-CoV antibodies targeting the
RBD were also analysed with the SARS-CoV-2 RBD, providing insights in-
to the future identification of cross-reactive antibodies.

Wang Q, Zhang Y, Wu L, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using
Human ACE2. Cell. 2020 Apr 7. PubMed: https://pubmed.gov/32275855. Full-text:
https://doi.org/10.1016/j.cell.2020.03.045
Atomic details of the crystal structure of the C-terminal domain of SARS-
CoV-2 spike protein in complex with human ACE2 are presented. The
hACE2 binding mode of SARS-CoV-2 seems to be similar to SARS-CoV,
but some key residue substitutions slightly strengthen the interaction
and lead to higher affinity for receptor binding. Antibody experiments
indicated notable differences in antigenicity between SARS-CoV and
SARS-CoV-2

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Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2
by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-1448. PubMed:
https://pubmed.gov/32132184. Full-text: https://doi.org/10.1126/science.abb2762
Using cryo–electron microscopy, this paper shows how SARS-CoV-2
binds to human cells. The first step in viral entry is the binding of the vi-
ral trimeric spike protein to the human receptor angiotensin-converting
enzyme 2 (ACE2). The authors present the structure of human ACE2 in
complex with a membrane protein that it chaperones, B0AT1. The struc-
tures provide a basis for the development of therapeutics targeting this
crucial interaction.

Starr TN, Greaney AJ, Hilton SK, et al. Deep mutational scanning of SARS-CoV-2 receptor
binding domain reveals constraints on folding and ACE2 binding. Cell August 11, 2020.
Full-text: https://doi.org/10.1016/j.cell.2020.08.012
The authors have systematically changed every amino acid in the RBD
and determine the effects of the substitutions on Spike expression, fold-
ing, and ACE2 binding. The work identifies structurally constrained re-
gions that would be ideal targets for COVID-19 countermeasures and
demonstrates that mutations in the virus which enhance ACE2 affinity
can be engineered but have not, to date, been naturally selected during
the pandemic.

Yang J, Petitjean SJL, Koehler M. Molecular interaction and inhibition of SARS-CoV-2 binding
to the ACE2 receptor. Nat Commun 11, 4541 (2020). Full-text:
https://doi.org/10.1038/s41467-020-18319-6
How the receptor binding domain serves as the binding interface within
the S-glycoprotein with the ACE2 receptor. Kinetic and thermodynamic
properties of this binding pocket.

Cell entry
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and
TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4.
PubMed: https://pubmed.gov/32142651. Fulltext:
https://doi.org/10.1016/j.cell.2020.02.052
This work shows how viral entry happens. SARS-CoV-2 uses the SARS-
CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S pro-
tein priming. In addition, sera from convalescent SARS patients cross-
neutralized SARS-2-S-driven entry.

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Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for
SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020 Apr;5(4):562-569.
PubMed: https://pubmed.gov/32094589. Full-text: https://doi.org/10.1038/s41564-020-0688-y
Important work on viral entry, using a rapid and cost-effective platform
which allows to functionally test large groups of viruses for zoonotic po-
tential. Host protease processing during viral entry is a significant barri-
er for several lineage B viruses. However, bypassing this barrier allows
several coronaviruses to enter human cells through an unknown recep-
tor.

Ou X, Liu Y, Lei X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry

and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020 Mar 27;11(1):1620.
PubMed: https://pubmed.gov/32221306. Fulltext: https://doi.org/10.1038/s41467-020-
15562-9
More on viral entry and on (the limited) cross-neutralization between
SARS-CoV and SARS-CoV-2.

Yuan M, Wu NC, Zhu X, et al. A highly conserved cryptic epitope in the receptor-binding
domains of SARS-CoV-2 and SARS-CoV. Science. 2020 Apr 3. PubMed:
https://pubmed.gov/32245784. Full-text: https://doi.org/10.1126/science.abb7269
Insights into antibody recognition and how SARS-CoV-2 can be targeted
by the humoral response, revealing a conserved epitope shared between
SARS-CoV and SARS-CoV-2. This epitope could be used for vaccines and
the development of cross-protective antibodies.

Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis
for design of improved alpha-ketoamide inhibitors. Science. 2020 Mar 20. PubMed:
https://pubmed.gov/32198291. Fulltext: https://doi.org/10.1126/science.abb3405
Description of the X-ray structures of the main protease (Mpro, 3CLpro)
of SARS-CoV-2 which is essential for processing the polyproteins that are
translated from the viral RNA. A complex of Mpro and an optimized pro-
tease α-ketoamide inhibitor is also described.

Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry
and infectivity. Science 2020, published 20 October. Full-text:
https://doi.org/10.1126/science.abd2985
Neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significant-
ly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal
blocking antibody against NRP1.

Daly JL, Simonetti B, Klein K, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection.
Science 2020, published 20 October. Full-text: https://doi.org/10.1126/science.abd3072
More on how S binds to cell surface neuropilin-1 (NRP1) and neuropilin-2
(NRP2) receptors.

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RNA-dependent RNA polymerase (RdRp)

Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-
19 virus. Science. 15 May 2020: Vol. 368, Issue 6492, pp. 779-782. Full-text:
https://doi.org/10.1126/science.abb7498
Using cryogenic electron microscopy, the authors describe the structure
of the RNA-dependent RNA polymerase, another central enzyme of the
viral replication machinery. It is also shown how remdesivir and sofos-
buvir bind to this polymerase. The authors determined a 2.9-angstrom-
resolution structure of the RNA-dependent RNA polymerase (also known
as nsp12), which catalyzes the synthesis of viral RNA, in complex with
two cofactors, nsp7 and nsp8.

Hillen HS, Kokic G, Farnung L et al. Structure of replicating SARS-CoV-2 polymerase. Nature
2020. Full-text: https://doi.org/10.1038/s41586-020-2368-8
The cryo-electron microscopic structure of the SARS-CoV-2 RdRp in ac-
tive form, mimicking the replicating enzyme. Long helical extensions in
nsp8 protrude along the exiting RNA, forming positively charged ‘sliding
poles’. These sliding poles can account for the known processivity of the
RdRp that is required for replicating the long coronavirus genome. A
nice video provides an animation of the replication machine.

Chen J, Malone B, Llewellyn E, et al. Structural basis for helicase-polymerase coupling in the
SARS-CoV-2 replication-transcription complex. Cell 2020, 27 July, 2020. Full-text:
https://doi.org/10.1016/j.cell.2020.07.033
A cryo-electron microscopic structure of the SARS-CoV-2 holo-RdRp with
an RNA template-product with two molecules of the nsp13 helicase and
identify a new potential target for future antiviral drugs.

Wolff G, Limpnes RW, Zevenhoven-Dobbe JC, et al. A molecular pore spans the double mem-
brane of the coronavirus replication organelle. Science 06 Aug 2020: eabd3629. Full-
text: https://doi.org/10.1126/science.abd3629
Coronavirus replication is associated with virus-induced cytosolic dou-
ble-membrane vesicles, which may provide a tailored micro-
environment for viral RNA synthesis in the infected cell. Visualization of
a molecular pore complex that spans both membranes of the double-
membrane vesicle and would allow export of RNA to the cytosol. Alt-
hough the exact mode of function of this molecular pore remains to be
elucidated, it would clearly represent a key structure in the viral replica-
tion cycle that may offer a specific drug target.

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Animals and animal models

Bao L, Deng W, Huang B, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.
Nature. 2020 May 7. PubMed: https://pubmed.gov/32380511. Full-text:
https://doi.org/10.1038/s41586-020-2312-y
In transgenic mice bearing human ACE2 and infected with SARS-CoV-2,
the pathogenicity of the virus was demonstrated. This mouse model will
be valuable for evaluating antiviral therapeutics and vaccines as well as
understanding the pathogenesis of COVID-19.

Chan JF, Zhang AJ, Yuan S, et al. Simulation of the clinical and pathological manifestations of
Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications
for disease pathogenesis and transmissibility. Clin Infect Dis. 2020 Mar 26. PubMed:
https://pubmed.gov/32215622. Fulltext: https://doi.org/10.1093/cid/ciaa325
A readily available hamster model as an important tool for studying
transmission, pathogenesis, treatment, and vaccination against SARS-
CoV-2.

Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge
in rhesus macaques. Science. 2020 May. PubMed: https://pubmed.gov/32434946. Full-text:
https://doi.org/10.1126/science.abc4776
No re-infection in macaques. Following initial viral clearance, 9 rhesus
macaques were re-challenged on day 35 with the same doses of virus that
were utilized for the primary infection. Very limited viral RNA was ob-
served in BAL on day 1 after re-challenge, with no viral RNA detected at
subsequent timepoints. These data show that SARS-CoV-2 infection in-
duced protective immunity against re-exposure in nonhuman primates.

Halfman PJ, Hatta M, Chiba S, et al. Transmission of SARS-CoV-2 in Domestic Cats. NEJM May
13, 2020. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMc2013400
Three domestic cats were inoculated with SARS-CoV-2. One day later, an
uninfected cat was cohoused with each of the inoculated cats. All six cats
became infected and developed antibody titers but none showed any
symptoms. Cats may be a silent intermediate host.

Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in
a nonhuman primate model. Science 17 Apr 2020. Full text:
https://science.sciencemag.org/content/early/2020/04/16/science.abb7314
Macaques may serve as a model to test therapeutic strategies. Virus was
excreted from nose and throat in the absence of clinical signs, and was
detected in type I and II pneumocytes in foci of diffuse alveolar damage
and in ciliated epithelial cells of nasal, bronchial, and bronchiolar muco-
sae. In SARS-CoV infection, lung lesions were typically more severe,
while they were milder in MERS-CoV infection, where virus was detected
mainly in type II pneumocytes.

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Munster VJ, Feldmann F, Williamson BN, et al. Respiratory disease in rhesus macaques inocu-
lated with SARS-CoV-2. Nature 2020. Full-text: https://doi.org/10.1038/s41586-020-2324-7
SARS-CoV-2 caused respiratory disease in 8 rhesus macaques, lasting 8-
16 days. High viral loads were detected in swabs as well as in bron-
choalveolar lavages. This “model” recapitulates COVID-19, with regard to
virus replication and shedding, the presence of pulmonary infiltrates,
histological lesions and seroconversion.

Sia SF, Yan L, Chin AWH. et al. Pathogenesis and transmission of SARS-CoV-2 in golden ham-
sters. Nature 2020. Full-text: https://doi.org/10.1038/s41586-020-2342-5
In most cases, you don’t need monkeys. Golden Syrian hamsters may also
work. SARS-CoV-2 transmitted efficiently from inoculated hamsters to
naïve hamsters by direct contact and via aerosols. Transmission via fom-
ites in soiled cages was less efficient. Inoculated and naturally-infected
hamsters showed apparent weight loss, and all animals recovered with
the detection of neutralizing antibodies.

Sit TH, Brackman CJ, Ip SM et al. Infection of dogs with SARS-CoV-2. Nature 2020. Full-text:
https://www.nature.com/articles/s41586-020-2334-5
Two out of fifteen dogs (one Pomeranian and one German Shepherd)
from households with confirmed COVID-19 cases in Hong Kong were
found to be infected. Both dogs remained asymptomatic but later devel-
oped antibody responses detected using plaque reduction neutralization
assays. Genetic analysis suggested that the dogs caught the virus from
their owners. It still remains unclear whether infected dogs can transmit
the virus to other animals or back to humans.

Dinnon KH, Leist SR, Schäfer A et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19
countermeasures. Nature, August 27, 2020. Full-text: https://doi.org/10.1038/s41586-020-
2708-8
Unfortunately, standard laboratory mice do not support infection with
SARS-CoV-2 due to incompatibility of the S protein to the murine
ortholog (mACE2) of the human receptor. This work has developed a re-
combinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry.
This model may be helpful in studying COVID-19 pathogenesis.

Muñoz-Fontela C, Dowling WE, Funnell SGP, et al. Animal models for COVID-19. Nature. 2020
Sep 23. PubMed: https://pubmed.gov/32967005. Full-text: https://doi.org/10.1038/s41586-
020-2787-6
Mice, hamsters, ferrets, minks, cats, pigs, fruit bats, monkeys: a variety
of murine models for mild and severe COVID-19 have been described or
are under development. All will be useful for vaccine and antiviral evalu-

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ation and some share features with the human disease. Review (per-
formed by a huge international collaboration).

Vaccine (see also Immunology)

Le TT, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nature
reviews drug discovery. 09 April 2020. Full-text: https://www.nature.com/articles/d41573-
020-00073-5.
Brief data-driven overview by seven experts. The conclusion is that ef-
forts are unprecedented in terms of scale and speed and that there is an
indication that vaccine could be available by early 2021. As of 8 April
2020, the global vaccine landscape includes 115 candidates, of which the
5 most advanced candidates have already moved into clinical develop-
ment, including mRNA-1273 from Moderna, Ad5-nCoV from CanSino Bio-
logics, INO-4800 from Inovio, LV-SMENP-DC and pathogen-specific aAPC
from Shenzhen Geno-Immune Medical Institute. The race is on!

Callaway E. The race for coronavirus vaccines: a graphical guide, Eight ways in which scien-
tists hope to provide immunity to SARS-CoV-2. Nature 2020, 28 April 2020. 580, 576-577.
Full-text: https://doi.org/10.1038/d41586-020-01221-y
Fantastic graphic review on current vaccine development. Easy to under-
stand, it explains different approaches such as virus, viral-vector, nucle-
ic-acid and protein-based vaccines.

Zhu FC, Li YH, Guan XH. Safety, tolerability, and immunogenicity of a recombinant adenovi-
rus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-
randomised, first-in-human trial. Lancet May 22, 2020. Full-text:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31208-3/fulltext
Open label Phase I trial of an Ad5 vectored COVID-19 vaccine, using the
full-length spike glycoprotein. A total of 108 healthy adults aged between
18 and 60 years from Wuhan, China, were given three different doses.
ELISA antibodies and neutralising antibodies increased significantly and
peaked 28 days post-vaccination. Specific T cell response peaked at day
14 post-vaccination. Follow up is still short and authors are going to fol-
low up the vaccine recipients for at least 6 months, so more data will be
obtained. Of note, adverse events were relatively frequent, encompassing
pain at injection sites (54%), fever (46%), fatigue (44%) and headache
(39%). Phase II studies are underway.

Pathogenesis
Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2
Drives Development of COVID-19. Cell May 15, 2020. Full-text:
https://doi.org/10.1016/j.cell.2020.04.026

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Incredible in-depth analysis of host response to SARS-CoV-2 and other

human respiratory viruses in cell lines, primary cell cultures, ferrets, and
COVID-19 patients. Data consistently revealed a unique and inappropri-
ate inflammatory response to SARS-CoV-2 which is imbalanced with re-
gard to controlling virus replication versus activation of the adaptive
immune response. It is defined by low levels of type I and III interferons
juxtaposed to elevated chemokines and high expression of IL-6. The au-
thors propose that reduced innate antiviral defenses coupled with exu-
berant inflammatory cytokine production are the defining and driving
features of COVID-19. Given this dynamic, treatments for COVID-19 have
less to do with the IFN response and more to do with controlling inflam-
mation.

Bordoni V, Sacchi A, Cimini E. An inflammatory profile correlates with decreased frequency

of cytotoxic cells in COVID-19. Clinical Infectious Diseases 2020, May 15. Full-text:
https://doi.org/10.1093/cid/ciaa577
The increase in inflammatory mediators is correlated with a reduction of
innate and adaptive cytotoxic antiviral function. The authors found a
lower perforin+ NK cell number in 7 intensive care unit (ICU) patients
compared to 41 non-ICU patients, suggesting an impairment of the im-
mune cytotoxic arm as a pathogenic mechanism.

Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 corona-
virus in humans with COVID-19 disease and unexposed individuals. Cell 2020. Full-text:
https://doi.org/10.1016/j.cell.2020.05.015
Cellular response is a major knowledge gap. This important study identi-
fied circulating SARS-CoV-2−specific CD8 and CD4 T cells in 70-100% of 20
COVID-19 convalescent patients, respectively. CD4 T cell responses to
spike protein were robust and correlated with the magnitude of IgG ti-
ters. Of note, the authors detected SARS-CoV-2−reactive CD4 T cells in 40-
60% of unexposed individuals, suggesting cross-reactive T cell recogni-
tion between circulating seasonal coronaviruses and SARS-CoV-2.

Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet.
2020 May 9;395(10235):1517-1520. PubMed: https://pubmed.gov/32311318. Full-text:
https://doi.org/10.1016/S0140-6736(20)30920-X
Brief but nice review and several hypotheses about SARS-CoV-2 patho-
genesis. What happens during the second week - when resident macro-
phages initiating lung inflammatory responses are unable to contain the
virus after SARS-CoV-2 infection and when both innate and adaptive
immune responses are inefficient to curb the viral replication so that the
patient would recover quickly?

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Shen B, Yi X, Sun Y, et al. Proteomic and Metabolomic Characterization of COVID-19 Patient

Sera. Cell May 27, 2020. Full-text:
https://www.sciencedirect.com/science/article/pii/S0092867420306279
Molecular insights into the pathogenesis of SARS-CoV-2 infection. The
authors applied proteomic and metabolomic technologies to analyze the
proteome and metabolome of sera from COVID-19 patients and several
control groups. Pathway analyses and network enrichment analyses of
the 93 differentially expressed proteins showed that 50 of these proteins
belong to three major pathways, namely activation of the complement
system, macrophage function and platelet degranulation. It was found
that 80 significantly changed metabolites were also involved in the three
biological processes revealed in the proteomic analysis.

Tay MZ, Poh CM, Rénia L et al. The trinity of COVID-19: immunity, inflammation and inter-
vention. Nat Rev Immunol (2020). Full-text: https://www.nature.com/articles/s41577-020-
0311-8
Brilliant overview of the pathophysiology of SARS-CoV-2 infection. How
SARS-CoV-2 interacts with the immune system, how dysfunctional im-
mune responses contribute to disease progression and how they could be
treated.

Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: current state of the science.
Immunity 2020, May 05. Full-text: https://www.cell.com/immunity/fulltext/S1074-
7613(20)30183-7
Fantastic review on the current knowledge of innate and adaptive im-
mune responses elicited by SARS-CoV-2 infection and the immunological
pathways that likely contribute to disease severity and death.

Other key papers

Monto AS, DeJonge P, Callear AP, et al. Coronavirus occurrence and transmission over 8 years
in the HIVE cohort of households in Michigan. J Infect Dis. 2020 Apr 4. PubMed:
https://pubmed.gov/32246136. Full-text: https://doi.org/10.1093/infdis/jiaa161
It’s not clear whether SARS-CoV-2 behaves like other human corona-
viruses (hCoVs). A longitudinal surveillance cohort study of children and
their households from Michigan found that hCoV infections were sharply
seasonal, showing a peak for different hCoV types (229E, HKU1, NL63,
OC43) in February. Over 8 years, almost no hCoV infections occurred af-
ter March.

Thao TTN, Labroussaa F, Ebert N, et al. Rapid reconstruction of SARS-CoV-2 using a synthetic
genomics platform. Nature. 2020 May 4. PubMed: https://pubmed.gov/32365353. Full-
text: https://doi.org/10.1038/s41586-020-2294-9
An important technical advance, enabling the rapid generation and func-
tional characterization of evolving RNA virus variants. The authors show

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the functionality of a yeast-based synthetic genomics platform to genet-

ically reconstruct diverse RNA viruses (which are cumbersome to clone
and manipulate due to size and instability). They were able to engineer
and resurrect chemically-synthetized clones of SARS-CoV-2 only a week
after receipt of the synthetic DNA fragments.

Gordon DE, Hiatt J, Bouhaddou M, et al. (Total: 200 authors) Comparative host-coronavirus
protein interaction networks reveal pan-viral disease mechanisms. Science 2020, pub-
lished 15 October. Full-text: https://doi.org/10.1126/science.abe9403
A group of 200 researchers uncovers molecular processes used by coro-
naviruses MERS, SARS-CoV1 and SARS-CoV2 to manipulate host cells.

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5. Vaccines
Thomas Kamradt
Bernd Sebastian Kamps

Advanced SARS-CoV-2 Candidates

The development of SARS-CoV-2 vaccines will one day be recorded as one of
the greatest research efforts in science. Never before have so many vaccines
moved so quickly into trials for one disease (Dagotto 2020). More people will
be able to get vaccinated more quickly than ever before.
An ideal pandemic vaccine would be acceptably safe for everyone, effective in
inducing a durable protective immune response, rapidly scalable, stable at
room temperature, single dose and cost effective (Bingham 2020). The current
situation:
1. On 1 November 2020, 10 SARS-CoV-2 vaccines had reached Phase III
development (Table 1 and page 208). The first preliminary trial re-
sults are expected soon.
2. So far, no vaccine has been approved after thorough clinical testing.
(The “approvals” in Russia and China do not meet state-of-the-art
approval criteria after thorough safety and efficacy testing.)
3. If a vaccine is shown to be both effective and safe, it will first be of-
fered to risk groups and essential professionals (medical staff, elderly
people, police, fire fighters, etc.)
4. Massive nationwide vaccine campaigns will not be available until
well into 2021.
5. Massive global vaccine campaigns are unlikely to have a more than
marginal impact on the SARS-CoV-2 pandemic before 2022, if ever.
Data from Phase II trials show that adverse effects, although generally not
severe, are nonetheless frequent (rule of thumb: 50%) – pain at injection site,
hyperthermia, headache, asthenia, muscle and joint pain (Folegatti 2020, Zhu
2020, Jackson 2020, Mulligan 2020, Logunov 2020). The “Big Three” vaccines
in Phase III for which results are expected within the next months are:
• BNT162b2 (BioNTech/Pfizer/Fosun)
• ChAdOx1 (University of Oxford/AstraZeneca)
• mRNA-1273 (Moderna/NIH)

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Table 1. Vaccines in Phase III trials*

Developer Candidate Vaccine Reference News

vaccine platform release

AstraZeneca / Oxford ChAdOx1 Non- Folegatti 28 June ‘20

University replicating 2020
(NCT04324606) vector

Pfizer / BioNTech / BNT162b1 RNA Mulligan 27 July ‘20

Fosun 2020
(NCT04368728)

Moderna / NIAID mRNA-1273 RNA Jackson 27 July ‘20

(NCT04283461) 2020

Sinovac Biotech CoronaVac Inactivated Gao 2020 6 July ‘20

(NCT04352608)

CanSino Biologics / CTII-nCoV Replication- Zhu 2020

Beijing Institute of incompetent
Biotechnology vector
(NCT04341389)

Wuhan Institute of Inactivated Xia S 2020

Biological Products /
Sinopharm
(ChiCTR2000031809)

Beijing Institute of Inactivated

Biological Products /
Sinopharm

Novavax NVX-CoV2373 Replication- Keech 2020 2 Sep ‘20

(NCT04533399) incompetent
vector

Janssen (Johnson & Ad26.COV2.S Mercado NYTimes

Johnson; 2020 17 July ‘20
NCT04505722)

Gamaleya Research Sputnik V Replication- Logunov NYTimes

Institute incompetent 2020, Bucci 11 August
(NCT04530396) vector 2020 ‘20

* In Phase III trials, a vaccine is given to tens of thousands of people (50% will receive the
true vaccine, 50% will receive a placebo injection) in order to show efficacy and reveal
evidence of relatively rare side effects that might have been missed in earlier studies. The
FDA expects that an acceptable COVID-19 vaccine would prevent disease or decrease its
severity in at least 50% of people who are vaccinated (FDA 20200630).

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The Future of SARS-CoV-2 vaccines

Questions
The questions which are currently being addressed in Phase III vaccine trials
have been summarized by Naor Bar-Zeev and William Moss (Bar-Zeev 2020):
• Will a single dose be sufficient in older adults, or is a booster dose re-
quired?
• Does longevity of response or rates of waning differ with a two-dose
regimen, and does longevity of clinical protection require cell-
mediated responses?
• Are there host-specific differences in immunogenicity by age, sex, or
ethnicity?
• Do T cell responses correlate with protection irrespective of antibody
titers?
• Are there specific adverse events in pregnant women?
After the beginning of mass vaccinations, more questions will arise:
• How will risk groups fare (e.g. elderly people with hypertension, dia-
betes, obesity, etc.)?
• Are re-vaccinations needed at regular intervals?
• Will SARS-CoV-2 mutate so that the vaccines will have to be adapted
like the annual flu vaccines?

Vaccine Approval
As of 1 November 2020, no vaccine had been approved after thorough safety
and efficacy testing.

Efficacy
WHO recommends that successful vaccines should show an estimated risk
reduction of at least one-half (WHO 20200409). Well aware of the fact that
rushing an ineffective or unsafe vaccine to the market could do substantial
damage to people and their reputation, on 8 September 2020, nine pharma-
ceutical companies (AstraZeneca, BioNTech, Pfizer, Moderna, Glax-
oSmithKline, Johnson & Johnson, Merck, Novavax and Sanofi) issued a joint
pledge that they would “stand with science” and not put forward a vaccine
until it had been thoroughly vetted for safety and efficacy (Thomas 2020).

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Humane challenge studies

Human challenge studies (HCS) could assess the effectiveness of experimental
vaccines more rapidly and thereby accelerate vaccine development. The pro-
spect of deliberately infecting young adults — even those at low risk of severe
disease — with SARS-CoV-2, a deadly pathogen that has few proven treat-
ments, is uncharted medical and bioethical territory (Callaway 2020, Deming
2020). Typically, undertaking human challenge studies in vaccine develop-
ment requires that the disease for which a challenge would be introduced
either has an available rescue therapy to treat those who become infected or
the disease is known to be self-limiting (Kahn 2020).
In the UK, the first COVID-19 human challenge studies could begin in January
2021. The first phase aims to discover the smallest amount of virus it takes to
cause the infection in up to 90 healthy young people, aged between 18 and 30
years, who are at the lowest risk of harm from COVID-19 (Kirky 2020, Cookson
2020).
WHO has published criteria for the ethical acceptability of COVID-19 human
challenge studies (WHO 20200506). An ethical study design would involve
healthy participants in inpatient settings with immediate access to high-
quality health care and strict infection control measures (Jamrozik 2020).
Some authors argue that human challenge studies face unacceptable ethics
challenges, and, further, undertaking them would do a disservice to the pub-
lic by undermining already strained confidence in the vaccine development
process (Kahn 2020). If the studies procede, it will be interesting to under-
stand the relationship between efficacy data from human challenge studies in
young individuals and protection of the elderly – the population which is at
highest risk from SARS-CoV-2 infection (Hodgson 2020).

Setbacks
Vaccine development is fraught with obstacles. As demonstrated by the ChA-
dOx1 experience (Oxford/AstraZeneca), serious adverse events can at any
time grind a trial to a halt (Phillips 2020). Should a tranverse myelitis (Shah
2020) be recognized as triggered by the vaccine, the trial would be stopped
immediately. Vaccine-related adverse events, either debilitating or fatal,
might even be recognized years after approval and lead to the withdrawel of
the vaccine. Both the public and vaccine developers should be prepared for
unanticipated turns in the COVID Vaccine Saga. There is a piece of good news,
though: the D614G mutation of the SARS-CoV-2 spike protein does not seem
to affect adversely the efficacy of vaccines (McAuley 2020).

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Vaccine distribution
Access to a safe vaccine might be unequal, both within countries and between
them. Within countries, health authorities will prepare strategic prioritiza-
tion plans (Lipsitch 2020). Vaccines will be offered first to healthcare workers;
then to people at high risk of severe COVID-19 and maybe those living in epi-
demiological hotspots; and, finally, to the rest of the population – if they want
to get vaccinated (Schwartz 2020, Bingham 2020). Between countries, there is
no doubt that those that produce vaccines will get the vaccine before coun-
tries that don’t. On 24 August 2020, wealthy countries had pre-ordered
around two billion vaccine doses without knowing which one may prove ef-
fective (see an overview of the August situation in Callaway 2020). However, it
is not acceptable that low-risk people in wealthy countries get the vaccine
while health care workers in low- and middle-income countries do not. To
avoid such a scenario, GAVI, the Vaccine Alliance (a Geneva-based funder of
vaccines for low-income countries), the Coalition for Epidemic Preparedness
Innovation (CEPI2) and the World Health Organization have set up the COVID-
19 Vaccines Global Access (COVAX) Facility (Kupferschmidt 2020, Jeyanathan
2020). COVAX aims to accelerate the development and manufacture of
COVID-19 vaccines, and to guarantee fair and equitable access for every coun-
try in the world by securing 2 billion vaccine doses. One billion have already
been reserved for 92 low- and middle-income countries and economies
(LMICS), which make up half the world’s population.

Impact of vaccines on the pandemic

A vaccine against SARS-CoV-2 might act against infection, disease, or trans-
mission and a vaccine capable of reducing any of these elements could con-
tribute to disease control (Hodgson 2020). It is too early to predict if SARS-
CoV-2 vaccines will have a measurable impact on the course of the SARS-CoV-
2 pandemic over the coming years.

2
The Coalition for Epidemic Preparedness Innovation (CEPI), an international
nongovernmental organization funded by the Wellcome Trust, the Bill and
Melinda Gates Foundation, the European Commission, and eight countries (Aus-
tralia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United
Kingdom), is supporting development of vaccines against five epidemic patho-
gens on the World Health Organization (WHO) priority list (Lurie 2020).

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Vaccines in Phase III

ChAdOx1
ChAdOx1, developed by the University of Oxford, AstraZeneca and the Serum
Institute of India, uses replication-deficient simian adenovirus vector ChA-
dOx1 which contains the full-length, unmodified structural surface glycopro-
tein (spike protein) of SARS-CoV-2. Results from a Phase I/II randomized trial
showed that in ChAdOx1 vaccinees, T cell responses peaked on day 14, anti-
spike IgG responses rose by day 28, and neutralizing antibody responses
against SARS-CoV-2 were detected in > 90%. Adverse events such as fatigue,
headache, and local tenderness commonly occurred, but there were no seri-
ous adverse events (Folegatti 2020).

BNT162b1
BNT162b1, developed by BioNTech, Pfizer and Fosun, is a lipid nanoparticle-
formulated, nucleoside-modified mRNA vaccine 3 that encodes trimerized
SARS-CoV-2 spike glycoprotein receptor-binding domain. Early studies indi-
cated that well-tolerated dose levels of BNT162b1 efficiently elicited high ti-
ter, broad serum neutralizing responses, Th1 phenotype CD4+ T helper cell
responses, and strong interferon γ and interleukin-2 producing CD8+ cytotox-
ic T-cell responses (Sahin 2020, Mulligan 2020). On 27 July, the companies
announced a Phase II/III trial with 30,000 volunteers in the US, Germany, Ar-
gentina, and Brazil, among others. If the clinical studies are successful, BioN-
Tech and Pfizer want to apply for approval of the vaccine as early as this year.
If approved, BioNTech, Pfizer and Fosun could manufacture up to 100 million
vaccine doses by the end of 2020 and over 1.3 billion by the end of 2021.

3
mRNA vaccines: Two mRNA vaccine formulations against COVID-19 have
now been tested in tens of thousands of volunteers: one developed by a col-
laboration between Pfizer and BioNTech, and the other by Moderna and the
National Institute of Allergy and Infectious Diseases (NIAID) in the US (Nat
Biomed Eng 2020). mRNA vaccines like BNT162b2 have the potential to be
truly transformative but have never been tested in large-scale human trials;
see Abbasi 2020 for a tour of mRNA vaccines today and beyond COVID-19. Bi-
oNTech, Moderna, CureVac and GSK own nearly half of the mRNA vaccine
patent applications (Martin 2020).

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mRNA-1273
mRNA-1273, developed by Moderna, is a lipid nanoparticle–encapsulated,
nucleoside-modified messenger RNA (mRNA)–based vaccine that encodes the
SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation.
mRNA-1273 induced potent neutralizing antibody responses to both wild type
(D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and
protects against SARS-CoV-2 infection in mice (Corbett 2020) and non-human
primates (Corbett 2020b). In early clinical trials, it induced anti–SARS-CoV-2
immune responses in all participants, and no trial-limiting safety concerns
were identified (Jackson 2020). The Phase III trial, launched on 27 July 2020,
will enroll 30,000 healthy people in the US.

CoronaVac (Sinovac)
CoronaVac© is an inactivated virus vaccine developed by Sinovac Biotech, Ltd.
In macaques, the vaccine provided partial or complete protection against a
SARS-CoV-2 challenge (Gao 2020). In September 2020, the company reported
data from healthy adults aged 60 years and above in Phase I/II clinical trials
where the seroconversion rate for elderly participants would have been com-
parable to that in a group of 18 to 59 years healthy people. The data have not
yet been published in a peer-reviewed journal. Phase III trials enrolled 24,000
people in Brazil, Indonesia and Turkey. Enrolment of children younger than
18 started in September 2020. The company is planning to produce 300 mil-
lion vaccine doses in 2021.

CTII-nCoV
CTII-nCoV, developed by CanSino Biologics in partnership with the Institute
of Biology at the Chinese Academy of Military Medical Sciences, is based on
an adenovirus called Ad5. Results from Phase II trials demonstrated that the
vaccine produced significant neutralizing antibody responses to live SARS-
CoV-2 (Zhu 2020). In a Phase II trial, a single injection of the Ad5-vectored
COVID-19 vaccine at 1 × 1011 viral particles and 5 × 1010 viral particles induced
comparable specific immune responses to the spike glycoprotein at day 28.
Positive specific T cell responses were found in 90% and 88% of participants
receiving the vaccine at 1 × 1011 and 5 × 1010 viral particles, respectively. 95%
of participants in the 1 × 1011 viral particles dose group and 91% of the recipi-
ents in the 5 × 1010 viral particles dose group showed either cellular or hu-
moral immune responses at day 28 post- vaccination (Zhu 2020). The authors
found that compared with the younger population, older people had a signifi-
cantly lower immune response, but higher tolerability, to the Ad5-vector
COVID-19 vaccine. Pre-existing immunity to the Ad5 vector and increasing

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age could partially hamper the specific immune responses to vaccination,

particularly for the humoral immune responses. Adverse events such as fever,
fatigue, headache, or local site pain were comparable to the ChAdOx1 study
above.
On 25 June, the Chinese military approved the vaccine for a year as a “special-
ly needed drug.” CanSino would not say whether vaccination was to be man-
datory or optional for soldiers.

Wuhan Institute vaccine

An inactivated virus vaccine developed by the Wuhan Institute of Biological
Products, put into clinical trials by the state-owned Chinese company Si-
nopharm, showed that the vaccine produced antibodies in volunteers (Xia S
2020). Some volunteers experienced fevers and other side effects. Phase III
trials are under way in China, Peru, Morocco and the United Arab Emirates.

Beijing Institute vaccine

Another inactivated virus vaccine developed by the Beijing Institute of Bio-
logical Products (again put into clinical trials by Sinopharm), is currently be-
ing tested in Phase III trials in China and in the United Arab Emirates.

NVX-CoV2373
NVX-CoV2373, developed by Novavax, is a recombinant nanoparticle vaccine
(rSARS-CoV-2) composed of trimeric full-length SARS-CoV-2 spike glycopro-
teins and Matrix-M1 adjuvant (Keech 2020). In a Phase I/II trial, the vaccine
induced levels of neutralizing antibodies that closely correlated with anti-
spike IgG. After the second vaccination neutralizing antibody responses ex-
ceeded values seen in symptomatic COVID-19 outpatients and were of the
magnitude seen in convalescent serum from hospitalized patients with
COVID-19.

Ad26.COV2.S
Ad26.COV2.S, developed by Janssen, is a recombinant replication-
incompetent adenovirus type 26 (Ad26) vector-based COVID-19 vaccine en-
coding a prefusion-stabilized SARS-CoV-2 Spike immunogen. Its potency in
eliciting protective immunity against SARS-CoV-2 infection was successfully
demonstrated in a non-human primate challenge model (Mercado 2020).
Ad26.COV2.S induced robust neutralizing antibody responses and provided
complete protection against a SARS-CoV-2 challenge in five out of six rhesus
macaques and near-complete protection in one out of six macaques (Mercado
2020). The vaccine platform for the development of this optimized S protein-

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based vaccine has been recently described (Bos 2020). A Phase III study plans
to enrol up to 60,000 participants.

Sputnik V
Sputnik V (formerly Gam-COVID-Vac Lyo), developed by the Gamaleya Re-
search Institute, is a combination of two adenoviruses, Ad5 and Ad26, each
carrying an S antigen of the new coronavirus. Phase III trials, initially
planned for just 2,000 volunteers, were expanded to 40,000.

Immunization Fundamentals
The SARS-CoV-2 pandemic and the unprecedented research effort to develop
multiple vaccines on different platforms is a good occasion to recall some
immunization fundamentals. Recovery from infections often induces long-
term and sometimes life-long immunity against the causative pathogen. After
the resolution of the infection, immunological memory protects against re-
infection and is mediated by specific antibodies and T-cells.
In contrast, immunizations confer immunity without exposure to virulent
pathogens. Immunization can be passive or active. In passive immunisation
protective antibodies are transfered from a donor into a recipient whereas
active immunization induces a protective immune response in the recipient.

Passive immunization against SARS-CoV-2

Passive immunization against SARS-CoV-2 can be achieved with convalescent
plasma or with neutralizing monoclonal antibodies.

Convalescent plasma
Treatment with human convalescent plasma (CP) is based on the assumption
that protective antibodies against the causative pathogen are present in the
blood of people who have overcome an infectious disease. For example, CP
has been used to treat some infectious diseases such as Argentine hemorrhag-
ic fever (Casadevall 2004). CP was also used to treat SARS patients in the
2002/2003 epidemic but not in controlled clinical studies; a later meta-
analysis concluded that the treatment was probably safe and perhaps helpful
(Mair-Jenkins 2015).
CP could become an option for prevention and treatment of COVID-19 disease
when there are sufficient numbers of people who have recovered and can
donate immunoglobulin-containing serum (Casadevall 2020). Antibodies that
are found in CP are very stable. Pathogen inactivation (using psoralen and UV
light) did not impair the stability and neutralizing capacity of SARS-CoV-2-

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specific antibodies that was also preserved at 100% when the plasma was
shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma
for up to 9 days (Tonn 2020). However, in a recently published open label
randomized controlled trial (the largest to date with results) 464 patients
were assigned either to two doses of 200 mL CP or best standard of care only.
The result was sobering: progression to severe disease or all-cause mortality
at 28 days after enrolment occurred in 44 (19%) participants in the CP arm
and 41 (18%) in the control arm (Agarwal 2020).
The major caveat of CP is quantity and quality of antibody titers. In plasma
from 149 patients collected on average 39 days after the onset of symptoms,
neutralizing titers were extremely variable. Most plasmas did not contain
high levels of neutralizing activity (Robbiani 2020). There seems to be a corre-
lation between serum neutralizing capacity and disease severity, suggesting
that the collection of CP should be restricted to those with more severe symp-
toms (Chen 2020). Another, unintended, consequence of receiving CP may be
that recipients will not develop their own immunity, putting them at risk for
re-infection.
In addition, in light of the possibility of antibody-dependent disease en-
hancement (ADE), safety is still a hypothetical consideration in the ongoing
CP trials. One study on macaques found that passive transfer of anti-SARS-
CoV-S immunoglobulin from immunized monkeys into naïve recipients re-
sulted in acute lung injury after infection. The proposed mechanism was a
diversion of macrophage activation from wound healing to pro-inflammatory
(Liu 2019). Enhanced lung-pathology upon antibody-transfer was also ob-
served in a rabbit model of MERS (Houser 2017). Convalescent plasma has
been given to MERS patients and one case-report raises the possibility of
acute lung Injury following convalescent plasma transfusion (Chun 2016).
The future development of anti-SARS-CoV-2 convalescent plasma should take
into account 1) the potential harms of the non-immune components of conva-
lescent plasma (especially prothrombotic risks); 2) that only donor plasma
with detectable titers of neutralizing antibodies be given to trial participants;
3) ensure double blind designs with placebo controls as the gold standard for
future trials; 4) preclude non-immune plasma as a control intervention, be-
cause of potential harms and availability of lower risk alternatives such as
normal saline (Pathak 2020).
Find more information on CP in the Treatment chapter, page 344.

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Monoclonal antibodies
Competition is heating up to produce targeted monoclonal antibodies which
could both prevent and treat COVID-19 (Cohen 2020). The development of
highly successful monoclonal antibody-based therapies for cancer and im-
mune disorders has created a wealth of expertise and manufacturing capabili-
ties (Biopharma 2020) and neutralising monoclonal antibodies are now a
plausible therapeutic option against infectious diseases (Marston 2018). Mon-
oclonal antibodies against rabies virus and against the respiratory syncytial
virus (RSV) are approved for the treatment of patients and other monoclonal
antibodies are in advanced stages of clinical trials (Walker 2018). Both protec-
tive and pathogenic effects were observed (Wang Q 2016, Chen X 2020).
SARS-CoV-2 neutralizing human monoclonal antibodies were intensely stud-
ied in 2020 (Robbiani 2020, Wec 2020, Ju B 2020). It was shown that REGN-CoV-
2, a cocktail of two antibodies, might preclude the appearance of escape mu-
tants (Baum 2020) and decrease virus-induced pathological sequalae in rhesus
macaques (Baum 2020b). In hamsters, the cocktail limited weight loss and
evidence of pneumonia in the lungs. The first (not yet peer reviewed!) pub-
lished clinical results of REGN-CoV-2 describe the results in non-hospitalized
COVID-19 patients with symptom onset ≤ 7 days from randomization and not
on any putative COVID-19 therapy. After single doses of REGN-CoV-2 at 2.4 g
IV (lower dose), 8 g IV (higher dose) or placebo, the company found a reduc-
tion of “viral load” in nasopharyngeal (NP) swabs of -1.92 and -1.64 log10 cop-
ies/mL, compared to -1.41 with placebo (Regeneron 2020). These results are
not particularly impressive.
The ‘COVID-19 antibodysphere’ features companies like Amgen, AstraZeneca,
Vir, Regeneron, Lilly and Adagio (Biopharma 2020). However, the future role
of monoclonal antibodies as a bridging solution before the general availability
of vaccines and efficient antiviral drugs is unclear. These drugs are complex
and expensive to produce, leaving people from poor countries locked out
(Ledford 2020, Ledford 2020b) and fears have been voiced that they could split
the world into the haves and have-nots, like many other drugs before (Cohen
2020). Fortunately, these fears may not materialize. As soon as the first truly
effective antiviral drugs become available – as for HSV in 1981, HIV in 1996
and HCV in 2013 – there will be no need for monoclonal antibodies anymore.
Find more details on monoclonal antibodies in the Treatment chapter, page
340.
Active immunization against SARS-CoV-2
At the time of this writing (October 2020), there are more than 170 COVID-19
vaccine candidates in different stages of preclinical development. Ten candi-

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date vaccines are in Phase III clinical trials (Thanh Le 2020). If one considers
that the development of a vaccine usually takes well over 10 years to com-
plete (Heaton 2020), it becomes clear how quickly progress is being made
(Slaoui 2020).
This rapid development is based on a massive global effort, including the par-
allelization of development and production steps that have traditionally been
carried out sequentially (Lurie 2020), the knowledge generated in attempts to
develop vaccines against SARS-CoV-1 and MERS-CoV, and innovative tech-
niques (Hekele 2013) that were not available until recently. The speed of
SARS-CoV-2 vaccine development is breathtaking. On 11 January 2020 Chi-
nese researches published the sequence of the SARS-CoV-2 genome on the
internet. Approximately 2 months later, on 16 March, an mRNA-based vac-
cine entered a Phase I clinical trial (Arnold 2020).
Earlier work had identified the S protein of SARS-CoV and MERS-CoV as a
suitable vaccine target. The S protein binds to its cellular receptor, ACE2, to
infect human cells. With the sequencing of the genome of SARS-CoV-2, the
high homology between the S proteins of the 3 viruses was known and a little
later the interaction of SARS-CoV-2 with ACE was confirmed (Hoffmann 2020).
A relevant target structure for immune responses was identified in record
time.
However, there are still some hurdles to overcome in vaccine development.
This includes the fact that the correlates of protective immunity against
SARS-CoV-2 are currently incompletely understood, that the available data
indicate that immunity against SARS-CoV-2 may not be very long-lasting and
that preclinical studies on vaccine candidates against SARS-CoV and MERS-
CoV have given indications of possible side effects (see below).

SARS-CoV-2 vaccine platforms

The platforms used for SARS-CoV-2 vaccine developments have recently been
summarized in an excellent review by Florian Krammer (Krammer 2020). Cur-
rent SARS-CoV-2 vaccine candidates include (the letters in the brackets refer
to Figure 3 of the Krammer review):
• inactivated virus vaccines (c)
• live attenuated vaccines (d)
• recombinant protein vaccines based on the spike protein (e), the RBD
(f) or on virus-like particles (g)
• replication-incompetent vector vaccines (h)
• replication-competent vector vaccines (i)

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• inactivated virus vector vaccines that display the spike protein on

their surface (j)
• DNA vaccines (k)
• RNA vaccines (l)
The most traditional way to produce vaccines is the use of whole viruses,
which are either attenuated or inactivated. Currently licensed examples include
the vaccines against measles and yellow fever (attenuated virus) and influen-
za and polio (inactivated viruses). Two inactivated vaccines protect rhesus
monkeys from SARS-CoV-2. The vaccines were well tolerated preclinically; in
particular, no type 2 immunopathology was found in the lungs (see below:
pathological immune responses) (Gao Q 2020, Wang H 2020). Various vaccines
that use inactivated SARS-CoV-2 as an immunogen are currently available in
different phases of clinical trials, three of which are already in Phase III stud-
ies (WHO Landscape 2020).
Another approach is to use recombinant viral proteins as vaccine; licensed
examples include the vaccines against hepatitis B and human papilloma virus.
Efforts are ongoing to develop recombinant SARS-CoV-2 S protein as an im-
munogen. Nine vaccines that use recombinant SARS-CoV-2 S protein as an
immunogen are in the early phases of clinical trials (Phase I or I/II) (WHO
Landscape 2020).
A more recent approach is to use recombinant viral vectors in which a rele-
vant antigen of the pathogenic virus is expressed.
Currently, the Ebola vaccine is the only approved vaccine based on this prin-
ciple (Henao-Restrepo 2017). A recombinant vaccine protected rhesus mon-
keys from SARS-CoV-2. The vaccine was well tolerated; in particular, no type
2 immunopathology was found in the lungs (see below: pathological immune
responses) (van Doremalen 2020). Three different adenovirus-based recombi-
nant vaccines against SARS-CoV-2 are currently in clinical Phase III studies
(WHO Landscape 2020). A potential problem with these vaccines could be pre-
existing immune responses of the vaccinees against adenoviruses (Zhu FC
2020).
Four DNA vaccines against SARS-CoV-2 are currently in the early phases of
clinical trials (Phase I or I/II) (WHO Landscape 2020). There are currently no
approved DNA vaccines, which could make the approval process more com-
plicated compared to other vaccines.
An mRNA vaccine intended to induce immune responses against SARS-CoV-2
was already tested in a clinical Phase I study in March 2020 (Jackson 2020).
Two mRNA vaccines are currently in Phase III clinical trials, another is in a

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Phase II trial, and others are in earlier phases of clinical trials (WHO Land-
scape 2020). The approval process for RNA vaccines could be more complicat-
ed than for conventional vaccines because currently there are no approved
mRNA vaccines for any indication.

Issues to address during vaccine development

Vaccines against coronaviruses can induce pathological immune re-
sponses.
Rarely, vaccines can enhance disease rather than protect from disease (Kim
1969, Openshaw 2001). Some vaccine candidates against SARS-CoV-1 or MERS-
CoV have caused disease-intensifying immunopathological effects in some
pre-clinical models. The safety of a vaccine against SARS-CoV-2 is of course of
essential importance (Lambert 2020).

Immunization with recombinant SARS-CoV spike (S) -coding modified

vaccinia virus Ankara (rMVA) causes hepatitis in ferrets.
Ferrets are susceptible to SARS-CoV and SARS-CoV-2 infections (Kim YI 2020).
Weingartl et al. immunized ferrets with a recombinant modified vaccinia vi-
rus Ankara (rMVA), which encoded the SARS-CoV S protein (Weingartl 2004).
After infection with the virus, high titers of neutralizing antibodies were de-
tectable in the immunized animals. Nevertheless, the immunized infected
ferrets developed severe hepatitis while the non-immunized did not
(Weingartl 2004).

Type 2 immunopathology in the lungs of immunized mice

Bolles et al. (Bolles 2011) immunized mice with inactivated SARS-CoV with or
without adjuvant. The vaccine protected young and old animals from morbid-
ity and mortality after infection with high doses of virus. If the mice were
infected with a heterologous virus strain, the immunized animals developed
more pronounced inflammatory infiltrates and pulmonary eosinophilia than
the non-immunized (Bolles 2011). These results were later confirmed by an-
other working group (Tseng CT 2012). Eosinophilic lung infiltrates were also
observed in mice after immunization with a recombinant baculovirus (S pro-
tein) or coronavirus-like particles (VLPs) that expressed SARS-CoV S protein.
It is important to note that these are histopathological findings; the immun-
ized mice still had reduced virus titers after infection (Tseng CT 2012, Loku-
gamage 2008). Nevertheless, the findings are worrying. They are similar to
the histopathological changes seen in the 1960s in children who became ill
after immunization with a vaccine against RSV (Castilow 2007). Pathological

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changes in the lungs and even pneumonia after infection with SARS-CoV were
also observed in mice in other SARS-CoV vaccine candidates (Yasui 2008).
Similar findings have been reported for vaccine candidates for MERS-CoV. An
inactivated MERS-CoV vaccine induced neutralizing antibodies in mice. Nev-
ertheless, after infection, the immunized mice developed an increased type 2
pathology in the lungs with increased eosinophilic infiltrates and increased
concentrations of IL-5 and IL-13 (Agrawal 2016). Recent studies suggest that
the development of type 2 immunopathology can be influenced by the choice
of appropriate adjuvants, e.g. TLR ligands, for inactivated viruses, or recom-
binant S protein can be avoided (Iwata-Yoshikawa 2014, Honda-Okubo 2015).
Overall, these findings are a clear indication that during the preclinical de-
velopment of vaccines against SARS-CoV-2, an intensive search should be
made for immunopathological changes in the lungs of the immunized ani-
mals. It is encouraging that many of the pre-clinical studies published to date
on SARS-CoV-2 vaccine candidates explicitly indicate that such changes have
been sought and not found.

Type 2 immunopathology in the lungs of immunized primates

In a recent study Chinese macaques were vaccinated with a modified vaccinia
Ankara (MVA) virus encoding full-length SARS-CoV S glycoprotein (ADS-
MVA) and challenged with SARS-CoV 8 weeks later (Liu 2019). Vaccination
induced high levels of antibodies and reduced virus loads. However, the vac-
cinated monkeys had diffuse alveolar damage (DAD) (Liu 2019). These findings
are similar to those of an earlier study in which macaques were immunized
with inactivated SARS-CoV. Three monkeys were protected upon challenge
whereas one macaque had lung pathology consistent with antibody-
dependent disease enhancement (ADE) (Wang 2016). The authors suspect that
only antibodies against certain SARS-CoV S epitopes induce the immuno-
pathology. In the previously published SARS-CoV-2 vaccination studies in
monkeys, no lung pathology was observed (Gao Q 2020, Wang H 2020, van
Doremalen 2020). Overall, there is no evidence of immunopathology after
vaccination and infection in the preclinical studies published to date.

Questions for the Future

The diverse and massive efforts in vaccine development and the unprece-
dented pace of progress give rise to hope that an effective and safe vaccine
will soon be available. However, some important questions remain unan-
swered.

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Correlates of Protection
Knowledge about the immune responses against SARS-CoV-2 is growing rap-
idly (Vabret 2020); it seems clear that neutralizing antibodies against the S
protein can mediate protection. SARS-CoV-2-specific T cells can also be pre-
sent in people without detectable antibodies against SARS-CoV-2 (Braun 2020,
Grifoni 2020, Sekine 2020). Preclinical studies on SARS (Li CK 2008) and MERS
(Zhao J 2017) suggest that virus-specific CD4+ (Zhao J 2016) and CD8+
(Channappanavar 2014) T cells can be protective even in the absence of sero-
logically detectable antibodies (Tang F 2011).

Longevity of the immunological memory against SARS-CoV-2

Ideally, a vaccine induces long-term immunity; unfortunately, this goal may
not be realistic for SARS-CoV-2. Infections with common cold coronaviruses
generate only a short-lived immunity. Experiments from the 1980s have
shown that just one year after inoculation with coronavirus 229E, the majori-
ty of the test subjects could be infected again. They did have milder symp-
toms than non-inoculated subjects, so a certain protection was seen despite
renewed infection (Callow 1990).
Experiences from the 2002-2004 SARS-CoV outbreak, too, suggest that SARS-
CoV-2 immune responses will be short-lived. Six years after having suffered
SARS disease, antibodies to SARS-CoV were no longer detectable in 21/23 pa-
tients (Tang F 2011). In contrast, SARS-CoV-specific T cells were still detecta-
ble, which suggests the possibility that T cell memory against corona viruses
may be more long-lasting than serological memory (Tang F 2011). Similar
findings have been described for the immune response after MERS disease
(Zhao J 2017); however, there is currently no reliable knowledge about the
longevity of T cell memory against SARS-CoV 2. There have been reports of
renewed SARS-CoV-2 infections after surviving the first infection (To KK
2020).
After almost one year of research, the picture of immunological memory
against SARS-CoV-2 is becoming clearer. The kinetics of the neutralizing an-
tibody response to SARS-CoV-2 is typical of an acute viral infection where a
peak response is detected 3–4 weeks post-infection, which then wanes (Seow
2020). More than 90% of of infected individuals with mild-to-moderate
COVID-19 experience might develop robust IgG antibody responses against
the viral spike protein and titers will be relatively stable for months Anti-
spike binding titers correlate with neutralization of authentic SARS-CoV-2
(Gudbjartsson 2020, Wajnberg 2020, Alter 2020). Patients with a worse clinical
classification may have higher neutralizing antibody titer (Wang X 2020).

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However, asymptomatic individuals have a weaker immune response to

SARS-CoV-2 infection than patients with severe COVID-19 (Long QX 2020) and
humoral immunity against SARS-CoV-2 may not be long lasting in this large
group that composes the majority of infected persons (Ibarrondo 2020, Weis
2020). One group showed that in individuals who develop a low neutralizing
antibody response (ID50 100–300), titers can return to baseline over a relative-
ly short period, whereas those who develop a robust neutralizing antibody
response maintain titers > 1,000 despite the initial decline (Seow 2020).

Pre-existing immune responses against SARS-CoV-2

SARS-CoV-2-specific CD4+ and CD8+ T lymphocytes can be detected in around
20 to 100% of non-exposed healthy volunteers (Braun 2020, Grifoni 2020,
Mateus 2020, Bacher 2020). It has been speculated that these cross-reactive T
lymphocytes could be protective against SARS-CoV-2 or influence the course
of the disease. As a matter of fact, it is known that cross-reactive T cells can
influence the course of viral infections both positively and negatively (Ngono
2018). Antibodies that neutralize SARS-CoV-2 have also been detected in un-
infected and non-exposed healthy volunteers (Ng KW 2020).
We might not rely on protection without exposure, though. In a recently pub-
lished pre-print study from Rockefeller University, the authors measured
neutralizing activity against SARS-CoV-2 in pre-pandemic sera from patients
with prior PCR-confirmed seasonal coronavirus infection. While neutralizing
activity against seasonal coronaviruses was detected in nearly all sera, cross-
reactive neutralizing activity against SARS-CoV-2 was undetectable (Posten
2020). The authors conclude that while it is possible that there are rare in-
stances of individuals possessing antibodies from prior seasonal HCoV infec-
tion who may be able to also target SARS-CoV-2 S, their data would argue
against a broad role for pre-existing protective humoral immunity against
SARS-CoV-2.
Recently, a provocative concept was introduced by Alexander Scheffold and
colleagues. The authors propose the immunological age as an independent
risk factor to develop severe COVID-19 (Bacher 2020). Their reasoning:
1. Unexposed individuals harbor SARS-CoV-2-specific memory T cells
with marginal cross-reactivity to common cold corona and other un-
related viruses.
2. These T cells display low functional avidity and broad protein target
specificities and their frequencies correlate with the overall size of
the CD4+ memory compartment reflecting the immunological age of
an individual.

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3. COVID-19 patients generate strong pro-inflammatory T cells re-

sponses, that increase with disease severity.
4. Unexpectedly, severe disease is associated with lower functional
avidity and TCR clonality.
5. Low avidity pre-existing T cell memory negatively impacts on the T
cell response against neoantigens such as SARS-CoV-2, which may
predispose to develop inappropriate immune reactions especially in
the elderly.
Find more about this topic in the 6th edition of COVID Reference.

Outlook
Vaccines are the most potent medical products of all times to prevent mor-
bidity and mortality. Over the last two centuries, no other medical interven-
tion has saved as many lives. Without vaccines, many of today’s anti-vaccine
activists (Burki 2020) would not have been born (and maybe neither you nor
me) because of lack of ancestors – one or more of them would have suc-
cumbed to infectious disease before reaching mating age. Vaccines train the
body’s immune system to recognize and fight pathogens and on the next ex-
posure to the pathogen, the immune system is ready to fight the invader off.
The vaccination procedure is simple: introduce certain molecules from the
pathogen into the body and trigger an immune response. Vaccines are ‘ele-
gant medicine’ – they prevent rather than treat a disease.
At the end of this COVID Year One, virology, biologic chemistry and immu-
nology are the celebrated fields of medicine. Virology explores the structure
and functioning of the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) and, together with biologic chemistry, prepares the terrain for
future drug development. In the meantime, immunology explores the virus-
human interface and describes how the human body fights back and forms a
memory after the first encounter with SARS-CoV-2: it examines why most
people recover from the infection while a few die and other remain disabled;
and it contributes to the understanding of the biological mechanisms that
lead to illness and death. Why do older people die from coronavirus disease
2019 (COVID-19) while younger people don’t? Why are people with hyperten-
sion, diabetes or obesity at increased risk of severe COVID-19? Immunology
also tries to elucidate the mystery of superspreader individuals, those few
acutely SARS-CoV-2 infected people who are thought to be responsible for the
vast majority of transmissions. Finally, immunology will spin out the most
powerful antiviral weapon: vaccines.

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 Vaccines | 221

One challenge for the developers of COVID-19 vaccine(s) is that the elderly
are most susceptible to the infection and carry a particularly high risk for
severe or lethal disease. Due to immunosenescence, the elderly are notorious-
ly difficult to immunize, requiring higher doses or particular immunization
schemes in order to generate a protective immune response. Studies in mice
indicate that older animals are also more likely to develop immunopathology
upon vaccination.
The SARS-CoV-2 pandemic is a colossal challenge for healthcare systems and
societies. It is also the time of the ‘Great Rehearsal’. By coordinating global
resources and supra-national structures to react swiftly, science is currently
creating the infrastructure to fight any other new and potentially far deadlier
viral disease that emerges in the future. SARS-CoV-2 is not the last pathogen
humanity will have to deal with in the 21st century and more enzootic viruses
will jump from their animal reservoirs to humans. However, after this pan-
demic, hopefully we will be better prepared for future challenges, with new
vaccine platforms that can quickly be adapted to newly emerging viral dis-
eases. There is even a final twist to the unexpected events of 2020: the SARS-
CoV-2 pandemic is opening up a new era of vaccine development. In 10 years
we can expect to have a wide range of new and innovative vaccines we would
not have dared to previously dream of.

Weekend Reference
If you have not read this article, read it next weekend: Krause P, Fleming TR,
Longini I, Henao-Restrepo AM, Peto R; World Health Organization Solidarity
Vaccines Trial Expert Group. COVID-19 vaccine trials should seek worth-
while efficacy. Lancet. 2020 Aug 27:S0140-6736(20)31821-3. PubMed:
https://pubmed.gov/32861315. Full-text: https://doi.org/10.1016/S0140-
6736(20)31821-3. Brilliant review of SARS-CoV-2 vaccines: vaccine platforms,
results from studies on non-human primates and results from Phase I/II trials
in humans.

New References (5th Edition)

The following pages add short comments to the papers published since the
previous edition (June-October). The comments are from
https://covidreference.com/daily-science. The complete list of references
starts at page 241.

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SARS-CoV-2 Vaccine Candidates

Dagotto G, Yu J, Barouch DH. Approaches and Challenges in SARS-CoV-2
Vaccine Development. Cell Host Microbe 2020, published 10 August. Full-
text: https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(20)30455-
8
Progress in SARS-CoV-2 vaccine development to date has been faster than for
any other pathogen in history. In this perspective, Dan Barouch, Gabriel Da-
gotto and Jingyou Yu discuss three topics that are critical for SARS-CoV-2
vaccine development:
1. Antigen selection and engineering
2. Pre-clinical challenge studies in non-human primate models
3. Immune correlates of protection

Phase 3 vaccine candidates

CHADOX1 (ASTRAZENECA)

Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the
ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a
phase 1/2, single-blind, randomised controlled trial. Lancet. 2020 Aug
15;396(10249):467-478. PubMed: https://pubmed.gov/32702298. Full-text:
https://doi.org/10.1016/S0140-6736(20)31604-4
Andrew Pollard and colleagues report their Phase I/II randomized trial of a
chimpanzee adenovirus-vector vaccine (ChAdOx1 nCoV-19) expressing the
SARS-CoV-2 spike protein. Study participants received either ChAdOx1 nCoV-
19 (n = 543) or a meningococcal conjugate vaccine (MenACWY) as control (n =
534). In ChAdOx1 vaccinees, T cell responses peaked on day 14, anti-spike IgG
responses rose by day 28, and neutralizing antibody responses against SARS-
CoV-2 were detected in > 90% (find more details in the paper, especially about
results after a booster dose). Adverse events such as fatigue, headache, and
local tenderness commonly occurred. There were no serious adverse events.

van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccine pre-

vents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020, published
30 July. Full-text: https://doi.org/10.1038/s41586-020-2608-y
ChAdOx1 vaccine (see also the July 20 Top 10) induced a balanced Th1/Th2
humoral and cellular immune response in rhesus macaques. The bad news

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(for prevention policies in general and for anti-vaxxers in particular): there

was no difference in nasal shedding between vaccinated and control animals.

BNT162B1 (PFIZER / BIONTECH)

Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study of COVID-19 RNA
vaccine BNT162b1 in adults. Nature. 2020 Aug 12. PubMed:
https://pubmed.gov/32785213. Full-text: https://doi.org/10.1038/s41586-
020-2639-4
Mark Mulligan, Kirsten Lyke, Nicholas Kitchin, Judith Absalon and colleagues
report the safety, tolerability, and immunogenicity data from an ongoing
study in 45 healthy adults, randomized to receive 2 doses, separated by 21
days, of 10 µg, 30 µg, or 100 µg of BNT162b1. BNT162b1, developed by BioN-
Tech and Pfizer, is a lipid nanoparticle-formulated, nucleoside-modified
mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein recep-
tor-binding domain (RBD). A clear dose-level response in elicited neutralizing
titers was observed after doses 1 and 2 with a particularly steep dose response
between the 10 μg and 30 μg dose levels. Geometric mean neutralizing titers
reached 1.9- to 4.6-fold that of a panel of COVID-19 convalescent human sera
at least 14 days after a positive SARS-CoV-2 PCR. The clinical testing of
BNT162b1 is taking place in the context of a broader, ongoing COVID-19 vac-
cine development program by both companies. That program includes the
clinical testing of three additional vaccine candidates, including candidates
encoding the full-length spike.

Abbasi J. COVID-19 and mRNA Vaccines-First Large Test for a New Ap-
proach. JAMA. 2020 Sep 3. PubMed: https://pubmed.gov/32880613. Full-text:
https://doi.org/10.1001/jama.2020.16866
mRNA vaccines like BNT162b2 from BioNTech and Pfizer and mRNA-1273 by
Moderna have ‘the potential to be truly transformative’ (Drew Weissman) but
have never been tested in large-scale human trials. Now both vaccines have
entered Phase III trials, which together will enroll an estimated 60,000 volun-
teers. Follow Jennifer Abbasi on a tour of ‘proof in the pudding’ and mRNA
vaccines beyond COVID-19.

Sahin U, Muik A, Derhovanessian E, et al. Concurrent human antibody and

TH1 type T-cell responses elicited by a COVID-19 RNA vaccine. medRxiv
2020, posted 20 July. Full-text: https://doi.org/10.1101/2020.07.17.20140533

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The authors present antibody and T cell responses after BNT162b1 vaccina-
tion from a non-randomized open-label Phase I/II trial in healthy adults.
BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody
responses, with RBD-binding IgG concentrations clearly above those in a
COVID-19 convalescent human serum panel. Most participants had Th1
skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell ex-
pansion. Interferon (IFN)γ was produced by a high fraction of RBD-specific
CD8+ and CD4+ T cells.

Nat Biomed Eng (Editors). Fast-and-fit vaccines. Nat Biomed Eng 2020, pub-
lished 10 August 2020. Full-text: https://doi.org/10.1038/s41551-020-00605-9
Two mRNA vaccine formulations against COVID-19, one developed by a col-
laboration between Pfizer and BioNTech, and the other by Moderna and the
National Institute of Allergy and Infectious Diseases (NIAID) in the US (Nat
Biomed Eng 2020), have the potential to be truly transformative; however,
they have never been tested in large-scale human trials.

RNA-1273 (MODERNA)

Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine
against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 2020b, published
28 July. Full-text: https://doi.org/10.1056/NEJMoa2024671
Vaccination of non-human primates with mRNA-1273 induces robust SARS-
CoV-2 neutralizing activity, rapid protection in the upper and lower airways,
and no pathologic changes in the lung. For this important vaccine trial, Bar-
ney Graham, Robert Seder and colleagues divided 12 female and 12 male Indi-
an-origin rhesus macaques into groups of three and vaccinated them intra-
muscularly at week 0 and at week 4 with either 10 or 100 μg of mRNA-1273 or
placebo. At week 8 (4 weeks after the second vaccination), all animals were
challenged with SARS-CoV-2. mRNA-1273 induced antibody levels exceeding
those found in human convalescent phase serum. Vaccination also induced
type 1 helper T cell (Th1)–biased CD4 T cell responses and low or undetectable
Th2 or CD8 T cell responses. No viral replication was detectable in the nose of
any of the eight animals in the 100 μg dose group by day 2 after challenge (8
weeks after the first vaccination). The ability to limit viral replication in both
the lower and the upper airways will have important implications for vac-
cine-induced prevention of both SARS-CoV-2 disease and transmission.

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Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against
SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020 Jul 14. PubMed:
https://pubmed.gov/32663912. Full-text:
https://doi.org/10.1056/NEJMoa2022483
This study conducted in Washington and Atlanta evaluated the candidate
vaccine mRNA-1273 that encodes the stabilized prefusion SARS-CoV-2 spike
protein. In a Phase I open label trial, 45 healthy adults received two vaccina-
tions, 28 days apart, at three different doses. Antibody responses were higher
with a higher dose and further increased after the second vaccination, lead-
ing to serum-neutralizing activity in all participants. Values were similar to
those in the upper half of the distribution of a panel of control convalescent
serum specimens. Solicited adverse events that occurred in > 50% included
fatigue, chills, headache, myalgia, and pain at the injection site.

CORONAVAC© (SINOVAC)

Gao Q, Bao L, Mao H, et al. Development of an inactivated vaccine candi-

date for SARS-CoV-2. Science. 2020 Jul 3;369(6499):77-81. PubMed:
https://pubmed.gov/32376603. Full-text:
https://doi.org/10.1126/science.abc1932
The authors developed a purified inactivated SARS-CoV-2 virus vaccine can-
didate, which induced SARS-CoV-2–specific neutralizing antibodies in mice,
rats, and non-human primates. These antibodies neutralized 10 representa-
tive SARS-CoV-2 strains, suggesting a possible broader neutralizing ability
against other strains.

CTII-NCOV (CANSINO)
Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant
adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18
years or older: a randomised, double-blind, placebo-controlled, phase 2
trial. Lancet. 2020 Aug 15;396(10249):479-488. PubMed:
https://pubmed.gov/32702299. Full-text: https://doi.org/10.1016/S0140-
6736(20)31605-6
Wei Chen and colleagues report results from a randomized Phase II trial of an
Ad5-vector COVID-19 vaccine from a single center in Wuhan. More than 90%
of participants had T cell responses, seroconversion of binding antibody oc-
curred in more than 96%, and neutralizing antibodies were seen in about 85%.
The authors found that compared with the younger population, older people

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had a significantly lower immune response, but higher tolerability, to the

Ad5-vector COVID-19 vaccine. In a Phase IIb trial, an additional dose might
therefore be needed to induce a better immune response in an older popula-
tion. Adverse events such as fever, fatigue, headache, or local site pain were
comparable to the ChAdOx1 study above.

SPUTNIK V (GAMALEYA)

Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity
of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19
vaccine in two formulations: two open, non-randomised phase 1/2 stud-
ies from Russia. Lancet 2020, published 4 September. Full-text:
https://doi.org/10.1016/S0140-6736(20)31866-3
It was high time to see some data on an “approved” vaccine. See also the
comment by Naor Bar-Zeev and Tom Inglesby [Bar-Zeev N, Inglesby T.
COVID-19 vaccines: early success and remaining challenges. Lancet 2020,
published 4 September. Full-text: https://doi.org/10.1016/S0140-
6736(20)31867-5].
On September 5, we commented that it was high time to see some data on an
“approved” vaccine, consisting of two recombinant adenovirus vectors carry-
ing the spike glycoprotein (Sputnik V, presented as the world’s “premiere”,
like planting a tiny flag in the sea bed two and a half miles beneath the North
Pole in 2007).
Bucci E, Andreev, Björkman A, et al. Safety and efficacy of the Russian
COVID-19 vaccine: more information needed. Lancet September 21, 2020.
Full-text: https://doi.org/10.1016/S0140-6736(20)31960-7
A few days later, the study received these notes of serious concerns. Dozens of
authors raised doubts about the reliability of the data. The main issue (among
many others): there were several data patterns which appeared repeatedly
for the reported experiments. A Photoshop fake? Enrico Bucci and colleagues
conclude that “in lack of the original numerical data, no conclusions can be
definitively drawn on the reliability of the data presented, especially regard-
ing the apparent duplications detected”. For more details see also
https://cattiviscienziati.com/2020/09/07/note-of-concern/
Logunov DY, Dolzhikova IV, Tukhvatullin AI. Safety and efficacy of the Rus-
sian COVID-19 vaccine: more information needed – Authors’ reply. Lancet
September 21, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31970-
X

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The author’s reply. They “confirm that individual participant data will be
made available on request to DYL and that after approval of a proposal, data
can be shared through a secure online platform”. Shall we hold our breath?

SINOPHARM WUHAN
Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against
SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis
of 2 Randomized Clinical Trials. JAMA. 2020 Aug 13:e2015543. PubMed:
https://pubmed.gov/32789505. Full-text:
https://doi.org/10.1001/jama.2020.15543
An Pan, Xiaoming Yang and colleagues provide the first interim safety, toler-
ability, and immune response results for a β-propiolactone–inactivated
whole-virus vaccine adjuvanted in 0.5 mg of aluminum hydroxide. The inci-
dence rate of adverse reactions in the current study (15.0% among all partici-
pants) was not significantly different between the vaccine groups and the
active control (alum) groups; it was also lower compared with results of other
SARS-CoV-2 candidate vaccines. The neutralizing antibody response suggest-
ed that the inactivated vaccine may effectively induce antibody production,
but the optimal interval between injections and times of booster injections of
the inactivated vaccine remains unclear. In the discussion, find more about
ADE and VAERD. See also the comment by Mark Mulligan: An Inactivated
Virus Candidate Vaccine to Prevent COVID-19. JAMA. 2020 Aug 13. Pub-
Med: https://pubmed.gov/32789500. Full-text:
https://doi.org/10.1001/jama.2020.15539

NVX-COV2373 (NOVAVAX)
Keech C, Albert G, Cho I, et al. Phase 1-2 Trial of a SARS-CoV-2 Recombi-
nant Spike Protein Nanoparticle Vaccine. N Engl J Med. 2020 Sep 2. Pub-
Med: https://pubmed.gov/32877576. Full-text:
https://doi.org/10.1056/NEJMoa2026920
NVX-CoV2373 is a recombinant SARS-CoV-2 nanoparticle vaccine composed
of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adju-
vant. In 83 participants younger than 60 years of age, two injections of NVX-
CoV2373 delivered in the deltoid muscle on day 0 and 21 appeared to be safe.
Immune responses exceeded levels in COVID-19 convalescent serum, showing
high neutralizing antibody responses and T cells with a predominant Th1
phenotype. Phase II has started.

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AD26.COV2.S (JANSSEN)

Mercado NB, Zahn R, Wegmann F et al. Single-shot Ad26 vaccine protects

against SARS-CoV-2 in rhesus macaques. Nature 2020, published 30 July.
Full-text: https://doi.org/10.1038/s41586-020-2607-z
For global deployment and pandemic control, a vaccine that requires only a
single immunization would be optimal. Hanneke Schuitemaker, Dan Barouch
and colleagues developed a series of adenovirus serotype 26 (Ad26) vectors
encoding different variants of the SARS-CoV-2 spike (S) protein and showed
the immunogenicity and protective efficacy of a single dose of Ad26 vector-
based vaccines in 52 rhesus macaques. The optimal Ad26 vaccine induced ro-
bust neutralizing antibody responses and provided complete or near-
complete protection in bronchoalveolar lavage and nasal swabs following
SARS-CoV-2 challenge.

The Future of SARS-CoV-2 vaccines

Questions
Bar-Zeev N, Moss WJ. Encouraging results from phase 1/2 COVID-19 vac-
cine trials. Lancet. 2020 Aug 15;396(10249):448-449. PubMed:
https://pubmed.gov/32702300. Full-text: https://doi.org/10.1016/S0140-
6736(20)31611-1
A comment on the two papers above as well as a list of questions to be ad-
dressed by the coming Phase III trials:
• Will a single dose be sufficient in older adults, or is a booster dose re-
quired?
• Does longevity of response or rates of waning differ with a two-dose reg-
imen, and does longevity of clinical protection require cell-mediated re-
sponses?
• Are there host-specific differences in immunogenicity by age, sex, or
ethnicity?
• Do T cell responses correlate with protection irrespective of humoral
titers?
• Are there specific adverse events in pregnant women?

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Vaccine Approval
FDA 20200630. FDA News Release. Coronavirus (COVID-19) Update: FDA
Takes Action to Help Facilitate Timely Development of Safe, Effective
COVID-19 Vaccines. Published 30 June 2020. Full-text:
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-
19-update-fda-takes-action-help-facilitate-timely-development-safe-
effective-covid
This press release announces guidance with recommendations for companies
and researchers developing COVID-19 vaccines for the purpose of licensure.
The guidance describes the agency’s current recommendations regarding the
data needed to facilitate the manufacturing, clinical development, and ap-
proval of a COVID-19 vaccine. It also that the FDA would expect that a COVID-
19 vaccine would prevent disease or decrease its severity in at least 50% of
people who are vaccinated.

SETBACKS

Phillips N, Cyranoski D, Mallapathy S. A leading coronavirus vaccine trial is

on hold: scientists react. Nature News September 9, 2020. Full-text:
https://www.nature.com/articles/d41586-020-02594-w
This article summarizes what is known about the news of the day: AstraZene-
ca has reported a case of a transverse myelitis in a person who received
AZD1222, an adenoviral-vector vaccine that harnesses a cold-causing ‘adeno-
virus’ isolated from chimpanzees. The Phase III trial was “voluntarily
paused”. However, details of the adverse event, including how serious it was
and when it happened, have not been reported. It is still unclear whether the
person received the vaccine or placebo. Let’s wait for the details.

Shah S, Patel J, Alchaki AR. Development of Transverse Myelitis after Vac-

cination. A CDC/FDA Vaccine Adverse Event Reporting System (VAERS)
Study, 1985–2017. Neurology April 10, 2018; 90. Abstract:
https://n.neurology.org/content/90/15_Supplement/P5.099
In the meantime, you may read this review of 119 cases of transverse myelitis
(TM) occurring after vaccination, reported during a period of over 30 years to
the FDA. Although the reporting rate of post-vaccination TM was in the range
expected in the general population, the unbalanced distribution of these cas-
es in the first 6 weeks after vaccination suggested that the association be-
tween vaccination and some cases may not be coincidental. (For antivaxxers:
this is rare!)

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McAuley AJ, Kuiper MJ, Durr PA, et al. Experimental and in silico evidence
suggests vaccines are unlikely to be affected by D614G mutation in SARS-
CoV-2 spike protein. npj Vaccines 5, 96 (2020).
https://doi.org/10.1038/s41541-020-00246-8
The D614G mutation of the SARS-CoV-2 spike protein has been speculated to
adversely affect the efficacy of vaccines. In this article, S. Vasan, Alexander
McAuley and colleagues claim that there is no experimental evidence to sup-
port this speculation. They performed virus neutralization assays using sera
from ferrets that received two doses of the INO-4800 COVID-19 vaccine, and
Australian virus isolates (VIC01, SA01 and VIC31) which either possess or lack
this mutation.

HUMAN CHALLENGE STUDIES

Callaway E. Dozens to be deliberately infected with coronavirus in UK

‘human challenge’ trials. Nature 2020, published 20 October. Full-text:
https://www.nature.com/articles/d41586-020-02821-4
Proponents of the trials say they can be run safely and help to identify effec-
tive vaccines, but others have questioned their value.

Cookson C. UK to test vaccines on volunteers deliberately infected with

Covid-19. Financial Times 2020, published 23 September. Full-text:
https://www.ft.com/content/b782f666-6847-4487-986c-56d3f5e46c0b
In the world’s first COVID-19 ‘human challenge trials’ healthy volunteers will
be deliberately infected with SARS-CoV-2 to assess the effectiveness of exper-
imental vaccines.

Jamrozik E, Selgelid MJ. COVID-19 human challenge studies: ethical issues.

Lancet Infect Dis. 2020 May 29:S1473-3099(20)30438-2. PubMed:
https://pubmed.gov/32479747. Full-text: https://doi.org/10.1016/S1473-
3099(20)30438-2
Human challenge studies could accelerate vaccine development, helping to
test multiple candidate vaccines. This personal view on ethical issues explains
why this will be difficult. The authors argue that human challenge studies can
“reasonably be considered ethically acceptable insofar as such studies are
accepted internationally and by the communities in which they are done, can
realistically be expected to accelerate or improve vaccine development, have

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considerable potential to directly benefit participants, are designed to limit

and minimise risks to participants, and are done with strict infection control
measures to limit and reduce third-party risks.”

Deming ME, Michael NL, Robb M, et al. Accelerating Development of SARS-

CoV-2 Vaccines — The Role for Controlled Human Infection Models. NEJM
July 1, 2020. Full-text: https://doi.org/10.1056/NEJMp2020076. Full-text:
https://www.nejm.org/doi/full/10.1056/NEJMp2020076
The authors review practical considerations relevant to the development of a
SARS-CoV-2 controlled human infection models (CHIMs) and the prerequi-
sites for using such a model. Large, randomized, controlled trials of SARS-
CoV-2 vaccines are still the most efficient, generalizable, and scientifically
robust path to establishing vaccine efficacy. However, SARS-CoV-2 CHIM de-
velopment might be able to accelerate the development of later rounds of
vaccine candidates.

Kirby T. COVID-19 human challenge studies in the UK. Lancet October 30,
2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30518-X
Some thoughts about feasibility and ethics of human challenge trials that
could potentially accelerate the development of vaccines. The first study
phase, which could begin in January 2021, aims to discover the smallest
amount of virus it takes to cause the infection in up to 90 healthy young peo-
ple, aged between 18 and 30 years. The study will probably take place in the
high-level isolation unit of the Royal Free Hospital, London, UK. Some com-
mentators have questioned both the timing and the ethical dilemmas pre-
sented by the study.

Kahn JP, Henry LM, Mastroianni C, et al. Opinion: For now, it’s unethical to
use human challenge studies for SARS-CoV-2 vaccine development. PNAS
October 29, 2020. Full-text: https://doi.org/10.1073/pnas.2021189117
Important comment: see title. According to the authors, human challenge
studies (HCS) to address SARS-CoV-2 face unacceptable ethics challenges, and,
further, undertaking them would do a disservice to the public by undermin-
ing already strained confidence in the vaccine development process. Ulti-
mately, the social value of these HCS (in terms of deaths averted) hinges on
the premise that people at greatest risk of COVID-19-related mortality will
receive a safe and efficacious vaccine sooner than they would without HCS.

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Read why this will be probably not the case and why HCS would do more
harm than good.

PREVIEW

Jeyanathan M, Afkhami S, Smaill F, et al. Immunological considerations for

COVID-19 vaccine strategies. Nat Rev Immunol 2020, published 4 Septem-
ber. Full-text: https://doi.org/10.1038/s41577-020-00434-6
In this review, Zhou Xing, Mangalakumari Jeyanathan and colleagues describe
the immunological principles of SARS-CoV-2 vaccine development and ana-
lyze the current vaccine candidates, their strengths and potential shortfalls.
They also make inferences about their chances of success. A hazardous under-
taking.

Vaccine distribution
Kupferschmidt K. ‘Vaccine nationalism’ threatens global plan to distrib-
ute COVID-19 shots fairly. Science 2020, 28 July. Full-text:
https://www.sciencemag.org/news/2020/07/vaccine-nationalism-threatens-
global-plan-distribute-covid-19-shots-fairly
‘We will not sell it at cost.” (We will sell it for profit.) That was the statement,
a few days ago, of a company that is receiving almost 1,000,000,000 dollars
from US tax payers for developing a COVID-19 vaccine. Fortunately, other
companies, too, are producing vaccines and good old WHO and other interna-
tional organizations have set up a system to accelerate and equitably distrib-
ute vaccines, the COVID-19 Vaccines Global Access (COVAX) Facility. Kai Kup-
ferschmidt summarizes the current state-of-affairs.

Callaway E. The unequal scramble for coronavirus vaccines — by the

numbers. Nature 2020, published 24 August. Full-text:
https://www.nature.com/articles/d41586-020-02450-x
Will SARS-CoV-2 vaccines be only for the rich? Ellen Callaway shows how
wealthy countries have struck deals to buy more than two billion doses of
coronavirus vaccine. Find out that the UK is the world’s highest per capita
buyer, with 340 million doses purchased: around 5 doses for each citizen. And
read more about COVAX, spearheaded by GAVI, a Geneva-based funder of
vaccines for low-income countries, along with CEPI and the World Health Or-
ganization. It aims to secure 2 billion doses of vaccines. One billion are for 92

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low- and middle-income countries and economies (LMICS), which make up

half the world’s population.

Schwartz JL. Evaluating and Deploying Covid-19 Vaccines — The Im-

portance of Transparency, Scientific Integrity, and Public Trust. N Engl J
Med 2020; 383:1703-1705. Full-text: https://doi.org/10.1056/NEJMp2026393
The situation in the US is dire, public confidence in vaccination is fragile. Ja-
son Schwartz insists that COVID-19 vaccination programs will succeed only if
there is widespread belief that available vaccines are safe and effective and
that policies for prioritizing their distribution are equitable and evidence-
based. He clearly sees that trust in science and expertise are threatened, as
the pandemic has shown with catastrophic results. Listen also to the audio
interview (12:02).

Impact of vaccines on the pandemic

Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KWR, Pollard AJ. What
defines an efficacious COVID-19 vaccine? A review of the challenges as-
sessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect
Dis 2020, published 27 October. Full-text: https://doi.org/10.1016/S1473-
3099(20)30773-8
A vaccine against SARS-CoV-2 might act against infection, disease, or trans-
mission and a vaccine capable of reducing any of these elements could con-
tribute to disease control. However, the most important efficacy endpoint,
protection against severe disease and death, is difficult to assess in Phase III
clinical trials. In this review, Susanne Hodgson and colleagues explore the
challenges in assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss
the caveats needed to interpret reported efficacy endpoints, and provide in-
sight into answering the seemingly simple question, “Does this COVID-19 vac-
cine work?” Remember: the fundamental understanding of the pathogen is
still evolving.

Lipsitch M, Dean NE. Understanding COVID-19 vaccine efficacy. Science.

2020 Oct 21:eabe5938. PubMed: https://pubmed.gov/33087460. Full-text:
https://doi.org/10.1126/science.abe5938
Marc Lipsitch and Natalie Dean publish the shortest abstract in months:
“Vaccine efficacy in high-risk groups and reduced viral shedding are im-
portant for protection.” Explore strategic prioritization plans.

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Immunization Fundamentals
Passive immunization against SARS-CoV-2
CONVALESCENT PLASMA

Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P;

PLACID Trial Collaborators. Convalescent plasma in the management of
moderate covid-19 in adults in India: open label phase II multicentre
randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939.
PubMed: https://pubmed.gov/33093056. Full-text:
https://doi.org/10.1136/bmj.m3939
Convalescent plasma (CP; giving neutralizing antibodies of people who made
it through SARS-CoV-2 infection) has been one of the biggest hopes. This
open label randomized controlled trial (RCT; the largest to date with results)
investigated the effectiveness of CP in adults with moderate COVID-19 in 39
public and private hospitals across India. In total, 235 patients were assigned
to two doses of 200 mL CP and 229 to standard of care only (control arm).
Progression to severe disease or all-cause mortality at 28 days after enrol-
ment occurred in 44 (19%) participants receiving CP and in 41 (18%) in the
control arm. Moreover, CP treatment did not show anti-inflammatory proper-
ties and there was no difference between patients with or without neutraliz-
ing antibodies at baseline (who had produced their own antibodies or not).
The main limitation: the authors did not measure the antibody titers in CP
before transfusion because validated, reliable commercial tests were not
available when the trial started. Let’s hope that low antibody titers were the
reason for the lack of efficacy.

Pathak EB. Convalescent plasma is ineffective for covid-19. BMJ. 2020 Oct
22;371:m4072. PubMed: https://pubmed.gov/33093025. Full-text:
https://doi.org/10.1136/bmj.m4072
A strong statement, after all (and some thoughts on how to deal with the bad
results of the PLACID trial).

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 Vaccines | 235

MONOCLONAL ANTIBODIES

Cohen J. Designer antibodies could battle COVID-19 before vaccines ar-

rive. Science 2020, published 4 August. Full-text:
https://www.sciencemag.org/news/2020/08/designer-antibodies-could-
battle-covid-19-vaccines-arrive
Science writer Jon Cohen describes how the competition is heating up to pro-
duce targeted monoclonal antibodies which could both prevent and treat
COVID-19. Read about treatment and prevention trials, antibody cocktails and
the role monoclonal antibodies might play even after the general availability
of effective vaccines. Read also about the final problem of monoclonal anti-
bodies: their cost, especially for the higher doses needed for treatment. Don’t
expect monoclonals to be affordable globally. Rather, they might split the
world into the haves and have-nots, like many previous drugs. Another rea-
son why accessible vaccines are so important!

Ledford H. Antibody therapies could be a bridge to a coronavirus vaccine

— but will the world benefit? Nature 2020, published 11 August. Full-text:
https://www.nature.com/articles/d41586-020-02360-y
Are monoclonal antibodies a bridging solution before the general availability
of a vaccine? Heidi Lenford reminds us that monoclonals are complex and
expensive to produce, leaving people from poor countries locked out.

Ledford H. The race to make COVID antibody therapies cheaper and more
potent. Nature 2020, published 23 October. Full-text:
https://www.nature.com/articles/d41586-020-02965-3
Injections of antibodies might prevent mild COVID-19 from becoming severe,
but the treatments are expensive and difficult to make.

Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and conva-
lescent humans yield a SARS-CoV-2 antibody cocktail. Science. 2020 Aug
21;369(6506):1010-1014. PubMed: https://pubmed.gov/32540901. Full-text:
https://doi.org/10.1126/science.abd0827
Researchers from Regeneron generated a large panel of antibodies against the
spike protein from humanized mice and from three recovered patients. From
this panel, approximately 40 antibodies with distinct sequences and potent
neutralization activities were chosen for additional characterization, includ-
ing antibody pairs that do not compete for binding to the receptor binding
domain (RBD). REGN10987 and REGN10933 represent such a pair of antibod-

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ies: REGN10933 binds at the top of the RBD, extensively overlapping the bind-
ing site for ACE2. The epitope for REGN10987 is located on the side of the RBD,
away from the REGN10933 epitope, and has little to no overlap with the ACE2
binding site.

Baum A, Fulton BO, Wloga E, et al. Antibody cocktail to SARS-CoV-2 spike

protein prevents rapid mutational escape seen with individual antibod-
ies. Science. 2020 Aug 21;369(6506):1014-1018. PubMed:
https://pubmed.gov/32540904. Full-text:
https://doi.org/10.1126/science.abd0831
Proof of principle in a cell model, using vesicular stomatitis virus pseudopar-
ticles expressing the SARS-CoV-2 spike protein. Simultaneous treatment with
REGN10933 and REGN10987 precluded the appearance of escape mutants.
Thus, this cocktail did not rapidly select for mutants, presumably because
escape would require the unlikely occurrence of simultaneous viral mutation
at two distinct genetic sites, so as to ablate binding and neutralization by
both antibodies in the cocktail.

Baum A, Ajithdoss D, Copin R, et al. REGN-COV2 antibodies prevent and

treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science
2020b, published 9 October. Full-txt: https://doi.org/10.1126/science.abe2402
The authors evaluate REGN-COV2, a cocktail of two neutralizing antibodies
(REGN10987+REGN10933) targeting non-overlapping epitopes on the SARS-
CoV-2 spike protein, in rhesus macaques and golden hamsters. REGN-COV-2
can reduce virus load and decrease virus-induced pathological sequalae in
rhesus macaques. In hamsters, the cocktail limited weight loss and evidence
of pneumonia in the lungs. It is too early to predict the clinical usefulness of
this cocktail in COVID-19 patients. It is currently being tested in clinical trials.

Hunting for antibodies to combat COVID‑19. Biopharma dealmakers 2020,

published 1 September. Full-text: https://www.nature.com/articles/d43747-
020-01115-y
The development of highly successful monoclonal antibody-based therapies
for cancer and immune disorders has created a wealth of expertise and manu-
facturing capabilities. Is there room for monoclonals for prevention or treat-
ment of severe COVID-19 before the general availability of vaccines and effi-
cient antiviral drugs? Find out how the ‘COVID-19 antibodysphere’ (Amgen,
AstraZeneca, Vir, Regeneron, Lilly, Adagio) is building partnerships.

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 Vaccines | 237

Active immunization against SARS-CoV-2

SARS-CoV-2 vaccine platforms
Martin C, Lowery D. mRNA vaccines: intellectual property landscape. Nat
Rev Drug Discov 2020, 27 July. Full-text:
https://www.nature.com/articles/d41573-020-00119-8
Overall filing activity aims at protecting methods to improve mRNA delivery
efficiency as well as pharmacological modifications to reduce mRNA instabil-
ity and innate immunogenicity. Moderna, CureVac, BioNTech and GSK own
nearly half of the mRNA vaccine patent applications in the world.

Questions for the Future

Longevity of the immunological memory against SARS-CoV-2
Wajnberg A, Amanat F, Firpo A, et al. Robust neutralizing antibodies to
SARS-CoV-2 infection persist for months. Science 2020, published 28 Octo-
ber. Full-text: https://doi.org/10.1126/science.abd7728
Assessing the antibody response to SARS-CoV-2 infection in mild and asymp-
tomatic cases is of high importance since they constitute the majority of in-
fections. Now, Ania Wajnberg, Florian Krammer, Carlos Cordon-Cardo and
colleagues show that the vast majority of infected individuals with mild-to-
moderate COVID-19 experience had robust IgG antibody responses against the
viral spike protein. The authors from Icahn School of Medicine at Mount Si-
nai, New York, analyzed a dataset of 30,082 individuals. Titers were relatively
stable for at least a period approximating 5 months. Anti-spike binding titers
correlated with neutralization of authentic SARS-CoV-2. The data suggests
that more than 90% of seroconverters make detectible neutralizing antibody
responses.

Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response

to SARS-CoV-2 in Iceland. N Engl J Med 2020, published 1 September. Full-
text: https://doi.org/10.1056/NEJMoa2026116
How long will people be protected from reinfection by SARS-CoV-2? General-
ly, many months, as may be expected from a coronavirus infection. In this
study by Kari Stefansson, Daniel Gudbjartsson and colleagues, over 90% of
1215 qPCR-positive persons tested positive with two pan-Ig SARS-CoV-2 anti-
body assays and remained seropositive 120 days after diagnosis, with no de-
crease of antibody levels. Another piece of good news: the infection fatality
risk in Iceland was 0.3%. Less good news: only 0.9% of Icelanders were infect-

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ed with SARS-CoV-2 indicating that the Icelandic population is vulnerable to a

second wave of infection.
See also the editorial by Galit Alter and Robert Seder: Alter G, Seder R: The
Power of Antibody-Based Surveillance. N Engl J Med 2020, published 1 Sep-
tember. Full-text: https://doi.org/10.1056/NEJMe2028079. In particular, they
stress the utility of antibody assays as highly cost-effective alternatives to
PCR testing for population-level surveillance, which is critical to the safe reo-
pening of cities and schools.

Ibarrondo FJ, Fulcher JA, Goodman-Meza D, et al. Rapid Decay of Anti-SARS-

CoV-2 Antibodies in Persons with Mild Covid-19. N Engl J Med. 2020 Sep
10;383(11):1085-1087. PubMed: https://pubmed.gov/32706954. Full-text:
https://doi.org/10.1056/NEJMc2025179
Comments:
Bölke E, Matuschek C, Fischer JC. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl
J Med. 2020 Oct 22;383(17):1694-1695. PubMed: https://pubmed.gov/32966710. Full-text:
https://doi.org/10.1056/NEJMc2027051
Terpos E, Mentis A, Dimopoulos MA. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N
Engl J Med. 2020 Oct 22;383(17):1695. PubMed: https://pubmed.gov/32966711. Full-text:
https://doi.org/10.1056/NEJMc2027051
Kutsuna S, Asai Y, Matsunaga A. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl
J Med. 2020 Oct 22;383(17):1695-1696. PubMed: https://pubmed.gov/32966712. Full-text:
https://doi.org/10.1056/NEJMc2027051
The controversy about anti-SARS-CoV-2 antibody decay continues. Some
groups found a marked decline while others obtained conflicting results that
suggest stability over time.

Seow J, Graham C, Merrick B, et al. Longitudinal observation and decline of

neutralizing antibody responses in the three months following SARS-
CoV-2 infection in humans. Nat Microbiol (2020). Full-text:
https://doi.org/10.1038/s41564-020-00813-8
Antibody responses to SARS-CoV-2 can be detected in most infected individu-
als 10–15 d after the onset of COVID-19 symptoms. But how long will antibody
responses be maintained, and will they provide protection from reinfection?
To answer these questions, Katie Doores, Jeffrey Seow and colleagues collect-
ed sequential serum samples up to 94 d post onset of symptoms from 65 indi-
viduals with SARS-CoV-2 infection. They show that the kinetics of the neu-
tralizing antibody response to SARS-CoV-2 is typical of an acute viral infec-
tion where a peak response is detected 3–4 weeks post-infection, which then
wanes. Their results suggest that for individuals who develop a low neutraliz-
ing antibody response (ID50 100–300), titers can return to baseline over a rela-

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 Vaccines | 239

tively short period, whereas those who develop a robust neutralizing anti-
body response maintain titers > 1,000 despite the initial decline. Should we
already reconsider widespread serological testing and antibody protection
against reinfection with SARS-CoV-2? The authors conclude that vaccine
boosters might be required to provide long-lasting protection.

Pre-existing immune responses against SARS-CoV-2

Posten D, Weisblum Y, Wise H, et al. Absence of SARS-CoV-2 neutralizing
activity in pre-pandemic sera from individuals with recent seasonal
coronavirus infection. medRxiv 2020, published 11 October. Full-text:
https://doi.org/10.1101/2020.10.08.20209650
Bad news from Rockefeller University. Paul Bieniasz, Daniel Poston and col-
leagues measured neutralizing activity against SARS-CoV-2 in pre-pandemic
sera from patients with prior PCR-confirmed seasonal coronavirus infection.
While neutralizing activity against seasonal coronaviruses was detected in
nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was
undetectable. The authors conclude that while it is possible that there are
rare instances of individuals possessing antibodies from prior seasonal HCoV
infection may be able to also target SARS-CoV-2 S, their data would argue
against a broad role for pre-existing protective humoral immunity against
SARS-CoV-2. These findings have not yet been peer reviewed.

Outlook
VACCINE SKEPTICISM
Burki T. The online anti-vaccine movement in the age of COVID-19. Lancet
Digit Health. 2020 Oct;2(10):e504-e505. PubMed:
https://pubmed.gov/32984795. Full-text: https://doi.org/10.1016/S2589-
7500(20)30227-2
About 31 million people follow anti-vaccine groups on Facebook, with 17 mil-
lion people subscribing to similar accounts on YouTube. Within a decade, the
anti-vaccination movement could overwhelm pro-vaccination voices online.
If that came to pass, the consequences would stretch far beyond COVID-19.
This article discusses some strategies.

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SPEED

Slaoui M, Hepburn M. Developing Safe and Effective Covid Vaccines — Op-

eration Warp Speed’s Strategy and Approach. N Engl J Med 2020, published
26 August. Full-text: https://doi.org/10.1056/NEJMp2027405
What is OWS and what does it do? Moncef Slaoui and Matthew Hepburn from
Operation Warp Speed explain the forces behind a national vaccine strategy.
The players: Pfizer and BioNTech, AstraZeneca and Oxford University,
Janssen, Moderna, Janssen, Novavax, Sanofi/GSK. Will they succeed in this
unprecedented endeavor?

Arnold C. How computational immunology changed the face of COVID-19

vaccine development. Nat Med. 2020 Jul 15. PubMed:
https://pubmed.gov/32669667. Full-text: https://doi.org/10.1038/d41591-
020-00027-9
After more than two decades of work, computational immunology now ena-
bles the development of a candidate vaccine in just a few hours. However, no
in silico analysis, no matter how high-quality the input and how exacting the
computational algorithms, will ever be a substitute for experimental data.

Corbett KS, Edwards DK, Leist SR et al. SARS-CoV-2 mRNA vaccine design
enabled by prototype pathogen preparedness. Nature 2020, published 5
August. Full-text: https://doi.org/10.1038/s41586-020-2622-0
The authors provide a paradigm for rapid vaccine development: a generaliza-
ble vaccine solution for Betacoronavirus and a commercial mRNA vaccine de-
livery platform; a vaccine development programme initiated on the basis of
pathogen sequences alone; a proof of concept for the prototype-pathogen
approach to pandemic preparedness and response that is predicated on iden-
tifying generalizable solutions for medical countermeasures within virus fam-
ilies or genera. The authors anticipate a huge potential for future vaccine
research: “There are 24 other virus families that are known to infect humans,
and sustained investigation of those potential threats will improve our readi-
ness for future pandemics.”

Price WN 2nd, Rai AK, Minssen T. Knowledge transfer for large-scale vac-
cine manufacturing. Science. 2020 Aug 21;369(6506):912-914. PubMed:
https://pubmed.gov/32792464. Full-text:
https://doi.org/10.1126/science.abc9588

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Identifying an effective SARS-CoV-2 vaccine and prove its safety in huge clin-
ical trials is only the first step. The next step is not less challenging: manufac-
turing vaccines at enormous scale. In this Policy Forum, law school scholars
Nicholson Price, Arti Rai and Timo Minssen explain that fast manufacturing
will require not only physical capacity but also access to knowledge not con-
tained in patents or in other public disclosures. Follow the authors on a path
through the jungle of licenses, know-how transfer, hostage taking and manu-
facturing secrecy, and discover why large biopharmaceutical firms are now
willing to share information that they might previously have viewed as
providing competitive advantage.

COMPRENHENSIVE VACCINE TESTING

Helfland BK, Webb M, Gartaganis SL, et al. The Exclusion of Older Persons
From Vaccine and Treatment Trials for Coronavirus Disease 2019—
Missing the Target. JAMA Intern Med, September 28, 2020. Full-text:
https://doi.org/10.1001/jamainternmed.2020.5084
Those most in need are excluded: in this important review, Benjamin Helfland
and colleagues analyzed clinical COVID-19 trials for age exclusions. In 232
Phase III clinical trials, 38 included age cut-offs and 77 had exclusions prefer-
entially affecting older adults. Of 18 vaccine trials, 11 included age cut-offs,
and the remaining 7 had broad non-specified exclusions. These findings indi-
cate that older adults are likely to be excluded from more than 50% of COVID-
19 clinical trials and 100% of vaccine trials. Why? Such exclusion will limit the
ability to evaluate the efficacy, dosage, and adverse effects of the intended
treatments.

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6. Diagnostic Tests and Procedures

Christian Hoffmann

Diagnosis
Rapid identification and isolation of infected individuals is crucial. Diagnosis
is made using clinical, laboratory and radiological features. As symptoms and
radiological findings of COVID-19 are non-specific, SARS-CoV-2 infection has
to be confirmed by nucleic acid-based polymerase chain reaction (PCR), am-
plifying a specific genetic sequence in the virus. Within just a few days after
the first cases were published, a validated diagnostic workflow for SARS-CoV-
2 was presented (Corman 2020), demonstrating the enormous response capac-
ity achieved through coordination of academic and public laboratories in na-
tional and European research networks.
There is an interim guidance for diagnostic testing for COVID-19 in suspected
human cases, published by WHO in March and updated on September 11, 2020
(WHO 20200911). Several comprehensive up-to-date reviews of laboratory
techniques in diagnosing SARS-CoV-2 have been published recently (Kilic
2020, Loeffelholz 2020).
According to WHO, the decision to test “should be based on both clinical and
epidemiological factors”, in order to support clinical management of patients
and infection control measures. In symptomatic patients, a PCR test should be
immediately carried out, especially for medical professionals with symptoms.
In particular, this applies to nursing homes and other long-term facilities
where large outbreaks with high resident mortalty may occur. In these set-
tings, every day counts: both residents and health-care workers should be
tested immediately. In regression analyses among 88 nursing homes with a
documented case before facility-wide testing occurred, each additional day
between identification of the first case and completion of facility-wide testing
was associated with identification of 1.3 additional cases (Hatfield 2020).
However, the predictive value of the tests markedly varies with time from
exposure and symptom onset. The false-negative rate is lowest 3 days after
onset of symptoms, or approximately 8 days after exposure (see below).
In settings with limited resources, however, patients should only be tested if a
positive test results in imperative action. It does not necessarily make sense
to attempt to ascertain the prevalence of infection by PCR. For example, in a
family which was put on quarantine after the infection was confirmed in one

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member, not all household contacts have to be tested, especially younger per-
sons with only mild symptoms.
For many countries and regions, there are constantly updated recommenda-
tions by authorities and institutions about who should be tested by whom and
when: these recommendations are constantly changing and have to be
adapted to the local epidemiological situation. The lower the infection rates
and the higher the testing capacities, the more patients will be able to be
tested.

Specimen collection
Respiratory tract
SARS-CoV-2 can be detected in a wide range of different tissues and body flu-
ids. In a study on 1,070 specimens collected from 205 patients with COVID-19
(Wang X 2020), bronchoalveolar lavage fluid specimens showed the highest
positive rates (14 of 15; 93%), followed by sputum (72 of 104; 72%), nasal swabs
(5 of 8; 63%), fibrobronchoscopy brush biopsy (6 of 13; 46%), pharyngeal
swabs (126 of 398; 32%), feces (44 of 153; 29%), and blood (3 of 307; 1%).
Though respiratory secretions may be quite variable in composition, respira-
tory samples remain the sample type of choice for diagnostics. Viral replica-
tion of SARS-CoV-2 is very high in upper respiratory tract tissues which is in
contrast to SARS-CoV (Wolfel 2020). According to WHO, respiratory material
for PCR should be collected from upper respiratory specimens (nasopharyn-
geal and oropharyngeal swab or wash) in ambulatory patients (WHO 2020). It
is preferred to collect specimens from both nasopharyngeal and oropharyn-
geal swabs which can be combined in the same tube. Besides nasopharyngeal
swabs, samples can be taken from sputum (if producible), endotracheal aspi-
rate, or bronchoalveolar lavage. It is likely that lower respiratory samples are
more sensitive than nasopharyngeal swabs. Especially in seriously ill patients,
there is often more virus in the lower than in the upper respiratory tract
(Huang 2020). However, there is always a high risk of “aerosolization” and
thus the risk that staff members become infected.
A prospective study in two regional hospitals in Hong Kong examined 563
serial samples collected during the viral shedding period of 50 patients: 150
deep throat saliva (DTS), 309 pooled nasopharyngeal (NP) and throat swabs,
and 104 sputum (instructions for deep throat saliva: first clear your throat by
gargling with your own saliva, and then spit out the DTS into a sterile bottle).
Deep throat saliva produced the lowest viral RNA concentration and a lower
RT-PCR positive rate compared to conventional respiratory specimens. Buccal
swabs do not work well either. In 11 children positive via nasopharyngeal

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swabs, 2 remained negative via buccal swabs. There was a general trend for
buccal specimens to contain lower SARS-CoV-2 viral loads compared with
nasopharyngeal specimens (Kam 2020).

Nasopharyngeal swabs – practical issues

It is important to carry out the swab process correctly. Both nasopharynx and
oropharyngeal swabs have a number of error options that all can lead to false
negative results. In addition, protective measures must be taken in order not
to endanger the examiner. Every swab carries a high risk of infection! Respir-
atory protection, protective glasses, gowns and gloves are required. The cor-
rect putting on and taking off of protective clothing should be practiced!
Many mistakes occur even just removing the protective mask. Gathering
specimens from nasopharyngeal and throat swabs can cause discomfort for
patients and put health-care workers at risk. If not performed properly or in
patients with complex and delicate anatomy, there is a risk for adverse events
such as cerebrospinal fluid leak (Sullivan 2020). There is a very useful video
on protection, preparation, equipment, handling, removing personal protec-
tive equipment, etc (Marty 2020).
For the smear, the patient should sit on a chair and put his head slightly back.
The examiner should stand at a slightly offset position in order to avoid any
possible cough droplet. Tell the patient that it might be uncomfortable for a
short time. Swabs should be used that are suitable for virus detection and
have the most flexible plastic shaft possible. Wooden sticks can inactivate
viruses and pose a high risk of injury. The swab should be held between
thumb and forefinger, like a pencil, so the end should not touch anything.
The posterior wall of the nasopharynx is often reached after 5-7 cm, indicated
by a slight resistance. Mid-turbinate nasal swabs may be less sensitive
(Pinninti 2020). Touching the teeth and tongue should be avoided when tak-
ing a throat swab; the swab should be removed from the back wall, directly
next to the uvula. Caution with the gag reflex! There is a wealth of practical
videos on the internet for the correct execution of the swab process.
In order to minimize the exposure risk to health care workers and depletion
of personal protective equipment, we have established swab instructions for
patients who are able to do this (ie, most of them!) at home. After appropriate
instruction, they can perform the swabs themselves. A courier with the tubes
is sent directly to the patient's home, and the courier places the tubes at the
door. Direct contact between patient and courier should be avoided. The swab
tubes should not be touched by the courier (either put them directly in a bag
or collect them with an inverted bag) and should be brought back directly (no
mailing!). This requires prior, precise instruction, but is usually quite feasible.

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Unsupervised home swab collection was comparable to clinician-collected

nasopharyngeal swab collection (McCulloch 2020). In one of the largest stud-
ies to date, a total of 530 patients with upper respiratory infection were pro-
vided with instructions and asked to collect tongue, nasal, and mid-turbinate
samples (Tu 2020). A nasopharyngeal sample was then collected from the pa-
tient by a healthcare worker. When this NP sample was used as the compara-
tor, the estimated sensitivities of the tongue, nasal, and mid-turbinate sam-
ples collected by the patients were 89.8%, 94.0% and 96.2%, respectively.
The swabs can be stored dry or in a small amount of NaCl solution; if neces-
sary, this should be clarified with the laboratory beforehand. Quick PCR ex-
amination is important, preferably on the same day if possible. Heat and
longer storage can lead to false negative results (Pan 2020).
Lower respiratory specimens may include sputum (if produced) and/or endo-
tracheal aspirate or bronchoalveolar lavage in patients with more severe res-
piratory disease. However, a high risk of aerosolization should be considered
(adhere strictly to infection prevention and control procedures). Additional
clinical specimens may be collected as COVID-19 virus has been detected in
blood and stools (see below).
In contrast to many respiratory viruses, SARS-CoV-2 is present in saliva and
several studies have shown that posterior oropharyngeal (deep throat) saliva
samples are feasible and more acceptable to patients and healthcare workers
(To 2020, Yu 2020, Wyllie 2020, Yokota 2020). In a large study on “enhanced”
saliva specimens (strong sniff, elicited cough, and collection of sali-
va/secretions) from 216 patients with symptoms deemed consistent with
COVID-19, there was a 100% positive agreement (38/38 positive specimens)
and 99.4% negative agreement (177/178 negative specimens).

Fecal shedding
Although no cases of transmission via fecal-oral route have yet been report-
ed, there is also evidence that SARS-CoV-2 is actively replicating in the gas-
trointestinal tract. Several studies showed prolonged presence of SARS-CoV-2
viral RNA in fecal samples (Chen 2020, Wu 2020). Combining results of 26
studies, a rapid review revealed that 54% of those patients tested for fecal
RNA were positive. Duration of fecal viral shedding ranged from 1 to 33 days
after a negative nasopharyngeal swab (Gupta 2020). In another meta-analysis
of 17 studies, the pooled detection rate of fecal SARS-CoV-2 RNA was 44% and
34% by patient and number of specimens, respectively. Patients who present-
ed with gastrointestinal symptoms (77% vs. 58%) or with a more severe dis-
ease (68% vs. 35%) tended to have a higher detection rate.

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These studies have raised concerns about whether patients with negative
pharyngeal swabs are truly virus-free, or sampling of additional body sites is
needed. However, the clinical relevance of these findings remains unclear and
there is one study that did not detect infectious virus from stool samples, de-
spite having high virus RNA concentrations (Wolfel 2020). Therefore, the
presence of nucleic acid alone cannot be used to define viral shedding or in-
fection potential (Atkinson 2020). For many viral diseases including SARS-CoV
or MERS-CoV, it is well known that viral RNA can be detected long after the
disappearance of infectious virus.

Specimens other than respiratory and gastrointestinal: blood, urine,

breast milk
• Blood – in patients with mild or moderate disease, SARS-CoV-2 is relative-
ly rarely detected in blood (Wang W 2020, Wolfel 2020). In a screening
study of 7,425 blood donations in Wuhan, plasma samples were found pos-
itive for viral RNA from 2 asymptomatic donors (Chang 2020). Another
study from Korea found seven asymptomatic blood donors who were later
identified as COVID-19 confirmed cases. None of 9 recipients of platelets
or red blood cell transfusions tested positive for SARS-CoV-2 RNA. Trans-
fusion transmission of SARS-CoV-2 was considered to be unlikely (Kwon
2020). As with feces, it remains unclear whether detectable RNA in the
blood signifies infectivity. In a study of 167 hospitalized patients, SARS-
CoV-2 was found in 64 patients at hospital admission, 3 of 106 serum PCR
negative patients and 15 of 61 positive patients died (Hagman 2020). How-
ever, the clinical significance of SARS-CoV-2 “RNAemia” needs to be de-
fined.
• Urine - None of 72 urine specimens tested positive (Wang X 2020).
• Breast milk – in a case report, SARS­CoV­2 RNA was detected in breast
milk samples from an infected mother on 4 consecutive days. Detection of
viral RNA in milk coincided with mild COVID­19 symptoms and a
SARS­CoV­2 positive diagnostic test of the newborn (Groß 2020). However,
this seems to be rare. Among 64 breast milk samples from 18 infected
women, SARS-CoV-2 RNA was detected in only one milk sample; the viral
culture for that sample was negative. These data suggest that SARS-CoV-2
RNA does not represent replication-competent virus and that breast milk
may not be a source of infection for the infant (Chambers 2020. Case re-
ports of transmitted antibodies in breast milk have also been reported
(Dong 2020).

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• Vaginal fluid - all samples of 10 women with COVID-19 were negative

(Saito 2020).
• Semen – Absence of virus in samples collected from 12 patients in their
recovery phase (Song 2020).
• Tears and conjunctival secretions - among 40 patients (10 with conjuncti-
vitis) who tested positive by RT-PCR of nasopharyngeal and oropharyngeal
swabs, conjunctival swab PCR was positive for 3 patients, among them one
with conjunctivitis (Atum 2020).

PCR
Dozens of in-house and commercial rRT-PCR assays are available as labs
worldwide have customized their PCR tests for SARS-CoV-2, using different
primers targeting different sections of the virus’s genetic sequence. A review
of different assays and diagnostic devices was recently published (Loeffelholz
2020). A protocol for real-time (RT)-PCR assays for the detection of SARS-CoV-
2 for two RdRp targets (IP2 and IP4) is described at
https://www.who.int/docs/default-source/coronaviruse/real-time-rt-pcr-
assays-for-the-detection-of-sars-cov-2-institut-pasteur-
paris.pdf?sfvrsn=3662fcb6_2
Novel real-time RT-PCR assays targeting the RNA-dependent RNA polymerase
(RdRp)/helicase, spike and nucleocapsid genes of SARS-CoV-2 may help to
improve the laboratory diagnosis of COVID-19. Compared to the reported
RdRp-P2 assay which is used in most European laboratories, these assays do
not cross-react with SARS-CoV in cell culture and may be more sensitive and
specific (Chan JF 2020).
The limits of detection of commercial kits may differ substantially. However,
most comparative studies have shown a high sensitivity and their suitability
for screening purposes worldwide:
• In a comparison of 11 different RT-PCR test systems used in seven labs in
Germany in March 2020, the majority of RT-PCR assays detected ca 5 RNA
copies per reaction (Münchhoff 2020). A reduced sensitivity was noted for
the original Charité RdRp gene confirmatory protocol, which may have
impacted the confirmation of some cases in the early weeks of the pan-
demic. The CDC N1 primer/probe set was sensitive and robust for detec-
tion of SARS-CoV-2 in nucleic acid extracts from respiratory material,
stool and serum from COVID-19 patients.
• Analytical limits of detection for seven SARS-CoV-2 assays using serial
dilutions of pooled patient material quantified with droplet digital PCR.

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Limits of detection ranged from ≤ 10 to 74 copies/ml for commercial high-

throughput laboratory analyzers (Roche cobas, Abbott m2000, and Hologic
Panther Fusion) and 167 to 511 copies/ml for sample-to-answer (DiaSorin
Simplexa, GenMark ePlex) and point-of-care instruments (Abbott ID NOW)
(Fung 2020).
• A total of 239 specimens (168 contained SARS-CoV-2) were tested by five
test methods (Procop 2020). The assays that lacked a nucleic acid extrac-
tion step produced more false-negative reactions than assays that includ-
ed this step. The false-negative rates were 0% for the CDC 2019 nCoV Real-
Time RT-PCR Diagnostic Panel, 3.5% for TIB MOLBIOL Assay (Roche), 2.4%
for Xpert Xpress SARS-CoV-2 (Cepheid), 11.9% for Simplexa COVID-19 Di-
rect Kit (DiaSorin), and 16.7% for the ID NOW COVID-19 (Abbott). Most
false negatives were seen in patients with low viral loads.

Qualitative PCR
A qualitative PCR (“positive or negative”) is usually sufficient in routine diag-
nostics. Quantification of viral RNA is currently (still) only of academic inter-
est.
False positive results are very rare. However, they do occur. Though the ana-
lytical specificity of these tests is usually 100%, the clinical specificity is less,
due to contamination (a significant problem for NAT procedures) and/or hu-
man error in the handling of samples or data (very hard to eliminate entire-
ly). As seen with serology (see below), these false positive results can have
substantial effects when prevalence is low (Andrew Cohen, personal commu-
nication).
Another problem of any qualitative PCR is false negative results which can
have many causes (review: Woloshin 2020). Incorrect smears are particularly
common, but laboratory errors also occur. In a review of 7 studies with a total
of 1,330 respiratory samples, the authors estimated the false-negative rate of
RT-PCR by day since infection. Over the 4 days before symptom onset, the
rate decreased from 100% to 67%. On the day of symptom onset (day 5), the
rate was 38%, decreasing to 20% (day 8) and then beginning to increase again
from 21% (day 9) to 66% (day 21). If clinical suspicion is high, infection should
not be ruled out on the basis of RT-PCR alone. The false-negative rate is low-
est 3 days after onset of symptoms, or approximately 8 days after exposure
(Kucirka 2020). Figure 1 illustrates PCR and antibody detection during SARS-
CoV-2 infection.

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Figure 1. Timeline of diagnostic markers for detection of SARS-CoV-2. AB = Antibody.

Do we need to re-test in the case of a negative PCR? Several studies argue

against this strategy, finding very low rates of negative-to-positive conver-
sion with repeated testing (Lepak 2020). Among 20,912 patients, one study
analyzed the frequency of SARS-CoV-2 RT-PCR test discordance among indi-
viduals initially testing negative by nasopharyngeal swab who were retested
on clinical grounds within 7 days. The frequency of subsequent positivity
within this window was only 3.5% and similar across institutions (Long 2020).
It appears that if the first PCR is negative, a second PCR only yields a small
number of positive results.
Several studies have shown that asymptomatic patients also have positive
PCR results and can transmit the virus (Bai 2020, Cereda 2020, Rothe 2020).
The cycle threshold values of RT-PCR for SARS-CoV-2 (“viral load”) in asymp-
tomatic patients are similar to those in symptomatic patients (Lee S 2020,
Lavezzo 2020).
In symptomatic patients, viral shedding may begin 2 to 3 days before the ap-
pearance of the first symptoms. Analyzing a total of 414 throat swabs in 94
patients, the highest viral load in throat swabs was found at the time of symp-
tom onset. Infectiousness started from 2.3 days (95% CI, 0.8–3.0 days) before
symptom onset and peaked at 0.7 days before symptom onset (He 2020). In-
fectiousness was estimated to decline quickly within 7 days.
In a cohort of 113 symptomatic patients, the median duration of detection of
SARS-CoV-2 RNA was 17 days (interquartiles 13-22 days), measured from the
onset of the disease. In some patients, PCR was positive even longer: male
gender and a severe course (invasive mechanical ventilation) were independ-
ent risk factors for prolonged shedding (Xu K 2020).

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Several reports from patients have repeatedly gained much media attraction,
showing positive results after repeated negative PCR and clinical recovery
(Lan 2020, Xiao AT 2020, Yuan 2020). These studies have raised the question of
re-activation or re-infection of COVID-19 (see below, chapter Clinical Presenta-
tion, page 279). However, it seems probable that the results are much more
likely due to methodological problems (Li 2020). At low virus levels, especially
during the final days of infection, the viral load can fluctuate and sometimes
be detectable, sometimes not (Wolfel 2020). Reactivation, and also a rapid
reinfection would be very unusual for coronaviruses.

Quantification of viral load

Several studies have evaluated the SARS-CoV-2 viral load in different speci-
mens. In a small prospective study, the viral load in nasal and throat swabs
obtained from 17 symptomatic patients was analyzed in relation to day-of-
onset of any symptoms (Zou 2020). Of note, the viral load detected in asymp-
tomatic patients was similar to that in symptomatic patients, which suggests
the transmission potential of asymptomatic or minimally symptomatic pa-
tients.
In another study on 82 infected individuals, the viral loads in throat swab and
sputum samples peaked at around 5–6 days after symptom onset, ranging
from around 79,900 copies/ml in the throat to 752,000 copies per mL in spu-
tum (Pan 2020). In a study on oropharyngeal saliva samples, unlike SARS, pa-
tients with COVID-19 had the highest viral load near presentation, which
could account for the fast-spreading nature of this epidemic (To 2020). The
median viral load in posterior oropharyngeal saliva or other respiratory spec-
imens at presentation was 5.2 log10 copies per mL (IQR 4.1-7.0) in this study. In
a total of 323 samples from 76 patients, the average viral load in sputum
(17,429 copies/test) was significantly higher than in throat swabs (2,552 cop-
ies) and nasal swabs (651 copies). Viral load was higher in the early and pro-
gressive stages than in the recovery stage (Yu 2020). According to a recently
published study, viral shedding may already begin 2-3 days before the ap-
pearance of the first symptoms and the infectiousness profile may more
closely resemble that of influenza than of SARS (He 2020).
Higher viral loads might be associated with severe clinical outcomes. In a
large cohort (n = 1145) of hospitalized, symptomatic patients from New York,
viral loads were measured. In a Cox proportional hazards model adjusting for
several confounders, there was a significant independent association between
viral load and mortality (hazard ratio 1.07, 95% CI 1.03–1.11, p = 0.0014), with
a 7% increase in hazard for each log transformed copy/mL (Pujadas 2020).

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However, prospective trials are needed to evaluate the role of SARS-CoV-2

viral load as a marker for assessing disease severity and prognosis.
Should we measure viral load? Probably yes. It may be helpful in clinical prac-
tice. A positive RT-qPCR result may not necessarily mean the person is still
infectious or that they still have any meaningful disease. The RNA could be
from non-viable virus and/or the amount of live virus may be too low for
transmission.
Cycle threshold (Ct) values
RT-qPCR provides quantification by first reverse transcribing RNA into DNA,
and then performing qPCR where a fluorescence signal increases proportion-
ally to the amount of amplified nucleic acid. The test is positive if the fluores-
cence reaches a specified threshold within a certain number of PCR cycles (Ct
value, inversely related to the viral load). Many qPCR assays use a Ct cut-off of
40, allowing detection of very few starting RNA molecules. Some experts
(Tom 2020) suggest using this Ct value or to calculate viral load which can
help refine decision-making (shorter isolation, etc). Unfortunately, there is
still a wide heterogeneity and inconsistency of the standard curves calculated
from studies that provide Ct values from serial dilution samples and the esti-
mated viral loads. According to other experts, precautions are needed when
interpreting the Ct values of SARS-CoV-2 RT-PCR results shown in COVID-19
publications to avoid misunderstanding of viral load kinetics for comparison
across different studies (Han 2020). Caution is needed when regarding Ct val-
ues as a surrogate indicator of ‘quantity’ in a qualitative PCR assay (“viral
load”). Results are not transferable across different assays, different gene
targets and different specimen types (Poon 2020).
However, some clinical key studies are listed here:
• In 678 patients with COVID-19, in-hospital mortality was 35.0% with a
“high viral load” (Ct < 25; n = 220), 17.6% with a “medium viral load” (Ct
25-30; n = 216), and 6.2% with a “low viral load” (Ct > 30; n = 242). High vi-
ral load was independently associated with mortality (adjusted odds ratio
6.05; 95% CI: 2.92-12.52) and intubation (aOR 2.73; 95% CI: 1.68-4.44) in
multivariate models (Magleby 2020).
• A prospective serial sampling of 70 patients revealed clinically relevant Ct
values, namely a Ct of 24 (“high viral load”), and > 40 (“negative”), oc-
curred 9 and 36 days after symptom onset (Lesho 2020).
• Among 93 household members (including index cases) who tested positive
for SARS-CoV-2 by NP swab, Ct values were lowest soon after symptom on-
set and were significantly correlated with time elapsed since onset; within

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7 days after symptom onset, the median Ct value was 26.5, compared with
a median Ct value of 35.0 at 21 days after onset (Salvatore 2020).
• Virus culture was attempted from 324 samples (from 253 cases) that tested
positive for SARS-CoV-2 by RT-PCR. Ct values correlated strongly with cul-
tivable virus. Probability of culturing virus declined to 8% in samples with
Ct > 35 and to 6% (95% CI: 0.9–31.2%) 10 days after onset (Singanayagam
2020).
• A cross-sectional study determined PCR positive samples for their ability
to infect cell lines. Of 90 samples, only 29% demonstrated viral growth.
There was no growth in samples with a Ct > 24 or duration of symptoms >
8 days (Bullard 2020).

Test systems other than conventional RT-PCR

Access to rapid diagnosis is key to the control of the SARS-CoV-2 pandemic. In
the future, point-of-care testing could relieve pressure on centralized labora-
tories and increase overall testing capacity. Besides PCR, additional potential-
ly valuable amplification/detection methods, such as CRISPR (targeting clus-
tered regularly interspaced short palindromic repeats), isothermal nucleic
acid amplification technologies (e.g. reverse transcription loop-mediated iso-
thermal amplification (RT-LAMP), and molecular microarray assays are under
development or are in the process of being commercialized. According to
WHO on September 11, validation of the analytic and clinical performance of
these assays, demonstration of their potential operational utility, rapid
sharing of data, as well as emergency regulatory review of manufactur-
able, well-performing tests “are encouraged to increase access to SARS-CoV-2
testing” (WHO 20200911).
Point-of-care tests
Point-of-care tests are easy-to-use devices to facilitate testing outside of la-
boratory settings (Guglielmi 2020, Joung 2020). They are eagerly awaited. But
will they be game-changers? On May 6, the FDA granted an emergency use
authorization for a CRISPR-based SARS-CoV-2 fluorescent assay marketed by
Sherlock Biosciences. This straightforward SARS-CoV-2 test combines simpli-
fied extraction of viral RNA with isothermal amplification and CRISPR-
mediated detection. The results are available within an hour with minimal
equipment. First results (n = 202 positive/200 negative samples): sensitivity
93.1%, specificity 98.5% (Joung 2020). However, its use still remains limited to
laboratories certified to perform high-complexity tests. There are other re-
ports of an all-in-one dual CRISPR-Cas12a assay (Ding 2020) which allows all
components to be incubated in one pot for CRISPR-based nucleic acid detec-

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tion, enabling simple, all-in-one molecular diagnostics without the need for
separate and complex manual operations.
On May 6, FDA also authorized (EUA) Quidel’s Sofia 2 SARS Antigen Fluores-
cent Immunoassay. This test must be read on a dedicated analyzer and de-
tects SARS-CoV-2 nucleocapsid protein from nasopharyngeal swabs in 15 min.
According to the manufacturer, the assay demonstrated acceptable clinical
sensitivity and detected 47/59 infections (80%). In another study, the so called
CovidNudge test had 94% sensitivity and 100% specificity when compared
with standard laboratory-based RT-PCR (Gibani 2020). In other studies, sensi-
tivity was much lower. The BIOCREDIT COVID-19 antigen test was 10,000 fold
less sensitive than RT-PCR and detected between 11.1 % and 45.7% of RT-PCR-
positive samples from COVID-19 patients (Mak 2020).
Besides antigen tests, several rapid nucleic acid amplification tests have been
recently released (Collier 2020). The Abbott ID NOW COVID-19 assay (using
isothermal nucleic acid amplification of the RdRp viral target) is capable of
producing positive results in as little as 5 minutes. In one stuy, results were
compared with RT-PCR Cepheid Xpert Xpress SARS-CoV-2 using nasopharyn-
geal swabs (Basu 2020). Regardless of method of collection and sample type,
the rapid test had negative results in a third of the samples that tested posi-
tive by PCR when using nasopharyngeal swabs in viral transport media and
45% when using dry nasal swabs. Such “Reverse Transcription Loop-Mediated
Isothermal Amplification” tests (RT-LAMP) could be used outside of a central
laboratory on various types of biological samples. They can be completed by
individuals without specialty training or equipment and may provide a new
diagnostic strategy for combating the spread of SARS-CoV-2 at the point-of-
risk (Lamb 2020).
Given the low (or still unproven) sensitivity, these tests may mainly serve as
an early adjunctive tool to identify infectious individuals very rapidly, i.e. in
the emergency unit. These tests help to avoid bed closure, allow discharge to
care homes and expedite access to hospital procedures. Some experts are
even more optimistic: the frequent use of cheap, simple, rapid tests is essen-
tial, even if their analytic sensitivities are vastly inferior to those of bench-
mark tests. The key question is not how well molecules can be detected in a
single sample - but how effectively infections can be detected in a population
by the repeated use of a given test as part of an overall testing strategy - the
sensitivity of the testing regimen (Mina 2020).

Diagnosis in the setting of a shortage of PCR test kits

There is no doubt that the overall goal must be to detect as many infections
as possible. However, in many countries, a shortage of supply test kits does

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not meet the needs of a growing infected population. Especially in low-

prevalence settings, sample pooling is an option to reduce costs and speed
results. In this approach, small volumes of samples from multiple patients are
combined into a single test, resulting in substantial reagent savings. Several
studies have shown that 5-10 samples can be pooled, without compromising
the results (Ben-Ami 2020, Schmidt 2020). However, pooling is not that trivial
(Mallapaty 2020). There are several caveats and careful and rigorous investi-
gation is necessary to assure that the pooling of specimens does not impact
the analytical sensitivity of the assay (review: Clark 2020).
Some studies have investigated whether the diagnosis in high prevalence pe-
riods and countries can be made without PCR detection if necessary. A large
retrospective case-control study from Singapore has evaluated predictors for
SARS-CoV-2 infection, using exposure risk factors, demographic variables,
clinical findings and clinical test results (Sun 2020). Even in the absence of
exposure risk factors and/or radiologic evidence of pneumonia, clinical find-
ings and tests can identify subjects at high risk of COVID-19. Low leukocytes,
low lymphocytes, higher body temperature, higher respiratory rate, gastroin-
testinal symptoms and decreased sputum production were strongly associat-
ed with a positive SARS-CoV-2 test. However, those preliminary prediction
models are sensitive to the local epidemiological context and phase of the
global outbreak. They only make sense during times of high incidence. In
other words: if I see a patient during the peak of an epidemic presenting with
fever, cough, shortness of breath and lymphopenia, I can be almost sure that
this patient suffers from COVID-19. During phases when the incidence is low-
er, these models do not make sense. There is no doubt that the nucleic acid
test serves as the gold standard method for confirmation of infection. When-
ever PCR is available, PCR should be performed.

Serology (antibody testing)

Detection of past viral infections by looking for antibodies an infected person
has produced will be among the most important goals in the fight against the
COVID-19 pandemic. Antibody testing is multipurpose: these serological as-
says are of critical importance to determine seroprevalence, previous expo-
sure and identify highly reactive human donors for the generation of conva-
lescent serum as therapeutic. They will support contact tracing and screening
of health care workers to identify those who are already immune. How many
people really got infected, in how many did the virus escape the PCR diagno-
sis, and for what reasons, how many patients are asymptomatic, and what is
the real mortality rate in a defined population? Only with comprehensive
serology testing (and well-planned epidemiological studies) will we be able to

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answer these questions and reduce the ubiquitous undisclosed number in the
current calculations. Several investigations are already underway in a wide
variety of locations worldwide.
In recent weeks it has become clear that serology testing may also aid as a
complementary diagnostic tool for COVID-19. The seroconversion of specific
IgM and IgG antibodies were observed as early as the 4th day after symptom
onset. Antibodies can be detected in the middle and later stages of the illness
(Guo L 2020, Xiao DAT 2020). If a person with a highly suspicious COVID-19
remains negative by PCR testing and if symptoms are ongoing for at least sev-
eral days, antibodies may be helpful and enhance diagnostic sensitivity.
However, antibody testing is not trivial. The molecular heterogeneity of
SARS-CoV-2 subtypes, imperfect performance of available tests and cross-
reactivity with seasonal CoVs have to be considered (reviews: Cheng 2020,
Krammer 2020). According to a Cochrane analysis on 57 publications with
15,976 samples, the sensitivity of antibody tests is too low in the first week
from symptom onset to have a primary role in the diagnosis of COVID-19.
However, these tests may still have a role in complementing other testing in
individuals presenting later, when RT-PCR tests are negative or are not done
(Deeks 2020). Antibody tests are likely to have a useful role in detecting pre-
vious SARS-CoV-2 infection if used 15 or more days after the onset of symp-
toms. Data beyond 35 days post-symptom onset is scarce. According to the
authors, studies of the accuracy of COVID-19 tests require considerable im-
provement. Studies must report data on sensitivity disaggregated by time
from onset of symptoms. A practical overview of the pitfalls of antibody test-
ing and how to communicate risk and uncertainty is given by Watson 2020.

Tests
Average sensitivity and specificity of FDA-approved antibody tests is 84.9%
and 98.6%, respectively. Given variable prevalence of COVID-19 (1%-15%) in
different parts, statistically the positive predictive value will be as low as 30%
to 50% in areas with low prevalence (Mathur 2020). A systematic review of 40
studies on sensitivity and specificity was recently published (Bastos 2020),
stratified by method of serological testing (enzyme linked immunosorbent
assays - ELISAs), lateral flow immunoassays (LFIAs), or chemiluminescent
immunoassays - CLIAs). The pooled sensitivity of ELISAs measuring IgG or IgM
was 84.3% (95% confidence interval 75.6% to 90.9%), of LFIAs was 66.0% (49.3%
to 79.3%), and of CLIAs was 97.8% (46.2% to 100%). According to the authors,
higher quality clinical studies assessing the diagnostic accuracy of serological
tests for COVID-19 are urgently needed.

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A nice overview of the different platforms, including binding assays such as

enzyme-linked immunosorbent assays (ELISAs), lateral flow assays, or West-
ern blot–based assays is given by Krammer 2020. In addition, functional as-
says that test for virus neutralization, enzyme inhibition, or bactericidal as-
says can also inform on antibody-mediated immune responses. Many caveats
and open questions with regard to antibody testing are also discussed.
Antibody testing usually focuses on antigens (proteins). In the case of SARS-
CoV-2, different ELISA kits based on recombinant nucleocapsid protein and
spike protein are used (Loeffelholz 2020). The SARS-CoV-2 spike protein
seems to be the best target. However, which part of the spike protein to use is
less obvious and there is a lot hanging on the uniqueness of the spike protein.
The more unique it is, the lower the odds of cross-reactivity with other coro-
naviruses—false positives resulting from immunity to other coronaviruses.
Cross reactivity to other coronaviruses can be challenging. So called confir-
mation tests (usually neutralization tests) can be used to reduce false positive
testings. However, detection and quantification of neutralizing antibodies are
relatively low-throughput and limited to Biosafety Level 3-equipped research
laboratories. To avoid neutralization tests that require live pathogen and a
biosafety level 3 laboratory, several studies have proposed tests based on an-
tibody-mediated blockage of the interaction between the ACE2 receptor pro-
tein and the receptor-binding domain. The tests achieved 99.93% specificity
and 95–100% sensitivity (Tan 2020).
Even with a very high specificity of 99% and above, however, especially in
low-prevalence areas, the informative value of antibody testing is limited and
a high rate of false positive tests can be assumed. An example: With a specific-
ity of 99%, it is expected that one test out of 100 is positive. In a high preva-
lence setting, this is less relevant. However, if a person is tested in a low
prevalence setting, the likelihood that a positive test is really positive (the
positive predictive value, i.e. the number of really positive tests divided by
the number of all positive tests) is low. In a population with a given preva-
lence of 1%, the predictive value would only be 50%! Current estimates from
Iceland, a well-defined but unselected population, still have shown a relative-
ly constant rate of around 0.8% in March 2020 (Gudbjartsson 2020). Even in
apparently more severely affected countries, the infection rates are only
slightly higher. General antibody screening in these populations will there-
fore produce a fairly high rate of false positive tests. When assessing anti-
SARS-CoV-2 immune status in individuals with low pre-test probability, it
may be better to confirm positive results from single measurements by alter-
native serology tests or functional assays (Behrens 2020).
Some key studies with head-to-head-assessments of different immunoassays

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• Abbott, EUROIMMUN and the Elecsys (Roche): The Abbott assay demon-
strated the fewest false negative results > 14d post-symptom onset and the
fewest false positive results. While the Roche assay detected more positive
results earlier after onset of symptoms, none of the assays demonstrated
high enough clinical sensitivity before day 14 from symptom onset to di-
agnose acute infection (Tang 2020).
• Abbott, LIAISON (DiaSorin), Elecsys (Roche), Siemens, plus a novel in-
house 384-well (Oxford) ELISA in 976 (!) pre-pandemic blood samples and
536 (!) blood samples with confirmed SARS-CoV-2 infection. All assays had
a high sensitivity (92.7-99.1%) and specificity (98.7-99.9%). The most sensi-
tive test assessed was the in-house ELISA. The Siemens assay and Oxford
immunoassay achieved 98% sensitivity/specificity without further optimi-
zation. However, a limitation was the small number of pauci-symptomatic
and asymptomatic cases analyzed (NAEG 2020).
• Abbott, Epitope Diagnostics, EUROIMMUN, and Ortho Clinical Diagnostics:
all four immunoassays performed similarly with respect to sensitivity in
COVID-19 hospitalized patients, and except for the Epitope assay, also in
individuals with milder forms of the infection (Theel 2020). The Abbott
and Ortho Clinical immunoassays provided the highest overall specificity,
of over 99%.

Indication in clinical practice

But outside clinical studies, who should be tested now? Testing actually
makes no sense for patients with a previous, proven COVID-19 disease. How-
ever, it can still be done if, for example, you want to validate a test. In addi-
tion to those involved in health care or working in other professions with a
high risk of transmission, such testing can also be useful in order to identify
possible contact persons retrospectively. However, we only measure antibod-
ies when the testing result might have consequences. Patients should be in-
formed about the low positive predictive value, especially in those without
any evidence of prior disease or exposition to COVID-19. In these patients,
antibody testing is not recommended. Outside epidemiological hot spots, in
low prevalence countries like Germany, virtually everybody is still seronega-
tive. If positive, the predictive value is too low.

The kinetics of antibodies

Serologic responses to coronaviruses are only transient. A brilliant systematic
review of antibody-mediated immunity to coronaviruses (kinetics, correlates

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of protection, and association with severity) was recently published (Huang

AT 2020).
Antibodies to other human, seasonal coronaviruses may disappear even after
a few months. Preliminary data suggest that the profile of antibodies to SARS-
CoV-2 is similar to SARS-CoV (Xiao DAT 2020). For SARS-CoV, antibodies were
not detected within the first 7 days of illness, but IgG titre increased dramati-
cally on day 15, reaching a peak on day 60, and remained high until day 180
from when it declined gradually until day 720. IgM was detected on day 15
and rapidly reached a peak, then declined gradually until it was undetectable
on day 180 (Mo 2006). As with other viruses, IgM antibodies occur somewhat
earlier than IgG antibodies which are more specific. IgA antibodies are rela-
tively sensitive but less specific (Okba 2020).
The first larger study on the host humoral response against SARS-CoV-2 has
shown that these tests can aid the diagnosis of COVID-19, including subclini-
cal cases (Guo 2020). In this study, IgA, IgM and IgG response using an ELISA-
based assay on the recombinant viral nucleocapsid protein was analyzed in
208 plasma samples from 82 confirmed and 58 probable cases (Guo 2020). The
median duration of IgM and IgA antibody detection were 5 days (IQR 3-6),
while IgG was detected on day 14 (IQR 10-18) after symptom onset, with a pos-
itive rate of 85%, 93% and 78% respectively. The detection efficiency by IgM
ELISA was higher than that of PCR after 5.5 days of onset of symptoms. In an-
other study of 173 patients, the seroconversion rates (median time) for IgM
and IgG were 83% (12 days) and 65% (14 days), respectively. A higher titer of
antibodies was independently associated with severe disease (Zhao 2020). In
other studies, however, antibody level did not correlate clearly with clinical
outcomes (Ren 2020).
In some patients, IgG occurs even faster than IgM. In a study on seroconver-
sion patterns of IgM and IgG antibodies, the seroconversion time of IgG anti-
body was earlier than IgM. IgG antibody reached the highest concentration
on day 30, while IgM antibody peaked on day 18, but then began to decline
(Qu J 2020). The largest study to date reported on acute antibody responses in
285 patients (mostly non-severe COVID-19). Within 19 days after symptom
onset, 100% of patients tested positive for antiviral IgG. Seroconversion for
IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers
plateaued within 6 days after seroconversion. The median day of seroconver-
sion for both IgG and IgM was 13 days post-symptom onset. No association
between plateau IgG levels and clinical characteristics was found (Long 2020).
However, there is some evidence that asymptomatic individuals develop less
strong antibody responses. Moreover, antibodies disappear from the blood.
Your COVID pass expires within a few weeks. Compared to symptomatic pa-

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tients, 37 asymptomatic patients had lower virus-specific IgG levels in the

acute phase (Long Q 2020). IgG levels and neutralizing antibodies started to
decrease within 2–3 months after infection. Of note, 40% became seronegative
(13% of the symptomatic group) for IgG in the early convalescent phase.
Among 19 health care workers who had anti–SARS-CoV-2 antibodies detected
at baseline, only 8 (42%) had antibodies that persisted above the seropositivi-
ty threshold at 60 days, whereas 11 (58%) became seronegative (Patel 2020). A
decrease in anti-RBD antibody level was also seen in 15 donors of convales-
cent plasma (Perreault 2020).
Taken together, antibody testing is not only an epidemiological tool. It may
also help in diagnosis. It will be seen in the coming months how the human
antibody response to SARS-CoV-2 evolves over time and how this response
and titres correlate with immunity. It is also conceivable that in some pa-
tients (e.g. those with immunodeficiency) the antibody response remains re-
duced.

Radiology
Chest computed tomography
Computed tomography (CT) can play a role in both diagnosis and assessment
of disease extent and follow-up. Chest CT has a relatively high sensitivity for
diagnosis of COVID-19 (Ai 2020, Fang 2020). However, around half of patients
may have a normal CT during the first 1-2 days after symptom onset
(Bernheim 2020). On the other hand, it became clear very early in the current
pandemic that a considerable proportion of subclinical patients (scans done
before symptom onset) may already have pathological CT findings (Chan
2020, Shi 2020). In some of these patients showing pathological CT findings
evident for pneumonia, PCR in nasopharyngeal swabs was still negative (Xu
2020). On the other hand, half of the patients who later develop CT morpho-
logically visible pneumonia can still have a normal CT in the first 1-2 days
after the symptoms appear (Bernheim 2020).
However, one should not overestimate the value of chest CT. The recommen-
dation by some Chinese researchers to include CT as an integral part in the
diagnosis of COVID-19 has led to harsh criticism, especially from experts in
Western countries. The Chinese studies have shown significant errors and
shortcomings. In view of the high effort and also due to the risk of infection
for the staff, many experts strictly reject the general CT screening in SARS-
CoV-2 infected patients or in those suspected cases (Hope 2020, Raptis 2020).
According to the recommendation of the British Radiology Society, which
made attempts to incorporate CT into diagnostic algorithms for COVID-19

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 Diagnostic Tests and Procedures | 269

diagnostics, the value of CT remains unclear – even if a PCR is negative or not

available (Nair 2020, Rodrigues 2020). A chest CT should only be performed if
complications or differential diagnoses are considered (Raptis 2020).
In blinded studies, radiologists from China and the United States have at-
tempted to differentiate COVID-19 pneumonia from other viral pneumonia.
The specificity was quite high, the sensitivity nuch lower (Bai 2020). A recent
metaanalysis found a high sensitivity but low specificity (Kim 2020). The sen-
sitivity of CT was affected by the distribution of disease severity, the propor-
tion of patients with comorbidities, and the proportion of asymptomatic pa-
tients. In areas with low prevalence, chest CT had a low positive predictive
value (1.5-30.7%).
If pathological, images usually show bilateral involvement, with multiple
patchy or ground-glass opacities (GGO) with subpleural distribution in multi-
ple bilateral lobes. Lesions may display significant overlap with those of SARS
and MERS (Hosseiny 2020). According to a review of 45 studies comprising
4410 (!) patients, ground glass opacities (GGOs), whether isolated (50%) or co-
existing with consolidations (44%) in bilateral and subpleural distribution,
were the most prevalent chest CT findings (Ojha 4410). Another systematic
review of imaging findings in 919 patients found bilateral multilobar GGO
with a peripheral or posterior distribution, mainly in the lower lobes and less
frequently within the right middle lobe as the most common feature (Salehi
2020). In this review, atypical initial imaging presentation of consolidative
opacities superimposed on GGO were found in a smaller number of cases,
mainly in the elderly population. Septal thickening, bronchiectasis, pleural
thickening, and subpleural involvement were less common, mainly in the
later stages of the disease. Pleural effusion, pericardial effusion, lymphade-
nopathy, cavitation, CT halo sign, and pneumothorax were uncommon (Salehi
2020).
The evolution of the disease on CT is not well understood. However, with a
longer time after the onset of symptoms, CT findings are more frequent, in-
cluding consolidation, bilateral and peripheral disease, greater total lung in-
volvement, linear opacities, “crazy-paving” pattern and the “reverse halo”
sign (Bernheim 2020). Some experts have proposed that imaging can be sort-
ed into four different phases (Li M 2020). In the early phase, multiple small
patchy shadows and interstitial changes emerge. In the progressive phase,
the lesions increase and enlarge, developing into multiple GGOs as well as
infiltrating consolidation in both lungs. In the severe phase, massive pulmo-
nary consolidations and “white lungs” are seen, but pleural effusion is rare.
In the dissipative phase, the GGOs and pulmonary consolidations were com-
pletely absorbed, and the lesions began to change into fibrosis.

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In a longitudinal study analyzing 366 serial CT scans in 90 patients with

COVID-19 pneumonia, the extent of lung abnormalities progressed rapidly
and peaked during illness days 6-11 (Wang Y 2020). The predominant pattern
of abnormalities after symptom onset in this study was ground-glass opacity
(45-62%). As pneumonia progresses, areas of lesions enlarge and developed
into diffuse consolidations in both lungs within a few days (Guan 2020).
Most patients discharged had residual disease on final CT scans (Wang Y
2020). Studies with longer follow-up are needed to evaluate long-term or
permanent lung damage including fibrosis, as is seen with SARS and MERS
infections. Pulmonary fibrosis is expected to be the main factor leading to
pulmonary dysfunction and decline of quality of life in COVID-19 survivors
after recovery. More research is needed into the correlation of CT findings
with clinical severity and progression, the predictive value of baseline CT or
temporal changes for disease outcome, and the sequelae of acute lung injury
induced by COVID-19 (Lee 2020).
Of note, chest CT is not recommended in all COVID-19 patients, especially in
those who are well enough to be sent home or those with only short sympto-
matic times (< 2 days). In the case of COVID-19, a large number of patients
with infection or suspected infection swarm into the hospital. Consequently,
the examination workload of the radiology department increases sharply.
Because the transmission route of SARS-CoV-2 is through respiratory drop-
lets and close contact transmission, unnecessary CT scan should be avoided.
An overview of the prevention and control of the COVID-19 epidemic in the
radiology department is given by An et al.

Ultrasound, PET and other techniques

Some experts have postulated that lung ultrasound (LUS) may be helpful,
since it can allow the concomitant execution of clinical examination and lung
imaging at the bedside by the same doctor (Buonsenso 2020, Soldati 2020).
Potential advantages of LUS include portability, bedside evaluation, safety
and possibility of repeating the examination during follow-up. Experience
especially from Italy with lung ultrasound as a bedside tool has improved
evaluation of lung involvement, and may also reduce the use of chest x-rays
and CT. A point scoring system is employed by region and ultrasound pattern
(Vetrugno 2020). However, the diagnostic and prognostic role of LUS in
COVID-19 is uncertain.
Whether there is any potential clinical utility of other imaging techniques
such as 18F-FDG PET/CT imaging in the differential diagnosis of complex cas-
es also remains unclear (Deng 2020, Qin 2020).

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In patients with neurological symptoms, brain MRI is often performed. In 27

patients, the most common imaging finding was cortical signal abnormalities
on FLAIR images (37%), accompanied by cortical diffusion restriction or lep-
tomeningeal enhancement (Kandemirli 2020). However, the complex clinical
course including comorbidities, long ICU stay with multidrug regimens, res-
piratory distress with hypoxia episodes can all act as confounding factors and
a clear cause-effect relationship between COVID-19 infection and MRI find-
ings will be hard to establish.

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Wyllie AL, Fournier J, Casanovas-Massana A, et al. Saliva or Nasopharyngeal Swab Specimens
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7. Clinical Presentation
Christian Hoffmann
Bernd Sebastian Kamps

After an average incubation time of around 5 days (range: 2-14 days), a typical
COVID-19 infection begins with dry cough and low-grade fever (38.1–39°C or
100.5–102.1°F), often accompanied by diminishment of smell and taste. In
most patients, COVID-19 remains mild or moderate and symptoms resolve
within a week and patients typically recover at home. Around 10% of patients
remain symptomatic through the second week. The longer the symptoms
persist, the higher the risk of developing more severe COVID-19, requiring
hospitalization, intensive care and invasive ventilation. The outcome of
COVID-19 is often unpredictable, especially in older patients with comorbidi-
ties. The clinical picture ranges from completely asymptomatic to rapidly
devastating courses.
In this chapter we discuss the clinical presentation, including
• The incubation period
• Asymptomatic patients
• Frequent and rare symptoms
• Laboratory findings
• Outcome: Risk factors for severe disease
• Reactivations and reinfections
• Long-term sequelae
The radiological findings are described in the diagnostic chapter, page 251.

Incubation period
A pooled analysis of 181 confirmed COVID-19 cases with identifiable exposure
and symptom onset windows estimated the median incubation period to be
5.1 days with a 95% CI of 4.5 to 5.8 days (Lauer 2020). The authors estimated
that 97.5% of those who develop symptoms will do so within 11.5 days (8.2 to
15.6 days) of infection. Fewer than 2.5% of infected persons will show symp-
toms within 2.2 days, whereas symptom onset will occur within 11.5 days in
97.5%. However, these estimates imply that, under conservative assumptions,
101 out of every 10,000 cases will develop symptoms after 14 days of active
monitoring or quarantine. Another analysis of 158 confirmed cases outside
Wuhan estimated a similar median incubation period of 5.0 days (95 % CI, 4.4

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to 5.6 days), with a range of 2 to 14 days (Linton 2020). In a detailed analysis of

36 cases linked to the first three clusters of circumscribed local transmission
in Singapore, the median incubation period was 4 days with a range of 1-11
days (Pung 2020). Taken together, the incubation period of around 4-6 days is
in line with that of other coronaviruses causing SARS or MERS (Virlogeux
2016). Of note, the time from exposure to onset of infectiousness (latent peri-
od) may be shorter. There is little doubt that transmission of SARS-CoV-2 dur-
ing the late incubation period is possible (Li 2020). In a longitudinal study, the
viral load was high 2-3 days before the onset of symptoms, and the peak was
even reached 0.7 days before the onset of symptoms. The authors of this Na-
ture Medicine paper estimated that approximately 44% (95% CI 25-69%) of all
secondary infections are caused by such presymptomatic patients (He 2020).

Asymptomatic cases
Understanding the frequency of asymptomatic patients and the temporal
course of asymptomatic transmission will be crucial for assessing disease dy-
namics. It is important to distinguish those patients who will remain asymp-
tomatic during the whole time of infection and those in which infection is
still too early to cause symptoms (presymptomatic). While physicians need to
be aware of asymptomatic cases, the true percentage is difficult to assess. To
evaluate symptoms systematically is not trivial and the ascertainment pro-
cess could lead to misclassification. If you do not ask precisely enough, you
will get false negative answers. If questions are too specific, the interviewees
may give false positive answers (confirmation bias). For example, in a large
study, only two thirds of patients reporting olfactory symptoms had abnor-
mal results in objective olfactory testing (see below). What is a symptom?
And, is it possible to interview the demented residents of a nursing home?
Sweet grandma will say she was fine over the last few weeks.
In a living systematic review (through June 10, 2020, analyzing 79 studies in a
range of different settings), 20% (95% CI 17%–25%) remained asymptomatic
during follow-up, but biases in study designs limit the certainty of this esti-
mate (Buitrago-Garcia 2020). In seven studies of defined populations screened
for SARS-CoV-2 and then followed, 31% (95% CI 26%–37%) remained asymp-
tomatic. Another review found that asymptomatic persons seem to account
for approximately 40-45% of infections, and that they can transmit the virus
to others for an extended period, perhaps longer than 14 days. The absence of
COVID-19 symptoms might not necessarily imply an absence of harm as sub-
clinical lung abnormalities are frequent (Oran 2020).
The probable best data come from 3,600 people on board the cruise ship Dia-
mond Princess (Mizumoto 2020) who became involuntary actors in a “well-

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controlled experiment” where passengers and crew comprised an environ-

mentally homogeneous cohort. Due to insufficient hygienic conditions, > 700
people became infected while the ship was quarantined in the port of Yoko-
hama, Japan. After systematic testing, 328 (51.7%) of the first 634 confirmed
cases were found to be asymptomatic. Considering incubation periods be-
tween 5.5 and 9.5 days, the authors calculated the true asymptomatic propor-
tion at 17.9% (Mizumoto 2020). The outbreak at the aircraft carrier USS Theo-
dore Roosevelt revealed that 146/736 infected sailors (19.8%) remained
asymptomatic for the duration of the study period.

Table 1. Larger studies with defined populations; proportion of asymptomatic patients (LTF =
long-term facilities)
Asymptomatic
Population, n
Alvarado 2020 Young sailors, 20%
US Aircraft Carrier (n=736)
Borras-Bermejo Nursing Homes Spain, 68% of residents, 56% of staff
2020 residents (n=768) and staff (n=403) (including pre-symptomatic)
Feaster 2020 LTFs California, 19-86% of residents, 17-31%
residents and staff (n=631) of staff
Gudbjartsson Icelandic Population (n=1,221) 43% (including pre-
2020 symptomatic)
Hoxha 2020 LTFs Belgium, 75% of residents, 74% of staff
residents (n=4,059) and staff (including pre-symptomatic)
(n=2,185)
Lavezzo 2020 (Small town) Vo, Italy, 43%
all residents (n=2,812)
Marossy 2020 LTFs London (n=2,455) 51% of residents, 69% of staff

There is no doubt that asymptomatic patients may transmit the virus (Bai
2020, Rothe 2020). In several studies from Northern Italy or Korea, viral loads
in nasal swabs did not differ significantly between asymptomatic and symp-
tomatic subjects, suggesting the same potential for transmitting the virus
(Lee 2020). Of 63 asymptomatic patients in Chongquing, 9 (14%) transmitted
the virus to others (Wang Y 2020).
Taken together, these preliminary studies indicate that a significant propor-
tion (20-60%) of all COVID-19 infected subjects may remain asymptomatic
during their infection. The studies show a broad range, depending on the
populations and probably on methodological issues. It will be very difficult (if
not impossible) to clarify the exact proportion.

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Symptoms
A plethora of symptoms have been described in the past months, clearly indi-
cating that COVID-19 is a complex disease, which in no way consists only of a
respiratory infection. Many symptoms are unspecific so that the differential
diagnosis encompasses a wide range of infections, respiratory and other dis-
eases. However, different clusters can be distinguished in COVID-19. The most
common symptom cluster encompasses the respiratory system: cough, spu-
tum, shortness of breath, and fever. Other clusters encompass musculoskele-
tal symptoms (myalgia, joint pain, headache, and fatigue), enteric symptoms
(abdominal pain, vomiting, and diarrhea); and less commonly, a mucocutane-
ous cluster. An excellent review on these extrapulmonary organ-specific
pathophysiology, presentations and management considerations for patients
with COVID-19 was recently published (Gupta 2020).

Fever, cough, shortness of breath

Symptoms occur in the majority of cases (for asymptomatic patients, see be-
low). In early studies from China (Guan 2020, Zhou 2020), fever was the most
common symptom, with a median maximum of 38.3 C; only a few had a tem-
perature of > 39 C. The absence of fever seems to be somewhat more frequent
than in SARS or MERS; fever alone may therefore not be sufficient to detect
cases in public surveillance. The second most common symptom was cough,
occurring in about two thirds of all patients. Among survivors of severe
COVID-19 (Zhou 2020), median duration of fever was 12.0 days (8-13 days) and
cough persisted for 19 days (IQR 12-23 days). According to a systemic review,
including 148 articles comprising 24,410 adults with confirmed COVID-19
from 9 countries (Grant 2020), the most prevalent symptoms were fever
(78%), cough (57%) and fatigue (31%).
Fever and cough do not distinguish between mild and severe cases nor do
they predict the course of COVID-19 (Richardson 2020, Petrilli 2020). In con-
trast, shortness of breath has been identified as a strong predictor of severe
disease in larger studies. In a cohort of 1,590 patients, dyspnea was associated
with an almost two-fold risk for critical disease (Liang 2020) and mortality
(Chen 2020). Others found higher rates of shortness of breath, and tempera-
ture of > 39.0 in older patients compared with younger patients (Lian 2020). In
the Wuhan study on patients with severe COVID-19, a multivariate analysis
revealed that a respiratory rate of > 24 breaths per minute at admission was
higher in non-survivors (63% versus 16%).
Over the last weeks, much cohort data from countries outside China have
been published. However, almost all data applies to patients who were admit-

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ted to hospitals, indicating selection bias towards more severe and sympto-
matic patients.
• Among 20,133 patients in the UK who were admitted to 208 acute care
hospitals in the UK between 6 February and 19 April 2020, the most com-
mon symptoms were cough (69%), fever (72%), and shortness of breath
(71%), showing a high degree of overlap (Docherty 2020).
• Among 5,700 patients who were admitted to any of 12 acute care hospitals
in New York between March 1, 2020, and April 4, 2020, only 30.7% had fe-
ver of > 38C. A respiratory rate of > 24 breaths per minute at admission
was found in 17.3% (Richardson 2020).
• Among the first 1,000 patients presenting at the NewYork Presbyteri-
an/Columbia University (Argenziano 2020), the most common presenting
symptoms were cough (73%), fever (73%), and dyspnea (63%).

Musculoskeletal symptoms
The cluster of musculoskeletal symptoms encompasses myalgia, joint pain,
headache, and fatigue. These are frequent symptoms, occurring each in 15-
40% of patients (Argenziano 2020, Docherty 2020, Guan 2020). Although sub-
jectively very disturbing and sometimes foremost in the perception of the
patient, these symptoms tell us nothing about the severity of the clinical pic-
ture. However, they are frequently overlooked in clinical practice, and head-
ache merits special attention.
According to a recent review (Bolay 2020), headache is observed in 11-34% of
hospitalized COVID-19 patients, occurring in 6-10% as the presenting symp-
tom. Significant features are moderate-severe, bilateral headache with pul-
sating or pressing quality in the temporo-parietal, forehead or periorbital
region. The most striking features are sudden to gradual onset and poor re-
sponse to common analgesics. Possible pathophysiological mechanisms in-
clude activation of peripheral trigeminal nerve endings by the SARS-CoV-2
directly or through the vasculopathy and/or increased circulating pro-
inflammatory cytokines and hypoxia.

Gastrointestinal symptoms
Cell experiments have shown that SARS-CoV and SARS-CoV-2 are able to in-
fect enterocytes (Lamers 2020). Active replication has been shown in both
bats and human intestinal organoids (Zhou 2020). Fecal calprotectin as a reli-
able fecal biomarker allowing detection of intestinal inflammation in inflam-
matory bowel diseases and infectious colitis, was found in some patients,
providing evidence that SARS-CoV-2 infection instigates an inflammatory

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response in the gut (Effenberger 2020). These findings explain why gastroin-
testinal symptoms are observed in a subset of patients and why viral RNA can
be found in rectal swabs, even after nasopharyngeal testing has turned nega-
tive. In patients with diarrhea, viral RNA was detected at higher frequency in
stool (Cheung 2020).
In the early Chinese studies, however, gastrointestinal symptoms were rarely
seen. In a meta-analysis of 60 early studies comprising 4,243 patients, the
pooled prevalence of gastrointestinal symptoms was 18% (95% CI, 12%-25%);
prevalence was lower in studies in China than other countries. As with oto-
laryngeal symptoms, it remains unclear whether this difference reflects geo-
graphic variation or differential reporting. Among the first 393 consecutive
patients who were admitted to two hospitals in New York City, diarrhea
(24%), and nausea and vomiting (19%) were relatively frequent (Goyal 2020).
Among 18,605 patients admitted to UK Hospitals, 29% of all patients com-
plained of enteric symptoms on admission, mostly in association with respir-
atory symptoms; however, 4% of all patients described enteric symptoms
alone (Docherty 2020).
It’s not all criticial illness. Another study compared 92 critically ill patients
with COVID-19–induced ARDS with 92 comparably ill patients with non–
COVID-19 ARDS, using propensity score analysis. Patients with COVID-19 were
more likely to develop gastrointestinal complications (74% vs 37%; p < 0.001).
Specifically, patients with COVID-19 developed more transaminitis (55% vs
27%), severe ileus (48% vs 22%), and bowel ischemia (4% vs 0%). High expres-
sion of ACE 2 receptors along the epithelial lining of the gut that act as host-
cell receptors for SARS-CoV-2 could explain this (El Moheb 2020).

Otolaryngeal symptoms (including anosmia)

Although upper respiratory tract symptoms such as rhinorrhea, nasal conges-
tion, sneezing and sore throat are relatively unusual, it has become clear
within a few weeks that anosmia and hyposmia are important signs of the
disease (Luers 2020). Interestingly, these otolaryngological symptoms appear
to be much more common in Europe than in Asia. However, it is still unclear
whether this is a real difference or whether these complaints were not rec-
orded well enough in the initial phase in China. There is now very good data
from Europe: the largest study to date found that 1,754/2,013 patients (87%)
reported loss of smell, whereas 1,136 (56%) reported taste dysfunction. Most
patients had loss of smell after other general and otolaryngologic symptoms
(Lechien 2020). Mean duration of olfactory dysfunction was 8.4 days. Females
seem to be more affected than males. The prevalence of self-reported smell
and taste dysfunction was higher than previously reported and may be char-

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acterized by different clinical forms. Anosmia may not be related to nasal

obstruction or inflammation. Of note, only two thirds of patients reporting
olfactory symptoms and who had objective olfactory testing had abnormal
results.
“Flu plus ‘loss of smell’ means COVID-19”. Among 263 patients presenting in
March (at a single center in San Diego) with flu-like symptoms, loss of smell
was found in 68% of COVID-19 patients (n=59), compared to only 16% in nega-
tive patients (n=203). Smell and taste impairment were independently and
strongly associated with SARS-CoV-2 positivity (anosmia: adjusted odds ratio
11, 95% CI: 5‐24). Conversely, sore throat was independently associated with
negativity (Yan 2020).
Among a total of 18,401 participants from the US and UK who reported poten-
tial symptoms on a smartphone app and who had undergone a SARS-CoV-2
test, the proportion of participants who reported loss of smell and taste was
higher in those with a positive test result (65 vs 22%). A combination of symp-
toms, including anosmia, fatigue, persistent cough and loss of appetite was
appropriate to identify individuals with COVID-19 (Menni 2020).
Post-mortem histological analysis of the olfactory epithelium in two COVID-
19 patients showed prominent leukocytic infiltrates in the lamina propria and
focal atrophy of the mucosa. However, it is unclear whether the observed in-
flammatory neuropathy is a result of direct viral damage or is mediated by
damage to supporting non-neural cells (Kirschenbaum 2020). Among 49 con-
firmed COVID-19 patients with anosmia, there were no significant pathologi-
cal changes in the paranasal sinuses on CT scans. Olfactory cleft and ethmoid
sinuses appeared normal while in other sinuses, partial opacification was de-
tected only in some cases (Naeini 2020).

Cardiovascular symptoms and issues

There is growing evidence of direct and indirect effects of SARS-CoV-2 on the
heart, especially in patients with pre-existing heart diseases (Bonow 2020).
SARS-CoV-2 has the potential to infect cardiomyocytes, pericytes and fibro-
blasts via the ACE2 pathway leading to direct myocardial injury, but the path-
ophysiological sequence remains unproven (Hendren 2020). Post-mortem
examination by in situ hybridization suggested that the most likely localiza-
tion of SARS-CoV-2 is not in the cardiomyocytes but in interstitial cells or
macrophages invading the myocardial tissue (Lindner 2020). A second hy-
pothesis to explain COVID-19-related myocardial injury centers on cytokine
excess and/or antibody-mediated mechanisms. It has also been shown that
the ACE2 receptor is widely expressed on endothelial cells and that direct

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SARS-CoV-2 infection of the endothelial cell is possible, leading to diffuse en-

dothelial inflammation (Varga 2020). Post-mortem examination cases indi-
cate a strong virus-induced vascular dysfunction (Menter 2020).
Clinically, COVID-19 can manifest with an acute cardiovascular syndrome
(termed “ACovCS”, for acute COVID-19 cardiovascular syndrome). Numerous
cases with ACovCS have been described, not only with typical thoracic com-
plaints, but also with very diverse cardiovascular manifestations. Troponin is
an important parameter (see below). In a case series of 18 COVID-19 patients
who had ST segment elevation, there was variability in presentation, a high
prevalence of non-obstructive disease, and a poor prognosis. 6/9 patients
undergoing coronary angiography had obstructive disease. Of note, all 18 pa-
tients had elevated D-dimer levels (Bangalore 2020). Among 2,736 COVID-19
patients admitted to one of five hospitals in New York City who had troponin-
I measured within 24 hours of admission, 985 (36%) patients had elevated tro-
ponin concentrations. After adjusting for disease severity and relevant clini-
cal factors, even small amounts of myocardial injury (0.03-0.09 ng/mL) were
significantly associated with death (Lala 2020).
In patients with a seemingly typical coronary heart syndrome, COVID-19
should also be considered in the differential diagnosis, even in the absence of
fever or cough (Fried 2020, Inciardi 2020). For more information, see the
chapter Comorbidities, page 379.
Beside ACovCS, a wide array of cardiovascular manifestations is possible, in-
cluding heart failure, cardiogenic shock, arrhythmia, and myocarditis. Among
100 consecutive patients diagnosed with COVID-19 infection undergoing
complete echocardiographic evaluation within 24 hours of admission, only
32% had a normal echocardiogram at baseline. The most common cardiac
pathology was right ventricular (RV) dilatation and dysfunction (observed in
39% of patients), followed by left ventricular (LV) diastolic dysfunction (16%)
and LV systolic dysfunction (10%). In another case series of 54 patients with
mild-to-moderate COVID-19 in Japan, relative bradycardia was also a common
finding (Ikeuchi 2020).

Thrombosis, embolism
Coagulation abnormalities occur frequently in association with COVID-19,
complicating clinical management. Numerous studies have reported on an
incredibly high number of venous thromboembolism (VTE), especially in
those with severe COVID-19. The initial coagulopathy of COVID-19 presents
with prominent elevation of D-dimer and fibrin/fibrinogen degradation
products, while abnormalities in prothrombin time, partial thromboplastin

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time, and platelet counts are relatively uncommon (excellent review: Connors
2020). Coagulation test screening, including the measurement of D-dimer and
fibrinogen levels, is suggested.
But what are the mechanisms? Some studies have found pulmonary embolism
with or without deep venous thrombosis, as well as presence of recent
thrombi in prostatic venous plexus, in patients with no history of VTE, sug-
gesting de novo coagulopathy in these patients with COVID-19. Others have
highlighted changes consistent with thrombosis occurring within the pulmo-
nary arterial circulation, in the absence of apparent embolism (nice review:
Deshpande 2020). Some studies have indicated severe hypercoagulability ra-
ther than consumptive coagulopathy (Spiezia 2020) or an imbalance between
coagulation and inflammation, resulting in a hypercoagulable state (review:
Colling 2020).
According to a systematic review of 23 studies, among 7,178 COVID-19 pa-
tients admitted to general wards and intensive care units (ICU), the pooled in-
hospital incidence of pulmonary embolism (PE) or lung thrombosis was 14.7%
and 23.4%, respectively (Roncon 2020).
Some of the key studies are listed here:
• In a single-center study from Amsterdam on 198 hospitalized cases, the
cumulative incidences of VTE at 7 and 21 days were 16% and 42%. In 74
ICU patients, cumulative incidence was 59% at 21 days, despite thrombosis
prophylaxis. The authors recommend performing screening compression
ultrasound in the ICU every 5 days (Middeldorp 2020).
• Among 3334 consecutive patients admitted to 4 hospitals in New York
City, a thrombotic event occurred in 16% (Bilaloglu 2020). Of these, 207
(6.2%) were venous (3.2% PE and 3.9% DVT) and 365 (11.1%) were arterial
(1.6% ischemic stroke, 8.9% MI, and 1.0% systemic thromboembolism). All-
cause mortality was 24.5% and was higher in those with thrombotic events
(43% vs 21%). D-dimer level at presentation was independently associated
with thrombotic events.
• In a retrospective multicentre study, 103/1240 (8.3%) consecutive patients
hospitalized for COVID-19 (patients directly admitted to an ICU were ex-
cluded) had evidence for PE. In a multivariate analysis, male gender, anti-
coagulation, elevated CRP, and time from symptom onset to hospitaliza-
tion were associated with PE risk (Fauvel 2020).
• Autopsy findings from 12 patients, showing that 7/12 had deep vein
thrombosis. Pulmonary embolism was the direct cause of death in four
cases (Wichmann 2020).

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• Acute pulmonary embolism (APE) can occur in mild-to moderate and is

not limited to severe or critical COVID-19 (Gervaise 2020).
• Careful examination of the lungs from deceased COVID-19 patients with
lungs from 7 patients who died from ARDS secondary to influenza A
showed distinctive vascular features. COVID-19 lungs displayed severe en-
dothelial injury associated with the presence of intracellular virus and
disrupted cell membranes. Histologic analysis of pulmonary vessels
showed widespread thrombosis with microangiopathy. Alveolar capillary
microthrombi and the amount of vessel growth were 9 and almost 3 times
as prevalent as in influenza, respectively (Ackermann 2020)
• Five cases of large-vessel stroke occurring in younger patients (age 33-49,
2 without any risk factors) (Oxley 2020).
• Five cases with profound hemodynamic instability due to the develop-
ment of acute cor pulmonale, among them 4 younger than 65 years of age
(Creel-Bulos 2020).
Empiric therapeutic anti-coagulation (AC) is now being employed in clinical
practice in many centers and will be evaluated in randomized clinical trials.
To adjust for bias due to non-random allocation of potential covariates among
COVID-19 patients, one study applied propensity score matching methods.
Among > 3000 patients, propensity matching yielded 139 patients who re-
ceived AC and 417 patients who did not receive treatment with balanced vari-
ables between the groups. Results suggest that AC alone is unlikely to be pro-
tective for COVID-19-related morbidity and mortality (Tremblay 2020).
There is also a quite controversial debate about a possible correlation be-
tween the use of ibuprofen and the increased risk of VTE development. Ac-
cording to a recent review (Arjomandi 2020), the causation between the ef-
fects of ibuprofen and VTE remains speculative. The role of ibuprofen on a
vascular level remains unclear as well as whether ibuprofen is able to interact
with SARS-CoV-2 mechanistically. However, the authors recommend careful
considerations on avoiding high dosage of ibuprofen in subjects at particular
risk of thromboembolic events.

Neurologic symptoms
Neuroinvasive propensity has been demonstrated as a common feature of
human coronaviruses. Viral neuroinvasion may be achieved by several
routes, including trans-synaptic transfer across infected neurons, entry via
the olfactory nerve, infection of vascular endothelium, or leukocyte migra-
tion across the blood-brain barrier (reviews: Zubair 2020, Ellul 2020). With
regard to SARS‐CoV‐2, early occurrences such as olfactory symptoms (see

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above) should be further evaluated for CNS involvement. Potential late neuro-
logical complications in cured COVID-19 patients are possible (Baig 2020). In a
study of 4491 hospitalized COVID-19 patients in New York City, 606 (13.5%)
developed a new neurologic disorder (Frontera 2020). The most common di-
agnoses were: toxic/metabolic encephalopathy (6.8%, temporary/reversible
changes in mental status in the absence of focal neurologic deficits or prima-
ry structural brain disease, excluding patients in whom sedative or other
drug effects or hypotension explained this), seizure (1.6%), stroke (1.9%), and
hypoxic/ischemic injury (1.4%). Whether these more non-specific symptoms
are manifestations of the disease itself remains to be seen. There are several
observational series of specific neurological features such as Guillain–Barré
syndrome (Toscano 2020), myasthenia gravis (Restivo 2020) or Miller Fisher
Syndrome and polyneuritis cranialis (Gutierrez-Ortiz 2020).
Especially in patients with severe COVID-19, neurological symptoms are
common. In an observational series of 58 patients, ARDS due to SARS-CoV-2
infection was associated with encephalopathy, prominent agitation and con-
fusion, and corticospinal tract signs. Patients with COVID-19 might experi-
ence delirium, confusion, agitation, and altered consciousness, as well as
symptoms of depression, anxiety, and insomnia (review: Rogers 2020). It re-
mains unclear which of these features are due to critical illness–related en-
cephalopathy, cytokines, or the effect or withdrawal of medication, and
which features are specific to SARS-CoV-2 infection (Helms 2020). However, in
a large retrospective cohort study comparing 1,916 COVID-19 patients and
1,486 influenza patients (with emergency department visits or hospitaliza-
tions), there were 31 acute ischemic strokes with COVID-19, compared to 3
with influenza (Merkler 2020). After adjustment for age, sex, and race, the
likelihood of stroke was almost 8-fold higher with COVID-19 (odds ratio, 7.6).
Of note, there is no clear evidence for CNS damage directly caused by SARS-
CoV-2. In a study on 21 cerebrospinal fluid (CSF) samples from patients with
confirmed COVID-19, all were negative. These data suggest that, although
SARS-CoV-2 is able to replicate in neuronal cells in vitro, SARS-CoV-2 testing
in CSF is not relevant in the general population (Destras 2020). In a large post-
mortem examination, SARS-CoV-2 could be detected in the brains of 21 (53%)
of 40 examined patients but was not associated with the severity of neuropa-
thological changes (Matschke 2020) which seemed to be mild, with pro-
nounced neuroinflammatory changes in the brainstem being the most com-
mon finding. In another study, brain specimens obtained from 18 patients
who died 0 to 32 days after the onset of symptoms showed only hypoxic
changes and did not show encephalitis or other specific brain changes refera-
ble to the virus (Solomon 2020).

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Dermatological symptoms
Numerous studies have reported on cutaneous manifestations seen in the
context of COVID-19. The most prominent phenomenon, the so-called “COVID
toes”, are chilblain-like lesions which mainly occur at acral areas. [Chilblain:
Frostbeule (de), engelure (fr), sabañón (es), gelone (it), frieira (pt), 冻疮 (cn)]
These lesions can be painful (sometimes itchy, sometimes asymptomatic) and
may represent the only symptom or late manifestations of SARS-CoV-2 infec-
tion. Of note, in most patients with “COVID toes”, the disease is only mild to
moderate. It is speculated that the lesions are caused by inflammation in the
walls of blood vessels, or by small micro-clots in the blood. However, whether
“COVID toes” represent a coagulation disorder or a hypersensitivity reaction
is not yet known. Key studies:
• Two different patterns of acute acro-ischemic lesions can overlap
(Fernandez-Nieto 2020). The chilblain-like pattern was present in 95 pa-
tients (72.0%). It is characterized by red to violet macules, plaques and
nodules, usually at the distal aspects of toes and fingers. The erythema
multiform-like pattern was present in 37 patients (28.0%).
• Five clinical cutaneous lesions are described (Galvan 2020): acral areas of
erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicu-
lar eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%)
and livedo or necrosis (6%). Vesicular eruptions appear early in the course
of the disease (15% before other symptoms). The pseudo-chilblain pattern
frequently appears late in the evolution of COVID-19 disease (59% after
other symptoms).
• In a case series on 22 adult patients with varicella-like lesions (Marzano
2020), typical features were constant trunk involvement, usually scattered
distribution and mild or absent pruritus, the latter being in line with most
viral exanthems but not like true varicella. Lesions generally appeared 3
days after systemic symptoms and disappeared by day 8.
• Three cases of COVID-19 associated ulcers in the oral cavity, with pain,
desquamative gingivitis, and blisters (Martin Carreras-Presas 2020).
Other case reports include digitate papulosquamous eruption (Sanchez 2020),
petechial skin rash (Diaz-Guimaraens 2020, Quintana-Castanedo 2020). How-
ever, it should be kept in mind that not all rashes or cutaneous manifesta-
tions seen in patients with COVID-19 can be attributed to the virus. Co-
infections or medical complications have to be considered. Newer studies
reporting in negative PCR and serology have questioned a direct association
between acral skin disease and COVID-19:

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• Of 31 patients (mostly teenagers) who had recently developed chilblains,

histopathologic analysis of skin biopsy specimens (22 patients) confirmed
the diagnosis of chilblains and showed occasional lymphocytic or micro-
thrombotic phenomena. In all patients, PCR and serology remained nega-
tive (Herman 2020).
• Among 40 young patients with chilblain lesions and with suspected SARS-
CoV-2 infection, serology was positive in 12 (30%). All had negative PCR
results at the time of presentation, suggesting that in young patients
SARS-CoV-2 is completely suppressed before a humoral immune response
is induced (Hubiche 2020).
• In a cohort series from Valencia following 20 patients aged 1 to 18 years
with new-onset acral inflammatory lesions, all lacked systemic manifesta-
tions of COVID-19. Surprisingly, both PCR and serologic test results were
negative for SARS-CoV-2 (Roca-Ginés 2020).
Comprehensive mucocutaneous examinations, analysis of other systemic clin-
ical features or host characteristics, and histopathologic correlation, will be
vital to understanding the pathophysiologic mechanisms of what we are see-
ing on the skin (Review: Madigan 2020).

Kidneys
SARS-CoV-2 has an organotropism beyond the respiratory tract, including the
kidneys and the liver. Researchers have quantified the SARS-CoV-2 viral load
in precisely defined kidney compartments obtained with the use of tissue
micro-dissection from 6 patients who underwent autopsy (Puelles 2020).
Three of these 6 patients had a detectable SARS-CoV-2 viral load in all kidney
compartments examined, with preferential targeting of glomerular cells. Re-
nal tropism is a potential explanation of commonly reported clinical signs of
kidney injury in patients with COVID-19, even in patients with SARS-CoV-2
infection who are not critically ill (Zhou 2020). Recent data indicate that renal
involvement is more frequent than described in early studies (Gabarre 2020).
Of the first 1,000 patients presenting at the NewYork-Presbyterian/Columbia
University, 236 were admitted or transferred to intensive care units
(Argenziano 2020). Of these, 78.0% (184/236) developed acute kidney injury
and 35.2% (83/236) needed dialysis. Concomitantly, 13.8% of all patients and
35.2% of patients in intensive care units required in-patient dialysis, leading
to a shortage of equipment needed for dialysis and continuous renal replace-
ment therapy.

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In recent months, some case reports of collapsing glomerulopathy akin to

those seen during the HIV epidemic have been published. All of these cases
were in patients of African ethnicity (Velez 2020).

Liver
One of the largest studies, evaluating liver injury in 2273 SARS-CoV-2 positive
patients, found that 45% had mild, 21% moderate, and 6.4% severe liver inju-
ry. In a multivariate analysis, severe acute liver injury was significantly asso-
ciated with elevated inflammatory markers including ferritin and IL‐6. Peak
ALT was significantly associated with death or discharge to hospice (OR 1.14,
p = 0.044), controlling for age, body mass index, diabetes, hypertension, intu-
bation, and renal replacement therapy (Phipps 2020). In another meta-
analysis of 9 studies with a total of 2115 patients, patients with COVID-19 with
liver injury were at an increased risk of severity (OR 2.57) and mortality
(1.66).

Ocular and atypical manifestations

Ocular manifestations are also common. In a case series from China, 12/38
patients (32%, more common in severe cases) had ocular manifestations con-
sistent with conjunctivitis, including conjunctival hyperemia, chemosis,
epiphora, or increased secretions. Two patients had positive PCR results from
conjunctival swabs (Wu 2020). The retina can also be affected, as has been
shown using optical coherence tomography (OCT), a non-invasive imaging
technique that is useful for demonstrating subclinical retinal changes. Twelve
adult patients showed hyper-reflective lesions at the level of the ganglion cell
and inner plexiform layers more prominently at the papillomacular bundle in
both eyes. Since their initial report, the authors have extended their findings
to more than 150 patients, demonstrating an absence of blood flow within the
retinal lesions of “many” patients (Marinho 2020).
Other new and sometimes puzzling clinical presentations have emerged (and
will emerge) in the current pandemic. There are case reports of non-specific
symptoms, especially in the elderly population, underlining the need for ex-
tensive testing in the current pandemic (Nickel 2020).

Laboratory findings
The most evident laboratory findings in the first large cohort study from Chi-
na (Guan 2020) are shown in Table 2. On admission, lymphocytopenia was
present in 83.2% of the patients, thrombocytopenia in 36.2%, and leukopenia
in 33.7%. In most patients, C-reactive protein was elevated to moderate levels;

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less common were elevated levels of alanine aminotransferase and D-dimer.

Most patients have normal procalcitonin on admission.

Table 2. Percentage of symptoms in first large cohort study from China

(Guan 2020). Disease severity was classified according to American Thoracic
Society (Metlay 2019) guidelines

Clinical symptoms All Severe Non-

Disease Severe
Fever, % 88.7 91.9 88.1
Cough, % 67.8 70.5 67.3
Fatigue, % 38.1 39.9 37.8
Sputum production, % 33.7 35.3 33.4
Shortness of breath, % 18.7 37.6 15.1
Myalgia or arthralgia, % 14.9 17.3 14.5
Sore throat, % 13.9 13.3 14.0
Headache, % 13.6 15.0 13.4
Chills, % 11.5 15.0 10.8
Nausea or vomiting, % 5.0 6.9 4.6
Nasal congestion, % 4.8 3.5 5.1
Diarrhea, % 3.8 5.8 3.5
Radiological findings
Abnormalities on X-ray, % 59.1 76.7 54.2
Abnormalities on CT, % 86.2 94.6 84.4
Laboratory findings
WBC < 4,000 per mm3, % 33.7 61.1 28.1
Lymphocytes < 1,500 per mm3, % 83.2 96.1 80.4
Platelets < 150,000 per mm3, % 36.2 57.7 31.6
C-reactive protein ≥ 10 mg/L, % 60.7 81.5 56.4
LDH ≥ 250 U/L, % 41.0 58.1 37.1
AST > 40 U/L, % 22.2 39.4 18.2
D-dimer ≥ 0.5 mg/L, % 46.6 59.6 43.2

Inflammation
Parameters indicating inflammation such as elevated CRP and procalcitonin
are very frequent findings. They have been proposed to be important risk
factors for disease severity and mortality (Chen 2020). For example, in a mul-
tivariate analysis of a retrospective cohort of 1590 hospitalized subjects with
COVID-19 throughout China, a procalcitonin > 0.5 ng/ml at admission had a
HR for mortality of 8.7 (95% CI: 3.4-22.3). In 359 patients, CRP performed bet-
ter than other parameters (age, neutrophil count, platelet count) in predict-
ing adverse outcome. Admission serum CRP level was identified as a moderate
discriminator of disease severity (Lu 2020). Of 5279 cases confirmed in a large

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medical center in New York, 52% of them admitted to hospital, a CRP > 200
was more strongly associated (odds ratio 5.1) with critical illness than age or
comorbidities (Petrilli 2019).
Some studies have suggested that the dynamic change of interleukin-6 (IL-6)
levels and other cytokines can be used as a marker in disease monitoring in
patients with severe COVID-19 (Chi 2020, Zhang 2020). In a large study of 1484
patients, several cytokines were measured upon admission to the Mount Sinai
Health System in New York (Del Valle 2020). Even when adjusting for disease
severity, common laboratory inflammation markers, hypoxia and other vi-
tals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels
remained independent and significant predictors of disease severity and
death. These findings were validated in a second cohort of 231 patients. The
authors propose that serum IL-6 and TNF-α levels should be considered in the
management and treatment of patients with COVID-19 to stratify prospective
clinical trials, guide resource allocation and inform therapeutic options.
There is also one study suggesting that serum cortisol concentration seems to
be a better independent predictor than other laboratory markers associated
with COVID-19, such as CRP, D-dimer, and neutrophil to leukocyte ratio (Tan
2020).

Hematological: Lymphocytes, platelets, RDW

Lymphocytopenia and transient but severe T cell depletion is a well-known
feature of SARS (He 2005). In COVID-19, lymphopenia is also among the most
prominent hematological features. Lymphopenia may be predictive for pro-
gression (Ji 2020) and patients with severe COVID-19 present with lymphocy-
topenia of less than 1500/µl in almost 100% of cases (Guan 2020). It’s not only
the total lymphocyte count. There is growing evidence for a transient deple-
tion of T cells. Especially the reduced CD4+ and CD8+ T cell counts upon ad-
mission were predictive of disease progression in a larger study (Zhang 2020).
In another large study on COVID-19 patients, CD3+, CD4+ and CD8+ T cells as
well as NK cells were significantly decreased in COVID-19 patients and related
to the severity of the disease. According to the authors, CD8+ T cells and CD4+
T cell counts can be used as diagnostic markers of COVID-19 and predictors of
disease severity (Jiang 2020). Beside T cells, B cells may also play a role. In 104
patients, a decrease in B cells was independently associated with prolonged
viral RNA shedding (Hao 2020).
Another common hematological finding is low platelet counts that may have
different causes (Review: Xu 2020). A meta-analysis of 24 studies revealed a
weighted incidence of thrombocytopenia in COVID-19 patients of 12.4% (95%

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CI 7.9%–17.7%). The meta-analysis of binary outcomes (with and without

thrombocytopenia) indicated an association between thrombocytopenia and
a 3-fold enhanced risk of a composite outcome of ICU admission, progression
to acute respiratory distress syndrome, and mortality (Zong 2020). Cases of
hemorrhagic manifestation and severe thrombocytopenia responding to im-
munoglobulins fairly quickly with a sustained response over weeks have been
reported (Ahmed 2020).
Red blood cell distribution width (RDW) is another component of complete
blood counts that quantifies the variation of individual red blood cell (RBC)
volumes and has been shown to be associated with elevated risk for morbidity
and mortality in a wide range of diseases. In a large cohort study including
1641 adults diagnosed with SARS-CoV-2 infection and admitted to 4 hospitals
in Boston (Foy 2020), RDW was associated with mortality risk in Cox models
(hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW > 14.5% vs ≤
14.5%).
However, there are also cohorts in which hematological parameters such as
thrombocytes, neutrophil-to-lymphocyte ratio or D-dimers do not allow pre-
diction of patient outcome (Pereyra 2020). These routine parameters, despite
giving guidance on the overall health of the patient, might not always accu-
rately indicate COVID-19-related complications.

Cardiac: Troponin
Given the cardiac involvement especially in severe cases (see above), it is not
surprising that cardiac parameters are frequently elevated. A meta-analysis
of 341 patients found that cardiac troponin I levels are significantly increased
only in patients with severe COVID-19 (Lippi 2020). In 179 COVID-19 patients,
cardiac troponin ≥ 0.05 ng/mL was predictive of mortality (Du 2020). Among
2736 COVID-19 patients admitted to one of five hospitals in New York City
who had troponin-I measured within 24 hours of admission, 985 (36%) pa-
tients had elevated troponin concentrations. After adjusting for disease se-
verity and relevant clinical factors, even small amounts of myocardial injury
(0.03-0.09 ng/mL) were significantly associated with death (adjusted HR: 1.75,
95% CI 1.37-2.24) while greater amounts (> 0.09 ng/dL) were significantly as-
sociated with higher risk (adjusted HR 3.03, 95% CI 2.42-3.80). However, it
remains to be seen whether troponin levels can be used as a prognostic fac-
tor. A comprehensive review on the interpretation of elevated troponin levels
in COVID-19 has been recently published (Chapman 2020).

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Coagulation: D-dimer, aPTT

Several studies have evaluated the coagulation parameter D-dimer in the
progression of COVID-19. Among 3334 consecutive patients admitted to 4
hospitals at New York City, a thrombotic event occurred in 16.0%. D-dimer
level at presentation was independently associated with thrombotic events,
consistent with early coagulopathy (Bilaloglu 2020). In the Wuhan study, all
patients surviving had low D-dimer during hospitalization, whereas levels in
non-survivors tended to increase sharply at day 10. In a multivariate analysis,
D-dimer of > 1 µg/mL remained the only lab finding which was significantly
associated with in-hospital death, with an odds ratio of 18.4 (2.6-129, p =
0.003). However, D-dimer has a reported association with mortality in pa-
tients with sepsis and many patients died from sepsis (Zhou 2020).
In a considerable proportion of patients, a prolonged aPTT can be found. Of
216 patients with SARS-CoV-2, this was the case in 44 (20%). Of these, 31/34
(91%) had positive lupus anticoagulant assays. As this is not associated with a
bleeding tendency, it is recommended that prolonged aPTT should not be a
barrier to the use of anti-coagulation therapies in the prevention and treat-
ment of venous thrombosis (Bowles 2020). Another case series of 22 patients
with acute respiratory failure present a severe hypercoagulability rather than
consumptive coagulopathy. Fibrin formation and polymerization may predis-
pose to thrombosis and correlate with a worse outcome (Spiezia 2020).

Lab findings as risk factor

It is not very surprising that patients with severe disease had more promi-
nent laboratory abnormalities than those with non-severe disease. It remains
unclear how a single parameter can be of clinical value as almost all studies
were retrospective and uncontrolled. Moreover, the numbers of patients were
low in many studies. However, there are some patterns which may be helpful
in clinical practice. Lab risk factors are:
• Elevated CRP, procalcitonin, interleukin-6 and ferritin
• Lymphocytopenia, CD4 T cell and CD8 T cell depletion, leukocytosis
• Elevated D-dimer and troponin
• Elevated LDH

Clinical classification
There is no broadly accepted or valid clinical classification for COVID-19. The
first larger clinical study distinguished between severe and non-severe cases
(Guan 2020), according to the Diagnosis and Treatment Guidelines for Adults

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with Community-acquired Pneumonia, published by the American Thoracic

Society and Infectious Diseases Society of America (Metlay 2019). In these
validated definitions, severe cases include either one major criterion or three
or more minor criteria. Minor criteria are a respiratory rate > 30
breaths/min, PaO2/FIO2 ratio < 250, multilobar infiltrates, confu-
sion/disorientation, uremia, leukopenia, low platelet count, hypothermia,
hypotension requiring aggressive fluid resuscitation. Major criteria comprise
septic shock with need for vasopressors or respiratory failure requiring me-
chanical ventilation.
Some authors (Wang 2020) have used the following classification including
four categories:
1. Mild cases: clinical symptoms were mild without pneumonia manifesta-
tion through image results
2. Ordinary cases: having fever and other respiratory symptoms with pneu-
monia manifestation through image results
3. Severe cases: meeting any one of the following: respiratory distress, hy-
poxia (SpO2 ≤ 93%), abnormal blood gas analysis: (PaO2 < 60mmHg, PaCO2
> 50mmHg)
4. Critical cases: meeting any one of the following: Respiratory failure which
requires mechanical ventilation, shock, accompanied by other organ fail-
ure that needs ICU monitoring and treatment.
In the report of the Chinese CDC, estimation of disease severity used almost
the same categories (Wu 2020) although numbers 1 and 2 were combined.
According to the report, there were 81% mild and moderate cases, 14% severe
cases and 5% critical cases. There are preliminary reports from the Italian
National Institute of Health, reporting on 24.9% severe and 5.0% critical cases
(Livingston 2020). However, these numbers are believed to strongly overesti-
mate the disease burden, given the very low number of diagnosed cases in
Italy at the time. Among 7,483 US heath care workers with COVID-19, a total
of 184 (2.1–4.9%) had to be admitted to ICUs. Rate was markedly higher in
HCWs > 65 years of age, reaching 6.9–16.0% (CDC 2020).

Outcome
We are facing rapidly increasing numbers of severe and fatal cases in the cur-
rent pandemic. The two most difficult but most frequently asked clinical
questions are 1. How many patients end up with severe or even fatal courses
of COVID-19? 2. What is the true proportion of asymptomatic infections? We
will learn more about this shortly through serological testing studies. Howev-

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er, it will be important that these studies are carefully designed and carried
out, especially to avoid bias and confounding.

Case fatality rates (CFR)

The country-specific crude case fatality rates (CFR), the percentage of COVID-
19-associated deaths among confirmed SARS-CoV-2 infections, have been the
subject of much speculation. There are still striking differences between
countries. According to worldometer.com assessed on October 12, 2020, the
crude CFR between the 100 most affected countries (in terms of absolute
numbers) ranged from 0.05 (Singapore) to 10.2 (Mexico). Within the 10 most
affected countries in Europe, the CFR range was between 0.8% (Czechia) and
10.2% (Italy).
Although it is well known that the CFR of a disease can be biased by detection,
selection or reporting (Niforatos 2020), and although it became quickly clear
that older age is a major risk factor for mortality (see below), many other fac-
tors contributing to regional differences throughout the world have been
discussed in recent months. These factors include not only differences in the
overall age structure of the general population of a country and co-residence
patterns, but also co-morbidity burden, obesity prevalence and smoking hab-
its as well as societal and social psychological factors. Others include hetero-
geneity in testing and reporting approaches, variations in health care system
capacities and health care and even political regime. Different virus strains or
even environmental factors such as air pollution have also been discussed, as
well as potential differences in genetic variability or even “trained immunity”
induced by certain live vaccines such as bacillus Calmette-Guérin (for refer-
ences see Hoffmann C 2020).
We can probably exclude most of these speculations. SARS-CoV-2 is not dead-
lier in Italy (CFR 10.2%), United Kingdom (7.1%), or Sweden (6.0%), compared
to Slovakia (0.3%), Israel (0.8%), India (1.5%) or USA (2.7%). Instead, there are
three major factors that have to be taken into account:
• The age of the pandemic, especially of the population which is first affect-
ed. Data from the 20 most affected European countries and the USA and
Canada show that the variance of crude CFR of COVID-19 is predomi-
nantly (80-96%) determined by the proportion of older individuals who
are diagnosed with SARS-CoV-2 (Hoffmann C 2020). Of note, the age dis-
tribution of SARS-CoV-2 infections is still far from homogeneous. The
proportion of individuals older than 70 years among confirmed SARS-
CoV-2 cases still differs markedly between the countries, ranging from
5% to 40% (Figure 1).

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Countries’ testing policies (and capacities). The fewer people you test (all
people, only symptomatic patients, only those with severe symptoms),
the higher the mortality. In Germany, for example, testing systems and
high lab capacities were established rapidly, within weeks in January
(Stafford 2020).
• Stage of the epidemic. Some countries have experienced their first (or
second) waves early while others lagged a few days or weeks behind.
Death rates only reflect the infection rate of the previous 2 to 4 weeks.
There is no doubt that the marked variation of CFR across countries will di-
minish over time, for example, if less affected countries such as Korea or Sin-
gapore fail to protect their older age groups; or if countries with high rates at
the beginning (such as Italy, Belgium or Sweden) start to implement broad
testing in younger age groups. This process has already begun. In Belgium, for
example, CFR peaked on May 11 with an appalling rate of 16.0%; it has now
dropped to 6.3%. The CFR in the USA peaked on May 16 (6.1%) and is now less
than half that. Germany started with a strikingly low CFR of 0.2% by the end
of March (prompting much attention even in scientific papers), peaked on
June 18 (4.7%) and is now (October 10) at 3.0%.

Figure 1. Association between case fatality rate (CFR) and the proportion of persons over
75 years of age among all confirmed SARS-CoV-2 cases (R2=0.8034, p<0.0001). The circle
sizes reflect the country-specific numbers of COVID-19 associated deaths per million
habitants; the linear fit prediction plot with a 95% confidence interval was estimated by
weighted linear regression (weight = total number of COVID-19 associated deaths).

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CFR among health care workers, well-defined populations

In well-monitored populations in which under-reporting is unlikely or can be
largely determined, the mortality rates may better reflect the “true” CFR of
COVID-19. This applies to healthcare workers (HCW) but also to populations
of “well-defined” (limited) outbreaks and in populations with available serol-
ogy data. The low mortality rates in these populations are remarkable.
• In a large study of 3387 HCW from China infected with SARS-CoV-2, only
23 died, corresponding to a mortality rate of 0.68%. The median age was 55
years (range, 29 to 72), and 11 of the 23 deceased HCW had been reactivat-
ed from retirement (Zhan 2020). Current studies in the US have found sim-
ilar mortality estimates of 0.3-0.6% (CDC 2020). Of the 27 HCW who died
from COVID-19 until mid-April, 18 were over 54 years of age. The overall
low mortality rates were probably due to the fact that HCWs were younger
and healthier, but also that they had been tested earlier and more fre-
quently.
• On the cruise ship Diamond Princess, as of May 31, the total number of
infected reached 712, and 13 patients died from the disease leading to a
CFR of 1.8% (Moriarty 2020). Of note, around 75% of the patients on the
Diamond Princess were 60 years or older, many of them in their eighties.
Projecting the Diamond Princess CFR onto the age structure of the general
population, mortality would be in a range of 0.2-0.4%.
• According to an investigation of the shore-based USS Theodore Roosevelt
outbreak, only 6/736 infected sailors were hospitalized, and one (a “senior
listed member in his 40s”) died during the study period (CFR 0.1%)
(Alvarado 2020).
• Using population-based seroprevalences in Geneva (Switzerland) and after
accounting for demography, the population-wide infection fatality rate
(IFR) was 0.64% (0.38–0.98) (Perez-Saez 2020).

CFR compared to influenza

More time and data are needed before the COVID-19 pandemic can be accu-
rately compared with past pandemics. But what makes SARS-CoV-2 different
from pandemic influenza virus? It’s not only that SARS-CoV-2 is a new patho-
gen and influenza is not and that the diseases differ clinically. The picture is
more complex. It also depends on which flu season you are talking about – the
influenza pandemic excess mortality ranged from extreme (1918) to mild
(2009) over the past 100 years. Another key difference between SARS-CoV-2
and pandemic influenza is the age distribution of patients who are severely

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ill. Mortality due to SARS-CoV-2 and SARS-CoV is strongly skewed towards

people older than 70 years, very dissimilar to the 1918 and 2009 influenza
pandemics.
Pooled estimates of all-cause mortality for 24 European countries for the pe-
riod March–April 2020 showed that excess mortality of COVID-19 particularly
affected ≥ 65-year-olds (91% of all excess deaths) and to a far lesser extent
those 45–64 (8%) and 15–44-year-olds (1%) (Vestergaard 2020). The excess
mortality of COVID-19 is markedly higher than for major influenza pandemics
in the past. For example, the 2009 pandemic influenza A H1N1 globally led to
201,200 respiratory deaths (range 105,700-395,600) with an additional 83,300
cardiovascular deaths (Dawood 2012). This is by far lower than the deaths
caused by COVID-19 to date. According to a recent review, the population risk
of admission to the intensive care unit is five to six times higher in patients
infected with SARS-CoV-2 than in those with the fairly mild 2009 influenza
pandemic (Petersen 2020).
In New York City, a study analyzed standardized mortality ratios (SMR) of
comparator pandemics and epidemics relative to the first 2020 wave of
COVID-19 (Muscatello 2020). In older people, COVID-19 mortality until June
2020 was more than 10-fold higher than a severe influenza season, and more
than 300-fold higher than the 2009–10 influenza pandemic. Compared to the
catastrophic 1918–19 winter wave of the influenza pandemic, there are
marked differences for different age groups. The 1918-19 influenza had a high
mortality, especially in younger persons (5–15 years; ~25% of total deaths),
possibly due to antibody-dependent enhancement and ‘cytokine storms’ in
younger people but also due to some protective cross-immunity from previ-
ous influenza outbreaks among those older. Compared to COVID-19, the over-
all age-adjusted, all-age mortality rate of the influenza 1918-19 was 6.7 times
higher. In younger people (< 45 years), the SMR was 42; that is, 42 times high-
er for influenza in 1918–19 than for COVID-19. However, in people older than
44 years of age, the SMR was 0.56; that is, 44% lower in 1918–19 than for
COVID-19.
Modeling scenarios without appropriate mitigation measures, simulations
predict incredibly high peaks in active cases and alarmingly high numbers of
deaths far into the future. In Germany, for example, 32 million total infec-
tions would result in 730,000 deaths over the course of the epidemic, which
would seem to occur only by the end of the summer 2021 under the assump-
tion that no reliable treatment is available before then (Barbarossa 2020).

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Older Age
From the beginning of the epidemic, older age has been identified as an im-
portant risk factor for disease severity (Huang 2020, Guan 2020). In Wuhan,
there was a clear and considerable age dependency in symptomatic infections
(susceptibility) and outcome (fatality) risks, by multiple folds in each case
(Wu 2020). The summarizing report from the Chinese CDC found a death rate
of 2.3%, representing 1023 among 44,672 confirmed cases (Wu 2020). Mortali-
ty increased markedly in older people. In cases aged 70 to 79 years, CFR was
8.0% and cases in those aged 80 years older had a 14.8% CFR. There is now
growing data from serology-informed estimates that the same is true for the
infection fatality risk (IFR). After accounting for demography and age-specific
seroprevalence, IFR was 0.0092% (95% CI 0.0042–0.016) for individuals aged
20–49 years, 0.14% (0.096–0.19) for those aged 50–64 years but 5.6% (4.3–7.4)
for those aged 65 years and older (Perez-Saez 2020).
In recent months, these data have been confirmed by almost all studies pub-
lished throughout the world. In almost all countries, age groups of 60 years or
older contribute to more than 90% of all death cases.
• In a large registry analysing the epidemic in the UK in 20,133 patients, the
median age of the 5165 patients (26%) who died in hospital from COVID-19
was 80 years (Docherty 2020).
• Among 1591 patients admitted to ICU in Lombardy, Italy, older patients (>
63 years) had markedly higher mortality than younger patients (36% vs
15%). Of 362 patients older than 70 years of age, mortality was 41%
(Grasselli 2020).
• According to the Italian National Institute of Health, an analysis of the
first 2003 death cases, median age was 80.5 years. Only 17 (0.8%) were 49
years or younger, and 88% were older than 70 years (Livingston 2020).
• Detailed analysis of all-cause mortality at Italian hot spots showed that the
deviation in all-cause deaths compared to previous years during epidemic
peaks was largely driven by the increase in deaths among older people,
especially in men (Piccininni 2020, Michelozzi 2020).
• In 5700 patients admitted to New York hospitals, there was a dramatic
increase of mortality among older age groups, reaching 61% (122/199) in
men and 48% (115/242) in women over 80 years of age (Richardson 2020).
• The median age of 10,021 adult COVID-19 patients admitted to 920 German
hospitals was 72 years. Mortality was 53% in patients being mechanically
ventilated (n=1727), reaching 63% in patients aged 70–79 years and 72% in
patients aged 80 years and older (Karagiannidis 2020).

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• In an outbreak reported from King County, Washington, a total of 167 con-

firmed cases was observed in 101 residents (median age 83 years) of a
long-term care facility, in 50 healthcare workers (HCW, median age 43
years), and 16 visitors. The case fatality rate was 33.7% among residents
and 0% among HCW (McMichael 2020).
There is no doubt that older age is by far the most important risk factor for
mortality. Countries failing to protect their elderly population for different
reasons (such as Italy, Belgium or Sweden) are facing a higher CFR, while
those without many older patients infected by SARS-CoV-2 (such as the Re-
public of Korea, Singapore, Australia) have markedly lower rates.
What are the reasons? Severe endothelial injury as seen in critically ill pa-
tients (Ackermann 2020) and endotheliopathy is an essential part of the
pathological response to severe COVID-19, leading to respiratory failure, mul-
ti-organ dysfunction and thrombosis (Goshua 2020). Circulating endothelial
cells are a marker of endothelial injury in severe COVID-19 (Guervilly 2020)
and there is a direct and rapid cytotoxic effect of plasma collected from criti-
cally ill patients on vascular endothelial cells (Rauch 2020). It is therefore
tempting to speculate that endothelial injury will be particularly harmful in
older patients with atherosclerosis.
But maybe not all is due to arteriosclerosis. “Inflammaging”, a common de-
nominator of age-associated frailty, may also contribute to the severe COVID-
19 course in older people. One hypothesis is that pre-existing inflammatory
cells, including senescent populations and adipocytes, create the inflammag-
ing phenotype that amplifies subsequent inflammatory events. Nevertheless,
high amounts of inflammation alone do not explain the devastating tissue
destruction and it may be that age-associated changes in T cells have a role in
the immunopathology (review: Akbar 2020). There is growing evidence that
coordination of SARS-CoV-2 antigen-specific responses is disrupted in older
individuals. Scarcity of naive T cells was also associated with ageing and poor
disease outcomes (Rydyznski 2020).

Sex and ethnicity

A striking finding is the lower mortality in female patients, evident through
almost all available data. In Italy, for example, male gender was an independ-
ent risk factor associated with mortality at ICU with a hazard ratio of 1.57
(Grasselli 2020). Using a health analytics platform covering 40% of all patients
in England, COVID-19-related death was associated with being male, with a
hazard ratio of 1.59 (95% CI 1.53–1.65) (Williamson 2020). The hitherto largest
registry study with detailed data on demographics and other clinical factors

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is shown in Table 3. There is some evidence that there are sex-specific differ-
ences in clinical characteristics and prognosis and that the presence of
comorbidities is of less impact in females (Meng 2020). It has been speculated
that the higher vulnerability in men is due to the presence of subclinical sys-
temic inflammation, blunted immune system, down-regulation of ACE2 and
accelerated biological aging (Bonafè 2020).

Table 3. Age and co-morbidities in a large registry study

(Docherty 2020), providing multivariate analyses and
hazard ratios.
UK, n = 15,194
Hazard Ratio (95% CI) Death
Age 50-59 vs < 50 2.63 (2.06-3.35)
Age 60-69 vs < 50 4.99 (3.99-6.25)
Age 70-79 vs < 50 8.51 (6.85-10.57)
Age > 80 vs < 50 11.09 (8.93-13.77)
Female 0.81 (0.75-0.86)
Chronic cardiac disease 1.16 (1.08-1.24)
Chronic pulmonary disease 1.17 (1.09-1.27)
Chronic kidney disease 1.28 (1.18-1.39)
Hypertension
Diabetes 1.06 (0.99-1.14)
Obesity 1.33 (1.19-1.49)
Chronic neurological disorder 1.18 (1.06-1.29)
Dementia 1.40 (1.28-1.52)
Malignancy 1.13 (1.02-1.24)
Moderate/severe liver disease 1.51 (1.21-1.88)

An in-depth analysis performed on 137 COVID-19 patients found that male

patients had higher plasma levels of innate immune cytokines such as IL-8
and IL-18 along with more robust induction of non-classical monocytes. A
poor T cell response negatively correlated with patients’ age and was associ-
ated with worse disease outcome in male patients, but not in female patients.
Conversely, higher innate immune cytokines were associated with worse dis-
ease progression in female patients, but not in male patients (Takahashi
2020). Emerging knowledge on the basic biological pathways that underlie
gender differences in immune responses needs to be incorporated into re-
search efforts on SARS-CoV-2 pathogenesis and pathology to identify targets
for therapeutic interventions aimed at enhancing antiviral immune function

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and lung airway resilience while reducing pathogenic inflammation in

COVID-19 (review: Bunders 2020).
Ethnic minorities may be disproportionately affected by the COVID-19 pan-
demic. Among the first 1.3 million lab-confirmed COVID-19 cases reported to
CDC until May 30, 2020, 33% of persons were Hispanic (accounting for 18% of
the US population), 22% (13%) were black, and 1.3% (0.7%) were non-Hispanic
American Indian or Alaska Native (Stoke 2020). However, in a large cohort
study on 5902 COVID-19 patients treated at a single academic medical center
in New York, survival outcomes of non-Hispanic Black and Hispanic patients
were at least as good as those of their non-Hispanic White counterparts when
controlling for age, sex, and comorbidities (Kabarriti 2020). Several other US
studies have also found no differences, after controlling for confounders such
as age, gender, obesity, cardiopulmonary comorbidities, hypertension, and
diabetes (McCarty 2020, Muñoz-Price 2020, Yehia 2020). There is some evi-
dence indicating a longer wait to access care among black patients in the US,
resulting in more severe illness on presentation to health care facilities
(Price-Haywood 2020).

Obesity
Several studies have found obesity to be an important risk factor (Goyal 2020,
Petrilli 2019). Among the first 393 consecutive patients who were admitted to
two hospitals in New York City, obese patients were more likely to require
mechanical ventilation. Obesity was also an important risk factor in France
(Caussy 2020), Singapore and the US, especially in younger patients (Ong
2020, Anderson 2020). Of 3222 young adults (age 18 to 34 years) hospitalized
for COVID-19 in the US, 684 (21%) required intensive care and 88 patients
(2.7%) died. Morbid obesity and hypertension were associated with a greater
risk of death or mechanical ventilation. Importantly, young adults aged 18 to
34 years with multiple risk factors (morbid obesity, hypertension, and diabe-
tes) faced risks similar to 8862 middle-aged (age 35-64 years) adults without
these conditions (Cunningham 2020). A recent review has described some
hypotheses regarding the deleterious impact of obesity on the course of
COVID-19 (Lockhart 2020), summarizing current knowledge on the underly-
ing mechanisms. These are:
1. Increased inflammatory cytokines (potentiate the inflammatory re-
sponse)
2. Reduction in adiponectin secretion (abundant in the pulmonary en-
dothelium)
3. Increases in circulating complement components

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4. Systemic insulin resistance (associated with endothelial dysfunction

and with increased plasminogen activator inhibitor-1)
5. Ectopic lipid deposited in type 2 pneumocytes (predisposing to lung
injury).

Comorbidities
Besides older age and obesity, many risk factors for severe disease and mor-
tality have been evaluated in the current pandemic.
Early studies from China found comorbidities such as hypertension, cardio-
vascular disease and diabetes to be associated with severe disease and death
(Guan 2020). Among 1,590 hospitalised patients from mainland China, after
adjusting for age and smoking status, COPD (hazard ratio, 2.7), diabetes (1.6),
hypertension (1.6) and malignancy (3.5) were risk factors for reaching clinical
endpoints (Guan 2020). Dozens of further studies have also addressed risk
factors (Shi 2020, Zhou 2020). The risk scores that have been mainly proposed
by Chinese researchers are so numerous that they cannot be discussed here.
They were mainly derived from uncontrolled data and their clinical relevance
remains limited. An interactive version of a relatively simple, so called
“COVID-19 Inpatient Risk Calculator” (CIRC) evaluated in 787 patients admit-
ted with mild-to-moderate disease between March 4 and April 24 in five US
hospitals in Maryland and Washington (Garibaldi 2020), is available at
https://rsconnect.biostat.jhsph.edu/covid_predict.
Smoking as a risk factor is under discussion, as well as COPD, kidney diseases
and many others (see chapter Comorbidities, page 379). Among 1150 adults
admitted to two NYC hospitals with COVID-19 in March, older age, chronic
cardiac disease (adjusted HR 1.76) and chronic pulmonary disease (2.94) were
independently associated with in-hospital mortality (Cummings 2020).
The main problem of all studies published to date is that their uncontrolled
data is subject to confounding and they do not prove causality. Even more
importantly, the larger the numbers, the more imprecise the definition of a
given comorbidity. What is a “chronic cardiac disease”, a mild and well-
controlled hypertension or a severe cardiomyopathy? The clinical manifesta-
tions and the relevance of a certain comorbidity may be very heterogeneous
(see chapter Comorbidities, page 379).
There is growing evidence that sociodemographic factors play a role. Many
studies did not adjust for these factors. For example, in a large cohort of 3481
patients in Louisiana, US, public insurance (Medicare or Medicaid), residence
in a low-income area, and obesity were associated with increased odds of
hospital admission (Price-Haywood 2020). A careful investigation of the NYC

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epidemic revealed that the Bronx, which has the highest proportion of racial
and ethnic minorities, the most persons living in poverty, and the lowest lev-
els of educational attainment, had higher rates (almost two-fold) of hospitali-
zation and death related to COVID-19 than the other 4 NYC boroughs Brook-
lyn, Manhattan, Queens and Staten Island (Wadhera 2020).
Taken together, large registry studies have found slightly elevated hazard
ratios of mortality for multiple comorbidities (Table 3). It seems, however,
that most patients with preexisting conditions are able to control and eradi-
cate the virus. Co-morbidities play a major role in those who do not resolve
and who fail to limit the disease to an upper respiratory tract infection and
who develop pneumonia. Facing the devastation that COVID-19 can inflict not
only on the lungs but on many organs, including blood vessels, the heart and
kidneys (nice review: Wadman 2020), it seems plausible that a decreased car-
diovascular and pulmonary capacity ameliorate clinical outcome in these pa-
tients.
However, at this time, we can only speculate about the precise role of co-
morbidities and their mechanisms to contribute to disease severity.
Is there a higher susceptibility? In a large, population-based study from Italy,
patients with COVID-19 had a higher baseline prevalence of cardiovascular
conditions and diseases (hypertension, coronary heart disease, heart failure,
and chronic kidney disease). The incidence was also increased in patients
with previous hospitalizations for cardiovascular or non-cardiovascular dis-
eases (Mancia 2020). A large UK study found some evidence of potential socio-
demographic factors associated with a positive test, including deprivation,
population density, ethnicity, and chronic kidney disease (Lusignan 2020).
However, even these well perfomed studies cannot completely rule out the
(probably strong) diagnostic suspicion bias. Patients with co-morbidities
could be more likely to present for assessment and be selected for SARS-CoV-
2 testing in accordance with guidelines. Given the high number of nosocomial
outbreaks, they may also at higher risk for infection, just due to higher hospi-
talization rates.

Predisposition
COVID-19 shows an extremely variable course, from completely asymptomat-
ic to fulminantly fatal. In some cases it affects young and apparently healthy
people, for whom the severity of the disease is neither caused by age nor by
any comorbidities – just think of the Chinese doctor Li Wenliang, who died at
the age of 34 from COVID-19 (see chapter The First 8 Months, page 429). So far,
only assumptions can be made. The remarkable heterogeneity of disease pat-
terns from a clinical, radiological, and histopathological point of view has led

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to the speculation that the idiosyncratic responses of individual patients may

be in part related to underlying genetic variations. Many single nucleotide
polymorphisms (SNPs) across a variety of genes (eg, ACE2, TMPRSS2, HLA,
CD147, MIF, IFNG, IL6) have been implicated in the pathology and immunolo-
gy of SARS-CoV-2 and other pathogenic coronaviruses (Ovsyannikova 2020).
The ‘COVID-19 Host Genetics Initiative’ brings together the human genetics
community to generate, share, and analyze data to learn the genetic determi-
nants of COVID-19 susceptibility, severity, and outcomes (CHGI 2020). It seems
that regions on chromosome 3 are significantly associated with severe COVID-
19 at the genome-wide level. The risk variant in this region confers an odds
ratio for requiring hospitalization of 1.6 (95% confidence interval: 1.42-1.79).
Some further key studies are listed here:
• A large study identified a 3p21.31 gene cluster as a genetic susceptibility
locus in patients with COVID-19 with respiratory failure and confirmed a
potential involvement of the ABO blood-group system (Elinghaus 2020). A
higher risk in blood group A was found compared to other blood groups
(odds ratio, 1.45; 95% CI, 1.20 to 1.75) and a protective effect in blood
group O as compared with other blood groups (odds ratio, 0.65; 95% CI,
0.53 to 0.79)
• In a meta-analysis of 7 studies, comparing 7503 SARS-CoV-2 positive pa-
tients with 2,962,160 controls, SARS-CoV-2 positive individuals were more
likely to have blood group A (pooled OR 1.23, 95% CI: 1.09–1.40) and less
likely to have blood group O (pooled OR 0.77, 95% CI: 0.67–0.88) (Golinelli
2020).
• Associations between ApoEe4 alleles and COVID-19 severity, using the UK
Biobank data (Kuo 2020). ApoEe4e4 homozygotes were more likely to be
COVID-19 test positives (odds ratio 2.31, 95% CI: 1.65-3.24) compared to
e3e3 homozygotes. The ApoEe4e4 allele increased risks of severe COVID-19
infection, independent of pre-existing dementia, cardiovascular disease,
and type 2 diabetes.
• A report from Iran describes three brothers aged 54 to 66 who all died of
COVID-19 after less than two weeks of fulminating progress. All three had
previously been healthy, without underlying illnesses (Yousefzadegan
2020).
• Two families with rare germline variants in an innate immune-sensing
gene, toll-like receptor 7 (TLR7), that leads to severe disease even in young
males who inherit the mutated gene on a single copy of their X chromo-
some (van der Made 2020).

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In addition to the genetic predisposition, other potential reasons for a severe

course need to be considered: the amount of viral exposure (probably high for
Li Wenliang?), the route by which the virus enters the body, ultimately also
the virulence of the pathogen and a possible (partial) immunity from previ-
ous viral diseases. If you inhale large numbers of virus deeply, leading rapidly
to a high amount of virus in the pulmonary system, this may be much worse
than smearing a small amount of virus on your hand and, later, to your nose.
In this latter case, the immune system in the upper respiratory tract may
have much more time to limit further spread into the lungs and other organs.
After an outbreak at a Swiss Army base, soldiers had to keep a distance of at
least 2 m from each other at all times, and in situations where this could not
be avoided (e.g., military training), they had to wear a surgical face mask. Of
the 354 soldiers infected prior to the implementation of social distancing, 30%
fell ill from COVID-19. While no soldier in a group of 154 in which infections
appeared after implementation of social distancing developed COVID-19
(Bielecki 2020).
Pre-existing SARS-CoV-2 S-reactive T cells may also play a role, contributing
to the divergent manifestations of COVID-19. These cells represent cross-
reactive clones, probably acquired during previous infections with endemic
human coronaviruses (HCoVs). In healthy SARS-CoV-2-unexposed donors,
they were found in 35% (Braun 2020). However, the clinical effect of these T
cells and other immunological factors on clinical outcomes remains to be de-
termined. There are hundreds of immunological papers focusing on the unre-
solved question why some patients develop severe disease, while others do
not (review: Gutierrez 2020). It remains also to be seen whether T cells pro-
vide long-term protection from reinfection with SARS-CoV-2 and if there is a
natural immunity, induced by cross-reactive T cells (Le Bert 2020, Mateus
2020).
Over the coming months, we will get a clearer view of 1) correlates of im-
munoprotection, such as virus-specific antibodies that limit disease and 2)
correlates of immune dysregulation, such as cytokine over-production that
may promote disease.

Overburdened health care systems

Mortality may be also higher in situations where hospitals are unable to pro-
vide intensive care to all the patients who need it, in particular ventilator
support. Mortality would thus also be correlated with health-care burden.
Preliminary data show clear disparities in mortality rates between Wuhan (>
3%), different regions of Hubei (about 2.9% on average), and across the other
provinces of China (about 0.7% on average). The authors have postulated that

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this is likely to be related to the rapid escalation in the number of infections

around the epicenter of the outbreak, which resulted in an insufficiency of
health-care resources, thereby negatively affecting patient outcomes in Hu-
bei, while this was not the case in other parts of China (Ji 2020). Another
study estimated the risk of death in Wuhan as high as 12% in the epicentre
and around 1% in other more mildly affected areas (Mizumoto 2020).
Finally, there may be differences between hospitals. In a US cohort of 2215
adults with COVID-19 who were admitted to ICUs at 65 sites, 784 (35.4%) died
within 28 days. However, mortality showed a wide variation between hospi-
tals (range, 6.6%-80.8%). One of the well known factors associated with death
was a hospital with fewer intensive care unit beds (Gupta 2020)! Patients ad-
mitted to hospitals with fewer than 50 ICU beds versus at least 100 ICU beds
had a higher risk of death (OR 3.28; 95% CI, 2.16-4.99).

Reactivations, reinfections
Seasonal coronavirus protective immunity is not long-lasting (Edridge 2020).
There are several reports of patients infected with SARS-CoV-2 who became
positive again after negative PCR tests (Lan 2020, Xiao 2020, Yuan 2020).
These reports have gained much attention, because this could indicate reacti-
vations as well as reinfections. After closer inspection of these reports, how-
ever, there is no good evidence for reactivations or reinfections, and other
reasons are much more likely. Methodological problems of PCR always have
to be considered; the results can considerably fluctuate (Li 2020). Insufficient
material collection or storage are just two examples of many problems with
PCR. Even if everything is done correctly, it can be expected that a PCR could
fluctuate between positive and negative at times when the values are low and
the viral load drops at the end of an infection (Wölfel 2020). The largest study
to date found a total of 25 (14.5%) of 172 discharged COVID-19 patients who
had a positive test at home after two negative PCR results at hospital (Yuan
2020). On average, the time between the last negative and the first positive
test was 7.3 (standard deviation 3.9) days. There were no differences to pa-
tients who remained negative. This and the short period of time suggest that
in these patients, no reactivations are to be expected.
However, in recent months several case reports of true (virologically proven:
phylogenetically distinct strains) re-infections have been reported (To 2020,
Gupta 2020, Van Elslande 2020). In most cases, the second episode was milder
than the first. However, there is at least one case where the second infection
was more severe, potentially due to immune enhancement, acquisition of a
more pathogenic strain, or perhaps a greater in-oculum of infection as the

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second exposure was from within household contacts (Larson 2020). Up to

now, however, these are anecdotal case reports.
Animal studies suggest that re-infection is unlikely (Chandrashekar 2020).
Following initial viral clearance and on day 35 following initial viral infection,
9 rhesus macaques were re-challenged with the same doses of virus that were
utilized for the primary infection. Very limited viral RNA was observed in BAL
on day 1, with no viral RNA detected at subsequent timepoints. These data
show that SARS-CoV-2 infection induced protective immunity against re-
exposure in nonhuman primates. There is growing evidence for a long-lived
and robust T cell immunity that is generated following natural SARS-CoV-2
infection (Neidleman 2020).
Reactivations as well as rapid new infections would be very unusual, especial-
ly for coronaviruses. If a lot of testing is done, you will find a number of such
patients who become positive again after repeated negative PCR and clinical
convalescence. The phenomenon is likely to be overrated. Most patients get
well anyway; moreover, it is unclear whether renewed positivity in PCR is
synonymous with infectiousness.

Long-term sequelae
The profound physical impairments associated with critical COVID-19 illness
are well known. Many patients with severe COVID-19, especially older pa-
tients and those with ARDS, will suffer long-term complications from an in-
tensive care unit stay and from the effects of the virus on multiple body sys-
tems such as the lung, heart, blood vessels and the CNS. However, there is
growing evidence that even in some younger people with non-severe COVID-
19 the illness may continue for weeks, even months. The persistent symptoms
in these so-called “long haulers” fluctuate and range from severe fatigue,
breathlessness, fast heart rate with minimal exertion, chest pain, pericardi-
tis/myocarditis, hoarseness, skin manifestations and hair loss, acquired dys-
lexia, headaches, memory loss, relapsing fevers, joint pains, and diarrhea.
Symptoms may arise through several mechanisms including direct organ
damage and involvement of immune function and the autonomic nervous
system. The following key papers address post-acute findings in patients with
mild-to-moderate COVID-19.
• In Rome, 143 patients discharged from hospital were assessed after a
mean of 60 days after onset of the first COVID-19 symptom. During hospi-
talization, 73% had evidence of pneumonia but only 15% and 5% received
non-invasive or invasive ventilation, respectively. Only 13% were com-
pletely free of any COVID-19-related symptom, while 32% had 1-2 symp-

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toms and 55% had 3 or more. Many patients reported fatigue (53%), dysp-
nea (43%), joint pain (27%) and chest pain (28%). A worsened quality of life
(QoL) was observed in 44% of patient (Carfì 2020).
• In Paris, persistent symptoms and QoL were assessed in 120/222 patients
discharged from a COVID-19 ward unit, at a mean of 111 days after their
admission. The most common persistent symptoms were fatigue (55%),
dyspnea (42%), loss of memory (34%), concentration and sleep disorders
(28% and 31%, respectively) and hair loss (20%). Of note, ward and ICU pa-
tients showed no differences with regard to these symptoms. In both
groups, EQ-5D (mobility, self-care, pain, anxiety or depression, usual activ-
ity) showed a slight difference in pain in the ICU group (Garrigues 2020).
• The only US data to date, including a random sample of adults testing pos-
itive at an outpatient visit (Tenforde 2020). Telephone interviews were
conducted at a median of 16 (14–21) days after the test date. Among 292
respondents, 94% reported experiencing one or more symptoms at the
time of testing; 35% of these reported not having returned to their usual
state of health by the date of the interview, increasing from 26% (those
aged 18–34 years) to 47% (≥ 50 years).
• Physical fitness before and after infection in 199 young, predominantly
male military recruits (Crameri 2020) from Switzerland. Recruits had had
a “baseline” fitness test, performed 3 months prior to a large COVID-19
outbreak in the company, including a progressive endurance run. Baseline
fitness values were compared with a fitness test at a median of 45 days af-
ter SARS-CoV-2 diagnosis. Participants were grouped into convalescent
recruits with symptomatic COVID-19 (n=68), asymptomatic cases (n=77)
and a naive group without symptoms or laboratory evidence of SARS-CoV-
2 infection (n=54). Results: neither of the strength tests differed signifi-
cantly between the groups. However, there was a significant decrease in
VO2 max among convalescents compared with naive and asymptomatical-
ly infected recruits. Around 19% of the COVID-19 convalescents had a de-
crease of more than 10% in VO2 max, while none of the naive recruits
showed such a decrease.
• The best study to date on cardiac issues, including 100 COVID-19 patients
at a mean age of 49 years (Puntmann 2020). The median time between di-
agnosis and cardiac MRI (CMR) was 71 (64-92) days. Most patients recov-
ered at home (n=67), with only minor or moderate (n=49) or without any
symptoms (n=18). Compared with pre-COVID-19 status, 36% reported on-
going shortness of breath and general exhaustion, of whom 25 noted
symptoms during less-than-ordinary daily activities, such as household

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chores. CMR revealed cardiac involvement in 78% and ongoing myocardial

inflammation in 60%, independent of pre-existing conditions, severity of
COVID-19 or from the time of diagnosis. The authors concluded that “par-
ticipants with a relative paucity of pre-existing cardiovascular condition
and with mostly home-based recovery had frequent cardiac inflammatory
involvement, which was similar to the hospitalized subgroup”.
• A comprehensive CMR examination in 26 competitive athletes, among
them 14 asymptomatic and 12 with only mild symptoms. CMR was per-
formed 11-53 days after recommended quarantine (Rajpal 2020). In total
4/26 (15%) had CMR findings suggestive of myocarditis and 8/26 (31%) ex-
hibited changes suggestive of prior myocardial injury. In 7/12 of patients
with pathological findings, CMR had been performed at least three weeks
after the positive SARS-CoV-2 test result.
• MRI in 60 COVID-19 patients (47 classified as mild), performed at a mean
of 97 days from symptom onset. Compared with 39 age- and sex-matched
non-COVID-19 volunteers, recovered COVID-19 patients showed volumet-
ric and micro-structural abnormalities that were detected mainly in the
central olfactory cortices and partially in the white matter in the right
hemisphere. According to the authors, these abnormalities might cause
long-term burden to COVID-19 patients after recovery (Lu 2020).
Taken together, clinical data is still scarce. However, it is dismissive to solely
attribute persisting symptoms after mild or moderate COVID-19 to anxiety or
to depression or to label them as anecdotal. “COVID-19 long haulers” are not
hypochondriacs. There is an urgent need to quantify long-term complications
properly and accurately, including non-hospitalized patients with mild dis-
ease, and several prospective studies are underway (Reviews: Alwan 2020,
Greenhalgh 2020, Marshall 2020, Yelin 2020).

Outlook
Over the coming months, serological studies will give a clearer picture of the
true number of asymptomatic patients and those with unusual symptoms.
More importantly, we have to learn more about risk factors for severe dis-
ease, in order to adapt prevention strategies. Older age is the main but not
the only risk factor. Recently, a 106-year-old COVID-19 patient recently re-
covered in the UK. The precise mechanisms of how co-morbidities (and co-
medications) may contribute to an increased risk for a severe disease course
have to be elucidated. Genetic and immunological studies need to reveal sus-
ceptibility and predisposition for both severe and mild courses. Who is really
at risk, who is not? Quarantining only the old is too easy.

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S0140-6736(20)30566-3. PubMed: https://pubmed.gov/32171076. Full-text:
https://doi.org/10.1016/S0140-6736(20)30566-3
Zhou J, Li C, Liu X et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat
Medicine 2020. Full-text: https://doi.org/10.1038/s41591-020-0912-6
Zong Y, Gu Y, Yu H, et al. Thrombocytopenia Is Associated with COVID-19 Severity and
Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes.
Laboratory Medicine, 15 September 2020, lmaa067. Full-text:
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Zubair AS, McAlpine LS, Gardin T, et al. Neuropathogenesis and Neurologic Manifestations of
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May 29, 2020. Full-text: https://doi.org/10.1001/jamaneurol.2020.2065

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8. Treatment
Christian Hoffmann

Let’s face reality: at the beginning of the second pandemic wave, we have
some steroids which have been shown to reduce mortality in patients with
severe COVID-19 (see Corticosteroids, page 347); and then we have a drug,
remdesivir (Veklury®), which had a marginal benefit in a company-sponsored
trial (Beigel 2020). That’s the COVID-19 treatment armamentarium as of Octo-
ber 2020.
Thus, the next 35 pages will discuss many drugs that have shown so far NO
effect. So why read this chapter? Because doctors need to know the state-of-
the-art – even the ‘state-of-the-non-art’. Doctors must know why substances
have shown NO effect and why there may still be new, innovative and crea-
tive ideas; why the senior physician has been less enthusiastic about tocili-
zumab over the last few weeks and why the 89-year-old diabetic on Ward 1
still gets remdesivir and famotidine; and why the plasma therapy did not
work in the 51 yrs old obese woman who died on Ward 2.
Hopefully, within a few months, this chapter will contain only ten pages. We
only need one good drug (or, for that matter, five me-too-drugs). Only one
drug that must not even be perfect but could become a game changer in this
pandemic (perhaps even more so and even sooner than a vaccine) because
good enough to prevent people from becoming seriously ill. One drug to
downgrade SARS-CoV-2 to the rank of their stupid seasonal common cold
siblings nobody was really interested in during the last decades (except Chris-
tian Drosten).
Research activity is immense. A brief look at ClinicalTrials.gov illustrates the
efforts that are underway: on April 18, the platform listed 657 studies, with
284 recruiting, among them 121 in Phase III randomized clinical trials (RCTs).
On October 14, these numbers have increased to 3,598, 1,880 and 230. Unfor-
tunately, many trials exclude those patients most in need: the elderly. A data
query of ClinicalTrials.gov on June 8 revealed that 206/674 (31%) COVID-19
interventional trials had an upper age exclusion criterion. The median upper
age exclusion was 75 years. Exclusion of older patients dramatically increases
the risk of non-representative trial populations compared with their real-
world counterparts (Abi Jaoude 2020).
Different therapeutic approaches are under evaluation: antiviral compounds
that inhibit enzyme systems, those inhibiting the entry of SARS-CoV-2 into
the cell and, finally, immune therapies, including convalescent plasma and

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monoclonal antibodies. Some immune modulators may enhance the immune

system, others are supposed to reduce the cytokine storm and associated
pulmonary damage that is seen in severe cases. In this chapter, we will dis-
cuss the most promising agents (those for which at least a bit of clinical data
is available). We will not mention all compounds that may work in cell lines
or that have been proposed from virtual screening models. We will also forget
some.
On the following pages, the following agents will be discussed:

1. Inhibitors of viral RNA synthesis

RdRp Inhibitors Remdesivir, favipiravir, sofosbuvir
Protease Inhibitors Lopinavir/r

2. Other antiviral agents

Various APN1, Camostat, Umifenovir

Hydroxy/chloroquine
3. Antibodies

Monoclonal antibodies REGN-CoV-2, other mAbs

Convalescent plasma

4. Immune modulators

Corticosteroids Dexamethasone, hydrocortisone

Interferons IFN-α2b, IFN-β

JAK inhibitors Baricitinib, ruxolitinib

Cytokine blockers and anticom- Anakinra, canakinumab, infliximab,

plement therapies mavrilimumab, tocilizumab, Siltuximab,
sarilumab, vilobelimab
5.. Various treatments (with Acalabrutinib, ibrutinib, colchicine,
unknown or unproven famotidine, G-CSF, iloprost
mechanisms of action)

So please enjoy reading the following pages. Most of the options are ineffec-
tive (and in the end, page 357, we will make some brief recommendations).

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1. Inhibitors of the viral RNA synthesis

SARS-CoV-2 is a single-stranded RNA betacoronavirus. Potential targets are
some non-structural proteins such as protease, RNA-dependent RNA poly-
merase (RdRp) and helicase, as well as accessory proteins. Coronaviruses do
not use reverse transcriptase. There is only a total of 82% genetic identity
between SARS-CoV and SARS-CoV-2. However, the strikingly high genetic
homology for one of the key enzymes, the RdRp which reaches around 96%,
suggests that substances effective for SARS may also be effective for COVID-
19.

RdRp inhibitors
Remdesivir (Veklury®)
Remdesivir (RDV) is a nucleotide analog and the prodrug of an adenosine C
nucleoside which incorporates into nascent viral RNA chains, resulting in
premature termination. It received an “Emergency Use Authorisation” from
the FDA in May and a so-called “conditional marketing” authorization from
the EMA in July.
In vitro experiments have shown that remdesivir has broad anti-CoV activity
by inhibiting RdRp in airway epithelial cell cultures, even at submicromolar
concentrations. This RdRp inhibition works in rhesus macaques (Williamson
2020). The substance is very similar to tenofovir alafenamide, another nucleo-
tide analogue used in HIV therapy. Remdesivir was originally developed by
Gilead Sciences for the treatment of the Ebola virus but was subsequently
abandoned, after disappointing results in a large randomized clinical trial
(Mulangu 2019). Resistance to remdesivir in SARS was generated in cell cul-
ture but was difficult to select and seemingly impaired viral fitness and viru-
lence. However, there is a case report describing the occurrence of a muta-
tion in the RdRp (D484Y) gene following failure of remdesivir (Martinot 2020).
Animal models suggest that a once-daily infusion of 10 mg/kg remdesivir may
be sufficient for treatment; pharmacokinetic data for humans are still lack-
ing.
Safety was shown in the Ebola trial. In the Phase III studies on COVID-19, an
initial dose of 200 mg was started on day 1, similar to the Ebola studies, fol-
lowed by 100 mg for another 4-9 days. The key trials are listed here:
• Compassionate Use Program: this was a fragmentary cohort (Grein 2020)
on some patients (only 53/61 patients were analyzed) with varying disease
severity. Some improved, some didn’t: random noise. We believe, for a
number of reasons, that this case series published in the New England

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Journal of Medicine is a cautionary tale for “science in a hurry”, arousing

false expectations. It might have been preferable to postpone the publica-
tion (Hoffmann 2020).
• NCT04257656: This multicentre RCT at ten hospitals in Hubei (Wang 2020)
randomized a total of 237 patients with pneumonia, oxygen saturation of
94% or lower on room air and within 12 days of symptom onset to receive
10 days of single infusions or placebo. Clinical improvement was defined
as the number of days to the point of a decline of two levels on a six-point
clinical scale (from 1 = discharged to 6 = death). Patients were 65 years old
(IQR 56–71), and many were co-treated with lopinavir (28%) and cortico-
steroids. The trial did not attain the predetermined sample size because
the outbreak was brought under control in China. However, remdesivir
was not associated with a difference in time to clinical improvement. Day
28 mortality was 14% versus 13%. Of note, the viral load decreased similar-
ly in both groups. Some patients with remdesivir had dosing prematurely
stopped due to adverse events (12% versus 5%, mainly gastrointestinal
symptoms and increases of liver enzymes). The positive message from this
trial is that time to recovery was “numerically” shorter in the remdesivir
group, particularly in those treated within 10 days of symptom onset.
• SIMPLE 1: in this randomized, open-label RCT in 397 hospitalized patients
with severe COVID-19 and not requiring IMV, clinical improvement at day
14 was 64% with 5 days and 54% with 10 days of remdesivir (Goldman
2020). After adjustment for (significant) baseline imbalances in disease se-
verity, outcomes were similar. The most common adverse events were
nausea (9%), worsening respiratory failure (8%), elevated ALT level (7%),
and constipation (7%). Because the trial lacked a placebo control, it was
not a test of efficacy for remdesivir. An expansion phase will enroll an ad-
ditional 5,600 (!) patients around the world.
• The second open-label SIMPLE trial, NCT04292730 (GS-US-540-5774), eval-
uated the efficacy of two remdesivir regimens compared to standard of
care (SOC) in 584 hospitalized patients with moderate COVID-19, with re-
spect to clinical status assessed by a 7-point ordinal scale on day 11. Clini-
cal status distribution was significantly better for those randomized to a
5-day course of remdesivir compared with those randomized to SOC
(Spinner 2020). According to the authors, however, this “difference was of
uncertain clinical importance”. The difference for those randomized to a
10-day course (median length of treatment, 6 days) compared with stand-
ard of care was not significant. By day 28, 9 patients had died: 2 (1%) and 3
(2%) in the 5-day and 10-day remdesivir groups, and 4 (2%) in the SOC
group, respectively. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and

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headache (5% vs 3%) were more frequent among remdesivir-treated pa-

tients, compared with SOC.
• ACTT (Adaptive COVID-19 Treatment Trial): The conclusion of the final
report for this double-blinded RCT that had randomized 1,062 patients
throughout the world, was remarkably short: remdesivir “was superior to
placebo in shortening the time to recovery in adults who were hospital-
ized with COVID-19 and had evidence of lower respiratory tract infection”
(Beigel 2020). Median recovery time was 10 versus 15 days. On an eight-
category ordinal scale, patients who received remdesivir were more likely
to improve at day 15. The benefit in recovery persisted when adjustment
was made for glucocorticoid use. The Kaplan–Meier estimates of mortality
were 6.7% with remdesivir and 11.9% with placebo by day 15. Serious ad-
verse events were reported in 131 of the 532 patients who received
remdesivir (24.6%) and in 163 of the 516 patients who received placebo
(31.6%).
• WHO Solidarity Trial Consortium 2020: Not yet peer reviewed, but im-
portant: In SOLIDARITY, 11,266 adults (405 hospitals in 30 countries) were
randomized, with 2750 allocated to remdesivir, 954 HCQ, 1411 lopinavir/r,
651 interferon plus lopinavir/r, 1412 only interferon, and 4088 no study
drug. Kaplan-Meier 28-day mortality was 12%. No study drug definitely
reduced mortality (in unventilated patients or any other subgroup of en-
try characteristics), initiation of ventilation or hospitalisation duration.
What comes next? Several additional trials are ongoing. Let’s wait for the re-
sults, before we throw remdesivir into the dump. According to a recent re-
view, remdesivir (5 days) should be prioritized for hospitalized patients re-
quiring low-flow supplemental oxygen as it appears that these patients derive
the most benefit (Davis 2020). The data also support some benefit in hospital-
ized patients breathing ambient air (if there is adequate drug supply). Cur-
rent data do NOT suggest benefit for those requiring high-flow oxygen or me-
chanical ventilation (non-invasive or invasive). It has become “clear that
treatment with an antiviral drug alone is not likely to be sufficient for all pa-
tients” (Beigel 2020).
Of note, some new ideas on remdesivir as an inhalation therapy have been
published (Contini 2020). Local instillation or aerosol in the first phase of in-
fection, both in asymptomatic but nasopharyngeal swab positive patients,
together with antiseptic-antiviral oral gargles and povidone-iodine eye drops
for conjunctiva would attack the virus directly through the receptors to
which it binds, significantly decreasing viral replication and the risk of severe

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COVID-19. Gilead is working on this (knowing that “early intravenous infu-

sions” are not feasible).

Favipiravir
Favipiravir is another broad antiviral RdRp inhibitor that has been approved
for influenza in Japan (but was never brought to market) and other countries.
Favipiravir is converted into an active form intracellularly and recognized as
a substrate by the viral RNA polymerase, acting like a chain terminator and
thus inhibiting RNA polymerase activity (Delang 2018). In the absence of sci-
entific data, favipiravir has been granted five-year approval in China under
the trade name Favilavir® (in Europe: Avigan®). A loading dose of 2400 mg BID
is recommended, followed by a maintenance dose of 1200-1800 mg QD. How-
ever, in 7 patients with severe COVID-19, the favipiravir trough concentration
was much lower than that of healthy subjects in a previous clinical trial (Irie
2020). Potential drug-drug interactions (DDIs) have to be considered. As the
parent drug undergoes metabolism in the liver mainly by aldehyde oxidase
(AO), potent AO inhibitors such as cimetidine, amlodipine, or amitriptyline
are expected to cause relevant DDIs (review: Du 2020). Some encouraging pre-
liminary results in 340 COVID-19 patients were reported from Wuhan and
Shenzhen (Bryner 2020).
• A first open-label RCT posted on March 26 (Chen 2020) was conducted in 3
hospitals in China, comparing arbidol and favipiravir in 236 patients with
pneumonia. Primary outcome was the 7-day clinical recovery rate (recov-
ery of fever, respiratory rate, oxygen saturation and cough relief). In “or-
dinary” COVID-19 patients (not critical), recovery rates were 56% with ar-
bidol (n = 111) and 71% (n = 98) with favipiravir (p = 0.02), which was well
tolerated, except for some elevated serum uric acid levels. However, it
remains unclear whether these striking results are credible. In the whole
study population, no difference was seen. Many cases were not confirmed
by PCR. There were also imbalances between subgroups of “ordinary” pa-
tients.
• No effect of viral clearance was found in RCT on 69 patients with asymp-
tomatic to mild COVID-19 who were randomly assigned to early or late
favipiravir therapy (same regimen starting day 1 or day 6). Viral clearance
occurred within 6 days in 67% and 56%. Of 30 patients who had a fever (≥
37.5°C) on day 1, time to no fever was 2.1 days and 3.2 days (aHR, 1.88; 95%
CI 0.81–4.35). During therapy, 84% developed transient hyperuricemia.
Neither disease progression nor death occurred in any of the patients in
either treatment group during the 28-day study (Doi 2020).

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• In the pilot stage of a Phase II/III clinical trial, 60 patients hospitalized

with COVID-19 pneumonia were randomized to two different dosing
groups or standard of care (Ivashchenko 2020). Favipiravir enabled SARS-
CoV-2 viral clearance in 62.5% of patients within 4 days and was safe and
well-tolerated. The proportion of patients who achieved negative PCR on
day 5 on both dosing regimens was twice as high as in the control group (p
< 0.05).

Other RdRp inhibitors: sofosbuvir, galidesivir

Some other RdRp inhibiting compounds have also been discussed. Sofosbuvir
is a polymerase inhibitor which is also used as a direct-acting agent in hepati-
tis C. It is usually well tolerated. Modelling studies have shown that sofos-
buvir could also inhibit RdRp by competing with physiological nucleotides for
the RdRp active site (Elfiky 2020). Sofosbuvir could be combined with HCV PIs.
The first randomized controlled trial in adult patients hospitalized with
COVID-19 in Iran to evaluate the efficacy and safety of the two HCV drugs
sofosbuvir and daclatasvir in combination with ribavirin (SDR) compared
these drugs with standard of care (Abbaspour Kasgari 2020). Though there
were trends in favor of the SDR arm for recovery and lower death rates, the
trial was too small to make definite conclusions. In addition, there was an
imbalance in the baseline characteristics between the arms.
Galidesivir is a nucleoside RNA polymerase inhibitor with broad-spectrum
activity in vitro against more than 20 RNA viruses in nine different families,
including coronaviruses and other viral families. A NIAID-funded, random-
ized, double-blind, placebo-controlled clinical trial to assess the safety, clini-
cal impact and antiviral effects of galidesivir in patients with COVID-19 is un-
derway. Of note, the drug also works against Zika: in the study presented
here, galidesivir dosing in rhesus macaques was safe and offered post-
exposure protection against Zika virus infection (Lim 2020).

Protease inhibitors (PIs)

A promising drug target is the viral main protease Mpro, which plays a key
role in viral replication and transcription. Some HIV PIs have been extensive-
ly studied in COVID-19 patients.

Lopinavir
Lopinavir/r is thought to inhibit the 3-chymotrypsin-like protease of corona-
viruses. To achieve appropriate plasma levels, it has to be boosted with an-
other HIV PI called ritonavir (usually indicated by “/r”: lopinavir/r). Due to
some uncontrolled trials in SARS and MERS, lopinavir/r was widely used in

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the first months, despite the lack of any evidence. In an early retrospective
study on 280 cases, early initiation of lopinavir/r and/or ribavirin showed
some benefits (Wu 2020).
• The first open-label RCT in 199 adults hospitalized with severe COVID-19
did not find any clinical benefit beyond standard of care in patients re-
ceiving the drug 10 to 17 days after onset of illness (Cao 2020). There was
no discernible effect on viral shedding.
• A Phase II, multicentre, open-label RCT from Hong Kong randomized 127
patients with mild-to-moderate COVID-19 (median 5 days from symptom
onset) to receive lopinavir/r only or a triple combination consisting of
lopinavir/r, ribavirin and interferon (Hung 2020). The results indicate that
the triple combination can be beneficial when started early (see below, in-
terferon). As there was no lopinavir/r-free control group, this trial does
not prove lopinavir/r efficacy.
• After preliminary results were made public on June 29, 2020, we are now
facing the full paper on the lopinavir/r arm in the RECOVERY trial: In
1,616 patients admitted to hospital who were randomly allocated to re-
ceive lopinavir/r (3,424 patients received usual care), lopinavir/r had no
benefit. Overall, 374 (23%) patients allocated to lopinavir/r and 767 (22%)
patients allocated to usual care died within 28 days. Results were con-
sistent across all prespecified subgroups. No significant difference in time
until discharge alive from hospital (median 11 days in both groups) or the
proportion of patients discharged from hospital alive within 28 days was
found. Although the lopinavir/r, dexamethasone, and hydroxychloro-
quine groups have now been stopped, the RECOVERY trial continues to
study the effects of azithromycin, tocilizumab, convalescent plasma, and
REGN-CoV2.
At least two studies suggested that lopinavir pharmacokinetics in COVID-19
patients may differ from those seen in HIV-infected patients. In both studies,
very high concentrations were observed, exceeding those in HIV-infected
patients by 2-3 fold (Schoergenhofer 2020, Gregoire 2020). However, concen-
trations of protein-unbound lopinavir achieved by current HIV dosing is
probably still too low for inhibiting SARS-CoV-2 replication. The EC50 for HIV
is much lower than for SARS-CoV-2. It remains to be seen whether these lev-
els will be sufficient for (earlier) treatment of mild cases or as post-exposure
prophylaxis.

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 Treatment | 337

Other PIs
For another HIV PI, darunavir, there is no evidence from either cell experi-
ments or clinical observations that the drug has any prophylactic effect (De
Meyer 2020).
It is hoped that the recently published pharmacokinetic characterization of
the crystal structure of the main protease SARS-CoV-2 may lead to the design
of optimized protease inhibitors. Virtual drug screening to identify new drug
leads that target protease which plays a pivotal role in mediating viral repli-
cation and transcription, have already identified several compounds. Six
compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM,
among them two approved drugs, disulfiram and carmofur (a pyrimidine ana-
log used as an antineoplastic agent) drugs (Jin 2020). Others are in develop-
ment but still pre-clinical (Dai 2020).

2. Various antiviral agents

Most coronaviruses attach to cellular receptors via their spike (S) protein.
Within a few weeks after the discovery of SARS-CoV-2, several groups eluci-
dated the entry of the virus into the target cell (Hoffmann 2020, Zhou 2020).
Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2
(ACE2) as a key receptor, a surface protein that is found in various organs and
on lung AT2 alveolar epithelial cells. The affinity for this ACE2 receptor ap-
pears to be higher with SARS-CoV-2 than with other coronaviruses. The hy-
pothesis that ACE inhibitors promote severe COVID-19 courses through in-
creased expression of the ACE2 receptor remains unproven (see chapter Clini-
cal Presentation, page 279).

Human recombinant soluble ACE2 (APN01)

HrsACE2 is a therapeutic candidate that neutralizes infection by acting as a
decoy. It may act by binding the viral spike protein (thereby neutralizing
SARS-CoV-2) and by interfering with the renin–angiotensin system. APN01
has been shown to be safe and well-tolerated in a total of 89 healthy volun-
teers and patients with pulmonary arterial hypertension (PAH) and ARDS in
previously completed Phase I and Phase II clinical trials. It is developed by
APEIRON, a privately-held European biotech company based in Vienna, Aus-
tria. There is a report of an Austrian case of a 45-year-old woman with severe
COVID-19 who was treated with hrsACE2. The virus disappeared rapidly from
the serum and the patient became afebrile within hours (Zoufaly 2020). Sev-
eral Phase II/III studies of hrsACE2 are ongoing.

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Camostat (Foipan®)
In addition to binding to the ACE2 receptor, priming or cleavage of the spike
protein is also necessary for viral entry, enabling the fusion of viral and cellu-
lar membranes. SARS-CoV-2 uses the cellular protease transmembrane prote-
ase serine 2 (TMPRSS2). Compounds inhibiting this protease may therefore
inhibit viral entry (Kawase 2012). The TMPRSS2 inhibitor camostat, approved
in Japan for the treatment of chronic pancreatitis (trade name Foipan®), may
block the cellular entry of the SARS-CoV-2 virus (Hoffmann 2020). Clinical
data are pending. At least five trials are ongoing, mostly in mild-to-moderate
disease.

Umifenovir
Umifenovir (Arbidol®) is a broad-spectrum antiviral drug approved as a
membrane fusion inhibitor in Russia and China for the prophylaxis and
treatment of influenza. Chinese guidelines recommend it for COVID-19 - ac-
cording to a Chinese press release it is able to inhibit the replication of SARS-
CoV-2 in low concentrations of 10-30 μM (PR 2020). In a small retrospective
and uncontrolled study in mild to moderate COVID-19 cases, 16 patients who
were treated with oral umifenovir 200 mg TID and lopinavir/r were compared
with 17 patients who had received lopinavir/r as monotherapy for 5–21 days
(Deng 2020). At day 7 (day 14) in the combination group, SARS-CoV-2 naso-
pharyngeal specimens became negative in 75% (94%), compared to 35% (53%)
with lopinavir/r monotherapy. Chest CT scans were improving for 69% versus
29%, respectively. Similar results were seen in another retrospective analysis
(Zhu 2020). However, a clear explanation for this remarkable benefit was not
provided. Another retrospective study on 45 patients from a non-intensive
care unit in Jinyintan, China failed to show any clinical benefit (Lian 2020).
There is a preliminary report of a randomized study indicating a weaker ef-
fect of umifenovir compared to favipiravir (Chen 2020).

Oseltamivir
Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is approved for the
treatment and prophylaxis of influenza in many countries. Like lopinavir,
oseltamivir has been widely used for the current outbreak in China (Guan
2020). Initiation immediately after the onset of symptoms may be crucial.
Oseltamivir is best indicated for accompanying influenza co-infection, which
has been seen as quite common in MERS patients at around 30% (Bleibtreu
2018). There is no valid data for COVID-19. It is more than questionable

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whether there is a direct effect in influenza-negative patients with COVID-19

pneumonia. SARS-CoV-2 does not require neuramidases to enter target cells.

Hydroxychloroquine (HCQ) and chloroquine (CQ)

HCQ is an anti-inflammatory agent approved for certain autoimmune diseases
and for malaria. The story of HCQ in the current pandemic is a warning ex-
ample of how medicine shouldn’t work. Some lab experiments, a mad French
doctor, bad uncontrolled studies, many rumors and hopes, reports without
any evidence and an enthusiastic tweet that this had “a real chance to be one
of the biggest game changers in the history of medicine” - hundreds of thou-
sands people received an ineffective (and potential dangerous) drug. Moreo-
ver, many turned away from clinical trials of other therapies that would have
required them to give up HCQ treatments. In some countries, the HCQ frenzy
prompted serious delays in trial enrolment, muddled efforts to interpret data
and endangered clinical research (Ledford 2020). Some countries stockpiled
CQ and HCQ, resulting in a shortage of these medications for those that need
them for approved clinical indications. Only a few months later, we are now
facing an overwhelming amount of data strongly arguing against any use of
both HCQ and CQ. So please, let’s forget it. Completely. But let us learn from
the bad HQC story which should never happen again (Kim 2020, Ledford
2020).

No clinical benefit from Hydroxychloroquine (HCQ)

• In an observational study from New York City (Geleris 2020) of 1376 hospitalized
patients, 811 received HCQ (60% received also azithromycin, A). After adjusting for
several confounders, there was no significant association between HCQ use and
intubation or death.
• Another retrospective cohort of 1438 patients from 25 hospitals in the New York
metropolitan region (Rosenberg 2020), there were no significant differences in
mortality for patients receiving HCQ + Azithromycin (A), HCQ alone, or A alone.
Cardiac arrest was significantly more likely seen with HCQ + A (adjusted OR 2.13).
• A randomized, Phase IIb trial in Brazil on severe COVID-19 patients was terminated
early (Borba 2020). By day 13 of enrolment, 6/40 patients (15%) in the low-dose CQ
group had died, compared with 16/41 (39%) in the high-dose group. Viral RNA was
detected in 78% and 76%, respectively.
• In a study of 251 patients receiving HCQ plus A, extreme new QTc prolongation to >
500 ms, a risk marker for torsades, occurred in 23% (Chorin 2020).
• In 150 patients with mainly persistent mild to moderate COVID-19, conversion to
negative PCR by day 28 was similar between HCQ and SOC (Tang 2020). Adverse
events were recorded more frequently with HCQ (30% vs 9%, mainly diarrhea).
• Symptomatic, non-hospitalized adults with lab-confirmed or probable COVID-19 and
high-risk exposure were randomized within 4 days of symptom onset to HCQ or
placebo. Among 423 patients, change in symptom severity over 14 days did not differ.

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At 14 days, 24% receiving HCQ had ongoing symptoms compared with 30%
receiving placebo (p = 0.21). Adverse events occurred in 43% versus 22% (Skipper
2020).
• HCQ does not work as a prophylaxis. In 821 asymptomatic participants randomized to
receive HCQ or placebo within 4 days of exposure, incidence of confirmed SARS-
CoV-2 was 12% with CQ and 14% with placebo. Side effects were more common
(40% vs. 17%) (Boulware 2020).
• No, HCQ does not work as prophylaxis, even in HCW. This double-blind, placebo-
controlled RCT included 132 health care workers and was terminated early. There
was no significant difference in PCR-confirmed SARS-CoV-2 incidence between HCQ
and placebo (Abella 2020).
• And finally, the RECOVERY Collaborative Group discovered that among 1561
hospitalized patients, those who received HCQ did not have a lower incidence of
death at 28 days than the 3155 who received usual care (27% versus 25%).

3. Monoclonal Antibodies and Convalescent Plasma

The development of highly successful monoclonal antibody-based therapies
for cancer and immune disorders has created a wealth of expertise and manu-
facturing capabilities. As long as all other therapies fail or have only modest
effects, monoclonal antibodies are the hope for the near future. There is no
doubt that antibodies with high and broad neutralizing capacity, many of
them directed to the receptor binding domain (RBD) of SARS-CoV-2, are
promising candidates for prophylactic and therapeutic treatment. On the
other hand, these antibodies will have to go through all phases of clinical trial
testing programs, which will take time. Safety and tolerability, in particular,
is an important issue. The production of larger quantities is also likely to
cause problems. Finally, there is the issue that mAbs are complex and expen-
sive to produce, leaving people from poor countries locked out (Ledford
2020).
No antibody has been thoroughly tested in humans to date. However, some
are very promising. The ‘COVID-19 antibodysphere’ (Amgen, AstraZeneca,
Vir, Regeneron, Lilly, Adagio) is building partnerships. Several mAbs entered
clinical trials in the summer of 2020. Trials will include treatment of patients
with SARS-CoV-2 infection, with varying degrees of illness, to block disease
progression. Given the long half-life of most mAbs (approximately 3 weeks for
IgG1), a single infusion should be sufficient.

REGN-COV2
The antibodies given to Trump. REGN10933 binds at the top of the RBD, ex-
tensively overlapping the binding site for ACE2, while the epitope for
REGN10987 is located on the side of the RBD, away from the REGN10933

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epitope, and has little to no overlap with the ACE2 binding site. Proof of prin-
ciple was shown in in a cell model, using vesicular stomatitis virus pseudopar-
ticles expressing the SARS-CoV-2 spike protein. Simultaneous treatment with
REGN10933 and REGN10987 precluded the appearance of escape mutants
(Baum 2020, Hansen 2020). Thus, this cocktail called REGN-COV2 did not rap-
idly select for mutants, presumably because escape would require the unlike-
ly occurrence of simultaneous viral mutation at two distinct genetic sites, so
as to ablate binding and neutralization by both antibodies in the cocktail.
• The first clinical data on REGN-COV2 (REGN10933 + REGN10987) were pub-
lished online on September 29 (not peer reviewed). Regeneron called it “a
descriptive analysis on the first ~275 patients”, derived from a broad on-
going clinical development program. Adult, non-hospitalized COVID-19
patients with symptom onset ≤ 7 days from randomization were random-
ized to receive single doses of REGN-COV2 at 2.4 g or 8 g IV or placebo. Be-
fore treatment, serology was used to divide patients into positive (n = 123)
versus negative (n = 113). As expected, “viral load” in nasopharyngeal (NP)
swabs was higher in seronegative patients (7.18 versus 3.49 log10 cop-
ies/mL). Main results showed a modest viral load reduction mainly in ser-
onegative patients and a lack of a numerical dose-response relationship:
REGN-COV2 appeared to reduce viral load through day 7 mainly in sero-
negative patients: the mean NP viral load reduction was -1.98 (high dose)
and -1.89 log10 copies/mL (low dose), compared to -1.38 with placebo (dif-
ference versus placebo -0.56 for both dosage groups, p = 0.02). If all pa-
tients were included (including seropositives), the reduction was -1.92 and
-1.64 log10 copies/mL, compared to 1.41 with placebo (significance only
seen with high dose). Patients with higher baseline viral levels had corre-
spondingly greater reductions in viral load. Median time to symptom alle-
viation for the overall population (median) was 8, 6 and 9 days for high,
low dose and placebo, respectively (seronegative only: 8, 6 and 13). As for
medical visits, there was a numerical reduction versus placebo, but with
just 12 visits in total there was no way of discerning the relevance. Most
non-hospitalized patients recovered well at home. Both doses were well-
tolerated. Infusion reactions and severe adverse events were balanced
across all groups, no deaths occurred.
Did this save Trump’s life? There is no doubt that larger data are needed in
patients with more severe disease. Let’s see what happens. Half a log viral
load reduction is not impressive although it may be clinically relevant. If ap-
proved, Regeneron will distribute REGN-COV2 in the US and Roche will be
responsible for distribution outside the US.

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Other mAbs, some key papers:

• Bamlanivimab (LY-CoV555) is a neutralizing IgG1 monoclonal antibody
(mAb) directed against the spike protein of SARS-CoV-2. The interim anal-
ysis of an ongoing Phase II study in 452 patients with mild to moderate
COVID-19 showed some clinical benefit (Chen P 2020). Those who received
a single dose bamlanivimab (three different dosages) had fewer hospitali-
zations (1.6% versus 6.3%) and a lower symptom burden than those who
received placebo, with the most pronounced effects observed in high-risk
cohorts. However, the viral load at day 11 (the primary outcome) was low-
er than that in the placebo group only among those who received the
2800-mg dose.
• The first report of a human monoclonal antibody that neutralizes SARS-
CoV-2 (Wang 2020). 47D11 binds a conserved epitope on the spike RBD
explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using
a mechanism that is independent of receptor-binding inhibition. This an-
tibody could be useful for development of antigen detection tests and se-
rological assays targeting SARS-CoV-2.
• From 60 convalescent patients, 14 potent neutralizing antibodies were
identified by high-throughput single B cell RNA-sequencing (Cao 2020).
The most potent one, BD-368-2, exhibited an IC50 of 15 ng/mL against
SARS-CoV-2, displaying strong therapeutic efficacy in mice. The epitope
overlaps with the ACE2 binding site.
• Several mAbs from ten convalescent COVID-19 patients. The most inter-
esting mAb, named 4A8, exhibited high neutralization potency but did not
bind the RBD (like most other mAbs). Cryo-EM revealed that the epitope of
4A8 seems to be the N terminal domain (NTD) of the S protein (Chi 2020).
• Isolation and characterization of 206 RBD-specific monoclonal antibodies
derived from single B cells of eight SARS-CoV-2 infected individuals. Some
antibodies showed potent anti-SARS-CoV-2 neutralization activity that
correlates with their competitive capacity with ACE2 for RBD binding (Ju
2020).
• CR3022 tightly binds the RBD and neutralizes SARS-CoV-2 (Huo 2020). The
highly conserved, structure-stabilising epitope is inaccessible in the pre-
fusion Spike, suggesting that CR3022 binding facilitates conversion to the
fusion-incompetent post-fusion state. The mechanism of neutralisation is
new and was not seen for coronaviruses.
• H014 neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as au-
thentic SARS-CoV-2 at nanomolar level by engaging the S receptor binding

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domain. In the hACE2 mouse model, H014 prevented pulmonary patholo-

gy. H014 seems to prevent attachment of SARS-CoV-2 to its host cell re-
ceptors (Lv 2020).
• Four human neutralizing monoclonal antibodies were isolated from a
convalescent patient. B38 and H4 blocked the binding between the virus S
protein RBD and the cellular receptor ACE2. A competition assay indicates
their different epitopes on the RBD. In a mouse model, both antibodies re-
duced viral titers in infected lungs. The RBD-B38 complex structure re-
vealed that most residues on the epitope overlap with the RBD-ACE2 bind-
ing interface, explaining the blocking effect and neutralizing capacity (Wu
2020).
• Of a total of 178 S1 and RBD binding human monoclonal antibodies from
the memory B cells of 11 recently recovered patients, the best one, 414-1,
showed neutralizing IC50 at 1.75 nM (Wan J 2020). Epitope mapping re-
vealed that the antibodies bound to 3 different RBD epitopes, and epitope
B antibody 553-15 could substantially enhance neutralizing abilities of
most other neutralizing antibodies.
• Isolation and characterization of two ultra-potent SARS-CoV-2 human
neutralizing antibodies (S2E12 and S2M11) that were identified among
almost 800 screened Abs isolated from 12 COVID-19 patients (Tortorici
2020). Both nAbs protect hamsters against SARS-CoV-2 challenge. Cryo-
electron microscopy structures show that S2E12 and S2M11 competitively
block ACE2 attachment and that S2M11 also locks the spike in a closed
conformation by recognition of a quaternary epitope spanning two adja-
cent receptor-binding domains. Cocktails including S2M11, S2E12 or the
previously identified S309 antibody broadly neutralize a panel of circulat-
ing SARS-CoV-2 isolates and activate effector functions.
• Using a high-throughput rapid system for antibody discovery, more than
1000 mAbs were isolated from 3 convalescent donors by memory B cell se-
lection using SARS-CoV-2 S or RBD recombinant proteins. Of note, only a
small fraction was neutralizing, highlighting the value of deep mining of
responses to access the most potent Abs. RBD-nAbs that directly compete
with ACE2 are clearly the most preferred for prophylactic and therapeutic
applications, and as reagents to define nAb epitopes for vaccine. With
these nABs, Syrian hamsters were protected from weight loss. However,
animals that received higher doses also showed body weight loss, possibly
indicating antibody-mediated enhanced disease (Rogers 2020).
• Antibodies from convalescent patients had low levels of somatic hypermu-
tation. Electron microscopy studies illustrate that the SARS-CoV-2 spike

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protein contains multiple distinct antigenic sites. In total, 19 neutralizing

antibodies were identified that target a diverse range of antigenic sites on
the S protein, of which two showed picomolar (very strong!) neutralizing
activities (Brouwer 2020).
• Isolation of 61 SARS-CoV-2-neutralizing mAbs from 5 hospitalized pa-
tients, among which are 19 mAbs that potently neutralized the authentic
SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% vi-
rus inhibitory concentrations of 0.7 to 9 ng/mL (Liu 2020).
• Antibody domains and fragments such as VH (heavy chain variable do-
main, 15 kDa) are attractive antibody formats for candidate therapeutics.
They may have better tissue penetration compared to full-sized antibod-
ies. One of those VHs, ab8, in an Fc (human IgG1, crystallizable fragment)
fusion format, showed potent neutralization activity and specificity
against SARS-CoV-2 both in vitro and in mice and hamsters, possibly en-
hanced by its relatively small size (Li 2020).

Convalescent plasma (passive immunization)

Human convalescent plasma (CP) could be a rapidly available option for pre-
vention and treatment of COVID-19 disease when there are sufficient num-
bers of people who have recovered and can donate immunoglobulin-
containing serum (Casadevall 2020). Passive immune therapy appears to be
relatively safe. However, an unintended consequence of receiving CP may be
that recipients won’t develop their own immunity, putting them at risk for
re-infection. Other issues that have to be addressed in clinical practice
(Kupferschmidt 2020) are plasma supply (regulatory conderations; logistical
work flow may become a challenge) and rare but relevant risks (transfusion-
related acute lung injury, in which transferred antibodies damage pulmonary
blood vessels, or transfusion-associated circulatory overload). Fortunately,
antibodies that are found in CP are very stable. Pathogen inactivation (using
psoralen and UV light) did not impair the stability and neutralizing capacity
of SARS-CoV-2-specific antibodies that was also preserved at 100% when the
plasma was shock frozen at −30°C after pathogen-inactivation or stored as
liquid plasma for up to 9 days (Tonn 2020).
The major caveat of CP is consistency (concentration differs). In plasma from
149 patients collected on average 39 days after the onset of symptoms, neu-
tralizing titers were extremely variable. Most plasmas did not contain high
levels of neutralizing activity (Robbiani 2020). Pre-screening of CP may be
necessary for selecting donors with high levels of neutralizing activity for
infusion into patients with COVID-19 (Bradfute 2020). There seems to be a

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correlation between serum neutralizing capacity and disease severity, sug-

gesting that the collection of CP should be restricted to those with moderate
to severe symptoms (Chen 2020). Others have suggested more detailed selec-
tion criteria: 28 days after the onset of symptoms with a disease presentation
of fever lasting longer than 3 days or a body temperature exceeding 38,5°C.
Selection based on these criteria can ensure a high likelihood of achieving
sufficiently high titers (Li 2020).
On March 26, the FDA approved the use of plasma from recovered patients to
treat people who are critically ill with COVID-19 (Tanne 2020). This was a re-
markable decision, and the data is still scarce. Results are at least modest:
• Two small pilot studies with 5 and 10 criticially ill patients, showing rapid
improvement in their clinical status (Shen 2020, Duan 2020).
• The first RCT was published in June (Li 2020). Unfortunately, the study was
terminated prematurely (when the epidemic was under control in China,
no more patients could be recruited) and, consequently, underpowered. Of
103 patients who were randomized, clinical improvement (on a 6-point
disease severity scale) occurred within 28 days in 52% vs 43%. There was
no significant difference in 28-day mortality (16% vs 24%) or time from
randomization to discharge. Of note, CP treatment was associated with a
negative conversion rate of viral PCR at 72 hours in 87% of the CP group
versus 38% (OR, 11.39). Main take-homes: CP is not a silver bullet and anti-
viral efficacy does not necessarily lead to better survival.
• The second RCT came from India (Agarwal 2020). This open-label RCT in-
vestigated the effectiveness of CP in adults with moderate COVID-19, as-
signing 235 patients to two doses of 200 mL CP and 229 patients to a con-
trol arm. Progression to severe disease or all cause mortality at 28 days
occurred in 44 (19%) and 41 (18%). Moreover, CP treatment did not show
anti-inflammatory properties and there were no difference between pa-
tients with and without neutralizing antibodies at baseline. Main limita-
tion: the antibody titres in CP before transfusion were not measured be-
cause validated, reliable commercial tests were not available when the tri-
al started.
• In a retrospective, propensity score–matched case–control study in 39
patients, those who received CP required somewhat less oxygen; prelimi-
nary data might suggest a mortality benefit (Liu 2020).
• Compared to 20 matched controls with severe or life-threatening COVID-
19 infection, laboratory and respiratory parameters were improved in 20
patients following CP infusion. The 7- and 14-day case fatality rate in CP

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patients compared favorably (Hegerova 2020). However, this small study

was not randomized.
• Don’t be too late: Of 6 patients with respiratory failure receiving convales-
cent plasma at a median of 21 days after first detection of viral shedding,
all tested RNA negative by 3 days after infusion. However, 5 eventually
died (Zeng 2020).
• Uncontrolled, retrospective data on 1430 patients with severe COVID-19
who received standard treatment only, among them 138 patients who also
received ABO-compatible CP (Xia 2020). Despite the higher severity level,
only 3 CP patients (2.2%) died, compared to 4.1% patients without CP.
However, confounding factors (i.e., biased patient assignments) in this
retrospective study could not be ruled out. In addition, complete data on
neutralizing antibody titers were unavailable.

4. Immunomodulators
While antiviral drugs are most likely to prevent mild COVID-19 cases from
becoming severe, adjuvant strategies will be needed, particularly in severe
cases. Coronavirus infections may induce excessive and aberrant, ultimately
ineffective host immune responses that are associated with severe lung dam-
age (Channappanavar 2017). Similar to SARS and MERS, some patients with
COVID-19 develop acute respiratory distress syndrome (ARDS), often associ-
ated with a cytokine storm. This is characterized by increased plasma concen-
trations of various interleukins, chemokines and inflammatory proteins.
Various host-specific therapies aim to limit the immense damage caused by
the dysregulation of pro-inflammatory cytokine and chemokine reactions
(Zumla 2020). Immunosuppressants, interleukin-1 blocking agents such as
anakinra or JAK-2 inhibitors are also an option (Mehta 2020). These therapies
may potentially act synergistically when combined with antivirals. Numerous
drugs are discussed, including those for lowering cholesterol, for diabetes,
arthritis, epilepsy and cancer, but also antibiotics. They are said to modulate
autophagy, promote other immune effector mechanisms and the production
of antimicrobial peptides. Other immunomodulatory and other approaches in
clinical testing include bevacizumab, brilacidin, cyclosporin, fedratinib, fin-
golimod, lenadilomide and thalidomide, sildenafil, teicoplanin and many
more. However, convincing clinical data is pending for most strategies.

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Corticosteroids
Corticosteroids are thus far the only drugs which provide a survival benefit in
patients with severe COVID-19. During the first months of the pandemic, ac-
cording to current WHO guidelines, steroids were controversially discussed
and were not recommended outside clinical trials. With a press release on
June 16, 2020 reporting the results of the UK-based RECOVERY trial, the
treatment of COVID-19 underwent a major change. In the dexamethasone
group, the incidence of death was lower than that in the usual care group
among patients receiving invasive mechanical ventilation. The RECOVERY
results had a huge impact on other RCTs around the world. The therapeutic
value of corticosteroids has now been shown in numerous studies:
• RECOVERY: In this open-label trial (comparing a range of treatments),
hospitalized patients were randomized to receive oral or intravenous dexa
(at a dose of 6 mg once daily) for up to 10 days or to receive usual care
alone. Overall, 482 patients (22.9%) in the dexa group and 1110 patients
(25.7%) in the usual care group died within 28 days (age-adjusted rate ra-
tio, 0.83). The death rate was lower among patients receiving invasive me-
chanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen
without invasive mechanical ventilation (23.3% vs. 26.2%) but not among
those who were receiving no respiratory support (17.8% vs. 14.0%).
• REMAP-CAP (different countries): In this Bayesian RCT, 384 patients were
randomized to fixed-dose (n = 137), shock-dependent (n = 146), and no
(n = 101) hydrocortisone. Treatment with a 7-day fixed-dose course or
shock-dependent dosing of hydrocortisone, compared with no hydrocorti-
sone, resulted in 93% and 80% probabilities of superiority, respectively,
with regard to the odds of improvement in organ support free days within
21 days. However, due to the premature halt of the trial, no treatment
strategy met pre-specified criteria for statistical superiority, precluding
definitive conclusions.
• CoDEX (Brazil). A multicenter, open-label RCT in 299 COVID-19 patients
(350 planned) with moderate-to-severe ARDS (Tomazini 2020). Twenty mg
of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone
daily for 5 days or until ICU discharge, plus standard of care (n = 151) or
standard of care alone (n = 148). Patients randomized to the dexame-
thasone group had a mean 6.6 ventilator-free days during the first 28 days
vs 4.0 ventilator-free days in the standard of care group (difference, 2.26;
95% CI, 0.2-4.38; p = 0.04). There was no significant difference in the pre-
specified secondary outcomes of all-cause mortality at 28 days, ICU-free

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days during the first 28 days, mechanical ventilation duration at 28 days,

or the 6-point ordinal scale at 15 days.
• CAPE COD: Multicenter double-blinded RCT, in 149 (290 planned) critical-
ly-ill patients admitted to the intensive care unit (ICU) for COVID-19–
related acute respiratory failure (Dequin 2020). The primary outcome,
treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the
hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group
(p = 0.29).
• A prospective WHO meta-analysis that pooled data from 7 randomized
clinical trials that evaluated the efficacy of corticosteroids in 1703 critical-
ly ill patients with COVID-19. The fixed-effect summary odds ratios for the
association with mortality were 0.64 (95% CI, 0.50-0.82; p < 0.001) for dex-
amethasone compared with usual care or placebo, 0.69 (95% CI, 0.43-1.12;
p = 0.13) for hydrocortisone and 0.91 (95% CI, 0.29-2.87; p = 0.87) for
methylprednisolone, respectively. There was no suggestion of an in-
creased risk of serious adverse events.
• Another study with 206 patients suggested that the effect of corticoster-
oids on viral shedding may be in a dose-response manner. High-dose (80
mg/d) but not low-dose corticosteroids (40 mg/d) delayed viral shedding
of patients with COVID-19 (Li 2020).
• Treatments for respiratory disease, specifically inhaled corticosteroids
(ICSs) do not have a protective effect. In 148,557 persons with COPD and
818,490 persons with asthma who were given relevant respiratory medica-
tions in the 4 months before the index date (March 1), people with COPD
who were prescribed ICSs were at increased risk of COVID-19-related
death compared with those prescribed LABA–LAMA combinations (adjust-
ed HR 1.39) (Schultze 2020). Compared with those prescribed short acting
beta agonists only, people with asthma who were prescribed high-dose ICS
were at an increased risk of death (1.55, 1.10–2.18]), whereas those given a
low or medium dose were not. Sensitivity analyses showed that the appar-
ent harmful association could be explained by relatively small health dif-
ferences between people prescribed ICS and those not prescribed ICS.
Conclusions: The WHO suggests NOT to use corticosteroids in the treatment
of patients with non-severe COVID-19. The WHO recommends systemic corti-
costeroids for the treatment of patients with severe and critical COVID-19
(strong recommendation, based on moderate certainty evidence). However,
the WHO panel noted that the oxygen saturation threshold of 90% to define
severe COVID-19 was arbitrary and should be interpreted cautiously when
used for determining which patients should be offered systemic corticoster-

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oids. For example, clinicians must use their judgement to determine whether
a low oxygen saturation is a sign of severity or is normal for a given patient
suffering from chronic lung disease. Similarly, a saturation above 90–94% on
room air may be abnormal if the clinician suspects that this number is on a
downward trend.

Interferons
The interferon (IFN) response constitutes the major first line of defense
against viruses. This complex host defense strategy can, with accurate under-
standing of its biology, be translated into safe and effective antiviral thera-
pies. In a recent comprehensive review, the recent progress in our under-
standing of both type I and type III IFN-mediated innate antiviral responses
against human coronaviruses is described (Park 2020).
IFN may work on COVID-19 when given early. Several clinical trials are cur-
rently evaluating synthetic interferons given before or soon after infection, in
order to tame the virus before it causes serious disease (brief overview: Wad-
man 2020). In vitro observations shed light on antiviral activity of IFN-β1a
against SARS-CoV-2 when administered after the infection of cells, highlight-
ing its possible efficacy in an early therapeutic setting (Clementi 2020). In
patients with coronaviruses such as MERS, however, interferon studies were
disappointing. Despite impressive antiviral effects in cell cultures (Falzarano
2013), no convincing benefit was shown in clinical studies in combination
with ribavirin (Omrani 2014). Nevertheless, inhalation of interferon is still
recommended as an option in Chinese COVID-19 treatment guidelines. Of
note, in the large SOLIDARITY RCT (paper has not yet been peer-reviewed, see
above) there was no effect.
• A Phase II, multicentre, open-label RCT from Hong Kong randomized 127
patients with mild-to-moderate COVID-19 (median 5 days from symptom
onset) to receive lopinavir/r only or a triple combination consisting of
lopinavir/r, ribavirin and interferon (Hung 2020). This trial indicates that
the triple combination can be beneficial when started early. Combination
therapy was given only in patients with less than 7 days from symptom
onset and consisted of lopinavir/r, ribavirin (400 mg BID), and interferon
beta-1b (1-3 doses of 8 Mio IE per week). Combination therapy led to a sig-
nificantly shorter median time to negative results in nasopharyngeal swab
(7 versus 12 days, p = 0.001) and other specimens. Clinical improvement
was significantly better, with a shorter time to complete alleviation of
symptoms and a shorter hospital stay. Of note, all differences were driven
by the 76 patients who started treatment less than 7 days after onset of
symptoms. In these patients, it seems that interferon made the difference.

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Up to now, this is the only larger RCT showing a virological response of a

specific drug regimen.
• A retrospective multicenter cohort study of 446 COVID-19 patients, taking
“advantage of drug stock disparities” between two medical centers in Hu-
bei. Early administration ≤ 5 days after admission of IFN-α2b was associat-
ed with reduced in-hospital mortality in comparison with no admission of
IFN-α2b, whereas late administration of IFN-α2b was associated with in-
creased mortality (Wang 2020).

JAK inhibitors
Several inflammatory cytokines that correlate with adverse clinical outcomes
in COVID-19 employ a distinct intracellular signalling pathway mediated by
Janus kinases (JAKs). JAK-STAT signalling may be an excellent therapeutic
target (Luo 2020).
Baricitinib (Olumiant®) is a JAK inhibitor approved for rheumatoid arthritis.
Using virtual screening algorithms, baricitinib was identified as a substance
that could inhibit ACE2-mediated endocytosis (Stebbing 2020). Like other JAK
inhibitors such as fedratinib or ruxolitinib, signaling inhibition may also re-
duce the effects of the increased cytokine levels that are frequently seen in
patients with COVID-19. There is some evidence that baricitinib could be the
optimal agent in this group (Richardson 2020). Other experts have argued
that the drug would be not an ideal option due to the fact that baricitinib
causes lymphocytopenia, neutropenia and viral reactivation (Praveen 2020)
as well as pancreatitis (Cerda-Contreras 2020). There is also a dose-dependent
association with arterial and venous thromboembolic events (Jorgensen
2020). It is possible that the pro-thrombotic tendencies could exacerbate a
hypercoagulable state, underscoring the importance of restricting the use of
baricitinib to clinical trials. Several studies are underway in Italy and the US,
among them a huge trial (ACTT-II), comparing baricitinib and remdesivir to
remdesivir alone in more than 1,000 patients.
• So far, one observational study provides some evidence for a synergistic
effect of baricitinib and corticosteroids (Rodriguez-Garcia 2020). Patients
with moderate to severe SARS-CoV-2 pneumonia received lopinavir/r and
HCQ plus either corticosteroids (controls, n=50) or corticosteroids and
baricitinib (n=62). In the controls, a higher proportion of patients required
supplemental oxygen both at discharge (62% vs 26%) and 1 month later
(28% vs 13%),
Ruxolitinib (Jakavi®) is a JAK inhibitor manufactured by Incyte. It is used for
myelofibrosis, polycythemia vera (PCV) and certain chronic graft versus host

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diseases in patients following a bone marrow transplant. As many of the ele-

vated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these
pathways with ruxolitinib has the potential to mitigate the COVID-19-
associated cytokine storm and reduce mortality.
• In a retrospective study, 12/14 patients achieved significant reduction of
the “COVID-19 Inflammation Score” with sustained clinical improvement
in 11/14 patients (La Rosée 2020). Treatment was safe with some signals of
efficacy to prevent or overcome multi-organ failure. A Phase II RCT has
been initiated (NCT04338958).

Cytokine blockers and anticomplement therapies

The hypothesis that quelling the cytokine storm with anti-inflammatory
therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumour ne-
crosis factor TNF alpha might be beneficial has led to several ongoing trials. It
is suggestive that interleukin blocking strategies might improve the hyperin-
flammatory state seen in severe COVID-19. A recent review on this strategy,
however, was less enthusiastic and urged caution (Remy 2020). Past attempts
to block the cytokine storm associated with other microbial infections and
with sepsis have not been successful and, in some cases, have worsened out-
comes. Moreover, there is concern that suppressing the innate and adaptive
immune system to address increased cytokine concentrations, could enable
unfettered viral replication, suppress adaptive immunity, and delay recovery
processes. There is growing recognition that potent immunosuppressive
mechanisms are also prevalent in such patients. Following, we will briefly
discuss the evidence on cytokine blockers.
Anakinra (Kineret®) is an FDA-approved treatment for rheumatoid arthritis
and neonatal onset multisystem inflammatory disease. It is a recombinant
human IL-1 receptor antagonist that prevents the binding of IL-1 and blocks
signal transduction. Anakinra is thought to abrogate the dysfunctional im-
mune response in hyperinflammatory COVID-19 and is currently being inves-
tigated in almost 20 clinical trials. Some case series have reported on encour-
aging results.
• A study from Paris, comparing 52 “consecutive” patients treated with an-
akinra with 44 historical patients. Admission to the ICU for invasive me-
chanical ventilation or death occurred in 25% of patients in the anakinra
group and 73% of patients in the historical group. The treatment effect of
anakinra remained significant in the multivariate analysis (Hayem 2020).
According to the authors, their study was “not perfect from a statistical
point of view…”

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• A retrospective cohort study at the San Raffaele Hospital in Milan, Italy,

including 29 patients with moderate-to-severe ARDS and hyperinflamma-
tion (serum C reactive protein, CRP ≥ 100 mg/L) who were managed with
non-invasive ventilation and HCQ and lopinavir/r (Cavalli 2020). At 21
days, treatment with high-dose anakinra was associated with reductions
in CRP and progressive improvements in respiratory function in 21/29
(72%) patients.
• Another small case series of critically ill patients with secondary hemoph-
agocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hy-
percoagulation, acute kidney injury and hepatobiliary dysfunction. At the
end of treatment, ICU patients had less need for vasopressors and signifi-
cantly improved respiratory function. Although 3/8 patients died, the
mortality was lower than historical series of patients with sHLH in sepsis
(Dimopoulos 2020).
Canakinumab (Illaris®) is human monoclonal antibody against IL-1β, ap-
proved for the treatment of juvenile rheumatoid arthritis and other chronic
autoinflammatory syndromes. In a pilot trial, 10 patients with hyperinflam-
mation (defined as CRP ≥ 50 mg/L) and respiratory failure showed a rapid
improvement in serum inflammatory biomarkers and an improvement in
oxygenation (Ucciferri 2020).
Infliximab (Remicade®) is a chimeric monoclonal anti-TNF antibody, ap-
proved to treat a number of autoimmune diseases, including Crohn’s disease,
ulcerative colitis, rheumatoid arthritis and psoriasis. As a major component
of deteriorating lung function in patients with COVID-19 is capillary leak, a
result of inflammation driven by key inflammatory cytokines such as TNF,
making TNF-blocking agents an attractive strategy (Robinson 2020). Admin-
istration of anti-TNF to patients for treatment of autoimmune disease leads to
reductions in all of these key inflammatory cytokines. A small case series of
seven patients who were treated with a single infusion of IFX (5 mg/kg body
weight) has been reported (Stallmach 2020).
Mavrilimumab is an anti-granulocyte–macrophage colony-stimulating factor
(GM-CSF) receptor-α monoclonal antibody. GM-CSF is an immunoregulatory
cytokine with a pivotal role in initiation and perpetuation of inflammatory
diseases (Mehta 2020). In small uncontrolled pilot trial on 13 patients, mav-
rilimumab treatment was associated with improved clinical outcomes com-
pared with standard of care in non-mechanically ventilated patients with
severe COVID-19 pneumonia and systemic hyperinflammation. Treatment
was well tolerated (De Luca 2020).

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 Treatment | 353

Tocilizumab (TCZ, RoActemra® or Actemra®) is a monoclonal antibody that

targets the interleukin-6 receptor. It is used for rheumatic arthritis and has a
good safety profile. The initial dose should be 4-8 mg/kg, with the recom-
mended dosage being 400 mg (infusion over more than 1 hour). Several RCTs
are underway. Of note, the current level of evidence supporting the use of
TCZ is weak.
• In a retrospective cohort of COVID-19 patients who required ICU support,
deaths occurred in 102/210 (49%) patients with TCZ and in 256/420 (61%)
who did not receive TCZ (Biran 2020). After propensity matching, an asso-
ciation was noted between receiving TCZ and decreased mortality (HR
0.64, 95% CI 0.47–0.87).
• In another cohort from Italy (Guaraldi 2020), fewer deaths occurred in 179
patients treated with TCZ compared to 365 patients without TCZ (7% vs
20%). After adjustment for sex, age, duration of symptoms, and SOFA
score, TCZ treatment was associated with a reduced risk of ventilation or
death (adjusted HR 0.61, 95% CI 0.40–0.92).
• A large multicenter cohort included 3924 critically ill patients admitted to
ICU at 68 hospitals across the US (Gupta 2020). The risk of in-hospital
death was lower with TCZ (29% versus 41%). However, TCZ patients were
younger and had fewer comorbidities. According to the authors, the find-
ings “may be susceptible to unmeasured confounding, and further re-
search from randomized clinical trials is needed”.
• On July 29, Hoffmann-La Roche announced disappointing results from its
much-anticipated Phase III COVACTA trial. TCZ did not improve patient
mortality, although patients spent roughly a week less in hospital com-
pared with those given placebo (the full results of the trial have not yet
been published). However, it may be too early to quit this strategy (Furlow
2020). Cautious interpretation of COVACTA is needed, in view of the
study’s broad patient selection criteria and other study design factors.
• A double-blind, placebo-controlled RCT in 243 moderately ill hospitalized
patients, TCZ was not effective for preventing intubation or death (Stone
2020).
• An open label RCT in 126 patients hospitalized with COVID-19 pneumonia,
the rate of the primary clinical endpoint (clinical worsening) was not sig-
nificantly different between the control group and the TCZ group
(Salvarani 2020). The proportion of patients discharged within 14 and 30
days was the same. According to the authors, however, their results “do
not allow ruling out the possible role of tocilizumab in reducing the risk of
death or intubation in patients presenting with more advanced disease”.

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Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. However, this

chimeric monoclonal antibody targets interleukin-6 directly and not the re-
ceptor. Siltuximab has been approved for idiopathic multicentric Castleman’s
disease (iMCD). In these patients it is well tolerated. First results of a pilot
trial in Italy (“SISCO trial”) have shown encouraging results. According to
interim interim data, presented on April 2 from the first 21 patients treated
with siltuximab and followed for up to seven days, one-third (33%) of patients
experienced a clinical improvement with a reduced need for oxygen support
and 43% of patients saw their condition stabilise, indicated by no clinically
relevant changes (McKee 2020).
Sarilumab (Kevzara®) is another recombinant human IL-6 receptor antago-
nist. An open-label study of sarilumab in severe COVID-19 pneumonia with
hyperinflammation. Sarilumab 400 mg was administered intravenously in
addition to standard of care to 28 patients and results were compared with 28
contemporary matched patients treated with standard of care alone. At day
28, 61% of patients treated with sarilumab experienced clinical improvement
and 7% died. These findings were not significantly different from the compar-
ison group. However, sarilumab was associated with faster recovery in a sub-
set of patients showing minor lung consolidation at baseline (Della-Torre
2020).
Vilobelimab is an anaphylatoxin and complement protein C5a blocking mon-
oclonal antibody. In an open-label, randomized Phase II trial (part of the
PANAMO trial), 30 patients with severe COVID-19 were randomly assigned 1:1
to receive vilobelimab (up to seven doses of 800 mg intravenously) or best
supportive care only (control group). At day 5 after randomization, the pri-
mary endpoint of mean relative change in the ratio of partial pressure of ar-
terial oxygen to fractional concentration of oxygen in inspired air
(PaO2/FiO2) was not significantly different between groups. Kaplan-Meier
estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab
group and 27% (4–49) for the control group. The frequency of serious adverse
events was similar between groups and no deaths were considered related to
treatment assignment. According to the authors, the secondary outcome re-
sults support the investigation of vilobelimab in a Phase III trial using 28-day
mortality as the primary endpoint. Pharmacokinetic and pharmacodynamic
data, including C5a, have not yet been published (Campbell 2020). Investiga-
tors using the other C5 complement pathway inhibitors eculizumab and
ravulizumab have significantly increased their dose and dosing frequency in
the acute setting of COVID-19 compared with the doses approved for use in
atypical hemolytic uremic syndrome.

Kamps – Hoffmann
 Treatment | 355

Other treatments for COVID-19 (with unknown or un-

proven mechanisms of action)
Acalabrutinib and ibrutinib
Acalabrutinib and ibrutinib are bruton tyrosine kinase inhibitors, used for
CLL and lymphoma treatment. Ex vivo analysis revealed significantly elevated
BTK activity (BTK regulates macrophage signalling and activation), as evi-
denced by autophosphorylation, and increased IL-6 production in blood mon-
ocytes from patients with severe COVID-19 compared with blood monocytes
from healthy volunteers. In a pilot study, 19 patients with severe COVID-19
received the BTK inhibitor acalabrutinib (Roschewski 2020). Within 10-14
days, oxygenation improved “in a majority of patients”, often within 1-3 days,
and inflammation markers and lymphopenia normalized quickly in most pa-
tients. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the
supplemental oxygen cohort had been discharged on room air. These results
suggest that targeting excessive host inflammation with a BTK inhibitor can
be a therapeutic strategy. A confirmatory RCT is underway. Some reports
have speculated about a protective effect of ibrutinib, another BTK inhibitor
(Thibaud 2020).

Colchicine
Colchicine is one of the oldest known drugs which has been used for over
2000 years as a remedy for acute gout flares. Given its anti-inflammatory and
anti-viral properties, it is also being tested in COVID-19 patients. In a prospec-
tive, open-label RCT from Greece, 105 hospitalized patients were randomized
to either standard of care (SOC) or colchicine plus SOC (Deftereos 2020). Par-
ticipants who received colchicine had statistically “significantly improved
time to clinical deterioration”. However, there were no significant differences
in biomarkers and the observed difference was based on a narrow margin of
clinical significance; according to the authors their observations “should be
considered hypothesis generating” and “be interpreted with caution”. In a
retrospective cohort there was some evidence on clinical benefit (Brunetti
2020).

Famotidine
Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid
production. It has an excellent safety profile. Initially it was thought to inhib-
it the 3-chymotrypsin-like protease (3CLpro), but it seems to act rather as an
immune modulator, via its antagonism or inverse-agonism of histamine sig-

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naling. While results of the randomized clinical trial on the benefits of intra-
venous famotidine in treating COVID-19 (NCT04370262) are eagerly awaited,
we can only speculate on the potential mechanisms of action of this drug
(Singh 2020).
• In a retrospective study on 1620 patients, 84 (5.1%) received different dos-
es of famotidine within 24 hours of hospital admission (Freedberg 2020).
After adjusting for baseline patient characteristics, use of famotidine re-
mained independently associated with risk for death or intubation (ad-
justed hazard ratio 0.42, 95% CI 0.21-0.85) and this remained unchanged
after careful propensity score matching to further balance the co-
variables. Of note, there was no protective effect of PPIs. Plasma ferritin
values during hospitalization were lower with famotidine, indicating that
the drug blocks viral replication and reduces the cytokine storm.
• A second propensity-matched observational study included 878 consecu-
tive COVID-19-positive patients admitted to Hartford hospital, a tertiary
care hospital in Connecticut, USA (Mather 2020). In total, 83 (9.5%) pa-
tients received famotidine. These patients were somewhat younger (63.5
vs 67.5 years) but did not differ with respect to baseline demographics or
pre-existing comorbidities. Use of famotidine was associated with a de-
creased risk of in-hospital mortality (odds ratio 0.37, 95% CI 0.16-0.86) and
combined death or intubation (odds ratio 0.47, 95% CI 0.23-0.96). Patients
receiving famotidine displayed lower levels of serum markers for severe
disease including CRP, procalcitonin and ferritin levels. Logistic regression
analysis demonstrated that famotidine was an independent predictor of
both lower mortality and combined death/intubation.

G-CSF
G-CSF may be helpful in some patients (Cheng 2020). In an open-label trial at
3 Chinese centers, 200 patients with lymphopenia and no comorbidities were
randomized to standard of care or to 3 doses of recombinant human G-CSF (5
μg/kg, subcutaneously at days 0-2). Time to clinical improvement was similar
between groups. However, the proportion of patients progressing to ARDS,
sepsis, or septic shock was lower in the rhG-CSF group (2% vs 15%). Mortality
was also lower (2% vs 10%).

Iloprost
Iloprost is a prostacyclin receptor agonist that promotes vasodilation of cir-
culatory beds with minimal impact on hemodynamic parameters. It is li-
censed for the treatment of pulmonary arterial hypertension and is widely

Kamps – Hoffmann
 Treatment | 357

used for the management of peripheral vascular disease and digital vascu-
lopathy, including digital ulcers and critical digital ischemia in systemic scle-
rosis. There is a case series of three morbidly obese patients with severe
COVID-19 and systemic microvasculopathy who obviously benefitted from its
use (Moezinia 2020).

Other treatments with no effects

Azithromycin
Azithromycin as a macrolide antibiotic has probably no effect against SARS-
CoV-2 (see the many studies above, testing it in combination with HCQ). In a
large RCT conducted at 57 centers in Brazil, 214 patients who needed oxygen
supplementation of more than 4 L/min flow, high-flow nasal cannula, or me-
chanical ventilation (non-invasive or invasive) were assigned to the azithro-
mycin group and 183 to the control group. Azithromycin had no effect
(Furtado 2020).

Leflunomide
Leflunomide (Arava®) is an approved antagonist of dihydroorotate dehydro-
genase, has some antiviral and anti-inflammatory effects and has been widely
used to treat patients with autoimmune diseases. In a small RCT from Wuhan
on 50 COVID-19 patients with prolonged PCR positivity, no benefit in terms of
the duration of viral shedding was observed with the combined treatment of
leflunomide and IFN α-2a vs IFN α-2a alone (Wang 2020).

N-acetylcysteine
N-acetylcysteine had no effect, even at high-doses (De Alencar 2020). In an
RCT from Brazil of 135 patients with severe COVID-19, 16 patients (24%) in the
placebo group were submitted to endotracheal intubation and mechanical
ventilation, compared to 14 patients (21%) in the NAC group (p = 0.675). No
difference was observed on secondary endpoints.

Outlook and Recommendations

It is hoped that at least some of the options given in this overview will show
positive results over time. It is also important, though, that despite the im-
mense pressure, the basic principles of drug development and research in-
cluding repurposing are not abandoned. Time is needed.
The aim of the COVID Reference textbook is to scan the literature, not to
write guidelines. However, after reviewing the studies published until Octo-

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358 | CovidReference.com

ber 15 presented above, we would recommend reviewing the following treat-

ment options, considering the severity of the disease:

Outpatient, mild to moderate (no risk factors)

• Do NOTHING, except downtalking the patient. And make sure that he or
she (and their households) stays home

Outpatient, mild to moderate (with risk factors)

• Do NOT use dexamethasone (could be harmful) or remdesivir (daily infu-
sions not feasible)
• Do NOT use hydroxychloroquine, chloroquine, tocilizumab, convalescent
plasma or lopinavir (not efficient, plus side effects)
• Famotidine: why not? Potential harm seems to be limited
• Consider REGN-COV2 (if you are the personal doctor of a famous person)
• Interferon may work, if given early (optimal usage and administration is
unclear)

Hospital, severe
• Use dexamethasone (only a few days)
• Use remdesivir (5 days) as soon as possible (no benefit in those requiring
high-flow oxygen or mechanical ventilation)
• Consider tocilizumab or other cytokine blocking agents, if available

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9. Severe COVID-19
Markus Unnewehr
Peter Rupp
Matthias Richl

Definition and classification

In a small percentage of patients, COVID-19 will take a severe course. As seen
in the chapter Clinical Presentation (page 297), there was no broadly accepted
clinical definition for severe COVID-19 at the beginning of the pandemic. Ac-
cording to a brief and practical definition by IDSA (Infectious Diseases Society
of America), severe COVID is defined by “SpO2 ≤94% on room air, including
patients on supplemental oxygen” and critical COVID is “mechanical ventila-
tion and ECMO” (Bhimraj ). In this chapter, all symptomatic cases not mild or
moderate (i.e. severe and critical) are termed as severe.

Features, course and outcome

The course of the disease as well as the outcome have changed during the
pandemic. Most studies refer to the early pandemic phase and cover severely
affected regions and countries. The results vary greatly from country to
country and depend on the timing as well. The first data from China revealed
shocking numbers at a moment when local epidemics were taking off in Eu-
rope (Wu 2020). The spectrum of disease was classified as mild in 81% of cas-
es. In total, 14% were classified as severe, and 5% were critical cases. The case-
fatality rate was 14.8% in patients aged ≥ 80 years and 8.0% in patients aged
70-79 years. In a large single-center case study on 344 severe and critically ill
patients admitted to Tongji hospital in China from January 25 through Febru-
ary 25, 2020, 133 (38.7%) patients died at a median of 15 days (Wang 2020).
Besides older age, hypertension and COPD were more common in non-
survivors but not diabetes. No difference was seen between patients with or
without ACE inhibitors.
An observational study on 10,021 adult patients with a confirmed COVID-19
diagnosis, who were admitted to 920 hospitals in Germany between 26 Febru-
ary and 19 April 2020 revealed a huge death toll. The median age was 72 years
and 1,727 patients (17%) needed mechanical ventilation. Patients on mechan-
ical ventilation had more co-morbidities than patients without mechanical
ventilation. Morbidity and mortality were particularly high in older patients,
with a considerably lower mortality among patients younger than 60 years

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(Karagiannidis 2020). Mortality was 52% (906/1,727) in patients being me-

chanically ventilated, with lower rates reaching 63% of patients aged 70–79
years and 72% of patients aged 80 years and older (Table 1). In-hospital mor-
tality in ventilated patients who were also treated with dialysis was particu-
larly high at 73% (342 of 469), and 71% (84 of 119) of patients on extracorpo-
real membrane oxygenation (ECMO) died.

Table 1. In house mortality in patients with/without ventilation, percentage of absolute

numbers
Without ventilation With ventilation (all types)
18-59 years 0.7% (n = 2474) 27.7% (n = 422)
60-69 years 5.4% (n = 1239) 45.5% (n = 382)
70-79 years 14.6% (n = 1623) 62.6% (n = 535)
≥ 80 years 33.8% (n = 2958) 72.2% (n = 388)

High mortality rates were also seen in other countries. During the early phase
of the pandemic, chances of surviving an ICU stay in Lombardia, Italy, were
only 50% (Grasselli 2020). In a large cohort study of 3988 critically ill patients,
most required invasive mechanical ventilation, and mortality rate was high.
In the subgroup of the first 1715 patients, 915 patients died in the hospital for
an overall hospital mortality of 53.4%.
The mortality in patients requiring mechanical ventilation was equally large
in the New York City Area at the beginning of the pandemic (Richardson
2020). A case series from New York included 5700 COVID-19 patients admitted
to 12 hospitals between March 1 and April 4, 2020. Median age was 63 years
(IQR 52-75), the most common co-morbidities were hypertension (57%), obesi-
ty (42%), and diabetes (34%). At triage, 31% of patients were febrile, 17% had a
respiratory rate greater than 24 breaths/minute, and 28% received supple-
mental oxygen. Of 2634 patients with an available outcome, 14% (median age
68 years, IQR 56-78, 33% female) were treated in ICU, 12% received invasive
mechanical ventilation and 21% died. Mortality for those requiring mechani-
cal ventilation was 88.1%.
In another study in New York City among 1,150 adults who were admitted to
two NYC hospitals with COVID-19 in March, 257 (22%) were critically ill
(Cummings 2020). The median age of patients was 62 years (IQR 51-72), 67%
were men and 82% patients had at least one chronic illness. As of the end of
April, 101 (39%) patients had died and 94 (37%) remained hospitalized. 203
(79%) patients received invasive mechanical ventilation for a median of 18
days, 66% received vasopressors and 31% received renal replacement therapy.

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In a multivariate Cox model, older age, chronic cardiac disease (adjusted HR

1.76) and chronic pulmonary disease (2.94) were independently associated
with in-hospital mortality. This was also seen for higher concentrations of
interleukin-6 and D-dimer, highlighting the role of systemic inflammation
and endothelial-vascular damage in the development of organ dysfunction.
COVID-19 characteristics may vary considerably by location. In a United
States cohort of 2215 adults who were admitted to ICUs at 65 sites, 784
(35.4%) died within 28 days (Gupta 2020). However, mortality showed an ex-
tremely wide variation among hospitals, ranging from 6.6% to 80.8%. Factors
associated with death included older age, male sex, obesity, coronary artery
disease, cancer, acute organ dysfunction, and, importantly, admission to a
hospital with fewer intensive care unit beds. Of note, patients admitted to
hospitals with fewer than 50 ICU beds versus at least 100 ICU beds had a high-
er risk of death (OR 3.28; 95% CI, 2.16-4.99).
Another large prospective observational study in the United Kingdom pre-
sented clinical data from 20,133 patients, admitted to (or diagnosed in) 208
acute care hospitals in the UK until April 19 (Docherty 2020). Median age was
73 years (interquartile range 58-82) and 60% were men. Co-morbidities were
common, namely chronic cardiac disease (31%), diabetes (21%) and non-
asthmatic chronic pulmonary disease (18%). Overall, 41% of patients were
discharged alive, 26% died, and 34% continued to receive care. 17% required
admission to high dependency or intensive care units; of these, 28% were dis-
charged alive, 32% died, and 41% continued to receive care. Of those receiving
mechanical ventilation, 17% were discharged alive, 37% died, and 46% re-
mained in hospital. Increasing age, male sex, and co-morbidities including
chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic
kidney disease, liver disease and obesity were associated with higher mortali-
ty in hospital.

Spotlight: The situation in a German COVID-19 hospital

The Klinik Mühldorf am Inn Hospital was designated as a COVID-19 clinic on
March 16, 2020, in order to keep other facilities free for emergencies and
elective care. From that day, a total of 276 SARS-CoV-2 positive and 730 sus-
pected cases were treated there. The largest number of symptomatic patients
was admitted at the end of March, and the highest number of simultaneously
treated SARS-CoV-2 positive patients was 100 patients on April 6, 2020. In
total, 18.5% of these in-patients received intensive care during their hospital
stay. The peak of intensive care patients was highest on April 10, 2020 with 17
patients. Due to timely preparation, no triage decisions about withholding
ventilation treatments had to be made. All COVID-19 patients who had to be

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treated in the hospital until July 15th, 2020, and who were in need of mechan-
ical ventilation received it. A total of 51 COVID-19 patients required intensive
care treatment (18.5% of all COVID-19 in-patients) and 37 patients (13.4%)
were ventilated during their intensive care stay. Seven patients were directly
intubated and invasively ventilated without a non-invasive ventilation (NIV)
attempt after administration of oxygen through a nasal cannula or mask
alone. In total, 9/37 patients did not wish to be intubated. In 16 patients, a
prone positioning was carried out, including one patient under NIV.
Management and mechanical ventilation
The cardinal COVID-19 symptom leading to intensive care admission is hy-
poxemic respiratory failure with tachypnea (> 30/min). Initially, in order to
protect staff from aerosols as much as possible, intubation and invasive me-
chanical ventilation was preferred over non-invasive ventilation (NIV) and
nasal high-flow (HFNC).
Likewise, due to lack of knowledge and experience, recommendations on how
to deal with these patients were not homogeneous, and ARDS ventilation was
the preferred technique (Griffiths 2019). According to the ARDS recommenda-
tions, patients should be ventilated with a tidal volume (VT) of < 6ml/kg
standardized body weight, a peak pressure of < 30 cmH2O and a PEEP based
on the ARDS network table.
In one study, these ventilator settings were used except for the lower
PEEP/higher FiO2 table. The driving pressure should not exceed 15 mbar. In
addition, prone positioning was recommended in case of a PaO2/FiO2 < 150 for
more than 16 hours (Ziehr 2020).
Quickly it became obvious that acute respiratory distress syndrome (ARDS) in
COVID-19 is not the same as ARDS. COVID-19 in patients with ARDS – CARDs –
appears to include an important vascular insult that potentially mandates a
different treatment approach than customarily used for ARDS. It may be help-
ful to categorize patients as having either type L or H phenotype and accept
that different ventilatory approaches are needed, depending on the underly-
ing physiology (Marini 2020). In type L (low lung elastance, high compliance,
low response to PEEP), infiltrates are often limited in extent and initially
characterized by a ground-glass pattern on CT that signifies interstitial rather
than alveolar edema. Many patients do not appear overtly dyspneic and may
stabilize at this stage without deterioration. Others may transit to a clinical
picture more characteristic of typical ARDS: Type H shows extensive CT con-
solidations, high elastance (low compliance) and high PEEP response. Clearly,
types L and H are the conceptual extremes of a spectrum that includes inter-
mediate stages.

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Factors and characteristics to develop one type over the other have been
identified: severity of the initial infection, the patient’s immune response, the
patient’s physical fitness and comorbidities, the response of the hypoxemia to
the ventilation, and the time between first symptoms and hospital admission
(Gattinoni 2020). L type patients remain stable before improvement or deteri-
oration. In the latter case the patients develop H type pneumonia (Pfeifer
2020). According to this theory, a ventilation strategy starting with respirato-
ry support with high flow oxygen has been recommended (Gattinoni 2020).
To adequately assess oxygenation, the oxygen content (CaO2) in the blood is
helpul, as it describes the actual oxygen supply (DO2) better than the oxygen
partial pressure (pO2), particularly when combined with the cardiac output
(CO):
DO2 = CaO2 x CO and CaO2 = Hb x SaO2 x 1.4
With a CaO2 limit of 10 g/100 ml blood, and an appropriate cardiac output,
i.e., absence of cardiac failure, a lower O2 saturation (hypoxemia) can be tol-
erated in the blood before a critical oxygen shortage in the tissue (hypoxia)
develops.
Therefore, rather than strictly focusing on pO2 values as represented by the
oxygenation index PaO2/FiO2 of < 150, it is more reasonable to consider the
overall clinical picture while setting individual target values before intuba-
tion. Attempting high-flow oxygen and non-invasive ventilation in patients
with type L pneumonia is recommended. Intubation should only be per-
formed if there is significant clinical deterioration (Lyons 2020, Pfeifer 2020).

Special situations in severe COVID-19

Prone positioning
Prone position (PP) has become a therapeutic option, even in awake, non-
intubated patients, during spontaneous and assisted breathing (Telias 2020).
In one study, among 50 patients, the median SpO2 at triage was 80%. After
supplemental oxygen was given to patients on room air it was 84%. After 5
minutes of proning was added, SpO2 improved to 94% (Caputo 2020). Whether
PP prevents intubation is not known yet.
In a prospective before-after study in Aix-en-Provence, France among 24
awake, non-intubated, spontaneously breathing patients with COVID-19 and
hypoxemic acute respiratory failure requiring oxygen supplementation, the
effect of PP was only moderate. 63% were able to tolerate PP for more than 3
hours. Oxygenation increased in only 25% and was not sustained in half of

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those after resupination. However, prone sessions were short, partly because
of limited patient tolerance (Elharrar 2020).
In a small single-center cohort study, use of the prone position for 25 awake,
spontaneously breathing patients with COVID-19 was associated with im-
proved oxygenation. In addition, patients with an SpO2 of 95% or greater af-
ter 1 hour of the prone position had a lower rate of intubation. Unfortunately,
there was no control group and the sample size was very small. Ongoing clini-
cal trials of prone positioning in non–mechanically ventilated patients
(NCT04383613, NCT04359797) will hopefully help clarify the role of this sim-
ple, low-cost approach for patients with acute hypoxemic respiratory failure
(Thompson 2020).

Extracorporal Membrane Oxygenation (ECMO)

Since the beginning of the pandemic, extracorporeal lung replacement pro-
cedures such as ECMO have been recommended with caution and only in se-
lected patients with severe and persistant hypoxemia (PaO2/FiO2 < 80), with
minor comorbidities and with full usage of all other measures, such as relaxa-
tion and recruiting maneuvers (Smereka 2020).
In a single center narrative study regarding ECMO, support for 27 patients
with COVID-19 was described (Kon 2020). At the time of the paper submission,
survival was 96.3% (one death) in over 350 days of total ECMO support. Thir-
teen patients (48.1%) remained on ECMO support, while 13 patients (48.1%)
were successfully decannulated. Seven patients (25.9%) were discharged from
the hospital while six patients (22.2%) remained in the hospital, of which four
were on (unmodified) room air. The authors conclude that the judicious use
of ECMO support may be clinically beneficial.

Tracheostomy
During the pandemic, an old problem in a new situation arose: When to per-
form tracheostomy (and how) in COVID-19 patients? In a review of the cur-
rent evidence and misconceptions that predispose to uncontrolled variation
in tracheostomy among COVID-19 patients, the authors conclude that deci-
sions on tracheostomy must be personalized; that some patients may be
awake but cannot yet be extubated (favoring tracheostomy); while others
may have immediate, severe hypoxemia when lying supine or with any period
of apnea (favoring deferral) (Tay 2020, Schultz 2020). Meanwhile, detailed
consensus guidance has been published, including on important issues such
as timing of tracheostomy (delayed until at least day 10 of mechanical venti-
lation and considered only when patients are showing signs of clinical im-

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provement), optimal setting (hierarchic approach to operative location, en-

hanced PPE), optimal procedure and management after tracheostomy
(McGrath 2020).

Lung Transplantation
As in other terminal lung diseases, lung transplantation (LTX) can be a poten-
tial therapeutic option. Of course, the indication needs to be considered espe-
cially careful. In an editorial published in August 2020, the authors list ten
considerations that they believe should be carefully weighed when assessing
a patient with COVID-19-associated ARDS regarding potential candidacy for
lung transplantation (< 65 years, only single-organ dysfunction, sufficient
time for lung recovery, radiological evidence of irreversible lung disease,
such as severe bullous destruction or established fibrosis, etc) (Cypel 2020).
Up to now, only case reports have been published. After 52 days of critical
COVID-19, ECMO and several complications, a comprehensive interdiscipli-
nary discussion on the direction of treatment resulted in a consensus that the
lungs of the otherwise healthy 44-year-old woman from Klagenfurt, Austria
had no potential for recovery. On day 58, a suitable donor organ became
available, and a sequential bilateral lung transplant was performed. At day
144, the patient remained well. Despite the success of this case, the authors
emphasize that lung transplantation is an option for only a small proportion
of patients (Lang 2020).

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 Comorbidities | 379

10. Comorbidities
Christian Hoffmann

Hundreds of articles have been published over the last six months, making
well-meaning attempts to determine whether patients with different comor-
bidities are more susceptible for SARS-CoV-2 infection or at higher risk for
severe disease. This deluge of scientific publications has resulted in world-
wide uncertainty. For a number of reasons, many studies must be interpreted
with extreme caution.
First, in many articles, the number of patients with specific comorbidities is
low. Small sample sizes preclude accurate comparison of COVID-19 risk be-
tween these patients and the general population. They may also overestimate
mortality, especially if the observations were made in-hospital (reporting
bias). Moreover, the clinical manifestation and the relevance of a condition
may be heterogeneous. Is the hypertension treated or untreated? What is the
stage of the COPD, only mild or very severe with low blood oxygen levels? Is
the “cancer” cured, untreated or actively being treated? Are we talking about
a seminoma cured by surgical orchiectomy years ago or about palliative care
for pancreatic cancer? What is a “former” smoker: someone who decided to
quit 20 years ago after a few months puffing during adolescence or someone
with 40 package-years who stopped the day before his lung transplantation?
Does “HIV” mean a well controlled infection while on long-lasting, successful
antiretroviral therapy or an untreated case of AIDS? Unfortunately, many
researchers tend to combine these cases, in order to get larger numbers and
to get their paper published.
Second, there are numerous confounding factors to consider. In some case
series, only symptomatic patients are described, in others only those who
were hospitalized (and who have per se a higher risk for severe disease). In
some countries, every patient with SARS-CoV-2 infection will be hospitalized,
in others only those with risk factors or with severe COVID-19. Testing poli-
cies vary widely between countries. The control group (with or without
comorbidities) is not always well-defined. Samples may not be representative,
risk factors not correctly taken into account. Sometimes, there is incomplete
information about age distribution, ethnicity, comorbidities, smoking, drug
use and gender (there is some evidence that, in female patients, comorbidities
have no or less impact on the course of the disease, compared to male (Meng
2020)). All these issues present important limitations and only a few studies
have addressed all of them.

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Third, comorbidity papers have led to an information overload. Yes, virtually

every medical discipline and every specialist has to cope with the current
pandemic. And yes, everybody has to be alert these days, psychiatrists as well
as esthetic surgeons. Hundreds of guidelines or position papers have been
published, trying to thoughtfully balance fear of COVID-19 against the dire
consequences of not treating other diseases than COVID-19 in an effective or
timely manner – and all this in the absence of data. On May 15, a PubMed
search yielded 530 guidelines or considerations about specific diseases in the
context of COVID-19, among them those for grade IV glioma (Bernhardt 2020,
bottom line: do not delay treatment), but also for dysphonia and voice reha-
bilitation (Mattei 2020: can be postponed), infantile hemangiomas (Frieden
2020: use telehealth), ocular allergy (Leonardi 2020: very controversial), high
resolution anoscopy (Mistrangelo 2020: also controversial), migraine man-
agement (Szperka 2020: use telehealth) and breast reconstruction (Salgarello
2020: defer “whenever possible”), to name just a few. These recommendations
are usually not helpful. They apply for a few weeks, during acute health crisis
scenarios as seen in overwhelmed health care systems in Wuhan, Bergamo,
Madrid or New York. In other cities or even a few weeks later, proposed algo-
rithms are already outdated. Nobody needs a 60-page recommendation, con-
cluding that “clinical judgment and decision making should be exercised on a
case-by-case basis”.
However, some important papers have been published during the last
months, a couple of them with very helpful data, supporting the management
of patients with comorbidities. In the following, we will briefly go through
these.

Hypertension and cardiovascular comorbidities

From the beginning of the pandemic, hypertension and/or cardiovascular
disease (CVD) have been identified as potential risk factors for severe disease
and death (Table 1). However, all studies were retrospective, included only
hospitalized patients and did not distinguish between uncontrolled and con-
trolled hypertension or used different definitions for CVD. Multivariate anal-
yses adjusting for confounders were performed in only a few studies. Moreo-
ver, different outcomes and patient groups were analyzed. According to some
experts, current data do not necessarily imply a causal relationship between
hypertension and severity of COVID-19. There is no study that demonstrates
the independent predictive value of hypertension. It is “unclear whether un-
controlled blood pressure is a risk factor for acquiring COVID-19, or whether
controlled blood pressure among patients with hypertension is or is not less

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of a risk factor” (Schiffrin 2020). The same applies to CVD, with the difference
that the numbers here are even lower.
From a mechanistic point of view, however, it seems plausible that patients
with underlying cardiovascular diseases and pre-existing damage to blood
vessels such as artherosclerosis may face higher risks for severe diseases.
During recent weeks, it has become clear that SARS-CoV-2 may directly or
indirectly attack the heart, kidney and blood vessels. Various cardiac mani-
festations of COVID-19 do occur contemporarily in many patients (see chapter
Clinical Presentation, page 279). Infection may lead to cardiac muscle damage,
blood vessel constriction and to elevated levels of inflammation-inducing
cytokines. These direct and indirect adverse effects of the virus may be espe-
cially deleterious in those with already established heart disease. During the
next months, we will learn more about the role and contributions of arterio-
sclerosis in the pathogenesis of COVID-19.

Table 1. Hypertension in larger cohort studies, prevalence and outcome

Study Setting Hypertension present? Multivariate, hazard or odds

ratio (95% CI) for endpoint
Wang 344 ICU pts, Survivors vs Non- Not done
2020 Tongji, China Survivors: 34 vs 52%
Grasselli 521 ICU pts, Discharge from ICU vs Not done
2020 72 hospitals in Italy death at ICU: 40 vs
63%
Guan 1,099 hospitalized Non-severe disease vs Not done
2020 pts, 522 hospitals in severe: 13 vs 24%
China
Zhou 191 hospitalized pts Survivors vs Non- Not done
2020 from Jinyintan and Survivors: 23 vs 48%
Wuhan
Shi 487 hospitalized pts Non-severe disease at OR 2.7 (1.3-5.6) for severe
2020 in Zhejing Province admission vs severe: disease at admission
17 vs 53%
Guan 1,590 hospitalized Non-severe vs severe HR 1.6 (1.1-2.3) for severe
2020 pts, 575 hospitals in courses: 13 vs 33% course (ICU, IMV, death)
China
Goyal 393 hospitalized pts, No IMV vs IMV during Not done
2020 2 hospitals in New stay: 48 vs 54%
York
IMV invasive mechanical ventilation, ICU intensive care units

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Treatment of hypertension during the pandemic

There has hardly been a topic that has kept doctors and their patients as busy
as the question of whether antihypertensive drugs such as ACE inhibitors
(ACEIs) or angiotensin-receptor blockers (ARBs) can cause harm to patients.
The uncontrolled observations of increased mortality risk in patients with
hypertension, CVD (see above) and diabetes raised concerns. These conditions
share underlying renin-angiotensin-aldosterone system pathophysiology that
may be clinically insightful. In particular, activity of the angiotensin-
converting enzyme 2 (ACE2) is dysregulated (increased) in cardiovascular
disease (Vaduganathan 2020). As SARS-CoV-2 cell entry depends on ACE2
(Hoffmann 2020), increased ACE2 levels may increase the virulence of the
virus within the lung and heart.
ACEIs or ARBs may alter ACE2, and variation in ACE2 expression may in part
be responsible for disease virulence. However, the first substantial study to
examine the association between plasma ACE2 concentrations and the use of
ACEIs/ARBs did not support this hypothesis: in two large cohorts from the
pre-COVID-19 era, plasma concentrations of ACE2 were markedly higher in
men than in women, but not with ACEI/ARB use (Sama 2020). A recent review
of 12 animal studies and 12 human studies overwhelmingly implies that ad-
ministration of both drug classes does not increase ACE2 expression (Sriram
2020).
However, some concerns on deleterious effects remain and some media
sources and even scientific papers have called for the discontinuation of these
drugs. This is remarkable as clinical data actually points in the opposite direc-
tion. Although all were observational (with the possibility of confounding),
their message was consistent - none showed any evidence of harm.
• Among 2573 COVID-19 patients with hypertension from New York City,
there were no differences in the likelihood for severe COVID-19 for differ-
ent classes of antihypertensive medications – ACE inhibitors, ARBs, beta
blockers, calcium channel blockers, and thiazide diuretics (Reynolds
2020).
• Comparing 6272 Italian cases (positive for SARS-CoV-2) to 30,759 controls
(matched for sex, age, and municipality of residence), no evidence was
found that ACE inhibitors or ARBs modify susceptibility to COVID-19
(Mancia 2020). The results applied to both sexes as well as to younger and
older persons.
• In a retrospective study from Denmark (one of the countries with the best
epidemiological data) of 4480 COVID-19 patients, prior ACEI/ARB use,
compared with no use, was not significantly associated with mortality. In

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a nested case-control study of a cohort of 494,170 patients with hyperten-

sion, use of ACEI/ARB, compared with use of other antihypertensive medi-
cations, was not significantly associated with COVID-19 diagnosis (Fosbøl
2020).
In conclusion, ACE inhibitors and/or ARBs should not be discontinued. Sever-
al randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-
19 (Mackey 2020). According to a brief review, adjuvant treatment and con-
tinuation of pre-existing statin therapy could improve the clinical course of
patients with COVID-19, either by their immunomodulatory action or by pre-
venting cardiovascular damage (Castiglion 2020). In a retrospective study on
13,981 patients in Hubei Province, China, the use of statins was independently
associated with lower all-cause mortality (5.2% versus 9.4%). Randomized
controlled trials involving statin treatment for COVID-19 are needed.

Treatment of coronary heart disease during the pandemic

Pre-existing cardiovascular disease is linked with higher morbidity and mor-
tality in patients with COVID-19, whereas COVID-19 itself can induce myocar-
dial injury, arrhythmia, acute coronary syndrome and venous thromboembo-
lism (nice review: Nishiga 2020). Myocardial injury, evidenced by elevated
cardiac biomarkers, was recognized among early cases and myocardial infarc-
tion (STEMI or NSTEMI) and may represent the first clinical manifestation of
COVID-19. Of note, a culprit lesion is often not identifiable by coronary angi-
ography. In a study of 28 patients with STEMI, this was the case in 39%
(Stefanini 2020). According to the authors, a dedicated diagnostic pathway
should be delineated for COVID-19 patients with STEMI, aimed at minimizing
procedural risks and healthcare providers’ risk of infection. There are already
preliminary reports on a significant decline of 32% in the number of percuta-
neous coronary interventions for acute coronary syndromes (Piccolo 2020).
Other authors have suggested that, in settings with limited resources to pro-
tect the work force, fibrinolytic therapies may be prefered over primary per-
cutaneous coronary interventions (Daniels 2020).
Of note, several studies have found a spectacular drop in admissions for
STEMI during the peak of the epidemic. In France a steep decline of 25% was
found for both acute ( < 24hrs) and late presentation (> 24 hrs) STEMI (Rangé
2020). Similar observations have been made in Italy (De Filippo 2020) and the
US (Solomon 2020). Possible explanations for this phenomenon may be pa-
tients’ fear of coming to the hospital or disturbing busy caregivers, especially
in the case of mild STEMI clinical presentation. Other hypothetical reasons
are reduced air pollution, better adherence to treatment, limited physical
activity or absence of occupational stress during lockdown. However, there is

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some evidence that the lower incidence does not reflect a true decline but
just one more collateral damage of the pandemic. For example, Italian re-
searchers have found a 58% increase of out-of-hospital cardiac arrests in
March 2020 compared to the same period in 2019 (Baldi 2020). In New York,
this increase seemed to be even more pronounced (Lai 2020). Others have
observed an increased observed/expected mortality ratio during the early
COVID-19 period indicating that patients try to avoid hospitalization
(Gluckman 2020).

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Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-19 and es-
tablishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care. 2020
Mar 18;24(1):108. PubMed: https://pubmed.gov/32188484. Full-text:
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tients with COVID-19: Clinical and Angiographic Outcomes. Circulation. 2020 Apr 30.
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and Plea to Insurers. Headache. 2020 May;60(5):833-842. PubMed:
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6736(20)30566-3

Diabetes mellitus
Diabetes mellitus is a chronic inflammatory condition characterized by sever-
al macrovascular and microvascular abnormalities. As with hypertension and
CVD, many of the above cited studies have also revealed that diabetic patients
were overrepresented among the most severely ill patients with COVID-19
and those succumbing to the disease. Among the 23,698 in-hospital COVID-19-
related deaths during the first months in the UK, a third occurred in people
with diabetes: 7,434 (31.4%) in people with type 2 diabetes, 364 (1.5%) in those
with type 1 diabetes (Barron 2020).
Current data suggest that diabetes in patients with COVID-19 is associated
with a two-fold increase in mortality as well as severity of COVID-19, as com-
pared to non-diabetics. In a meta-analysis of 33 studies and 16,003 patients
(Kumar 2020), diabetes was found to be significantly associated with mortali-
ty from COVID-19 with a pooled odds ratio of 1.90 (95% CI: 1.37-2.64). Diabetes
was also associated with severe COVID-19 and a pooled odds ratio of 2.75 (95%
CI: 2.09-3.62). The pooled prevalence of diabetes in patients with COVID-19
was 9.8% (95% CI: 8.7%-10.9%). However, it is too early to say whether diabe-
tes is acting as an independent factor responsible for COVID severity and
mortality or if it is just a confounding factor.

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A large retrospective study on the impact of type 2 diabetes (T2D) carefully

analyzed 7337 cases of COVID-19 in Hubei Province, China, among them 952
with pre-existing T2D (Zhu 2020). The authors found that subjects with T2D
required more medical interventions and had a significantly higher mortality
(7.8% versus 2.7%; adjusted hazard ratio, 1.49) and multiple organ injury than
non-diabetic individuals. Of note, well-controlled blood glucose was associat-
ed with markedly lower mortality (in-hospital death rate 1.1% versus 11.0%)
compared to individuals with poorly controlled blood glucose. Similar results
were found in a large UK cohort (Holman 2020).
A recent review has made some suggestions on the possible pathophysiologi-
cal mechanisms of the relationship between diabetes and COVID-19, and its
management (Hussain 2020). Rigorous glucose monitoring and careful con-
sideration of drug interactions might attenuate worsening of symptoms and
adverse outcomes. In a retrospective cohort study of 1213 hospitalized indi-
viduals with COVID-19 and pre-existing T2D, metformin use was significantly
associated with a higher incidence of acidosis, particularly in cases with se-
vere COVID-19, but not with 28-day COVID-19-related mortality (Cheng 2020).
Some treatment strategies for COVID-19 such as steroids and lopinavir/r bear
a risk for hyperglycemia. On the other hand, hydroxychloroquine may im-
prove glycemic control in decompensated, treatment-refractory patients with
diabetes (Gerstein 2002, Rekedal 2010). However, it remains unclear which
COVID-19 treatment strategy works best and if treatment of diabetic patients
has to be different from those without diabetes. It is also unclear whether
specific diabetes drugs such as DPP4 inhibitors increase or decrease the sus-
ceptibility or severity of SARS-CoV-2 infection.

References
Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-
related mortality in England: a whole-population study. Lancet Diabetes Endocrinol
2020, published 13 August. Full-text: https://doi.org/10.1016/S2213-8587(20)30272-2
Cheng X, Liu YM, Li H, et al. Metformin Use Is Associated with Increased Incidence of Acido-
sis but not Mortality in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.
Cell Metabol August 20, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.08.013
Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in
patients with type 2 diabetes mellitus who are refractory to sulfonylureas--a random-
ized trial. Diabetes Res Clin Pract. 2002 Mar;55(3):209-19. PubMed:
https://pubmed.gov/11850097. Full-text: https://doi.org/10.1016/s0168-8227(01)00325-4
Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mor-tality in people
with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet
Diabetes Endocrinol 2020, published 13 August. Full-text: https://doi.org/10.1016/S2213-
8587(20)30271-0.
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress.
Diabetes Res Clin Pract. 2020 Apr;162:108142. PubMed: https://pubmed.gov/32278764. Full-
text: https://doi.org/10.1016/j.diabres.2020.10814

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Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and severity
of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020 May 6;14(4):535-545. PubMed:
https://pubmed.gov/32408118. Full-text: https://doi.org/10.1016/j.dsx.2020.04.044
Rekedal LR, Massarotti E, Garg R, et al. Changes in glycosylated hemoglobin after initiation of
hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic
diseases. Arthritis Rheum. 2010 Dec;62(12):3569-73. PubMed:
https://pubmed.gov/20722019. Full-text: https://doi.org/10.1002/art.27703
Zhu L, She ZG, Cheng X. Association of Blood Glucose Control and Outcomes in Patients with
COVID-19 and Pre-existing Type 2 Diabetes. Cell Metabolism, April 30, 2020. Full-text:
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30238-2

COPD and smoking

Chronic Obstructive Pulmonary Disease (COPD) is a common and preventable
dysfunction of the lung associated with limitation in airflow. It is a complex
disease associated with abnormalities of the airway and/or alveoli which is
predominantly caused by exposure to noxious gases and particulates over a
long period. A meta-analysis of 15 studies, including a total of 2473 confirmed
COVID-19 cases showed that COPD patients were at a higher risk of more se-
vere disease (calculated RR 1.88) and with 60% higher mortality (Alqahtani
2020). Unfortunately, the numbers in this review were very small and only 58
(2.3%) had COPD.
A meta-analysis of 5 early studies comprising 1399 patients observed only a
trend but no significant association between active smoking and severity of
COVID-19 (Lippi 2020). However, other authors have emphasized that current
data do not allow to draw firm conclusions about the association of severity
of COVID-19 with smoking status (Berlin 2020). In a more recent review, cur-
rent smokers were 1.45 times more likely to have severe complications com-
pared to former and never smokers. Current smokers also had a higher mor-
tality rate (Alqahtani 2020).
Ever-smoking increased pulmonary ACE2 expression by 25% (Cai 2020). The
significant smoking effect on ACE2 pulmonary expression may suggest an
increased risk for viral binding and entry of SARS-CoV-2 into the lungs of
smokers. Cigarette smoke triggers an increase in ACE2 positive cells by driv-
ing secretory cell expansion (Smith 2020). The overabundance of ACE2 in the
lungs of smokers may partially explain a higher vulnerability of smokers.
However, it’s not that easy – both quitting smoking and finding clinical corre-
lations to the above cell experiments. Within a surveillance center primary
care sentinel network, multivariate logistic regression models were used to
identify risk factors for positive SARS-CoV-2 tests (Lusignan 2020). Of note,
active smoking was associated with decreased odds (yes, decreased: adjusted
OR 0.49, 95% CI 0.34–0.71). According to the authors, their findings should not

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be used to conclude that smoking prevents SARS-CoV-2 infection, or to en-

courage ongoing smoking. Several explanations are given, such as selection
bias (smokers are more likely to have a cough, more frequent testing could
increase the proportion of smokers with negative results). Active smoking
might also affect RT-PCR test sensitivity.

References
Alqahtani JS, Oyelade T, Aldhahir AM, et al. Prevalence, Severity and Mortality associated
with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and
Meta-Analysis. PLoS One. 2020 May 11;15(5):e0233147. PubMed:
https://pubmed.gov/32392262. Full-text: https://doi.org/10.1371/journal.pone.0233147
Berlin I, Thomas D, Le Faou AL, Cornuz J. COVID-19 and smoking. Nicotine Tob Res. 2020 Apr 3.
pii: 5815378. PubMed: https://pubmed.gov/32242236. Full-text:
https://doi.org/10.1093/ntr/ntaa059
Cai G, Bosse Y, Xiao F, Kheradmand F, Amos CI. Tobacco Smoking Increases the Lung Gene
Expression of ACE2, the Receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2020 Apr 24.
PubMed: https://pubmed.gov/32329629. Full-text: https://doi.org/10.1164/rccm.202003-
0693LE
Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease
2019 (COVID-19). Eur J Intern Med. 2020 Mar 16. PubMed: https://pubmed.gov/32192856.
Full-text: https://doi.org/10.1016/j.ejim.2020.03.014
Lusignan S, Dorward J, Correa A, et al. Risk factors for SARS-CoV-2 among patients in the
Oxford Royal College of General Practitioners Research and Surveillance Centre pri-
mary care network: a cross-sectional study. Lancet Inf Dis 2020, May 15. Full-text:
https://doi.org/10.1016/S1473-3099(20)30371-6
Smith JC, Sauswille EL, Girish V, et al. Cigarette smoke exposure and inflammatory signaling
increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. De-
velopment Cell, May 16, 2020. Full-text: https://doi.org/10.1016/j.devcel.2020.05.012

HIV infection
HIV infection is of particular interest in the current crisis. First, many pa-
tients take antiretroviral therapies that are thought to have some effect
against SARS-CoV-2. Second, HIV serves as a model of cellular immune defi-
ciency. Third, and by far the most important point, the collateral damage
caused by COVID-19 in the HIV population may be much higher than that of
COVID-19 itself.
Preliminary data suggest no elevated incidence of COVID-19. In 5,700 patients
from New York, only 43 (0.8%) were found to be HIV-positive (Richardson
2020). In Barcelona, the standardized incidence rate was lower in persons
living with HIV (PLWH) than in the general population (Inciarte 2020). Given
the fact that HIV+ patients may be at higher risk for other infectious diseases
such as STDs, these percentages were so low that some experts have already
speculated on potential “protective” factors (i.e., antiviral therapies or im-
mune activation). Moreover, a defective cellular immunity could paradoxical-

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ly be protective for severe cytokine dysregulation, preventing the cytokine

storm seen in severe COVID-19 cases.
Appropriately powered and designed studies that are needed to draw conclu-
sions on the effect of COVID-19 are still lacking. However, our own retrospec-
tive analysis of 33 confirmed SARS-CoV-2 infections between March 11 and
April 17 in 12 participating German HIV centers revealed no excess morbidity
or mortality (Haerter 2020). The clinical case definition was mild in 25/33
cases (76%), severe in 2/33 cases (6%), and critical in 6/33 cases (18%). At the
last follow up, 29/32 of patients with documented outcome (90%) had recov-
ered. Three out of 32 patients had died. One patient was 82 years old, one had
a CD4 T cell count of 69/µl and one suffered from several comorbidities. A
similar observation was made in Milan, Italy, where 45/47 patients with HIV
and COVID-19 (only 28 with confirmed SARS-CoV-2 infection) recovered
(Gervasoni 2020). In another single center study from Madrid on 51 HIV pa-
tients with COVID-19 (35 confirmed cases), six patients were critically ill and
two died (Vizcarra 2020). In these studies, as in our cohort, severe immune
deficiency was rare. During recent months, there has been growing evidence
that HIV+ patients with uncontrolled viremia and/or low CD4 cells are at
higher risk for severe disease. In a large population study from South Africa,
HIV was independently associated with increased COVID-19 mortality, show-
ing an adjusted hazard ratio for mortality of 2.14 for HIV (95% CI 1.70-2.70)
(Boulle 2020). Among 286 HIV-infected patients who were included by US
healthcare providers, mortality rates were higher in patients with low CD4
counts (< 200 cells/mm³) (Dandachi 2020).
There is still an ongoing debate about potential effects of antiretroviral ther-
apies against SARS-CoV-2. For lopinavir/r (and darunavir/r), there is now
strong evidence that they don’t work (see Treatment chapter, page 329). An
ART regimen should not be changed to include a PI to prevent or treat COVID-
19 (EACS 2020, US 2020). Tenofovir alafenamide (TAF) has some chemical sim-
ilarities to remdesivir and has been shown to bind to SARS-CoV-2 RNA poly-
merase (RdRp) with high binding energies, and has been suggested as a po-
tential treatment for COVID-19 (Elfiky 2020). In Spain, a large randomized
Phase III placebo-controlled study (EPICOS, NCT04334928) compares the use
of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), hydroxychloro-
quine or the combination of both versus placebo as prophylaxis for COVID-19
in healthcare workers. Our observation that the majority (22/33) of HIV+ pa-
tients with COVID-19 were treated with tenofovir, including those developing
severe or critical disease, indicate no or only minimal clinical effect against
SARS-CoV-2 (Härter 2020). In the cohorts from Milan and Madrid, there was
no evidence that any specific antiretroviral drug (such as tenofovir or PIs)

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affected COVID-19 susceptibility or severity (Gervasoni 2020, Vizcarra 2020).

Most patients, however, have received TAF and not TDF for which prelimi-
nary data from Spain suggest a beneficial effect. Of 77,590 HIV+ persons re-
ceiving ART in Spain, 236 were diagnosed with COVID-19, 151 were hospital-
ized, 15 were admitted to the ICU, and 20 died (Del Amo 2020). The risk for
COVID-19 hospitalization was higher among patients receiving TAF/FTC and
ABC/3TC, compared to those receiving TDF/FTC. However, residual con-
founding by co-morbid conditions cannot be completely excluded. In a small
group from France, attack rates were not lower with TDF/FTC in PrEP users
(Charre 2020).
The most serious concern regarding HIV, however, is the collateral damage
induced by COVID-19. In Western countries, there exist few reports of HIV+
patients having problems in gaining access to their HIV medications or hav-
ing trouble taking them due to COVID-19 or the plans to manage it (Sanchez
2020). In contrast, disruption to delivery of health care in sub-Saharan Afri-
can settings could well lead to adverse consequences beyond those from
COVID-19 itself. Lockdown, transport restrictions and fear of coronavirus in-
fection have already led to a dramatic drop in HIV and TB patients collecting
medication in several African countries (Adepoju 2020). Using five different
existing mathematical models of HIV epidemiology and intervention pro-
grammes in sub-Saharan Africa, investigations have already estimated the
impact of different disruptions to HIV prevention and treatment services.
Predicted average relative excess in HIV-related deaths and new HIV infec-
tions (caused by unsuppressed HIV RNA during treatment interruptions) per
year over 2020-2024 in countries in sub-Saharan Africa that would result from
3 months of disruption of HIV-specific services, were 1.20-1.27 for death and
1.02-1.33 for new infections, respectively. A 6-month interruption of ART
would result in over 500,000 excess HIV deaths in sub-Saharan Africa (range
of estimates 471,000 - 673,000). Disrupted services could also reverse gains
made in preventing mother-to-child transmission. According to WHO, there is
a clear need for urgent efforts to ensure HIV service continuity and prevent-
ing treatment interruptions due to COVID-19 restrictions in sub-Saharan Af-
rica.

References
Adepoju P. Tuberculosis and HIV responses threatened by COVID-19. Lancet HIV. 2020
May;7(5):e319-e320. PubMed: https://pubmed.gov/32277870. Full-text:
https://doi.org/10.1016/S2352-3018(20)30109-0
Boulle A, Davies MA, Hussey H, et al. Risk factors for COVID-19 death in a population cohort
study from the Western Cape Province, South Africa. Clin Infect Dis. 2020 Aug
29:ciaa1198. PubMed: https://pubmed.gov/32860699. Full-text:
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Charre C, Icard V, Pradat P, et al. Coronavirus disease 2019 attack rate in HIV-infected pa-
tients and in preexposure prophylaxis users. AIDS. 2020 Oct 1;34(12):1765-1770. PubMed:
https://pubmed.gov/32889852. Full-text: https://doi.org/10.1097/QAD.0000000000002639
Dandachi D, Geiger G, Montgomery MW, et al. Characteristics, Comorbidities, and Outcomes in
a Multicenter Registry of Patients with HIV and Coronavirus Disease-19. Clin Inf Dis
2020 Sep 9. Full-text: https://doi.org/10.1093/cid/ciaa1339
Del Amo J, Polo R, Moreno S, et al. Incidence and Severity of COVID-19 in HIV-Positive Per-
sons Receiving Antiretroviral Therapy - A Cohort Study. Annals Int Med 2020, June 26.
Full-text: https://doi.org/10.7326/M20-3689
EACS & BHIVA. Statement on risk of COVID-19 for people living with HIV (PLWH).
https://www.eacsociety.org/home/covid-19-and-hiv.html
Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2
RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020 Mar
25;253:117592. PubMed: https://pubmed.gov/32222463. Full-text:
https://doi.org/10.1016/j.lfs.2020.117592
Gervasoni C, Meraviglia P, Riva A, et al. Clinical features and outcomes of HIV patients with
coronavirus disease 2019. Clin Infect Dis. 2020 May 14:ciaa579. PubMed:
https://pubmed.gov/32407467. Full-text: https://doi.org/10.1093/cid/ciaa579
Härter G, Spinner CD, Roider J, at al. COVID-19 in people living with human immunodeficiency
virus: a case series of 33 patients. Infection 2020, May 11.
https://doi.org/10.1007/s15010-020-01438-z. Full-text:
https://link.springer.com/article/10.1007/s15010-020-01438-z
Inciarte A, Gonzalez-Cordon A, Rojas J, et al. Clinical characteristics, risk factors, and inci-
dence of symptomatic COVID-19 in adults living with HIV: a single-center, prospec-
tive observational study. AIDS. 2020 Aug 7. PubMed: https://pubmed.gov/32773471. Full-
text: https://doi.org/10.1097/QAD.0000000000002643
Jewell B, Mudimu E, Stover J, et al. Potential effects of disruption to HIV programmes in sub-
Saharan Africa caused by COVID-19: results from multiple models. Pre-print,
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Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Ar-
ea. JAMA. 2020 Apr 22:e206775. PubMed: https://pubmed.gov/32320003. Full-text:
https://doi.org/10.1001/jama.2020.6775
Sanchez TH, Zlotorzynska M, Rai M, Baral SD. Characterizing the Impact of COVID-19 on Men
Who Have Sex with Men Across the United States in April, 2020. AIDS Behav. 2020 Apr
29:1-9. PubMed: https://pubmed.gov/32350773. Full-text: https://doi.org/10.1007/s10461-
020-02894-2
U.S. Department of Health and Human Services. Interim Guidance for COVID-19 and Persons
with HIV. https://aidsinfo.nih.gov/guidelines/html/8/covid-19-and-persons-with-hiv--
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Vizcarra P, Pérez-Elías MJ, Quereda C, et al. Description of COVID-19 in HIV-infected individu-
als: a single-centre, prospective cohort. Lancet HIV. 2020 May 28:S2352-3018(20)30164-8.
PubMed: https://pubmed.gov/32473657. Full-text: https://doi.org/10.1016/S2352-
3018(20)30164-8

Immunosuppression (other than HIV)

Immunosuppression may bear a higher risk for SARS-CoV-2 infection and
severe COVID-19. But the story is not that simple. Neither is it clear what im-
munosuppression actually means, nor are the available data sufficient to

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draw any conclusion. We just don’t know enough. Nevertheless, some authors
are trumpeting the news that there is an increased risk. A bad example? A
systematic review and meta-analysis on 8 studies and 4,007 patients came to
the conclusion that “immunosuppression and immunodeficiency were associ-
ated with increased risk of severe COVID-19 disease, although the statistical
differences were not significant” (Gao 2020). The authors also state that “in
response to the COVID-19 pandemic, special preventive and protective
measures should be provided.” There is null evidence for this impressive
statement. The total number of patients with immunosuppression in the
study was 39 (without HIV: 11!), with 6/8 studies describing less than 4 pa-
tients with different modalities of immunosuppression.
Despite the large absence of data, numerous viewpoints and guidelines have
been published on how to manage immunosuppressed patients that may be
more susceptible to acquire COVID-19 infection and develop severe courses.
There are recommendations for intranasal corticosteroids in allergic rhinitis
(Bousquet 2020), immunosuppressants for psoriasis and other cutaneous dis-
eases (Conforti 2020, Torres 2020), rheumatic diseases (Favalli 2020, Figueroa-
Parra 2020) or inflammatory bowel diseases (Kennedy 2020, Pasha 2020). The
bottom line of these heroic attempts to balance the risk of immune-modifying
drugs with the risk associated with active disease: what is generally needed,
has to be done (or to be continued). Exposure prophylaxis is important.
However, several studies have indeed found evidence for deleterious effects
of glucocorticoids, indicating that these drugs should be given with particular
caution these days.
• In 600 COVID-19 patients with rheumatic diseases from 40 countries, mul-
tivariate-adjusted models revealed a prednisone dose ≥ 10 mg/day to be
associated with higher odds of hospitalization. There was no risk with
conventional disease-modifying anti-rheumatic drugs (DMARD) alone or
in combination with biologics and Janus kinase (JAK) inhibitors
(https://doi.org/10.1136/annrheumdis-2020-217871).
• In 525 patients with inflammatory bowel disease (IBD) from 33 countries
(Brenner 2020), risk factors for severe COVID-19 included systemic corti-
costeroids (adjusted odds ratio 6.9, 95% CI 2.3-20.5), and sulfasalazine or
5-aminosalicylate use (aOR 3.1). TNF antagonist treatment was not asso-
ciated with severe COVID-19.
• In 86 patients with IBD and symptomatic COVID-19, among them 62 re-
ceiving biologics or JAK inhibitors, hospitalization rates were higher in
patients treated with oral glucocorticoids, hydroxychloroquine and
methotrexate but not with JAK inhibitors (Haberman 2020).

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References
Bousquet J, Akdis C, Jutel M, et al. Intranasal corticosteroids in allergic rhinitis in COVID-19
infected patients: An ARIA-EAACI statement. Allergy. 2020 Mar 31. PubMed:
https://pubmed.gov/32233040. Full-text: https://doi.org/10.1111/all.14302
Brenner Ej, Ungaro RC, Gearry RB, et al. Corticosteroids, but Not TNF Antagonists, Are Associ-
ated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseas-
es: Results From an International Registry. Gastroenterology 2020 May 18. Full-text:
https://doi.org/10.1053/j.gastro.2020.05.032
Conforti C, Giuffrida R, Dianzani C, Di Meo N, Zalaudek I. COVID-19 and psoriasis: Is it time to
limit treatment with immunosuppressants? A call for action. Dermatol Ther. 2020 Mar
11. Fulltext: https://doi.org/10.1111/dth.13298
Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and
rheumatoid arthritis: Faraway, so close! Autoimmun Rev. 2020 Mar 20:102523. PubMed:
https://pubmed.gov/32205186. Fulltext: https://doi.org/10.1016/j.autrev.2020.102523
Figueroa-Parra G, Aguirre-Garcia GM, Gamboa-Alonso CM, Camacho-Ortiz A, Galarza-Delgado DA.
Are my patients with rheumatic diseases at higher risk of COVID-19? Ann Rheum Dis.
2020 Mar 22. PubMed: https://pubmed.gov/32205336. Fulltext:
https://doi.org/10.1136/annrheumdis-2020-217322
Gao Y, Chen Y, Liu M, Shi S, Tian J. Impacts of immunosuppression and immunodeficiency on
COVID-19: a systematic review and meta-analysis. J Infect. 2020 May 14:S0163-
4453(20)30294-2. PubMed: https://pubmed.gov/32417309. Full-text:
https://doi.org/10.1016/j.jinf.2020.05.017
Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation
for COVID-19 in people with rheumatic disease: data from the COVID-19 Global
Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020 May 29. Pub-
Med: https://pubmed.gov/32471903. Full-text: https://doi.org/10.1136/annrheumdis-2020-
217871
Haberman R, Axelrad J, Chen A, et al. Covid-19 in Immune-Mediated Inflammatory Diseases -
Case Series from New York. N Engl J Med. 2020 Apr 29. PubMed:
https://pubmed.gov/32348641. Full-text: https://doi.org/10.1056/NEJMc2009567
Kennedy NA, Jones GR, Lamb CA, et al. British Society of Gastroenterology guidance for man-
agement of inflammatory bowel disease during the COVID-19 pandemic. Gut. 2020 Apr
17. PubMed: https://pubmed.gov/32303607. Full-text: https://doi.org/10.1136/gutjnl-2020-
321244
Pasha SB, Fatima H, Ghouri YA. Management of Inflammatory Bowel Diseases in the Wake of
COVID-19 Pandemic. J Gastroenterol Hepatol. 2020 Apr 4. PubMed:
https://pubmed.gov/32246874. Full-text: https://doi.org/10.1111/jgh.15056
Torres T, Puig L. Managing Cutaneous Immune-Mediated Diseases During the COVID-19
Pandemic. Am J Clin Dermatol. 2020 Apr 10. pii: 10.1007/s40257-020-00514-2. PubMed:
https://pubmed.gov/32277351. Full-text: https://doi.org/10.1007/s40257-020-00514-2.

Cancer
Providing continuous and safe care for cancer patients is challenging in this
pandemic. Oncologic patients may be vulnerable to infection because of their
underlying illness and often immunosuppressed status and may be at in-
creased risk of developing severe complications from the virus. On the other
hand, the COVID-19 triage and management may stretch an already fragile
system and potentially leave uncovered some vital activities, such as treat-

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ment administration or surgeries. It is well established that suboptimal tim-

ing and delayed oncologic treatment may lead to disease progression, leading
to worse survival outcomes. There are several recommendations to minimis-
ing exposure of oncology patients to COVID-19 without compromising onco-
logical outcome: Radiation for breast cancer (Coles 2020), hematopoietic cell
transplantion (Dholaria 2020) and leukemia treatment (Zeidan 2020).
What is known about risk factors, besides general risk factors such as age,
male gender and other comorbidities?
• Compared to 519 statistically matched patients without cancer, 232 pa-
tients from Wuhan were more likely to have severe COVID-19 (64% vs
32%). An advanced tumour stage was a risk factor (odds ratio 2.60, 95% CI
1.05–6.43) (Tian 2020).
• A systematic review of all studies until June 3 indicated that patients with
hematological malignancies, especially those diagnosed recently (and like-
ly those with myeloid malignancies), were at increased risk of death with
COVID‐19 compared to the general population. The evidence that this risk
is higher than for those with solid malignancies was conflicting (El-
Sharkawi 2020).
• Patients with Chronic Lymphatic Leukemia (CLL) seem to be at particular
high risk of death. Of 198 CLL patients diagnosed with symptomatic
COVID-19, 39% were treatment-naïve (“watch and wait”) while 61% re-
ceived at least one CLL therapy. At 16 days, the overall CFR was 33%, while
another 25% were still in hospital (Mato 2020).
• In a retrospective study from Italy, including 536 patients with a diagnosis
of a hematological malignancy, 198 (37%) had died. Progressive disease
status, diagnosis of acute myeloid leukemia, indolent or aggressive NHL
were associated with worse overall survival (Passamonti 2020).
• In a large cohort study of 928 cancer patients with COVID-19 from the
USA, Canada, and Spain, most prevalent malignancies were breast (21%)
and prostate (16%). In total 121 (13%) patients had died. Independent risk
factors were an ECOG status of 2 or higher and “active” cancer (Kuderer
2020).
• SARS-CoV-2 viral load in nasopharyngeal swab specimens of 100 patients
with cancer who were admitted to three New York City hospitals predict-
ed outcome. The authors also found that patients with hematologic malig-
nancies had higher median viral loads than patients without cancer
(Westblade 2020).
Does anti‐neoplastic treatment lead to increased risk of complications?

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• Among a total of 309 patients, cytotoxic chemotherapy administered with-

in 35 days of a COVID-19 diagnosis was not significantly associated with a
severe or critical COVID-19 event. However, patients with active hemato-
logic or lung malignancies, lymphopenia, or baseline neutropenia had
worse COVID-19 outcomes.
• Among 423 cases of symptomatic COVID-19 patients, 40% were hospital-
ized and 12% died within 30 days. Age older than 65 years and treatment
with immune checkpoint inhibitors were predictors for hospitalization
and severe disease, whereas receipt of chemotherapy and major surgery
were not (Robilotti 2020).
All these studies are not controlled. A myriad of potential factors may lead to
a difference in COVID-19 outcomes and risk for patients with malignancies,
compared to the rest of the population (nice review: El-Sharkawi 2020). These
include patient behaviour (exposure to the virus?), healthcare professional
behaviour (i.e., testing patients with a history of cancer for COVID‐19 more
frequently?), biological differences but also several confounders (more co-
morbidities, older age in cancer patients). Continued analysis of the data is
required to attain further understanding of the risk factors for cancer pa-
tients in this pandemic.
Finally, it’s not only treatment, it’s also diagnosis. Diagnostic delays may lead
to an increase in the numbers of avoidable cancers (Maringe 2020). During
the pandemic, a large cross-sectional study in the US has observed significant
declines in several cancer types, ranging from 24.7% for pancreatic cancer to
51.8% for breast cancer, indicating that a delay in diagnosis will likely lead to
presentation at more advanced stages and poorer clinical outcomes (Kaufman
2020).

References
Coles CE, Aristei C, Bliss J, et al. International Guidelines on Radiation Therapy for Breast
Cancer During the COVID-19 Pandemic. Clin Oncol (R Coll Radiol). 2020 May;32(5):279-
281. PubMed: https://pubmed.gov/32241520. Full-text:
https://doi.org/10.1016/j.clon.2020.03.006
Dholaria B, Savani BN. How do we plan hematopoietic cell transplant and cellular therapy
with the looming COVID-19 threat? Br J Haematol. 2020 Mar 16. Fulltext:
https://doi.org/10.1111/bjh.16597
El-Sharkawi D, Iyengar S. Haematological Cancers and the risk of severe COVID-19: Explora-
tion and critical evaluation of the evidence to date. Br J Haematol. 2020 Jun 19. PubMed:
https://pubmed.gov/32559308. Full-text: https://doi.org/10.1111/bjh.16956.
Kaufman HW, Chen Z, Niles J, Fesko Y. Changes in the Number of US Patients with Newly
Identified Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pan-
demic. JAMA Netw Open 2020;3(8):e2017267. Full-text:
https://doi.org/10.1001/jamanetworkopen.2020.17267.

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Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer
(CCC19): a cohort study. Lancet. 2020 May 28:S0140-6736(20)31187-9. PubMed:
https://pubmed.gov/32473681. Full-text: https://doi.org/10.1016/S0140-6736(20)31187-9
Lee J, Foote MB, Lumish M, et al. Chemotherapy and COVID-19 Outcomes in Patients With
Cancer. J Clin Oncol 2020, August 14, 2020. Full-text:
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Maringe C, Spicer J, Morris M, et al. The impact of the COVID-19 pandemic on cancer deaths
due to delays in diagnosis in England, UK: a national, population-based, modelling
study. Lancet Oncology, published: July 20, 2020. Full-text: https://doi.org/10.1016/S1470-
2045(20)30388-0.
Mato AR, Roeker LE, Lamanna N, et al. Outcomes of COVID-19 in Patients with CLL: A Multi-
center, International Experience. Blood. 2020 Jul 20:blood.2020006965. PubMed:
https://pubmed.gov/32688395. Full-text: https://doi.org/10.1182/blood.2020006965.
Passamonti F, Cattaneo C, Arcaini L, et al. Clinical characteristics and risk factors associated
with COVID-19 severity in patients with haematological malignancies in Italy: a ret-
rospective, multicentre, cohort study. Lancet Haematol 2020, published 13 August. Full-
text: https://doi.org/10.1016/S2352-3026(20)30251-9
Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in pa-
tients with cancer. Nat Med June 24, 2020. Full-text: https://doi.org/10.1038/s41591-020-
0979-0
Tian J, Yuan X, Xiao J, et al. Clinical characteristics and risk factors associated with COVID-19
disease severity in patients with cancer in Wuhan, China: a multicentre, retrospec-
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Westblade LF, Brar G, Pinheiro LC, et al. SARS-CoV-2. Viral Load Predicts Mortality in Patients
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Zeidan AM, Poddu P, Patniak MM, et al. Special considerations in the management of adult
patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recom-
mendations from a panel of international experts. Lancet Hematology 2020, June 18.
Full-text: https://doi.org/10.1016/S2352-3026(20)30205-2

Transplantation
During a health crisis such as the COVID pandemic, it is crucial to carefully
balance cost and benefits in performing organ transplantation (Andrea 2020).
There is no doubt that the current situation has deeply affected organ dona-
tion and that this represents an important collateral damage of the pandemic.
All Eurotransplant countries have implemented preventive screenings poli-
cies for potential organ donors. For detailed information on the national poli-
cy, please visit https://www.eurotransplant.org/2020/04/07/covid-19-and-
organ-donation/. Preliminary data indicate a significant reduction in trans-
plantation rates even in regions where COVID-19 cases are low, suggesting a
global and nationwide effect beyond the local COVID-19 infection prevalence
(Loupy 2020). During March and April, the overall reduction in deceased do-
nor transplantations since the COVID-19 outbreak was 91% in France and 51%
in the USA, respectively. In both France and the USA, this reduction was
mostly driven by kidney transplantation, but a substantial effect was also

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seen for heart, lung, and liver transplants, all of which provide meaningful
improvement in survival probability. Solid organ transplant recipients are
generally at higher risk for complications of respiratory viral infections (in
particular influenza), due to their chronic immunosuppressive regimen, and
this may hold particularly true for SARS-CoV-2 infection. The first cohort of
COVID-19 in transplant recipients from the US indeed indicated that trans-
plant recipients appear to have more severe outcomes (Pereira 2020). Some
key studies:
Liver: In the largest cohort, 16/100 patients died from COVID-19. Of note,
mortality was observed only in patients aged 60 years or older (16/73) and
was more common in males than in females (Belli 2020). Although not statis-
tically significant, more patients who were transplanted at least 2 years earli-
er died than did those who received their transplant within the past 2 years
(18% vs 5%). A systematic search on June 15 revealed 223 liver transplant re-
cipients with COVID-19 in 15 studies (Fraser 2020). The case fatality rate was
19.3%. Dyspnea on presentation, diabetes mellitus, and age 60 years or older
were significantly associated with increased mortality (p=0.01) with a trend to
a higher mortality rate observed in those with hypertension and those receiv-
ing corticosteroids at the time of COVID-19 diagnosis. However, in a multicen-
ter cohort study, comparing 151 adult liver transplant recipients from 18
countries with 627 patients who had not undergone liver transplantation,
liver transplantation did not significantly increase the risk of death in pa-
tients with SARS-CoV-2 infection (Webb 2020).
Kidney: In a single center with 36 kidney transplant recipients, 10/36 died
(Akalin 2020). Patients appear to have less fever as an initial symptom, lower
CD4 and CD8 T cell counts and more rapid clinical progression.
Heart: In a case series of 28 patients who had received a heart transplant in a
large academic center in New York, 22 patients (79%) were hospitalized. At
the end of the follow-up, 4 remained hospitalized and 7 (25%) had died (Latif
2020). In Germany, mortality was also high, and 7/21 patients died (Rivinius
2020).

References
Akalin E, Azzi Y, Bartash B. Covid-19 and Kidney Transplantation. N Engl J Med. 2020 Apr 24.
PubMed: https://pubmed.gov/32329975. Full-text: https://doi.org/10.1056/NEJMc2011117
Andrea G, Daniele D, Barbara A, et al. Coronavirus Disease 2019 and Transplantation: a view
from the inside. Am J Transplant. 2020 Mar 17. PubMed: https://pubmed.gov/32181969.
Fulltext: https://doi.org/10.1111/ajt.15853
Belli LC, Duvoux C, Karam V, et al. COVID-19 in liver transplant recipients: preliminary data
from the ELITA/ELTR registry. Lancet Gastroenterology & Hepatology, June 4, 2020. Full-
text: https://doi.org/10.1016/S2468-1253(20)30183-7

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Fraser J, Mousley J, Testro A, Smibert OC, Koshy AN. Clinical Presentation, Treatment, and
Mortality Rate in Liver Transplant Recipients With Coronavirus Disease 2019: A Sys-
tematic Review and Quantitative Analysis. Transplant Proc. 2020 Jul 30:S0041-
1345(20)32634-8. PubMed: https://pubmed.gov/32891405. Full-text:
https://doi.org/10.1016/j.transproceed.2020.07.012
Latif F, Farr MA, Clerkin KJ, et al. Characteristics and Outcomes of Recipients of Heart Trans-
plant With Coronavirus Disease 2019. JAMA Cardiol. Published online May 13, 2020. Full-
text: https://doi.org/10.1001/jamacardio.2020.2159
Loupy A, Aubert O, Reese PP, et al. Organ procurement and transplantation during the
COVID-19 pandemic. Lancet May 11, 2020. Full-text:
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Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in Solid Organ Transplant Recipients: Initial
Report from the US Epicenter. Am J Transplant. 2020 Apr 24. PubMed:
https://pubmed.gov/32330343. Full-text: https://doi.org/10.1111/ajt.15941
Rivinius R, Kaya Z, Schramm R, et al. COVID-19 among heart transplant recipients in Germa-
ny: a multicenter survey. Clin Res Cardiol. 2020 Aug 11. PubMed:
https://pubmed.gov/32783099. Full-text: https://doi.org/10.1007/s00392-020-01722-w
Webb GJ, Marjot T, Cook JA, et al. Outcomes following SARS-CoV-2 infection in liver trans-
plant recipients: an international registry study. Lancet Gastroenterol Hepatol 2020,
published 28 August. Full-text: https://doi.org/10.1016/S2468-1253(20)30271-5

Other comorbidities
Ultimately, the current situation might lead to substantial changes in how
research and medicine are practiced in the future. The SARS-CoV-2 pandemic
has created major dilemmas in almost all areas of health care. Scheduled op-
erations, numerous types of treatment and appointments have been cancelled
world-wide or postponed to priorities hospital beds and care for those who
are seriously ill with COVID-19. Throughout the world, health systems had to
consider rapidly changing responses while relying on inadequate infor-
mation. In some settings such as HIV or TB infection, oncology or solid organ
transplantation, these collateral damages may have been even greater than
the damage caused by COVID-19 itself. Treatment interruptions, disrupted
drug supply chains and consequent shortages will likely exacerbate this issue.
During the next months, we will learn more and provide more information on
the consequences of this crisis on various diseases.

Dialysis
Basile C, Combe C, Pizzarelli F, et al. Recommendations for the prevention, mitigation and
containment of the emerging SARS-CoV-2 (COVID-19) pandemic in haemodialysis cen-
tres. Nephrol Dial Transplant. 2020 Mar 20. pii: 5810637. PubMed:
https://pubmed.gov/32196116. Fulltext: https://doi.org/10.1093/ndt/gfaa069
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11. Pediatrics
Tim Niehues
Jennifer Neubert

Acknowledgements: Without the skillful help of Andrea Groth (Helios Klin-

ikum Krefeld), the preparation of this manuscript would not have been pos-
sible. We thank cand. med. Lars Dinkelbach (Heinrich Heine Universität
Düsseldorf) for critically reading the manuscript.

SARS-CoV-2 infection in children

Children are less susceptible to SARS-COV-2 infection, have a lower seroprev-
alence and a less severe COVID-19 disease course than adults (Castagnoli 2020,
Viner 2020, Merckx 2020, Zimmermann 2020, Parri 2020, Ludvigsson 2020). In
this regard, COVID is strikingly different from other virus-induced respirato-
ry diseases, which can be fatal in children (e.g. RSV in infants). The CoV-2
pandemic causes a large collateral damage to children because they are taken
out of their normal social environment (kindergartens, schools etc.), and be-
cause of parents’ resistance to seek medical care despite need e.g. for vaccina-
tion (Bramer 2020) or even if their children are having an emergency
(Lazzerini 2020).

Common coronaviruses in children: tropism, incubation period

and spreading
The first International Corona Virus Conference was organized by Volker
Termeulen in Würzburg/Germany in 1980. At the time only one human coro-
navirus, HCoV2229E, was known to be associated with the common cold
(Weiss 2020). Commonly circulating human coronaviruses (COV) can be iso-
lated from 4-8% of all children with acute respiratory tract infections, which
tend to be mild, unless the child is immunocompromised (Ogimi 2019). Seven
coronaviruses circulate among humans (Hufert 2020): α-Coronaviruses HCoV-
229e (discovered in 1966), HCoV-NL63 (in 2004); β-Coronaviruses HCoV-OC43
(in 1967)-HKU1 (in 2005), -OC43; MERS-CoV (in 2012), SARS-CoV (in 2003) and
SARS-CoV-2 that originally derive from bats (NL63, 229e, SARS-CoV), drome-
dary camels (229e, MERS-CoV), cattle (OC43) and pangolins (SARS-CoV-2)
(Zimmermann 2020). There appear to be re-infections with the earlier de-
scribed common COV despite the fact that most individuals seroconvert to
human coronaviruses. In many children there are co-infections with other
viruses such as Adeno-, Boca-, Rhino-, RSV-, Influenza- or Parainfluenza vi-

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rus. There seems to be a cyclical pattern with seasonal outbreaks between

December and May or March to November in the southern hemisphere.
Single-strand RNA coronaviruses are capable of mutation and recombination
leading to novel coronaviruses that can spread from animals to humans. They
have caused epidemics leading to significant case fatality rates (10% in SARS-
CoV, Hong Kong 2002; more than 30% in MERS-CoV, Saudi Arabia 2012). Be-
cause of the high case fatality rate, both SARS-COV and MERS-COV have a low
potential for long-term sustained community transmission. Accordingly, no
human SARS-CoV infections have been reported since July 2003.
It is estimated that in SARS-CoV-2, one person infects 2-3 other persons. In
clusters (e.g. nosocomial outbreaks) this number might be much higher. In
both SARS-CoV and MERS-CoV, super-spreading events with one individual
infecting up to 22 (SARS) or even 30 individuals (MERS) have been reported,
especially in nosocomial outbreaks. In SARS-CoV a total of 41 children were
reported with no deaths. Similarly, in MERS-CoV only 38 children were re-
ported in two studies, with two deaths (Zimmermann 2020).

Epidemiology of COVID-19 in children

On April 6 the US CDC reported 2572 (1.7%) children under 18 years among
149,082 reported cases from 12 February to 2 April 2020. The availability of
data was extremely limited (less than 10% available on symptoms, 13% on
underlying conditions, 33% on whether children were hospitalized or not).
Three deaths were reported to the CDC but no details were given. The median
age was 11 and they were 57% males. 15 children were admitted to an ICU (≤
2%). Children < 1 year accounted for the highest percentage (15-62%) of hos-
pitalization (CDC 2020). The Chinese CDC report (Dong 2020) comprises 2143
pediatric patients from January 16 to February 8 2020. Only 731 children
(34,1%) were laboratory confirmed cases. The median age was 7 years with
56,6% boys, less than 5% were classified as severe and less than 1% as critical..
The Korean Center for Disease Control and Prevention reported on 20 March
that 6.3% of all COVID-19 cases were children under 19 years of age; again, the
children had a mild form of the disease (Korean Center for Disease Control
and Prevention. Press releases, https://www.cdc.go.kr). Italian data published
on 18 March showed that only 1,2% of the 22,512 Italian cases with COVID-19
were children; no deaths were reported in this and in the Spanish cohort
from Madrid (2 March to 16 March) (Livingstone 2020, Tagarro 2020). In Ger-
many, 9657 children and adolescents with COVID-19 were reported up to May
4th, 2020; only 128 were admitted to 66 hospitals, only one child died
(Armann 2020).

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 Pediatrics | 403

The European Surveillance System (TESSy) collects data from EU/EEA coun-
tries and the UK on laboratory-confirmed cases of COVID-19. Out of 576,024
laboratory confirmed COVID-19 cases 0,7% were 0-4 years, 0,6% 5-9 years,
0,9% 10-14 years (https://covid19-surveillance-report.ecdc.europa.eu). The
multicentre cohort study (82 participating health-care institutions across 25
European countries), Paediatric Tuberculosis research Network (ptbnet) con-
firmed that COVID-19 is generally a mild disease in children. Of 582 children
and adolescents (median age 5.0 years, 25% with pre-existing conditions) with
PCR-confirmed SARS-CoV-2 infection, 363 (62%) were admitted to hospital
and 48 (8%) required ICU admission. Significant risk factors for requiring ICU
admission in multivariate analyses were being younger than 1 month (odds
ratio 5.1), male sex (2.1) and pre-existing medical conditions (3.3). Four chil-
dren died (Götzinger 2020).

Natural course and risk factors for complications

The incubation period is believed to be 3-7 days (range 1-14 days) (She 2020),
the clinical onset 5-8 days after infection with the virus. Children often have
an asymptomatic or less severe COVID-19 disease course than adults
(Zimmermann 2020, Parri 2020). Among a total of 100 children with SARS-
CoV-2 from Italy, 21% were asymptomatic, 58% had mild disease, 19% had
moderate disease, 1% had severe disease, and 1% were in critical condition
(Parri 2020).
Due to the paucity of data it is as yet unclear which group of children may be
at a higher risk for development of complications, e.g. children with underly-
ing chronic pulmonary or cardiac disease, severe neurologic deficits, immu-
nosuppressed or critically ill children, etc. Analogous to influenza there
might be genetic susceptibility in some children (see below, pathophysiology,
Clohisey 2019). Interestingly, in a flash survey from 25 countries with 10,000
children with cancer at risk and 200 tested, only 9 were found to be CoV-2
positive. They were asymptomatic or had mild disease (Hrusak 2020). Even in
the severely immunosuppressed and in children with significant cardiac and
pulmonary comorbidities COVID-19 can be overcome (Dinkelbach 2020).
In The European Surveillance System (TESSy) deaths among children aged
below 15 years are rare, 4 out of 44,695 (0.009%) were reported. The rate of
hospitalization was higher in children under the age of five especially in in-
fants compared to persons aged 5-29. However, it is believed that the thresh-
old for admission is lower in young children. A severe course requiring ad-
mission to ICU seems not to be more likely in younger children. The likeli-
hood of being hospitalised was higher when children had an underlying con-

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dition, and a severe course was rare (https://covid19-surveillance-

report.ecdc.europa.eu).
In a cross-sectional study including 48 children with COVID-19 (median age 13
years; admitted to 46 North American pediatric ICUs between March 14 and
April 3, 2020), forty patients (83%) had significant pre-existing co-morbidities
and 18 (38%) required invasive ventilation. Targeted therapies were used in
28 patients (61%, mainly HCQ). Two patients (4%) died and 15 (31%) were still
hospitalized, with 3 still requiring ventilatory support and 1 receiving ECMO
(Shekerdemian 2020). In an observational retrospective cohort study that
included 177 children and young adults with clinical symptoms and laborato-
ry confirmed SARS-CoV-2 infection treated between March 15 and April 30,
2020 at the Children’s National Hospital in Washington, 44 were hospitalized
and 9 were critically ill. Of these, 6/9 were adolescents and young adults > 15
years of age. Although asthma was the most prevalent underlying condition
overall, it was not more common among patients with severe disease (DeBiasi
2020).
Although the natural course of COVID-19 is uneventful in most pediatric pa-
tients, a very small percentage can develop a potentially fatal severe hyperin-
flammatory state 2-4 weeks after acute infection with SARS-CoV-2 (Riphagen
2020). This hyperinflammatory state is termed as pediatric inflammatory
multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-TS) (or
synonym Multisystem Inflammatory Syndrome in Children (MIS-C). Of the
570 MIS-C cases reported to the CDC by July 2020, 10 patients had died (1.8% )
and 364 (63.9%) patients required treatment in an intensive care unit. Obesity
was the most commonly reported underlying medical condition (Godfred-
Cato 2020).

Pathophysiology and immunopathology

It is unclear why COVID-19 in children is associated with a less severe disease
course.
The tissue expression pattern of the receptor for CoV-2 angiotensin convert-
ing enzyme (ACE2) and the transmembrane serine protease TMPRSS2 (essen-
tial for CoV-2 cell entry) as well as the tissue tropism of CoV-2 in childhood
are unknown but age-dependent differences in ACE2 receptor expression may
explain why outcomes differ in children versus adults (Bunyavanich 2020).
ACE2 is expressed on cells of the airways, the lungs, mucosal cells (lids, eye-
lids, nasal cavities), intestines and on immune cells (monocytes, lymphocytes,
neutrophils) (Molloy 2020, reviewed in Brodin 2020). It needs to be clarified

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 Pediatrics | 405

whether there is neurotropism (e.g. affecting the developing brain of new-

borns).
The main target of CoV-2 is the respiratory tract. As respiratory infections
are extremely common in children it is to be expected that there are other
viruses present in the respiratory tract of young children concomitantly with
the coronavirus, which may limit its growth and the number of CoV-2 copies
in the respiratory tract of children. Systematic viral load measurements in
the respiratory tract of different viruses in children are underway. Key to the
later immunopathologic stages of COVID-19 pneumonia is the macrophage
activation syndrome (MAS)-like hyperinflammatory phase with a cytokine
storm and acute respiratory distress syndrome (ARDS), usually within 10-12
days after symptom onset. In general, children are not less prone to develop
ARDS during respiratory tract infections than adults. In the H1N1 flu pan-
demic in 2009, being under the age of 1 year was a significant risk factor for
developing a severe form of the infection and ARDS (Bautista 2010). Why
ARDS is less common in children compared to adults with COVID-19 is un-
clear. SARS-CoV-2 infection of cardiac tissue can be a major contributor to
fatal myocarditis (Dolhnikoff 2020, Prieto 2020).
An explanation for the milder disease course in children could be age-related
differences in innate or adaptive immune responses to CoV-2 between adults
and children. In the innate immune response to any virus, Type I (IFN α, IFN
β) and type III (IFN Ω) interferons are the most important cytokines. In 659
patients (1 month to 99 years old) with life-threatening COVID-19 pneumonia,
inborn defects in the type 1 IFN signaling were found in 23 unrelated patients
(Zhang 2020). Moreover, neutralizing auto-antibodies to type I/III IFN were
found in 101/987 patients with life-threatening COVID-10 pneumonia
(Bastard 2020). These findings show that inborn defects in the IFN I/II path-
way or auto-antibodies to IFN I/III may predispose to life-threatening COVID-
19. Based on influenza animal models it has been proposed that BCG vaccina-
tion (for tuberculosis prevention, done in the first week of life in some coun-
tries) may enhance non-specific innate immunity in children to infections
like COVID-19 (so-called trained immunity) (Moorlag 2019). A search of the
BCG World Atlas and correlation with data of COVID-19 cases and death per
country found that countries without universal policies of BCG vaccination
(Italy, the Netherlands, USA) have been more severely affected compared to
countries with universal and long-standing BCG policies and that BCG vac-
cination also reduced the number of reported COVID-19 cases in a country
(Miyasaka 2020, Hauer 2020). Recent data from a large population-based
study did not show decreased infection rates in Israeli adults aged 35 to 41
years who were BCG-vaccinated in childhood as compared to non-BCG-

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vaccinated. Data on the effect of BCG vaccination on COVID-19 disease severi-

ty are unavailable (Hamiel 2020).
In the adaptive response to any virus, cytotoxic T cells play an important role
in regulating responses to viral infections and control of viral replication.
Children could benefit from the fact that the cytotoxic effector function of
CD8 T cells in viral infection in children may be less detrimental compared to
adults. Immune dysregulation with exhaustion of T cells has been reported in
adults with COVID-19 infection. Regarding humoral immunity, IgG maternal
antibodies are actively transferred to the child via placenta and/or IgA via
breast milk. They may not include anti CoV-2 antibodies, if the mother is na-
ïve to CoV-2 or infected late in pregnancy. In mothers with COVID-19 pneu-
monia serum and throat swabs of their newborns were negative for CoV-2 but
virus-specific IgG antibodies were detected (Zeng H 2020). Thus, neonates
may benefit from placental transmission of virus-specific antibodies from
pre-exposed mothers. As shown in SARS CoV-1 it is likely that in SARS-CoV-2
a newly infected child will mount a significant humoral response with neu-
tralizing IgM (within days) and IgG antibodies (within 1-3 weeks) to one of the
immunodominant epitopes, e.g. the crown-like spike proteins giving the
coronaviruses their name. Infections with non-SARS COV are very common in
children (see above); however, to what extent previous infections with non-
SARS coronaviruses may have led to protective cross-reactive antibodies is
unclear.
Data regarding IgG and IgM seroprevalence and quality of the immune re-
sponse in children are lacking. No human re-infections with CoV-2 have been
demonstrated yet but overall it is not clear whether children mount a durable
memory immune response to CoV-2. In summary, differences in the immune
system such as more efficient innate and adaptive immunity to COV-2 (asso-
ciated with better thymic function), cross-reactive immunity to common cold
coronaviruses and differences in the ACE2 receptor expression as well as bet-
ter overall health may be factors leading to a better COVID-19 outcome in
children (Consiglio 2020).

Transmission
Studies on the risk of acquiring SARS-CoV-2 infection in children in compari-
son to adults have shown contradicting results (Mehta 2020, Gudbjartsson
2020, Bi 2020). The exact role that children play in the transmission of SARS-
CoV-2 is not yet fully understood. Population based studies performed so far
indicate that children might not play a major factor in the spreading of
COVID-19 (Gudbjartsson 2020).

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 Pediatrics | 407

Vertical transmission
Contraction of COVID-19 in a pregnant woman may have an impact on fetal
outcome, namely fetal distress, potential preterm birth or respiratory dis-
tress if the mother gets very sick. Schwartz reviewed 5 publications from
China and was able to identify 38 pregnant women with 39 offspring among
whom 30 were tested for COVID-19 and all of them were negative (Schwartz
2020, Chen 2020). Among the 24 infants born to women with COVID-19, 15
(62.5%) had detectable IgG and 6 (25.0%) had detectable IgM; nucleic acid test
results were all negative. Among 11 infants tested at birth, all had detectable
IgG and 5 had detectable IgM. IgG titers with positive IgM declined more
slowly than those without (Gao 2020). In the PRIORITY study (n = 263), ad-
verse outcomes, including preterm birth, NICU admission, and respiratory
disease, did not differ between infants born to mothers testing positive for
SARS-CoV-2 (n = 184) and those born to mothers testing negative (n = 79),
suggesting that infants born to mothers infected with SARS-CoV-2 generally
do well in the first 6-8 weeks after birth (Flaherman 2020).
Transmission of COVID-19 appears unlikely to occur if correct hygiene pre-
cautions are undertaken. In 1481 deliveries at three hospitals in New York
City, 116 (8%) mothers tested positive for SARS-CoV-2; 120 neonates were
identified and none were positive for SARS-CoV-2 (Salvatore 2020).
In another study from New York, 101 newborns of SARS-CoV-2 infected
mothers no transmission was observed despite sleeping in the same room and
breastfeeding (Dumitriu 2020). Initially it was thought that CoV-2 is not verti-
cally transmitted, but in a more recent analysis of 31 mothers with SARS-CoV-
2, SARS-CoV-2 genome was detected in one umbilical cord blood, two at-term
placentas, one vaginal mucosa and one breast-milk specimen. Three cases of
vertical transmission of SARS-CoV-2 have been documented (Fenizia 2020).
In a UK national population-based cohort study on SARS-CoV-2 infected
pregnant women, twelve (5%) of 265 infants subsequently tested positive for
SARS-CoV-2 RNA, six of them within the first 12 hours after birth (Knight
2020). Postpartum acquisition appears to be the most common mode of infec-
tion; in a recent review only 4/1141 neonates born to SARS-CoV-2 infected
mothers were thought to have a congenital infection (Dhir 2020).

Horizontal transmission
Culture-competent SARS-CoV-2 has been grown from the nasopharynx of
symptomatic neonates, children, and adolescents: 12 (52%) of 23 symptomatic
SARS-CoV-2–infected children, the youngest being 7 days old. SARS-CoV-2
viral load and shedding patterns of culture-competent virus in the 12 symp-

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tomatic children resembled those in adults. Systematic measurements of

SARS-CoV-2 viral load measurements in children are lacking. Therefore,
transmission of SARS-CoV-2 from children is plausible (L’Huillier 2020). SARS-
CoV-2 in children is transmitted through family contacts and mainly through
respiratory droplets (Garazzino 2020). In a study from France, child-to-child
and child-to-adult transmission seems to be uncommon (Danis 2019). Pro-
longed exposure to high concentrations of aerosols may facilitate transmis-
sion (She 2020).
SARS-CoV-2 may theoretically also be transmitted through the digestive
tract. ACE2 is also found in upper esophageal and epithelial cells as well as
intestinal epithelial cells in the ileum and colon (She 2020). SARS-CoV-2 RNA
can be detected in the feces of patients (Holshue 2020). Cai revealed that viral
RNA is detected from feces of children at a high rate (and can be excreted for
as long as 2-4 weeks) (Cai 2020). However, direct evidence of a fecal-to-oral
transmission has not yet been documented.
Onward transmission from children to others is low (Viner 2020, Merckx
2020). In a study from Milan, Itlay, in 83 children and 131 adults hospitalized
and symptomatic in regard to COVID-19, adults were retrospectively more
likely to be CoV-2 positive, asymptomatic carriers as compared to children
(9% vs 1%) (Milani 2020).

Diagnosis and classification

Testing for the virus is only necessary in clinically suspect children. If the
result is initially negative, repeat nasopharyngeal or throat swab testing of
upper respiratory tract samples or testing of lower respiratory tract samples
should be done. Sampling of the lower respiratory tract (induced sputum or
bronchoalveolar lavage) is more sensitive (Han 2020). This is not always pos-
sible in critically ill patients and in young children.
Diagnosis is usually made by real-time polymerase chain reaction RT-PCR on
respiratory secretions. For SARS-CoV, MERS-CoV and SARS-CoV-2, higher
viral loads have been detected in samples from lower respiratory tract com-
pared with upper respiratory tract.
In some patients, SARS-CoV-2 RNA is negative in respiratory samples while
stool samples are still positive indicating that a viral gastrointestinal infec-
tion can last even after viral clearance in the respiratory tract. (Xiao 2020).
Fecal testing may thus be of value in diagnosing COVID-19 in these patients.
As in other viral infections, a CoV-2 IgM and IgG seroconversion will appear
in days (IgM) to 1-3 weeks (IgG) after infection and may or may not indicate
protective immunity (still to be determined). Interestingly, asymptomatic

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 Pediatrics | 409

seroconversion has been hypothesized in a very small series of health work-

ers (mean age 40 years) exposed to a child with COVID-19 in a pediatric dialy-
sis unit (Hains 2020).
Serology may be useful in patients with clinical symptoms highly suggestive
of SARS-CoV-2 who are RNA negative, i.e in children with pediatric inflamma-
tory multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-
TS). If serology indicates protective immunity, this will be extremely im-
portant from a public health perspective, e.g. it will allow for strategic staff-
ing in medical care and for the assessment of CoV-2 epidemiology (herd im-
munity).

Table 1. COVID classification in children (Shen 2020)

1 Asymptomatic without any clinical symptoms
2 Mild fever, fatigue, myalgia and symptoms of acute respiratory tract
infections
3 Moderate pneumonia, fever and cough, productive cough, wheezing
but no hypoxemia
4 Severe fever, cough, tachypnea, oxygen saturation less than 92%,
somnolence
5 Critical quick progress to acute respiratory distress syndrome (ARDS)
or respiratory failure

Laboratory and radiology findings

Laboratory and/or radiology studies in outpatient children who have mild
disease are not indicated. Upon admission to the hospital the white blood cell
count is usually normal. In a minority of children decreased lymphocyte
counts have been documented. In contrast, adults (with hyperinflammation
and cytokine release syndrome) often have an increase in neutrophils and
lymphopenia. The inflammation parameters C reactive protein and procalci-
tonin can be slightly elevated or normal while there are elevated liver en-
zymes, creatine kinase CK-MB and D dimers in some patients. LDH appears to
be elevated in severe cases and can be used to monitor severe disease.
A chest X-ray should only be done in children with moderate or more severe
disease as CT scans mean a very high radiation exposure for the child and
should only be done in complicated or high-risk cases. In the beginning of the
pandemic in China, children all received CT scans even when they were
asymptomatic and oligosymptomatic; surprisingly, they displayed very severe
changes. On chest radiography there are bilateral patchy airspace consolida-
tions and so-called ground-glass opacities. CT scans were more impressive

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than chest x-ray examinations. In 20 children with CT, 16 (80%) had some
abnormalities (Xia 2020).

Symptoms and signs: Acute infection

Children and adolescents
In a clinical trial of 171 children from Wuhan, fever was reported in 41% (71
of 171), cough in over 50% (83 of 171), tachypnea in 28% (49 of 171). In 27 of
the patients there were no symptoms at all (15,8%). At initial presentation
very few children required oxygen supplementation (4 of 171, 2,3%). Other
symptoms like diarrhea, fatigue, runny nose and vomiting were observed in
less than 10% of the children (Lu 2020). In the cohort from Zhejiang as many
as 10 out of 36 patients (28%) had no symptoms at all. None of the children
had an oxygen saturation below 92% (Qiu 2020). In a Korean case series of
children with COVID-19, 20 children (22%) were asymptomatic during the
entire observation period. Among 71 symptomatic cases, only 6 (9%) were
diagnosed at the time of symptom onset while 47 children (66%) had unrec-
ognized symptoms before diagnosis and 18 (25%) developed symptoms after
diagnosis. Fifty-one percent had “mild” disease, 22% “moderate” disease and
2% “severe” disease. No patient required intensive care (Han 2020). A larger
UK series reports on 651 children and young people aged less than 19 years.
Median age was 4.6 years, 35% (225/651) were under 12 months old. 18%
(116/632) of children were admitted to critical care. Six patients died in hos-
pital, all of whom had profound comorbidity (Swann 2020).
A recent comprehensive systematic review analysed 131 studies in 7780 pedi-
atric COVID-19 patients across 26 different countries (Hoang 2020). In this
review 19,3% of the patients were asymptomatic, the most common symp-
toms were fever (59%), cough (55,9%), rhinorrhea (20%) and myalgia/fatigue
(18,7%). The need for intensive care treatment was low (3,3%).
In 52 hospitalized children from London, UK, renal dysfunction was frequent
especially in those with pediatric inflammatory multisystem syndrome tem-
porarily associated with SARS-CoV-2. 24 (46%) had elevated serum creatinine,
and 15 (29%) met the diagnostic criteria for acute kidney injury (Stewart
2020).
In a case series of 4 children with PIMS-TS (see below) from London, UK, neu-
rological symptoms were described (encephalopathy, headaches, brainstem
and cerebellar signs, muscle weakness, reduced reflexes) with signal changes
in the splenium of the corpus callosum on neuroimaging and required inten-
sive care admission for the treatment of COVID-19 pediatric multisystem in-
flammatory syndrome (Abdel-Mannan 2020).

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 Pediatrics | 411

Neonates and infants

Zeng reports 33 newborns born to mothers with COVID-19 in Wuhan. Three of
the 33 infants (9%) presented with early-onset SARS-CoV-2 infection. In 2 of
the 3 neonates there were radiological signs of pneumonia. In one child dis-
seminated intravascular coagulation was described but eventually all children
had stable vital signs three weeks after the infection (Zeng L 2020). In a sec-
ond cohort, 9 infants aged 1 month to 9 months were described without any
severe complications (Wei 2020). Whether there are long-term complications
of COVID-19 in these newborns and infants is unclear at this stage of the pan-
demic.

Pediatric inflammatory multisystem syndrome temporarily associated

with SARS-CoV-2 (PIMS-TS) (or synonym Multisystem Inflammatory
Syndrome in Children (MIS-C) or Kawasaki-like Disease
While most children with COVID-19 have a very mild disease, in April 2020
clinicians from the UK, France, Italy, Spain and the US reported on children
with a severe inflammatory syndrome with Kawasaki-like features, some of
whom had tested positive for CoV-2, while others not. Prior to this, Jones had
described the case of a six-month-old baby girl with fever, rash and swelling
characteristic of a rare pediatric inflammatory condition, Kawasaki disease
(Jones 2020).
Eight patients from the UK and 10 patients from Bergamo in Italy with fea-
tures of Kawasaki disease were published including one death in a 14-year-old
boy in the UK during the SARS-CoV-2 epidemic (Riphagen 2020, Verdoni
2020). Some children presented with vasculitic skin rash (Schneider 2020). In
Bergamo, the region with the highest infection rate in Italy, a 30-fold in-
creased incidence of Kawasaki disease has been reported following the SARS-
CoV-2 epidemic (Verdoni 2020). Of 21 children and adolescents from London,
UK (19 with recent SARS-CoV-2 infection), 12 (57%) presented with Kawasaki
disease shock syndrome, 16 (76%) with myocarditis, 17 (81%) required inten-
sive care support. All had noticeable gastrointestinal symptoms and high lev-
els of inflammatory markers, received intravenous immunoglobulin and 10
(48%) corticosteroids; the outcome was favourable in all (Toubiana 2020).
In the UK, 78 of the PIMS-TS cases reported 36 (46%) were invasively ventilat-
ed, 28 (36%) had evidence of coronary artery abnormalities, three children
needed ECMO and two children died (Davies 2020).
In another study from the UK, 50% of the 58 “PIMS-TS” cases developed shock
and required inotropic support or fluid resuscitation; 22% met diagnostic cri-

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teria for Kawasaki disease; and 14% had coronary artery dilatation or aneu-
rysms (Whittaker 2020).
In a US MIS-C study on 186 patients 131 (70%) were positive for SARS-CoV-2
by RT-PCR or antibody testing. Detailed analysis of clinical manifestation re-
vealed the gastrointestinal system (92%), cardiovascular (80%), hematologic
(76%), mucocutaneous (74%), and respiratory involvement (70%). In total, 148
patients (80%) received intensive care, 37 (20%) received mechanical ventila-
tion, and 4 (2%) died. Coronary-artery aneurysms were documented in 15 pa-
tients (8%), and Kawasaki disease–like features were documented in 74 (40%)
(Feldstein 2020). In the largest cohort to date,
570 US MIS-C patients were reported as of July 29. A total of 203 (35.6%) of the
patients had a typical MIS-C clinical course (shock, cardiac dysfunction, ab-
dominal pain, and markedly elevated inflammatory markers) and almost all
had positive SARS-CoV-2 test results (Class 1). The remaining 367 (64.4%) of
MIS-C patients (Class 2 and 3) had manifestations that appeared to overlap
with acute COVID-19 or had features of Kawasaki disease. 364/570 patients
(63.9%) required care in an intensive care unit. Ten patients (1.8%) died. Ap-
proximately two thirds of the children had no pre-existing underlying medi-
cal conditions (Godfred-Cato 2020).
In summary, the pathophysiological overlap between COVID-19-associated
inflammation and Kawasaki disease is not yet clear, their features are sum-
marized in Table 2. The main pathophysiological differences appear to be an
IL17A-driven inflammation in Kawasaki disease (KD) and a stronger endothel
activation in coronary artery involvement in MIS-C. In both, MIS-C and KD
autoantibodies may play an important role and MIS-C patients show distinct
CD4 subset abnormalities. (Consiglio 2020).

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome

temporarily associated with SARS-CoV-2

Kawasaki (Hedrich 2017, PIMS-TS (pediatric inflammatory multisystem

ECDC 2020) (previously syndrome temporarily associated with SARS-
called mucocutaneous lymph CoV-2 or MIS-C (multisystem inflammatory
-node syndrome) syndrome in children) (Verdoni 2020;
Riphagen 2020, https://covid19-surveillance-
report.ecdc.europa.eu/)
“Kawasaki-like disease”

Epidemiology Incidence 5–19/100,000 Incidence unknown

annually < 5 years of age
230 suspected cases temporally
(EU, US), in north-east Asia
associated with COVID-19 reported to
higher; seasonal increase in
ECDC by May 15th (EU/EEA, UK). More
winter/spring, geographic
common in afro-caribbean descent,
wave-like spread of illness
obesity? (Riphagen 2020)
during epidemics (Rowley
2018)

Age, sex >90% < 5 years of age, more 5-15 years of age, sex distribution unclear
males

Etiology Unknown, hypothesis: Unknown, no working hypothesis yet.

infection with common Hyperinflammation/shock associates with
pathogens, e.g. bacteria, immune response to SARS-CoV-2. In CoV-
fungi and viruses which cause 1 antibody-dependent enhancement
immune-mediated damage (ADE): presence of antibodies can be
(Dietz 2017) (Jordan-Villegas detrimental, enable the virus to spread
2010, Kim 2012, Turnier (demonstrated in SARS-CoV)
2015). Genetic factors
(increased frequency in Asia
and among family members
of an index case)

Case fever ≥5 days, combined with 1. Persistent fever, inflammation (neutrophilia,

definition at least 4 of the 5 following elevated CRP and lymphopenia) and single or
items multi-organ dysfunction (shock, cardiac,
respiratory, renal, gastrointestinal or
1.Bilateral bulbar conjunctival
neurological disorder) with other additional
injection
clinical, laboratory or imagining and ECG
2. Oral mucous membrane features. Children fulfilling full or partial
changes, including injected or criteria for Kawasaki Disease may be
fissured lips, injected pharynx, included
or strawberry tongue
2. Exclusion of any other microbial cause,
3. Peripheral extremity including bacterial sepsis, staphylococcal or
changes, including erythema streptococcal shock syndromes, infections
of palms or soles, edema of associated with myocarditis such as
hands or feet (acute phase) enterovirus
or periungual desquamation
3. SARS-CoV-2 PCR testing positive or
(convalescent phase)
negative (Royal College of Paediatrics and
4. Polymorphous rash Child Health)

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome

temporarily associated with SARS-CoV-2
5. Cervical lymphadenopathy
(McCrindle 2017)

Children suspected of having

KD who do not fulfill
diagnostic criteria may have
incomplete or atypical KD
(Cimaz 2009)

CoV-2 status CoV-2 Ag (PCR); Abs (Elisa) CoV-2 Ag (PCR) negative and Abs (Elisa)
in most cases negative positive

Typical Lab Marked Elevation of acute- Marked elevation of acute phase reactants
phase reactants (eg, C- CRP, ESR
reactive protein [CRP] or
Thrombocytopenia
erythrocyte sedimentation
rate [ESR]) Leucopenia
Lymphopenia
Thrombocytosis (generally Hyperferritinemia
after day 7 of illness
Leukocytosis, left-shift
(increased immature Elevated myocarditis markers Troponin, pro-
BNP
neutrophils)

Acute Kawasaki disease shock Shock (common), features of macrophage

Complications syndrome (KSSS) (rare), activation syndrome (common), myocardial
features of macrophage involvement evidenced by markedly elevated
activation syndrom, MAS cardiac enzymes (common), myocardial
(rare), coronary artery infarction, aneurysms, disseminated
abnormalities, mitral intravascular coagulation
regurgitation, prolonged
Gastrointestinal complications (Ileitis,
myocardial dysfunction,
vomiting, abdominal pain) are very common
disseminated intravascular
coagulation (Kanegaye 2009)
Gastrointestinal complications
(Ileitis, vomiting, abdominal
pain) rare

Long term Artery abnormalities Aneurysms

(aneurysms of mid-sized
Complications
arteries, giant coronary artery
aneurysms CAAs)

Management High-dose intravenous So far, most patients published were treated

immunoglobulin (IVIG) (2g/kg) with high dose IVIG, glucocorticoids, ASS
first-line treatment; effective in (Verdoni 2020, Riphagen 2020, Ahmed 2020)
reducing the risk of coronary
IVIG resistance requiring adjunctive steroid

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome

temporarily associated with SARS-CoV-2
artery disease when treatment is common (Verdoni 2020,)
administered within 10 days
Management on the pediatric intensive care
of onset of fever. In addition,
unit is often necessary: progression to
acetylsalicylic acid,
vasoplegic shock is common
glucocorticoids and anti-TNF
monoclonal antibodies have Hemodynamic support, treatment with
been used noradrenaline and milrinone, mechanical
ventilation is often required (Riphagen 2020)

Prognosis Self-limited vasculitis lasting Overall prognosis not yet clear

for an average of 12 days
More severe course than KD
without therapy. Without
timely treatment, CAAs, and Potentially fatal in individual cases
in particular aneurysms, can
occur in up to 25% of children

Management
National guidelines and guidance documents have been published from dif-
ferent medical societies in China, North America, Italy, UK and Germany
(https://rcpch.ac.uk; Venturini 2020, Chiotos 2020, Liu 2020;
https://www.rcpch.ac.uk/key-topics/covid-19;
https://dgpi.de/stellungnahme-medikamentoese-behandlung-von-kindern-
mit-covid-19/)

Infection control in the medical setting

Early identification of COVID-19 and quarantine of contacts is imperative. In
the in- and out-patient setting it is advised to separate children who have
infectious diseases from healthy non-infectious children. Nosocomial out-
breaks have played a role in the clustering of COVID-19. It is advised to admit
children with COVID-19 to the hospital only if an experienced pediatrician
feels it is medically necessary (e.g. tachypnea, dyspnea, oxygen levels below
92%). In the hospital the child with COVID-19 or suspicion of COVID-19 needs
to be isolated in a single room or admitted to a COVID-19-only ward in which
COVID-19-exposed medical personnel is protected by non-pharmacological
interventions (wearing FFP-2 masks, gowns, etc.) and maintains distance and
is cohorted themselves (e.g. no shifts on other wards). The presence of one
parent is not negotiable in the care of the sick child both for emotional rea-
sons as well as for help in the nursing of the child.
At present it is not recommended to separate healthy newborns from moth-
ers with suspicion of COVID-19 (CDC-2 2020). Clearly, a preterm or newborn

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that has been exposed to CoV-2 needs to be closely monitored by the hospital
and/or the primary care pediatrician. If there are signs of COVID (e.g. poor
feeding, unstable temperature, tachy/dyspnea) it needs to be hospitalized
and tested and lab examinations and chest x-ray to be done. Testing for CoV-2
is not useful before day 5 because of the incubation period. There needs to be
strict hygiene as much as possible in this mother-child setting.
During peak phases of the COVID-19 pandemic, precautions in the outpatient
and hospital setting include entrance control, strict hand and respiratory
hygiene, daily cleaning and disinfection of the environment, and provision of
protection (gloves, mask, goggles) for all medical staff when taking care of a
COVID-19 or a suspected COVID-19 case (Wang 2020). In neonatal intensive
care units (NICU), negative pressure rooms and filtering of exhaust would be
ideal (Lu Q 2020). Respirators with closed circuit and filter systems should be
used. Aerosol generating procedures, e.g. intubation, bronchoscopy, humidi-
fied inhalations/nebulization should be avoided as much as possible.

Infection control outside the medical setting

Some of the interventions to control the COVID pandemic have caused signif-
icant damage to children and adolescents. The description of their impact is
beyond the scope of this artivcel and reviewed elsewhere.4

Supportive treatment (respiratory support, bronchodilatation

therapy, fever, superinfection, psychosocial support)
Having the child sitting in an upright position will be helpful for breathing. It
might be useful to have physiotherapy. Insufflation of oxygen via nasal can-
nula will be important to children as it will increase lung ventilation and per-
fusion. In neonates, high flow nasal cannula (HFNC) has been utilized widely
due to its superiority over other non-invasive respiratory support techniques.
The clinical use and safety of inhaling different substances is unclear in
COVID-19. In other common obstructive and infectious childhood lung dis-
eases, e.g. in bronchiolitis, the American Academy of Pediatrics is now rec-
ommending against the use of bronchodilators (Dunn 2020). Regarding the
inhalation of steroids as part of maintenance therapy for asthma bronchiale
there is no evidence to discontinue this treatment in children with COVID-19.
There is a large controversy over the extent of antipyretics usage in children.
Still, in a child with COVID-19 who is clinically affected by high-degree fever,

4
Recommendations regarding attendance to kindergartens and schools have
been published (Cohen 2020).

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 Pediatrics | 417

paracetamol or ibuprofen may be useful. There is no restriction despite initial

WHO warnings of using ibuprofen, there is no evidence that the use of para-
cetamol or ibuprofen is harmful in COVID-19 in children (Day 2020).
The differentiation between CoV-2-induced viral pneumonia and bacterial
superinfection is difficult unless there is clear evidence from culture results
or typical radiological findings. Bacterial superinfection will be treated ac-
cording the international and national guidelines (Mathur 2018).
The virus outbreak brings psychological stress to the parents and family as
well as medical staff; therefore, social workers and psychologists should be
involved when available.

Treatment of respiratory failure

The treatment of pediatric acute respiratory distress syndrome (pARDS) is
reviewed elsewhere (Allareddy 2019). For neonates with pARDS high-dose
pulmonary surfactant replacement, nitric oxide inhalation, and high-
frequency oscillatory ventilation might be effective. In critically ill neonates,
continuous renal replacement and extracorporeal membrane oxygenation
need to be implemented if necessary.

COVID-19-specific drug treatment

As of yet there are no data from controlled clinical trials and thus there is
currently no high-quality evidence available to support the use of any medi-
cation to treat COVID-19. The drugs listed below are repurposed drugs and
there is limited or almost no pediatric experience. In the case of a severe or
critically ill child with COVID the pediatrician has to make a decision whether
to try a drug or not. If initiation of a drug treatment is decided, children
should be included into clinical trials (https://www.clinicaltrialsregister.eu)
if at all possible. However, there are very few, if any, studies open for re-
cruitment in children.

When to treat with drugs

Under the lead of the German Society for Pediatric Infectiology (DGPI) an ex-
pert panel has proposed a consensus on when to start antiviral or immuno-
modulatory treatment in children (Table 3)).
A panel of pediatric infectious diseases physicians and pharmacists from
North American institutions published an initial guidance on the use of anti-
virals for children with SARS. It is advised to limit antiviral therapy to chil-
dren in whom the possibility for benefit outweighs the risk of toxicity and
remdesvir is the preferred agent (Chiotos 2020).

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Inhibitors of viral RNA synthesis

Remdesivir is available as 150 mg vials. Child dosing is
• < 40 kg: 5 mg/kg iv loading dose, then 2,5 mg/kg iv QD for 9 days
• ≥ 40 kg: 200 mg loading dose, then 100 mg QD for 9 days
Remdesivir is an adenosine nucleotide analogue with broad-spectrum antivi-
ral activity against various RNA viruses. The compound undergoes a metabol-
ic mechanism, activating nucleoside triphosphate metabolites for inhibiting
viral RNA polymerases. Remdesivir has demonstrated in vitro and in vivo activ-
ity in animal models against MERS and SARS-CoV. Remdesivir showed good
tolerability and a potential positive effect in regard to decrease of the viral
load and mortality in Ebola in Congo in 2018 (Mulangu 2019). In Europe this
drug has rarely been used in children so one should be extremely careful. It
can be obtained through compassionate use programs
(https://rdvcu.gilead.com).

Table 3. Consensus on antiviral or immunomodulatory treatment in children

Disease severity in child Intervention

Mild or moderate disease Treat symptomatically

pCAP, upper respiratory tract infection, no need No need for antiviral or immunomodulatory
for oxygen treatment

More severe disease and risk groups* Treat symptomatically

pCAP, need for oxygen Consider antiviral therapy

Critically ill, admitted to ICU Treat symptomatically

Consider antiviral therapy
Consider immunomodulatory treatment

Secondary HLH (hemophagocytic Treat with immunomodulatory or

lymphohistiocytosis) immunosuppressive drugs

* Congenital heart disease, immunosuppression, inborn/acquired immunodeficiencies, cystic

fibrosis, chronic lung disease, chronic neurological/kidney/liver disease, diabetes/metabolic
disease

Lopinavir/r (LPV/r, Kaletra®) is a co-formulation of lopinavir and ritonavir,

in which ritonavir acts as a pharmacokinetic enhancer (booster). LPV/r is an
HIV-1 protease inhibitor successfully used in HIV-infected children as part of
highly active antiretroviral combination therapy (PENTA Group, 2015). In the
SARS epidemics, LPV/r was recommended as a treatment. A recent study in
adult COVID-19 patients did not show an effect regarding the primary end
point in a controlled clinical trial. Despite the fact that there is long experi-
ence with LPV/r in HIV, it is not advised to use it in children with COVID-

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 Pediatrics | 419

19 as it does not appear to be effective at all (see Treatment chapter, page

329

Inhibitors of viral entry

Hydroxychloroquine (HCQ, Quensyl®), Chloroquine (CQ, Resochin junior®,
Resochin®) The experience among pediatricians with HCQ/CQ (except pedia-
triciancs working with malaria) is very limited. Authorities in the US are now
warning about a widespread use of HCQ/CQ in COVID-19
(https://mailchi.mp/clintox/aact-acmt-aapcc-joint-statement). It is not ad-
vised to use HCQ or CQ in children with COVID as neither drug appears
to be effective at all (see Treatment chapter, page 329).

Immunomodulatory drug treatment

The rational for immunomodulation in COVID-19 adult patients comes from a
high expression of pro-inflammatory cytokines (Interleukin-1 (IL-1) and in-
terleukin-6 (IL-6)), chemokines (“cytokine storm”) and the consumption of
regulatory T cells resulting in damage of the lung tissue as reported in pa-
tients with a poor outcome. In children, the proinflammatory cytokines TNF
and IL-6 do not appear to be central in CoV-2 induced hyperinflammation
(Consiglio 2020). Blocking IL-1 or IL-6 can be successful in children with (au-
to) inflammatory disease (reviewed in Niehues 2019), but both interleukins
are also key to the physiological immune response and severe side effects of
immunomodulators have been reported. In adults with COVID-19, blocking
interleukin-1/6 might be helpful (see the Treatment chapter). In the rare sit-
uation that the condition of the child deteriorates due to hyperinflam-
mation and they are resistant to other therapies, anakinra may be an
option as IL-1 seems to play a role in endothelial activation.
Steroids (e.g. prednisone, prednisolone) are available as oral solution, tab-
lets or different vials for intravenous application. Dosage in children is 0,5 to
1 mg/kg iv or oral BID. Short term use of steroids has few adverse events.
Administration of steroids will affect inflammation by inhibiting the tran-
scription of some of the pro-inflammatory cytokines and various other ef-
fects. Initially, the use of corticosteroids in children and adults with CoV-
induced ARDS was controversial (Lee 2004, Arabi 2018, Russell 2020). Only in
severe and critically ill children the use of dexamethasone appears justified in
children. In adults, the use of steroids in severe COVID-19 is clearly beneficial
although the corticosteroid-induced decrease of antiviral immunity (e.g. to
eliminate CoV-2 viruses) might be theoretically disadvantageous. The use of
low-dose hydrocortisone may be of advantage in adults with ARDS, whereas
its use is controversial in pediatric ARDS.

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Most patients with pediatric inflammatory multisystem syndrome associated

with SARS-CoV-2 (PIMS-TS) published so far were treated with high dose IVIG
and methylprednisolone (Verdoni 2020, Riphagen 2020). In these patients,
features of macrophage activation syndrome and IVIG resistance were com-
mon, requiring adjunctive steroid treatment (Verdoni 2020). Clearly, any
child severly affected by CoV-2 will need steroids at some stage.
Tocilizumab (Roactemra®) is available in 80/200/400 mg vials (20 mg/ml).
Dosing is
• < 30 kg: 12 mg/kg iv QD, sometimes repeated after 8 hrs
• ≥ 30 kg: 8mg/kg iv QD iv (max. 800 mg)
Adverse events (deriving largely from long term use in chronic inflammatory
diseases and use in combination with other immunomodulatory drugs): se-
vere bacterial or opportunistic infections, immune dysregulation (anaphylac-
tic reaction, fatal macrophage activation), psoriasis, vasculitis, pneumotho-
rax, fatal pulmonary hypertension, heart failure, gastrointestinal bleeding,
diverticulitis, gastrointestinal perforation (reviewed in Niehues 2019).
Anakinra (Kineret®) is available as 100 mg syringes (stored at 4-8° C). Dosing
is 2-4 mg/kg sc QD daily as long as hyperinflammation persists. Thereafter,
dose reduction by 10-30% per day. Adverse events (deriving largely from
long-term use in chronic inflammatory diseases and use in combination with
other immunomodulatory drugs): severe bacterial or opportunistic infec-
tions, fatal myocarditis, immune dysregulation, pneumonitis, colitis, hepati-
tis, endocrinopathies, nephritis, dermatitis, encephalitis, psoriasis, vitiligo,
neutropenia (reviewed in Niehues 2019).

Immunotherapy
There are no systematic data on the use of convalescent plasma in children
yet, but in a child with acute lymphoblastic leukemia and a young adult with
a SCID (Severe Combined Immunodeficiency) phenotype and a high CoV-2
viral load, administration of convalescent plasma resulted in complete viral
suppression (Shankar 2020, unpublished observation). Engineering monoclo-
nal antibodies against the CoV spike proteins or against its receptor ACE2 or
specific neutralizing antibodies against CoV-2 present in convalescent
plasma may provide protection but are generally not available yet.
Interferon α has been inhaled by children with COVID-19 in the original co-
horts but there are no data on its effect (Qiu 2020). Type I/III interferons (e.g.
interferon α) are central to antiviral immunity. When coronaviruses (or other
viruses) invade the host, viral nucleic acid activates interferon-regulating

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factors like IRF3 and IRF7 which promote the synthesis of type I interferons
(IFNs).

PIMS / MIS-C
Based on the information published so far, most patients were treated with
high dose intravenous Immunglobulin (see Table 2) and corticosteroids
(Verdoni 2020). More data are needed to determine the optimal treatment
strategies for patients with MIS-C.
DOI: Tim Niehues has received authorship fees from uptodate.com (Wellesley, Massachusetts, USA) and
reimbursement of travel expenses during consultancy work for the European Medicines Agency (EMA),
steering committees of the PENTA Paediatric European Network for Treatment of AIDS (Padua, Italy),
the Juvenile Inflammatory Cohort (JIR) (Lausanne, Switzerland), and, until 2017, the FIND-ID Initiative
(supported by the Plasma Protein Therapeutics Association [PPTA] [Brussels, Belgium]).

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12. The First Eight Months

Bernd Sebastian Kamps

Dezember - March
Sunday, 1 December
According to a retrospective study published in The Lancet on 24 January
20205, the earliest laboratory confirmed case of COVID-19 in Wuhan was in a
man whose symptoms began on 1 December 2019. No epidemiological link
could be found with other early cases. None of his family became ill.

Thursday, 12 December
In Wuhan, health officials start investigating a cluster of patients with viral
pneumonia. They eventually find that most patients have visits to the Huanan
Seafood Wholesale Market in common. The market is known for being a sales
hub for poultry, bats, snakes, and other wildlife.

Monday, 30 December 2019

Li Wenliang (en.wikipedia.org/wiki/Li_Wenliang), a 34-year-old ophthalmol-
ogist from Wuhan, posts a message on a WeChat group alerting fellow doctors
to a new disease at his hospital in late December. He writes that seven pa-
tients have symptoms similar to SARS and are in quarantine. Li askes his
friends to inform their families and advises his colleagues to wear protective
equipment.

Tuesday, 31 December 2019

The Wuhan police announce that they are investigating eight people for
spreading rumors about a new infectious diseases outbreak (see 30 Decem-
ber).
The Wuhan Municipal Health Commission reports 27 patients with viral
pneumonia and a history of exposure to the Huanan Seafood Wholesale Mar-

5
Huang, Chaolin et al., Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China January 24, 2020
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-
5/fulltext#%20

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ket. Seven patients are critically ill. The clinical manifestations of the cases
were mainly fever, a few patients had difficulty breathing, and chest radio-
graphs showed bilateral lung infiltrative lesions. The report says that the
“disease is preventable and controllable”. WHO is informed about the out-
break.

Thursday, 1 January
The Huanan Seafood Wholesale Market is shut down.

Friday, 3 January
While examining bronchoalveolar lavage fluid collected from hospital pa-
tients between 24 and 29 December, Chinese scientists at the National Insti-
tute of Viral Disease Control and Prevention ruled out the infection with 26
common respiratory viruses, determined the genetic sequence of a novel β-
genus coronaviruses (naming it '2019-nCoV') and identified three distinct
strains.6
Li Wenliang is summoned to a local public security office in Wuhan for
“spreading false rumours”. He is forced to sign a document where he admits
having made “false comments” and “disrupted social order.” Li signs a state-
ment agreeing not to discuss the disease further.
On the Weibo social network, Wuhan police say they have taken legal action
against people who “published and shared rumors online”, “causing a nega-
tive impact on society”. The following day, the information is taken up by
CCTV, the state television. CCTV does not specify that the eight people ac-
cused of “spreading false rumors” are doctors.

Sunday, 5 January
WHO issues an alert that 44 patients with pneumonia of unknown etiology
have been reported by the national authorities in China. Of the 44 cases re-
ported, 11 are severely ill while the remaining 33 patients are in stable condi-
tion. https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-
cause-china/en/

6
Notes from the Field: An Outbreak of NCIP (2019-nCoV) Infection in China —
Wuhan, Hubei Province, 2019−2020, China CDC Weekly, 2020, 2(5): 79-80
http://weekly.chinacdc.cn/en/article/id/e3c63ca9-dedb-4fb6-9c1c-
d057adb77b57

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Tuesday, 7 January
Chinese officials announce that they have identified a new coronavirus (CoV)
from patients in Wuhan (pre-published 17 days later:
https://doi.org/10.1056/NEJMoa2001017). Coronaviruses are a group of vi-
ruses that cause diseases in mammals and birds. In humans, the most com-
mon coronaviruses (HCoV-229E, -NL63, -OC43, and -HKU1) continuously cir-
culate in the human population; they cause colds, sometimes associated with
fever and sore throat, primarily in the winter and early spring seasons. Two
coronavirus have also been responsible for human outbreaks of SARS and
MERS. These viruses are spread by inhaling droplets generated when infected
people cough or sneeze, or by touching a surface where these droplets land
and then touching one’s face.

Friday, 10 January
The gene sequencing data of the new virus was posted on Virological.org by
researchers from Fudan University, Shanghai. A further three sequences were
posted to the Global Initiative on Sharing All Influenza Data (GISAID) portal.
On 10 January 2020, Li Wenliang, coronavirus whistleblower, started having
symptoms of a dry cough. Two days later, Wenliang started having a fever
and was admitted to the hospital on 14 January 2020. His parents also con-
tracted the coronavirus and were admitted to the hospital with him.
Wenliang tested negative several times until finally testing positive for the
coronavirus on 30 January 2020.

Sunday, 12 January
Using the genetic sequence of the new coronavirus made available to WHO,
laboratories in different countries start producing specific diagnostic PCR
tests.
The Chinese government reports that there is no clear evidence that the virus
passes easily from person to person.

Monday, 13 January
Thailand reports the first case outside of China, a woman who had arrived
from Wuhan. Japan, Nepal, France, Australia, Malaysia, Singapore, South Ko-
rea, Vietnam, Taiwan, and South Korea report cases over the following 10
days.

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Tuesday, 14 January
WHO tweeted that “preliminary investigations conducted by the Chinese au-
thorities have found no clear evidence of human-to-human transmission of
the novel coronavirus (2019-nCoV) identified in Wuhan, China”. On the same
day, WHO’s Maria Van Kerkhove said that there had been “limited human-to-
human transmission” of the coronavirus, mainly small clusters in families,
adding that “it is very clear right now that we have no sustained human-to-
human transmission”7

Saturday, 18 January
The Medical Literature Guide Amedeo (www.amedeo.com) draws the atten-
tion of 50,000+ subscribers to a study from Imperial College London, Estimat-
ing the potential total number of novel Coronavirus cases in Wuhan City, China, by
Imai et al. The authors estimate that “a total of 1,723 cases of 2019-nCoV in
Wuhan City (95% CI: 427 – 4,471) had onset of symptoms by 12th January
2020”. Officially, only 41 cases were reported by 16th January.

Monday, 20 January
China reports three deaths and more than 200 infections. Cases are now also
diagnosed outside Hubei province (Beijing, Shanghai and Shenzhen). Asian
countries begin to introduce mandatory screenings at airports of all arrivals
from high-risk areas of China.
After two medical staff were infected in Guangdong, the investigation team
from China's National Health Commission confirmed for the first time that
the coronavirus can be transmitted between humans. 8

Wednesday, 22 January 2020

A WHO China office field mission to Wuhan issued a statement saying that
there was evidence of human-to-human transmission in Wuhan, but more
investigation was needed to understand the full extent of transmission.9

7 WHO says new China coronavirus could spread, warns hospitals worldwide". Reuters. 14 Janu-
ary 2020.
8 https://www.theguardian.com/world/2020/jan/20/coronavirus-spreads-to-beijing-as-china-
confirms-new-cases
9 https://www.who.int/china/news/detail/22-01-2020-field-visit-wuhan-china-jan-2020

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 The First Eight Months | 433

Thursday, 23 January
In a bold and unprecedented move, the Chinese government puts tens of mil-
lions of people in quarantine. Nothing comparable has ever been done in
human history. Nobody knows how efficient it will be.
All events for the Lunar New Year (starting on January 25) are cancelled.
The WHO IHR (2005) Emergency Committee convened on 22-23 Janaury
acknowledged that human-to-human transmission was occurring with a pre-
liminary R0 estimate of 1.4-2.5 and that 25% of confirmed cases were reported
to be severe. However, the Committee felt that transmission was limited and
there was “no evidence” of the virus spreading at community level outside of
China. Since the members could not reach a consensus, the committee decid-
ed that it was still too early to declare a Public Health Emergency of Interna-
tional Concern (PHEIC) and agreed to reconvene in approximately ten days’
time. 10
A scientific preprint from the Wuhan institute of Virology, later published in
Nature, announced that a bat virus with 96% similarity had been sequenced in
a Yunnan cave in 2013. The sequence is posted the next day on public data-
bases.11 It is confirmed that the novel coronavirus uses this same entry recep-
tor as SARS-CoV.

Friday, 24 January
At least 830 cases have been diagnosed in nine countries: China, Japan, Thai-
land, South Korea, Singapore, Vietnam, Taiwan, Nepal, and the United States.
The first confirmed evidence of human-to-human transmission outside of
China was documented by the WHO in Vietnam.12
France reported its first three confirmed imported cases, the first occurrenc-
es in the EU.13
Zhu et al. publish their comprehensive report about the isolation of a novel
coronavirus which is different from both MERS-CoV and SARS-CoV (full-text:

10
https://www.who.int/news-room/detail/23-01-2020-statement-on-the-meeting-of-the-
international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-
novel-coronavirus-(2019-ncov)
11 Zhou, Peng et al. "A pneumonia outbreak associated with a new coronavirus of probable bat
origin". Nature. 579 (7798): 270–273 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095418/
12 "Novel Coronavirus (2019-nCoV) SITUATION REPORT - 4" WHO 24 January 2020.
13 "Coronavirus : un troisième cas d'infection confirmé en France". Le Monde.fr (in French). 24
January 2020.

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https://doi.org/10.1056/NEJMoa2001017). They describe sensitive assays to

detect viral RNA in clinical specimens.
Huang et al. publish on The Lancet the clinical features of 41 patients (full-
text: doi.org/10.1016/S0140-6736(20)30185-9). The report indicated the risk of
contagious infection without forewarning signs during the incubation period
and suggested a “pandemic potential” for the new virus.
Chan et al. describe a familial cluster of pneumonia associated with the 2019
novel coronavirus indicating person-to-person transmission (full-text:
doi.org/10.1016/S0140-6736(20)30154-9).

Saturday, 25 January
The Chinese government imposes travel restrictions on more cities in Hubei.
The number of people affected by the quarantine totals 56 million.
Hong Kong declares an emergency. New Year celebrations are cancelled and
links to mainland China restricted.

Monday, 27 January
In Germany, the first cluster of infections with person to person transmission
from asymptomatic patients in Europe was reported. The source of infection
was an individual from Shanghai visiting a company in Bavaria14. She devel-
oped symptoms on the way back to China. Contacts at the company were
tested and transmission was confirmed to asymptomatic contacts but also to
people who had no direct contact with the index patient. Authors state that
“The fact that asymptomatic persons are potential sources of 2019-nCoV in-
fection may warrant a reassessment of transmission dynamics of the current
outbreak.”15

Tuesday, 28 January
WHO DG Dr. Tedros Adhanom Ghebreyesus met China President Xi Jinping in
Beijing. They shared the latest information on the outbreak and reiterated
their commitment to bring it under control. The WHO delegation highly ap-
preciated the actions China has implemented in response to the outbreak, its

14
Böhmer MM, Buchholz U, Cormann VM: Investigation of a COVID-19 outbreak in Germany
resulting from a single travel-associated primary case: a case series. Published online
May 15, 2020. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-
3099(20)30314-5/fulltext
15
Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an
Asymptomatic Contact in Germany. N Engl J Med 2020;382:970-971.
https://pubmed.gov/32003551. Full-text: https://doi.org/10.1056/NEJMc2001468

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 The First Eight Months | 435

speed in identifying the virus and openness to sharing information with WHO
and other countries.16

Thursday, 30 January
On the advice of the IHR Emergency Committee, WHO DG declared a Public
Health Emergency of International Concern and advised “all countries should
be prepared for containment, including active surveillance, early detection,
isolation and case management, contact tracing and prevention of onward
spread of 2019-nCoV infection, and to share full data with WHO.” WHO had
received reports of 83 cases in 18 countries outside China and that there had
been evidence of human-to-human transmission in 3 countries.
China reports 7,711 cases and 170 deaths. The virus has now spread to all Chi-
nese provinces.
Giuseppe Conte, Italy’s Prime Minister, confirms the first two COVID-19 im-
ported cases in Italy.

Friday, 31 January
Li Wenliang publishes his experience with Wuhan police station (see 3 Janu-
ary) with the letter of admonition on social media. His post goes viral.
India, the Philippines, Russia, Spain, Sweden, the United Kingdom, Australia,
Canada, Japan, Singapore, the US, the UAE and Vietnam confirm their first
cases.

Sunday, 2 February
The first death outside China, of a Chinese man from Wuhan, is reported in
the Philippines. Two days later a death in Hong Kong is reported.

Thursday, 6 February
Li Wenliang, who was punished for trying to raise the alarm about corona-
virus, dies. His death sparks an explosion of anger, grief and demands for
freedom of speech: https://www.theguardian.com/global-
development/2020/feb/07/coronavirus-chinese-rage-death-whistleblower-
doctor-li-wenliang.

16
https://www.who.int/news-room/detail/28-01-2020-who-china-leaders-
discuss-next-steps-in-battle-against-coronavirus-outbreak

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Friday, 7 February
Hong Kong introduces prison sentences for anyone breaching quarantine
rules.

Saturday, 8 February
The French Health Minister confirmed that a cluster of 5 COVID-19 cases were
detected in a ski resort in the French Alps. The index patient was a UK citizen
who had traveled to Singapore on 20-23 January and then spent four days (24-
28 January) in a chalet in Contamines-Montjoie, in Haute-Savoie. He tested
positive upon return to England. Four contacts in the same chalet tested posi-
tive, including a 9-year old boy who was attending a local school. None of the
child’s contacts in school or at home became infected.

Monday, 10 February
Amedeo launches a weekly Coronavirus literature service which would later
be called Amedeo COVID-19.

Tuesday, 11 February
Less than three weeks after introducing mass quarantine measures in China,
the number of daily reported cases starts dropping.
The WHO announces that the new infectious disease would be called COVID-
19 (Coronavirus disease 2019) and that the new virus will be called SARS-
CoV-2.

Wednesday, 12 February
On board the Diamond Princess cruise ship docked in Yokohama, Japan, 175
people are infected with the virus. Over the following days and weeks, almost
700 people will be infected onboard.

Thursday, 13 February
China changed the COVID-19 case definition to include clinical (radiological)
diagnosis of patients without confirmatory test. As a result, Hubei reported
14,840 newly confirmed cases, nearly 10 times more than the previous day,
while deaths more than doubled to 242. WHO indicated that for consistency it
would report only the number of laboratory-confirmed cases.17

17
https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20200213-sitrep-24-covid-19.pdf

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Wednesday, 19 February
Iran reports two deaths from the coronavirus.
At the San Siro stadium in Milan, the Atalanta soccer team from Bergamo
wins the Champions League match against Valencia 4 to 1 in front of 44,000
fans from Italy (2,000 from Spain). The mass transport from Bergamo to Milan
and return, hours of shouting as well as the following festivities in innumera-
ble bars have been considered by some observers as a coronavirus ‘biological
bomb’.

Thursday, 20 February
A patient in his 30s tested positive for SARS-CoV-2 and was admitted to the
intensive care unit (ICU) in Codogno Hospital (Lodi, Lombardy, Italy). The
symptomatic patient had visited the hospital the day before but was not test-
ed as he did not meet the suspected case epidemiological criteria (no link
with China). His wife, 5 hospital staff, 3 patients and several contacts of the
index patients also tested positive to the COVID-19. Over the next 24 hours,
the number of reported cases would increase to 36, many without links to the
Codogno patient or previously identified positive cases. A first COVID-19
death in a 78-year-old man was also reported. It is the beginning of the Italian
epidemic. jamanetwork.com/journals/jama/fullarticle/2763188

Saturday, 22 February
South Korea reports a sudden spike of 20 new cases of coronavirus infection,
raising concerns about a potential “super spreader” who has already infected
14 people in a church in the south-eastern city of Daegu.

Sunday, 23 February
Italy confirms 73 new cases, bringing the total to 152, and a third death, mak-
ing Italy the third country in the world by number of cases, after China and
South Korea. A “red zone” area around Codogno is created, isolating 11 mu-
nicipal areas. Schools are closed.
Venice Carnival is brought to an early close and sports events are suspended
in the most-hit Italian regions.

Monday, 24 February
France, Bahrain, Iraq, Kuwait, Afghanistan and Oman report their first cases.

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Tuesday, 25 February
A report of a joint WHO mission of 25 international and Chinese experts is
presented to the public. The mission travelled to several different Chinese
provinces. The most important findings are that the Chinese epidemic peaked
and plateaued between the 23rd of January and the 2nd of February and de-
clined steadily thereafter (Table 1).
https://www.who.int/publications-detail/report-of-the-who-china-joint-
mission-on-coronavirus-disease-2019-(covid-19)
This was the first sign that the aggressive use of quarantine ordered by the
Chinese government was the right thing to do. Unfortunately, European
countries which did not experience the SARS epidemic in 2003, would lose
precious time before following the Chinese example.

Figure 1. COVID-19 cases in China, January/February 2020. Epidemic curves by symp-

tom onset and date of report on 20 February 2020 for laboratory confirmed COVID-19 cases
for all of China. Modified from Report of the WHO-China Joint Mission on Coronavirus Dis-
ease 2019 (COVID-19). 16-24 February 2020. https://www.who.int/publications-detail/report-
of-the-who-china-joint-mission-on-coronavirus-disease-2019-(covid-19)

Wednesday, 26 February
A president, fearing for his chances to be re-elected, downplays the threat
from the coronavirus pandemic, twittering: “Low Ratings Fake News...are
doing everything possible to make the Caronavirus [sic] look as bad as possi-
ble, including panicking markets, if possible.”
https://www.bmj.com/content/368/bmj.m941
Two days later, the same individual invokes magic: “It’s going to disappear.
One day, it’s like a miracle, it will disappear.”

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P.S. On 28 March, The Guardian would ask why this person

failed the biggest test of his life.

Friday, 28 February
A quick look at European cases diagnosed outside of Italy from February 24-27
reveals that 31 of 54 people (57%) had recently travelled to Northern Italy.
Epidemiologists immediately realize that an unusual situation is building up.

Saturday, 7 March
Official data show that China’s exports plunged 17.2 percent in the first two
months of the year.

Sunday, 8 March
The Italian government led by Prime Minister Giuseppe Conte, deserves cred-
it for instauring the first European lockdown, just two and a half weeks after
the first autoctone Italian COVID-19 case was detected. First, strict quarantine
measures are imposed on 16 million people in the state of Lombardy and 14
other areas in the north. Two days later, Conte would extend these to the en-
tire country of 60 million people, declaring the Italian territory a “security
zone”. All people are told to stay at home unless they need to go out for “valid
work or family reasons”. Schools are closed.

Monday, 9 March
A president on Twitter: “So last year 37,000 Americans died from the common
Flu. It averages between 27,000 and 70,000 per year. Nothing is shut down, life
& the economy go on. At this moment there are 546 confirmed cases of Coro-
naVirus, with 22 deaths. Think about that!” (The Guardian)
Iran releases 70,000 prisoners because of the coronavirus outbreak in the
country.

Tuesday, 10 March
Xi Jinping tours the city of Wuhan and claims a provisional victory in the
battle against COVID-19. The last two of 16 temporary hospitals in the city are
shut down.

Wednesday, 11 March
With more than 118,000 COVID-19 cases in 114 countries and 4,291 deaths,
WHO DG declares the coronavirus outbreak a pandemic.

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All schools in and around Madrid, from kindergartens to universities, are

closed for two weeks.

Thursday, 12 March
Italy closes all shops except grocery stores and pharmacies.
In Spain, 70,000 people in Igualada (Barcelona region) and three other munic-
ipalities are quarantined for at least 14 days. This is the first time Spain
adopts measures of isolation for entire municipalities.
Emmanuel Macron, the French president, announces the closure of nurseries,
schools and universities from Monday, 16 March. He declares: “One principle
guides us to define our actions, it guides us from the start to anticipate this
crisis and then to manage it for several weeks, and it must continue to do so:
it is confidence in science. It is to listen to those who know.” Some of his
colleagues should have listened, too.

Friday, 13 March
The prime minister of an ex-EU country introduces the notion of ‘herd im-
munity’ as a solution to repeated future episodes of coronavirus epidemics.
The shock treatment: accepting that 60% of the population will contract the
virus, thus developing a collective immunity and avoiding future coronavirus
epidemics. The figures are dire. With a little over 66 million inhabitants, some
40 million people would be infected, 4 to 6 million would become seriously ill,
and 2 million would require intensive care. Around 400,000 Britons would die.
The prime minister projects that “many more families are going to lose loved
ones before their time.”
P.S. Five weeks later, The Guardian would still ask, “How did Britain
get its coronavirus response so wrong?”

Saturday, 14 March
The Spanish government puts the whole country into lockdown, telling all
people to stay home. Exceptions include buying food or medical supplies, go-
ing to hospital, going to work or other emergencies.
The French government announces the closure of all “non-essential” public
places (bars, restaurants, cafes, cinemas, nightclubs) after midnight. Only
food stores, pharmacies, banks, tobacconists, and petrol stations may remain
open.

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Sunday, 15 March
France calls 47 million voters to the poll. Both government and opposition
leaders seem to be in favor of maintaining the municipal elections. Is this a
textbook example of unacceptable interference of party politics with the
sound management of a deadly epidemic? Future historians will have to in-
vestigate.

Monday, 16 March
Ferguson et al. publish a new modelling study on likely UK and US outcomes
during the COVID-19 pandemic. In the (unlikely) absence of any control
measures or spontaneous changes in individual behaviour, the authors expect
a peak in mortality (daily deaths) to occur after approximately 3 months. This
would result in 81% of the US population, about 264 million people, contract-
ing the disease. Of those, 2.2 million would die, including 4% to 8% of Ameri-
cans over age 70. More important, by the second week in April, the demand
for critical care beds would be 30 times greater than supply.
The model then analyzes two approaches: mitigation and supression. In the
mitigation scenario, SARS-CoV-2 continues to spread at a slow rate, avoiding
a breakdown of hospital systems. In the suppression scenario, extreme social
distancing measures and home quarantines would stop the spread of the vi-
rus. The study also offers an outlook at the time when strict “Stay at home”
measures are lifted. The perspective is grim: the epidemic would bounce back.
France imposes strict confinement measures.

Tuesday, 17 March
Seven million people across the San Francisco Bay Area are instructed to
“shelter in place” and are prohibited from leaving their homes except for
“essential activities” (purchasing food, medicine, and other necessities). Most
businesses are closed. The exceptions: grocery stores, pharmacies, restau-
rants (for takeout and delivery only), hospitals, gas stations, banks.

Thursday, 19 March
For the first time since the beginning of the coronavirus outbreak, there have
been no new cases in Wuhan and in the Hubei province.
Californian Governor Gavin Newsom orders the entire population of Califor-
nia (40 million people) to “stay at home”. Residents can only leave their
homes to meet basic needs like buying food, going to the pharmacy or to the
doctor, visiting relatives, exercising.

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Friday, 20 March
Italy reports 6,000 new cases and 627 deaths in 24 hours.
In Spain, the confinement due to the coronavirus reduces crime by 50%.
China reports no new local coronavirus cases for three consecutive days. Re-
strictions are eased, normal life resumes. The entire world now looks at
China. Will the virus spread again?
The state of New York, now the center of the U.S. epidemic (population: 20
million), declares a general lockdown. Only essential businesses (grocers, res-
taurants with takeout or delivery, pharmacies, and laundromats) will remain
open. Liquor stores? Essential business!

Sunday, 22 March
Byung-Chul Han publishes La emergencia viral y el mundo de mañana (El País):
“Asian countries are managing this crisis better than the West. While there
you work with data and masks, here you react late and borders are opened.”

Monday, 23 March
Finally, too late for many observers, the UK puts in place containment
measures. They are less strict than those in Italy, Spain and France.
German Chancellor Angela Merkel self-quarantines after coming into contact
with a person who tested positive for coronavirus.

Tuesday, 24 March
Off all reported cases in Spain, 12% are among health care
workers.
The Tokyo Olympics are postponed until 2021.
India orders a nationwide lockdown. Globally, three billion people are now in
lockdown.

Wednesday, 25 March
After weeks of stringent containment measures, Chinese authorities lift travel
restrictions in Hubei province. In order to travel, residents will need the
“Green Code” provided by a monitoring system that uses the AliPay app.
A 16-year-old girl dies in the south of Paris from COVID-19. The girl had no
previous illnesses.

Thursday, 26 March

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America First: the US is now the country with most known coronavirus cases
in the world.
For fear of reactivating the epidemic, China bans most foreigners from enter-
ing the country.

Friday, 27 March
The Prime Minister and the Ministre of Health of an ex-EU country tests posi-
tive for coronavirus.
The Lancet publishes COVID-19 and the NHS—”a national scandal”.
A paper by McMichael et al. describes a 33% case fatality rate for SARS-CoV-2
infected residents of a long-term care facility in King County, Washington,
US.

Sunday, 29 March
The Guardian and the Boston Globe ask who might have blood on their hands
in the current pandemic. The evolution of the US epidemic is being described
as the worst intelligence failure in US history.

Monday, 30 March
Flaxman S et al. from the Imperial College COVID-19 Response Team publish
new data on the possibly true number of infected people in 11 European
countries. Their model suggests that as of 28 March, in Italy and Spain, 5.9
million and 7 million people could have been infected, respectively (see Table
online). Germany, Austria, Denmark and Norway would have the lowest infec-
tion rates (proportion of the population infected). These data suggest that the
mortality of COVID-19 infection in Italy could be in the range of 0.4%
(0.16%-1.2%).
Moscow and Lagos (21 million inhabitants) go into lockdown.
The COVID-19 crisis causes some East European political leaders to consider
legislation giving them extraordinary powers. In one case, a law was passed
extending a state of emergency indefinitely.
SARS-CoV-2 is spreading aboard the aircraft carrier USS Theodore Roosevelt.
The ship’s commanding officer, Captain Brett Crozier, sends an email to three
admirals in his chain of command, recommending that he be given permis-
sion to evacuate all non-essential sailors, to quarantine known COVID-19 cas-
es, and sanitize the ship. “We are not at war. Sailors do not need to die,”
writes Crozier in his four-page memo. The letter leaks to the media and gen-
erates several headlines. Three days later, 2 April, Captain Crozier is sacked.

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Later, testing of 94% of the crew of roughly 4,800 people would reveal around
600 sailors infected, a majority of whom, around 350, were asymptomatic.

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April
Wednesday, 1 April
The United Nations chief warns that the coronavirus pandemic presents
the world’s “worst crisis” since World War II.

Thursday, 2 April
Worldwide more than one million cases are reported. The true number is
probably much higher (see the Flaxman paper on 30 March).
European newspapers run articles about why Germany has so few deaths
from COVID-19.

Friday, 3 April
Some economists warn that unemployment could surpass the levels reached
during the Great Depression in the 1930s. The good news: almost all govern-
ments rate saving tens or hundreds of thousands of lives higher than avoiding
a massive economic recession. Has humanity become more human?
Le Monde, the most influential French newspaper, points to a more mundane
side effect of the epidemic. As hairdressers are forbidden to work, colors and
cuts will degrade. The newspaper predicts that “after two months, 90% of
blondes will have disappeared from the face of the Earth”.

Saturday, 4 April
In Europe, there are signs of hope. In Italy, the number of people treated in
intensive care units decreases for the first time since the beginning of the
epidemic.
In France, 6,800 patients are treated in intensive care units. More than 500 of
these have been evacuated to hospitals from epidemic hotspots like Alsace
and the Greater Paris area to regions with fewer COVID-19 cases. Specially
adapted TGV high-speed trains and aircraft have been employed.
Lombardy decides that as of Sunday 5 April, people must wear masks or
scarves. Supermarkets must provide gloves and hydroalcoholic gel to their
customers.
An Italian politician, less penetrable to scientific reasoning on a par with
some of his colleagues in the US and Brazil, asks for churches to be open on
Easter (12 April), declaring that “science alone is not enough: the good God is
also needed”. Heureux les simples d’esprit, as the French would say.

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Figure 2. Patients treated in intensive care units in Italy. For the first time since the
beginning of the epidemic, the number decreases on 4 April.
Souce: Le Monde

Sunday, 5 April
The US surgeon general warns the country that it will face a “Pearl Harbor
moment“ in the next week.
US is the new epicenter of the COVID-19 epidemic. By the time of this writing
(5 April), more than 300,000 cases and almost 10,000 deaths were reported.
Almost half were reported from New York and New Jersey.

Tuesday, 7 April
Air quality improves over Italy, the UK and Germany, with falling levels of
carbon dioxide and nitrogen dioxide. Will a retrospective analysis of the cur-
rent lockdown reveal fewer cases of asthma, heart attacks and lung disease?

Wednesday, 8 April
Japan declares a state of emergency, Singapore orders a partial lockdown.
In Wuhan people are allowed to travel for the first time since the city was
sealed off 76 days ago.
The Guardian publishes a well-documented timeline: “Coronavirus: 100 days
that changed the world.”

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Thursday, 9 April
EU finance ministers agree to a common emergency plan to limit the impact
of the coronavirus pandemic on the European economy. The Eurogroup
reaches a deal on a response plan worth more than €500 billion for countries
hit hardest by the epidemic.
Passenger air travel has decreased by up to 95%. How many of the 700 airlines
will survive the next few months? Will the current interruption of global air
travel shape our future travel behaviors?
The epidemic is devastating the US economy. More than 16 million Americans
have submitted unemployment claims in the past three weeks.

Friday, 10 April
COVID-19 treatment for one dollar a day? British, American and Australian
researchers estimate that it could indeed cost only between 1 and 29 dollars
per treatment and per patient.
Message from your mobile phone: “You have been in contact with someone
positive for coronavirus.” Google and Apple announce that they are building
a coronavirus tracking system into iOS and Android. The joint effort
would enable the use of Bluetooth technology to establish a voluntary con-
tact-tracing network. Official apps from public health authorities would get
extensive access to data kept on phones that have been in close proximity
with each other (George Orwell is turning over in his grave). If users report
that they’ve been diagnosed with COVID-19, the system would alert people if
they were in close contact with the infected person.
Spain discovers COVID Reference. Within 24 hours, more than 15,000 people
download the PDF of the Spanish edition. The only explanation: a huge media
platform displayed the link of our book. Does anyone know who did it?

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Figure 3. Google Analytics data for www.CovidReference.com on 10 April. At one moment,

more than 500 people, mostly from Spain, were visiting the website simultaneously.

Saturday, 11 April
More than 400 of 700 long-term care facilities (EHPAD in French, Etablisse-
ment d’Hébergement pour Personnes Agées Dépendantes) in the greater Paris re-
gion (pop. – 10 million) have COVID-19 cases.
In Italy, 110 doctors and about 30 other hospital workers have died from
COVID-19, half of them nurses.

Sunday, 12 April

Figure 4. Daily number of COVID-19 deaths in Italy (red) and Spain (blue).

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 The First Eight Months | 449

Easter 2020. Italy reports 361 new deaths, the lowest number in 25 days
while Spain reports 603 deaths, down more than 30% from a high 10 days be-
fore.
The United Kingdom records its highest daily death toll of almost 1,000. The
number of reported COVID-19-linked fatalities now exceeds 10,000. As in
many other countries, the true numbers may be slightly higher due to un-
derreporting of people dying in care homes.
The number of COVID-19-related deaths in the United States passes 22,000,
while the number of cases tops 500,000. In New York there are signs that the
pandemic could be nearing its peak.

Monday, 13 April
The COVID-19 pandemic exposes bad governance, not only in Brazil. The
French newspaper Le Monde reveals the ingredients: denial of reality, search
for a scapegoat, omnipresence in the media, eviction of discordant voices,
political approach, isolationism and short-term vision in the face of the
greatest health challenge in recent decades. The culprit?
Emmanuel Macron announces announces a month-long extension to
France’s lockdown. Only on Monday, May 11, nurseries, primary and high
schools would gradually reopen, but not higher education. Cafés, restaurants,
hotels, cinemas and other leisure activities would continue to remain closed
after May 11.

Tuesday, 14 April
Austria is the first European country to relax lockdown measures. It opens
up car and bicycle workshops, car washes, shops for building materials, iron
and wood, DIY and garden centers (regardless of size) as well as smaller deal-
ers with a customer area under 400 square meters. These shops must ensure
that there is only one customer per 20 square meters. In Vienna alone, 4,600
shops are allowed to open today. Opening times are limited to 7.40 a.m. to 7
p.m. The roadmap for the coming weeks and months:
• 1 May: All stores, shopping malls and hairdressers reopen (see also
the April 3 entry, page 445).

• 15 May: Other services such as restaurants and hotels remain closed

at least until mid-May.

• 15 May or later: Possible re-opening of classes in schools.

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• July: possible – but improbable – organization of events of all sorts

(sport, music, theater, cinema etc.).
There is a general obligation to wear a mask when shopping and on public
transport.
The International Monetary Fund (IMF) forecasts a contraction of 3% of the
planet’s GDP in 2020. The possibility of an even more brutal fall in 2021 is
not excluded. The possibly worst economic downturn since the Great Depres-
sion in 1929 will not spare any continent. In a recession like no other in
peacetime for nearly a century, the countries of the eurozone, the United
Kingdom and the United States might see a contraction in activity of between
5.9% and 7.5%. China’s economy is expected to grow by about 1%.
US: The CDC (Centers for Disease Control and Prevention) reports that more
than 9,000 health care workers contracted COVID-19 as and at least 27 died.
The median age was 42 years, and 73% were female. Deaths most frequently
occurred in HCP aged ≥ 65 years.

Wednesday, 15 April
Philip Anfinrud and Valentyn Stadnytsky from the National Institutes of
Health, Bethesda, report a laser light-scattering experiment in which speech-
generated droplets and their trajectories were visualized. They find that
when a test person says, “stay healthy,” numerous droplets ranging from 20
to 500 µm are generated. When the same phrase is uttered three times
through a slightly damp washcloth over the speaker's mouth, the flash
(droplet) count remains close to the background level. The video supports the
recommendation of wearing face masks in public. The authors also found that
the number of flashes (droplets) increased with the loudness of speech. The
new message for billions of people caught in the COVID-19 epidemic: lower
your voice!

Friday, 17 April
Luiz Inácio Lula da Silva, the former Brazilian president says that the cur-
rent president is leading Brazil to “the slaughterhouse” with his irresponsible
handling of coronavirus. In an interview with The Guardian, Lula says that
Brazil’s “troglodyte” leader risks repeating the devastating scenes playing out
in Ecuador where families have to dump their loved ones’ corpses in the
streets.
On the French aircraft carrier Charles-de-Gaulle, a massive epidemic is.
Among the 1760 sailors, 1,046 (59%) are positive for SARS-CoV-2, 500 (28%)

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present symptoms, 24 (1.3%) sailors are hospitalized, 8 on oxygen therapy and

one in intensive care.

Saturday, 18 April
Chancellor Angela Merkel makes a television speech, her first in over 14 years
in office. She describes the coronavirus crisis “as the greatest challenge since
the Second World War” and exhorts the Germans: “It is serious. Take it seri-
ously.”
Care England, Britain’s largest representative body for care homes, suggests
that up to 7,500 residents may have died of COVID-19. This would be higher
than the 1,400 deaths estimated by the government.
In Catalunya alone, some 6,615 hospital professionals and another 5,934 in old
age care homes are also suspected of having or been diagnosed with COVID-
19.

Sunday, 19 April

Figure 5. Daily number of COVID-19 deaths in Germany (green) and the United Kingdom
(black).

Air traffic in Europe has plummeted more than 95% as nicely shown by this
YouTube video by The Guardian:
https://www.youtube.com/watch?v=lOVP2o3c4Gw

Monday, 20 April
For the first time in history, the West Texas Intermediate (WTI), the bench-
mark price for US oil, drops below $0. On certain specific contracts, it plunged
down to minus 37 US dollars (-34 euros). After nearly two months of continu-

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ous collapse of the oil market, this paradoxical situation is the result of the
COVID-19 pandemic which caused demand to fall by 30%. As oil wells contin-
ue to produce, there is no place to store the oil and investors are ready to pay
to get rid of it.
Germany’s Oktoberfest is cancelled. The iconic beer festival, colloquially
known as Die Wiesn or “the meadow”, attracts around 6 million visitors from
around the world. It runs for more than two weeks (September/October) in
packed tents with long wooden tables, where people celebrate traditional
food, dancing, beer and clothing. The loss for the city of Munich is estimated
to be around one billion euros.

Tuesday, 21 April
The Spanish newspaper El País publishes an intelligible overview of the battle
between SARS-CoV-2 and the human body: “Así es la lucha entre el sistema
inmune y el coronavirus.”¡Fantástico!
Cancer Research UK reports that every week, 2,300 people with cancer symp-
toms are no longer examined. Screening examinations for breast and uterine
cancer of over 200,000 women per week have been cancelled. According to
The British Heart Foundation, 50 percent fewer people suspected of having a
heart attack attended hospital emergency rooms in March. A 50% drop would
be “equivalent to approximately 5000 of the expected people every month, or
more than 1100 people every week, with possible heart attack symptoms not
being seen in emergency departments.” Will we discover a hidden epidemic
of COVID-19-related morbidity and mortality with millions of people dying
not from coronavirus, but from other, actually treatable diseases?

Thursday, 23 April
Pandemic hilarity, as a president known for his poor science record stammers
speculations about “injecting” “disinfectant” to cure COVID-19.

Sunday, 26 April
The city of Wuhan announces that all remaining COVID-19 cases have been
discharged from the hospitals.

Monday, 27 April
Are genes determining coronavirus symptoms? After studying 2,633 identical
and fraternal twins who were diagnosed with COVID-19, a group from King’s
College London reports that COVID-19 symptoms appear to be 50% genetic

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(fever, diarrhea, delirium and loss of taste and smell)18. It is as yet unclear
whether and to what extent reported deaths of identical twins can be at-
tributed to genetic factors.

18
Williams FMK et al. Self-reported symptoms of covid-19 including symptoms most
predictive of SARS-CoV-2 infection, are heritable. MedRxiv 27 April (accessed 8 May
2020). Abstract: https://www.medrxiv.org/content/10.1101/2020.04.22.20072124v2

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May
Friday, 1 May
A new SARS-CoV-2 test could be able to identify virus carriers before they are
infectious, according to a report by The Guardian. The blood-based test would
be able to detect the virus’s presence as early as 24 hours after infection –
before people show symptoms and several days before a carrier is considered
capable of spreading it to other people.

Sunday 3 May
Roche gets US Food and Drug Administration emergency use approval for its
antibody test, Elecsys Anti-SARS-CoV-2, which has a specificity rate of about
99.8% and a sensitivity rate of 100%.

Monday, 4 May
Italy is cautiously easing lockdown measures. People can go jogging but may
not go to the beach; they may surf but now swim; and they can visit 6th grade
relatives, but not friends, lovers or mistresses.
A French hospital that retested old samples from pneumonia patients discov-
ers that it treated a man with the coronavirus as early as 27 December, a
month before the French government confirmed its first cases.
Researchers from Bonn University, Germany, report a sero-epidemiological
study of 919 people from Gangelt, a small German town which was exposed to
a super-spreading event (carnival festivities). 15.5% were infected, with an
estimated infection fatality rate of 0.36%. 22% of infected individuals were
asymptomatic.

Tuesday, 5 May
Neil Ferguson, epidemiologist at the Imperial College, resigns his post as
member of the British government’s Scientific Advisory Group for
Emergiences (SAGE) over an “error of judgement”. A newspaper had reported
that he did not respect the rules of confinement (which he himself had con-
tributed to establishing!) by receiving at least twice a 38-year-old woman at
his home.
Anthony Fauci, the director of the United States National Institute of Allergy
and Infectious Diseases, says that there is no scientific evidence to back the

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theory that the coronavirus was made in a Chinese laboratory or leaked from
a laboratory after being brought in from the wild (CGTN).

Wednesday, 6 May
The official COVID-19 death toll in the UK exceeds 30,000.

Thursday, 7 May
According to data released by the US Department of Labor, more than 33 mil-
lion Americans have filed for initial jobless claims. This corresponds roughly
to 21% of the March labor force.
Only 15 countries in the world have not officially reported a case of COVID-19
to WHO, namely: North Korea, Turkmenistan, Kiribati, Marshall Islands, Mi-
cronesia, Samoa, Salomon Island, Tonga, Tuvalu, Vanuatu, Cook Island, Nauru,
Niue, Palau and Lesotho. (We know North Korea is cheating, and Turkmeni-
stan and Lesotho cannot deny for long… It’s a true pandemic!)
According to figures by the Office of National Statistics, black people are more
than four times more likely to die from COVID-19 than white people.

Friday, 8 May 2020

After pipedreams (German: Hirngespinste; French: élucubrations; Italian: vi-
sioni; Spanish: fantasías) about hydroxychloroqine and injecting desinfect-
ants, today is the day where COVID-19 will “go away without vaccine”. The
sad developments of the coronavirus pandemic have now accumulated suffi-
cient evidence that the individual doesn’t believe himself what he is saying.
The carefully timed and well-orchestrated ungrammatical utterings just obey
one supreme life mission: continue staying in the news. Alas, there is an even
more tragic aspect to the drama: Why on Earth do the world’s media insist on
talking about this individual? Why can’t we read the news without seeing his
face every single day? Why couldn’t we simply totschweigen him?
(Totschweigen is a superbly descriptive German verb: 1. tot dead; 2. schweigen
to be silent; 3. totschweigen make someone dead silent – English: to hush up;
French: passer sous silence; Italian: fare come se non esistesse; Portuguese:
não falar em alguém.)
Today, we make a funereal promise: we’ll never talk about the individual
again, not even on the day he dies.

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Sunday, 10 May
Italians are looking on aghast at the UK’s coronavirus response, says The
Guardian. Is it really no accident that Britain and America are the world’s
biggest coronavirus losers?
Everything you always wanted to know about false negatives and false posi-
tives* (*but were afraid to ask) is now summarized in 10 steps to understand
COVID-19 antibodies. The colors will help you memorize true and false nega-
tives and positives.
Spain’s best newspaper El País publishes ‘ccu ccg ccg gca – The 12 letters that
changed the world.’ (If you read Spanish, take a look.)

Monday, 11 May
France eases lockdown restrictions among a sense of incertainty. The news-
paper Le Monde reports that according to official figures 8,674 new positive
tests for SARS-CoV-2 were registered between May 1 and 9. Epidemiologist
Daniel Lévy-Bruhl, head of the respiratory infections unit of Santé Publique
France (Public Health France) estimates that the real figures are probably
twice or three times as high (3,000 to 4,000 new infections each day) – despite
barrier gestures, social distancing and general confinement.

Tuesday, 12 May
The MMWR publish a report about a high SARS-CoV-2 attack rate following
exposure at a choir practice.

Wednesday, 13 May
There is evidence that China is censoring COVID Reference. Google Analyt-
ics data of two dozen websites, both medical (Amedeo, Free Medical Journals,
FreeBooks4Doctors) and non-medical (TheWordBrain, Ear2Memory, GigaSar-
dinian, GigaMartinique, SardoXSardi, Polish Yiddish and ItalianWithElisa,
among others) show that by number of visitors, China was always among the
Top 10 countries, generating between 3.3% and 14.8% of website traffic (see
https://covidreference.com/censorship).
Not so with COVID Reference. Six weeks after the launch of COVID Reference,
China is 27th, after Paraguay, accounting for 0.39% of global traffic. Is some-
one standing on the data line between COVID Reference and China (Figure 6)?

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Figure 6. Google Analytics data for www.CovidReference.com on 13 May. Six weeks after
the launch of COVID Reference, China is 27th, after Paraguay and right before the
Netherlands and Russia.

Friday, 15 May
In a memorable blog entry for the British Medical Journal, Paul Garner, pro-
fessor of infectious diseases at Liverpool School of Tropical Medicine, discuss-
es his COVID-19 experience as having “been through a roller coaster of ill
health, extreme emotions, and utter exhaustion”.
A video experiment using black light and a fluorescent substance demon-
strates how quickly germs can be spread in environments such as restaurant
buffets and cruise ships: www.youtube.com/watch?v=kGQEuuv9R6E.

Saturday, 16 May
A new highly transmissible and potentially deadly virus is detected in Germa-
ny: SADS, Severe Acute Dementia Syndrome. The new syndrome manifests as
an irrepressible desire to ignore the danger of COVID-19. In several German
cities, an improbable alliance takes to the streets – left- and right-wing ex-
tremists, antisemites, conspiracy theorists and anti-vaxxers –, claiming the
right to live and to die without social distancing and face masks. The German
Government immediately informs WHO.

Monday, 18 May
Merkel and Macron announce a 500,000 million euro aid plan for the recon-
struction of Europe (El País).
Moderna announces that its experimental vaccine mRNA-1273 has generated
antibodies in eight healthy volunteers ages 18 to 55. The levels of neutralizing
antibodies matched or exceeded the levels found in patients who had recov-
ered from SARS-CoV-2 infection (The Guardian).

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Wednesday, 20 May
After an outbreak of coronavirus, Chinese authorities seal off the city of
Shulan, a city of 700,000 close to Russian border, imposing measures similar
to those used in Wuhan (The Guardian).
Google and Apple release their Exposure Notification System to notify users
of coronavirus exposure:
https://www.google.com/covid19/exposurenotifications.
We discover a website which shows where infected people in Hong Kong are
at all times: https://chp-dashboard.geodata.gov.hk/covid-19/en.html (Figure
7). There is no doubt that the tighter you control the infected, the less re-
striction you have to impose on the uninfected. In Europe, strict measures
such as those adopted in Hong Kong and South Korea are currently not com-
patible with existing legislation about privacy.

Figure 7. Screenshot of the “Latest Situation of Coronavirus Disease (COVID-19) in Hong

Kong", https://chp-dashboard.geodata.gov.hk/covid-19/en.html.

Thursday, 21 May
The Centers for Disease Control and Prevention (CDC) informs that rats rely
on the food and waste generated by restaurants and other commercial estab-
lishments, the closures of which have led to food shortage among rodents,
especially in dense commercial areas. CDC warns of unusual or aggressive
rodent behavior.

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Will SARS-CoV-2 seal the fate of the Airbus A380? Air France chooses to end
the operations of the aircraft, judged to be too expensive, too polluting and
not profitable enough (Le Monde).

Friday, 22 May
Zhu et al. publish Safety, Tolerability, and Immunogenicity of a Recombinant Ade-
novirus type-5 Vectored COVID-19 Vaccine.
Fafi-Kremer 2020 et al. pre-publish Serologic responses to SARS-CoV-2 infection
among hospital staff with mild disease in eastern France, reporting that neutraliz-
ing antibodies against SARS-CoV-2 were detected in virtually all hospital staff
(n=160) sampled from 13 days after the onset of COVID-19 symptoms (see also
Le Monde).

Saturday, 23 May
In Lower Saxony, Germany, 50 people are in quarantine after an outbreak in a
restaurant (Der Spiegel).
In Frankfurt, Germany, authorities report more than 40 people infected with
SARS-CoV-2 after a religious service (Der Spiegel).

Wednesday, 27 May
Colombian designers prepare cardboard hospital beds that double as coffins
(The Guardian).
Andrzej Krauze publishes a cartoon on the fallout from the COVID-19 pan-
demic.

Sunday, 31 May
More than 50 million people across the US could go hungry without help from
food banks or other aid (Feeding America).

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June
Wednesday, 3 June
In the hope of saving its tourist industry, Italy reopens its borders.

Tuesday, 4 June
The Lancet makes one of the biggest retractions in modern history (The Guardian).

Friday, 5 June
The chief investigators of the RECOVERY trial report that there is no clinical
benefit from use of hydroxychloroquine in hospitalised patients with COVID-
19.

Saturday, 6 June
The Guardian reports that nearly 600 US health workers have died of COVID-
19.

Sunday, 7 June
Three super-spreading events in an office, a restaurant and a bus show how
easily SARS-CoV-2 can be spread over distances of more than 1 meter. The
feature by El País is worth taking a look, even if you don’t understand Span-
ish: https://elpais.com/ciencia/2020-06-06/radiografia-de-tres-brotes-asi-se-
contagiaron-y-asi-podemos-evitarlo.html.

Monday, 8 June
Attending a sporting event, concert or play? Attending a wedding or a funer-
al? Stopping routinely wearing a face covering? Attending a church or other
religious service? Hugging or shaking hands when greeting a friend? Going
out with someone you don’t know well? When asked by The New York Times
when they would expect to resume these activities of daily life, 42% to 64% of
epidemiologists and infectious disease specialists answered they would prefer
waiting a year before doing it again. The enquiry by Margot Sanger-Katz,
Claire Cain Miller and Quoctrung Bui: When 511 epidemiologists expect to fly,
hug and do 18 other everyday activities again.
It becomes increasingly clear that not all patients recover fully from SARS-
CoV-2 infection. See ‘It feels endless’: four women struggling to recover from
Covid-19. (If you read Spanish, check also Los últimos de la UCI).

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Dozens of new infections reported in Kabukicho, a district of more than 4,000

bars, restaurants and commercial sex establishments in Tokyo.

Tuesday, 9 June
New Zealand returns back to pre-COVID-19 life.
In Brazil, “poverty, poor access to health services and overcrowding all play a
part in a disproportionate number of deaths”, reports The Guardian. Corona-
virus death rates expose Brazil’s deep racial inequalities.
Wednesday,V 10 June
The Guardian publishes an analysis of the Surgisphere scandal (the retracted
paper about hydroxychloroquine trial).
NIAID Director Anthony Fauci says the coronavirus pandemic is far from over.
The OECD says Britain will top the developing world’s recession league table.
British theatre might go out of business.

Thursday, 11 June
India, Mexico, Russia, Iran and Pakistan decide to end lockdowns.
Neil Ferguson, a former scientific adviser to the British government, says ear-
lier restrictions could have halved the death toll.
If you read Spanish: Las mascarillas, claves para evitar una segunda oleada de la
pandemia (El País).

Friday, 12 June
Beijing reimposes lockdown measures after a new COVID-19 outbreak around
the wholesale market of Xinfadi (北京新发地水果批发市场).
Northwestern Memorial Hospital in Chicago announces that a young woman
in her 20s whose lungs were destroyed by COVID-19 received a double lung
transplant.
If you read French: Coronavirus – au cœur de la bataille immunitaire contre le
virus.

Saturday, 13 June
What have Venice, Amsterdam and Barcelona in common? Before the COVID-
19 pandemic they were overrun by tourists. Tourism certainly contributes to
the wealth of these cities, but the vast majority of the populations – all those
who are not directly or indirectly employed in mass tourism – receive no

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benefits from millions of people transiting their neighborhood. The weekend

of 13/14 June, just before the reopening of the Schengen area (see 15 June
entry), is therefore a unique opportunity for people in hundreds of small and
big charming cities throughout Europe. They enjoy the place where they live
with those who were born there or chose to live there – like 10, 20 or 30 years
ago, before the beginning of the tourist pandemic.
According to figures from the British Office for National Statistics (ONS), peo-
ple living in more deprived areas are twice as likely to die from coronavirus
(ONS | The Guardian).
Most Europeans now trust their leaders generally a little less than when the
crisis began.
Malta’s abortion taboo leaves women in despair.

Sunday, 14 June
Lancet editor Richard Horton describes the management of the outbreak as
‘the greatest science policy failure of a generation’.
Immunologist Scott Canna and rheumatologist Rachel Tattersall publish a 23-
minute audio about cytokine storms.
A study by Ben Etheridge and Lisa Spantig shows that one third of women
suffered from lockdown loneliness.
Thailand, Malaysia, Vietnam... some countries managed to keep COVID at bay.
When should we send children back to school? Here is what 132 epidemiolo-
gists would be inclined to do.

Monday, 15 June
Mauro Giacca of King’s College London: “Covid-19 can result in complete dis-
ruption of the lung architecture.”
With a few exceptions, all borders in the European Schengen area are open
again for free travel of European citizens. The Balearic Islands open to 11,000
German tourists.
Every stairway a marathon? There is no standard therapy for patients who
have survived a severe corona infection. For many survivors, the way back to
a normal life begins in rehabilitation clinics. If you read German, read this.

Tuesday, 16 June
Results from the RECOVERY trial: Dexamethasone is the first life-saving
coronavirus drug (Study | The Guardian).

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After hundreds of infections at the Xinfadi market, the Chinese authorities

close all schools and call on residents to avoid “non-essential” travel outside
of the city. Around thirty residential areas surrounding the market are quar-
antined. Companies are encouraged to favor teleworking and people can no
longer, except in cases of force majeure, leave the capital. Around 67% of do-
mestic flights are canceled. Libraries, museums, art galleries and parks can
only operate at 30% of their capacity. Restaurants can no longer accommo-
date groups. Beijing begins screening tens of thousands of inhabitants, bring-
ing its daily testing capacity to more than 90,000 people.
The U.S. Food and Drug Administration revokes its emergency use authoriza-
tion for hydroxychloroquine sulfate and chloroquine phosphate to treat
COVID-19.
Coronavirus cases rise in US prisons.

Wednesday, 17 June
Investigations from Nanjing show that turbulence from a toilet bowl can cre-
ate a large plume that is potentially infectious to a bathroom’s next visitor
(Paper | The New York Times).
After two women recently arrived from Britain were infected with COVID-19
and allowed to leave quarantine without being tested, New Zealand puts
COVID-19 quarantine in the hands of the military.

Thursday, 18 June
The end of tourism? Christopher de Bellaigue publishes an insightful Guardi-
an long read about the devastated global tourism industry. One key paragraph:
“Tourism is an unusual industry in that the assets it monetizes – a view, a
reef, a cathedral – do not belong to it. The world’s dominant cruise companies
(…) pay little towards the upkeep of the public goods they live off. By incorpo-
rating themselves in overseas tax havens with benign environmental and la-
bor laws – respectively Panama, Liberia and Bermuda – cruising’s big three,
which account for three-quarters of the industry, get to enjoy low taxes and
avoid much irksome regulation, while polluting the air and sea, eroding
coastlines and pouring tens of millions of people into picturesque ports of call
that often cannot cope with them.”
Eric Rubin and Lindsey Baden discuss SARS-CoV-2 transmission in a 20-
minute audio by the New England Journal of Medicine.
A 13-day-old baby becomes one of the UK’s youngest victims.

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Antibodies may fade quickly in asymptomatic people (Nature | The New York
Times).
Again, meat processing plants are proving to be ideal transmission settings.
In the German town of Gütersloh, North Rhine-Westphalia, 657 employees
test positive for SARS-CoV-2.
Richard Horton publishes The COVID-19 Catastrophe: What’s Gone Wrong and How
to Stop It Happening Again. “The book returns again and again to the catastro-
phe in both the United Kingdom and the United States. It is haunted by the
question: how did two of the richest, most powerful and most scientifically
advanced countries in the world get it so wrong, and cause such ongoing pain
for their citizens?” (Nature)

Friday, 19 June
Beijing residents react with frustration and anxiety after finding almost 200
new cases of coronavirus.
A study by the Italian Istituto Superiore di Sanità detects SARS-CoV-2 RNA in
wastewater samples collected in Milan and Turin on 18 December 2019.
Investigations from the University of Sussex describe society as regressing
back to the 1950s for many women (The Guardian).
UK abandons developing its own contact-tracing app and switches to the al-
ternative design by Google and Apple.
Three experts exchange their views on the risks of travelling by plane.
Alexandra Villarreal describes a new American way of life: some Americans
return to bars, dining and beaches, others shy away, concerned that the virus
is still raging.

Sunday, 20 June
Spain plunges into the so-called new normal after 98 days of COVID-19 state-
of-alarm.
The coronavirus outbreak in the German meat processing plant Tönnies near
Gütersloh continues. By midday, 1,029 employees test positive and 2,098 neg-
ative for SARS-CoV-2. Nineteen people, almost all employees of Tönnies, are
being treated for COVID-19. Six of them are in intensive care, two patients are
ventilated (DIE ZEIT).
Those who might be tempted to attend a political rally should read the sum-
mary of COVID Reference’s Transmission chapter:

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1. It appears that a high percentage (as high as 80%?) of secondary trans-

missions could be caused by a small fraction of infectious individuals (as
low as 10%?; Endo 2020); if this is the case, then the more people are
grouped together, the higher the probability that a superspreader is
part of the group.
2. It also appears that aerosol transmission might play an important role in
SARS-CoV-2 transmission (Prather 2020); if this is the case, then building
a wall around this same group of people and putting a ceiling above them
further enhances the probability of SARS-CoV-2 infection.
3. It finally appears that shouting and speaking loudly emits thousands of
oral fluid droplets per second which could linger in the air for minutes
(Anfinrud 2020, Stadnytskyi 2020, Chao 2020, Asadi 2019); if this is the
case, then creating noise (machines, music) around people grouped in a
closed environment would create the perfect setting for a superspreader
event.
Stay away from mass gatherings.

Week 26
This week has seen important local outbreaks. The recurring patterns: family
celebrations (Melbourne, Berlin, Lagos) and people living (Malaga, Lisbon),
working (Gütersloh, Tokyo, Huesca) or playing (Adria Tennis Tour) close to-
gether. The next outbreaks are anticipated in Liverpool, Naples (football cele-
brations) and some Italian cities (movida).
On 24 June, the US established a new national SARS-CoV-2 record. In Texas,
the number of deaths is expected to increase about two to three weeks from
now.

Sunday, 21 June
The number of infections in the Gütersloh (Germany) meat-processing plant
exceeds one thousand. Nearly 7,000 employees are quarantined. After repeat-
ed outbreaks in the meat industry, The Guardian publishes Why you should go
animal-free: 18 arguments for eating meat debunked.
The Spanish authorities increase the purchase of flu vaccines. Immunizations
will start as soon as possible and priority will be given to health personnel.

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Monday, 22 June
France reopens schools, colleges, kindergartens, cinemas, game rooms and
small sports.
In India, 25 luxury hotels are to be transformed into COVID-19 care centers.
Injectable dexamethasone is more difficult to manufacture than tablets, and
could soon run out.
The New York Times publishes Lessons on Coronavirus Testing From the Adult
Film Industry.
Wednesday, 24 June
More than 1,500 workers have tested positive in Gütersloh, Germany. The
abattoir cooling systems may have contributed to spreading aerosol droplets
laden with coronavirus. The authorities order a lockdown for 640,000 people.
In the US, more than 38,000 cases are detected, a record since the start of the
coronavirus epidemic. The states that lifted containment measures, mainly
governed by Republicans, are the most affected.

Source: https://www.worldometers.info/coronavirus/usa/texas

Income emerges as a major predictor of coronavirus infections, along with

race.
Tennis player Novak Djokovic tests positive for COVID-19 amid Adria Tour
fiasco (dixit Le Monde: Adria Cluster Tour).
The Guardian publishes The coronavirus backlash: how the pandemic is destroying
women's rights.

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Thursday, 25 June
In young children, SARS-CoV-2 infection is largely asymptomatic or accom-
panied by few symptoms. Now, two pre-published studies by Fontanet et al.
from the Institut Pasteur, Paris, also suggest lower infection rates in a French
primary school (6 to 11-years-old) when compared to a high school in Crépy-
en-Valois, a small town 60 km northeast of Paris. The studies show that 38%
of high school students had antibodies against SARS-CoV-2, but only 8.8% of
primary school students in the same town (see following table).
A study of residents in the Alpine ski resort of Ischgl find that 42% have anti-
bodies for the virus.
More than 80 people test positive in an outbreak at a Red Cross center in Mal-
aga.
Tokyo detects new outbreaks of coronavirus in offices, with 55 new cases, its
biggest rebound in a month and a half.

High school students* Children in primary school**

Pupils 240 92 (38.3%) 510 45 (8.8%)
Parents 211 24 (11.4%) 641
n.n. (12%)
Close family 127*** 13 (10.2%) 119
Teachers 53 23 (43.4%) 42 3 (7%)
Staff 27 16 (59.3%) 28 1 (3.6%)
Others 3 3 (100%)
Total 661 171 (25.9%) 1 340

* Cluster of COVID-19 in northern France, By Fontanet A, et al.*

** Press report (Le Monde), incomplete data
*** Siblings

Sokolowska et al. publish Immunology of COVID-19: Mechanisms, Clinical Outcome,

Diagnostics and Perspectives - A Report of the European Academy of Allergy and Clin-
ical Immunology (EAACI)
The Guardian publishes On different planets: how Germany tackled the pandemic,
and Britain flailed.
The New York Times publishes How the Virus Won, analyzing travel patterns,
hidden infections and genetic data to show how the epidemic spun out of con-
trol.

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Liverpool wins Premier League. At the title party, thousands gather on the
streets without face masks. Rallies on UK beaches and at street parties in
London.

Friday, 26 June
The Challenges of Safe Reopening – NEJM audio Interview (17:33) with Eric
Rubin, Lindsey Baden and Stephen Morrissey.
The Guardian publishes I'm a viral immunologist. Here's what antibody tests for
Covid-19 tell us.
The New York Time publishes How the Coronavirus Short-Circuits the Immune
System and Can Covid Damage the Brain?

Saturday, 27 June
The European Union is preparing to restrict most US residents from visiting
the region.
If you read Spanish, read Más de 100 días arrastrando el coronavirus |by Isabel
Valdés.
If you read French, read Qu’est-ce que le « R0 », le taux de reproduction du virus ?
by Gary Dagorn.
If you read Portuguese, read Durante a Gripe Espanhola, houve uma Liga Anti-
Máscara. E tudo piorou.

Week 27
This week witnesses an important resurgence of SARS-CoV-2 infections in the
US and India. Meanwhile, Europe which has more or less successfully man-
aged the first wave, is holding its breath: will the economically all-important
tourist season smoothly go ahead or will it be grounded by a second COVID
wave? For now, smaller outbreaks (Gütersloh, Leicester, Lleida) are being kept
under control. In this context, the opening of closed space where strangers
can meet (bars, brothels and restaurants) may not be a good idea.
In the meantime, the EU opens its borders to 15 countries, car rental compa-
nies expect to lose up to 80%, Gilead imposes a price of about 350 euros per
dose for its (weak) anti-SARS-CoV-2 drug, China starts testing a vaccine on
military personnel, and asymptomatic spread continues – why shouldn’t it.
Astonishingly, the question of using face masks continues to be debated.
While you can probably do without them in low-prevalence areas such as
most parts of Southern Italy, you are well-advised to wear them in the US. A

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British journalist stated that not wearing face masks in epidemiological

hotspots is like driving drunk. Imagine how people feel who are governed by
drunkards.
Sunday, 28 June
Ten million official cases and 500,000 COVID-19 deaths.

Source: Johns Hopkins Coronavirus Resource Center.

Monday, 29 June
Chinese CanSino Biologics receives the green light to use a recombinant novel
coronavirus vaccine (Ad5-nCoV) within the military.

Tuesday, 30 June
Anthony Fauci warns that a “general anti-science, anti-authority, anti-
vaccine feeling” is likely to thwart vaccination efforts (The Guardian).
India has more than 450,000 confirmed cases, making it the world’s fourth-
worst-hit country. Major cities such as Delhi and Mumbai are particularly
badly affected (Nature).
China cuts off more than 400,000 people in Anxin county to tackle a small
COVID-19 cluster (The Guardian).
The new poor in Italy? Only a small percentage of companies have received
promised lockdown help (The Guardian).
The English city of Leicester is in local confinement again after 866 new cases
are diagnosed in two weeks.
The pharmaceutical company Gilead imposes a price of about 350 euros per
dose for its (weak) anti-SARS-CoV-2 drug.

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The New England Journal and The Lancet publish three articles (one | two |
three) and a comment about Multisystem Inflammatory Syndrome in Chil-
dren (MIS-C).

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July
Wednesday, 1 July
The New York Times publishes an update on super-spreaders.
Outbreak in Melbourne, Australia. The authorities confine 300,000 people in
30 neighborhoods for a month.
The EU publishes a list of 15 countries from where people should be allowed
into the Union. Visitors from the US to remain banned from entering the EU
because of the country’s rising infection rate.
We discover this YouTube video by Tang and al. visualizing airflow patterns
associated with common, everyday respiratory activities. In this case, talking
illustrates rapidly changing airflow patterns exchanged between talkers.
The US buys up the world stock of remdesivir.
Testing finds cases at US meat-processing plants but officials refuse to release
the information (The Guardian).
According to an article by Science, only 50% of Americans plan to get a
COVID-19 vaccine.

Thursday, 2 July
California rolls back the reopening of bars, restaurants and indoor venues
(The Guardian).
Anthony S. Fauci and H. Clifford Lane publish Four Decades of HIV/AIDS — Much
Accomplished, Much to Do.
Nicholas Kristof publishes Refusing to Wear a Mask Is Like Driving Drunk.

Friday, 3 July
Cheng et al. publish How to Safely Reopen Colleges and Universities During COVID-
19: Experiences From Taiwan.
The Guardian describes the new emergency in Los Angeles.

Saturday, 4 July
The HIV drug lopinavir/ritonavir fails to reduce mortality in an interim anal-
ysis of the Solidarity trial. WHO discontinues both the lopinavir/ritonavir and
the hydroxychloroquine treatment arms for COVID-19 (who.int).

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After SARS-CoV-2 outbreaks in fruit companies, a nursing home, a neighbor-

hood community and a hostel for homeless people, Catalonia imposes a lock-
down on 200,000 people around Lleida.
The epidemic is taking off in the US:

Source: https://www.worldometers.info/coronavirus/country/us/

Adam Gabbatt publishes Fourth of July celebrations increase risk of 'superspreader'

events.
Jesse Wegman publishes Seriously, Just Wear Your Mask.
Michelle Cottle publishes Florida, America’s Pandemic Playground.
Pubs reopen in England.

Week 28
Week 28 will be recorded as a watershed in the perception of SARS-CoV-2
transmission risk: yes, the virus is transmitted by fat droplets, and yes, it is
also transmitted tiny aerosol particles. If this shift is proven to be right,
SARS-CoV-2 may go down in history as the virus that unified the almost cen-
tury-old dichotomy of droplets vs. aerosol transmission. The merit goes to
Lidia Morawska and Donald K. Milton, supported by 237 scientists (see also
the comment in The Guardian and in The New York Times). In the next days,
we will publish an update of our Transmission chapter.
Paterson et al. publish a worrisome article about the neurological complica-
tions of COVID-19.
Second waves are leading to partial lockdowns in Australia, Spain, Serbia and
Israel while Catalonia and the Balearic Islands order wearing face masks even
when the required 1.5-metre social distancing can be observed.

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The first wave continues in the US. People in Mexico border towns try to stop
Americans from crossing.

Sunday, 5 July
Is it time to address airborne transmission of SARS-CoV-2? It may be high
time, say Lidia Morawska and Donald K Milton, supported by other 237 scien-
tists. See also WHO underplaying risk of airborne spread of Covid-19 (The Guardi-
an), 239 Experts With One Big Claim: The Coronavirus Is Airborne and Airborne Coro-
navirus: What You Should Do Now (The New York Times).
Spain puts part of Galicia back into lockdown.

Monday, 6 July
Find out how Anthony Fauci, Elizabeth Connick, Paul A. Volberding, Linda
Bell, Barry Bloom and David Satcher deal with COVID-19 risks in their every-
day lives.

Tuesday, 7 July
If you read Spanish, read “La enigmática mutación del coronavirus que ahora
domina el planeta” (El País).
Wednesday, 8 July
COVID-19 fears: People in Mexico border towns try to stop Americans from
crossing (The Guardian).
Paterson et al. publish The emerging spectrum of COVID-19 neurology: clinical,
radiological and laboratory findings. See also the article published in The Guard-
ian.
Violence at Belgrade protest over renewed lockdown measures
Churches at risk: SARS-CoV-2 infiltrates Sunday services, church meetings
and youth camps. More than 650 cases have been linked to reopened religious
facilities.
Second COVID-19 wave in Israel.

Thursday, 9 July
WHO update information about SARS-CoV-2 transmission (WHO 20200709):
“There have been reported outbreaks of COVID-19 in some closed settings,
such as restaurants, nightclubs, places of worship or places of work where
people may be shouting, talking, or singing. In these outbreaks, aerosol
transmission, particularly in these indoor locations where there are crowded

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and inadequately ventilated spaces where infected persons spend long peri-
ods of time with others, cannot be ruled out.”
Five million Melbourne residents are locked down again (read also this arti-
cle).
Catalonia orders wearing face masks even when the required 1.5-metre social
distancing can be observed. The fine for not observing the new rules: 100 eu-
ros. The Balearic islands is set to follow Catalonia’s lead soon.
The Tokyo authorities pay nightclubs as well as host and hostess bars thou-
sands of dollars if they close for more than 10 days.
Indonesia announces a new cluster of more than 1,000 cases at a military
training center in West Java.

Friday, 10 July
Guardian live (10 July): Bogotá to re-enter strict lockdown.
The Guardian Global report (10 July).
Rats torment New York alfresco diners.
Scotland asserts separateness from England.
If you read Spanish, read El mapa de los brotes de coronavirus: el 40% tiene su ori-
gen en encuentros familiares.

Saturday, 11 July
The Guardian: Coronavirus live + Global report.
New outbreak in Spain in L’Hospitalet, the second biggest city in the Barcelo-
na metropolitan area (3.2 million people; El País).
Over 40 Florida hospitals max out their intensive care unit capacity (The
Guardian).
Rapid serological tests are now available in French pharmacies. The test re-
quires taking a drop of blood by pricking the skin, usually at the fingertip,
then putting it in contact with a reagent. The result appears in a few minutes
(Le Monde).
The NY Times publishes ‘I Couldn’t Do Anything’: The Virus and an E.R. Doctor’s
Suicide.
If you read Spanish, read the Fauci interview “La cuestión es que todo el mundo
debería llevar mascarilla” (El País).
Is the governor of the hard-hit Lombardy region (almost 50% of all Italian
cases) opening the dance for the second wave in his country? In a bold (sui-
cidal?) move he allows discos to reopen open-air discos. The Repubblica

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newspaper reports that people “filled the slopes of the main Milanese discos
without wearing personal protective equipment and without respecting the
social distancing.” The countdown has begun.

Week 29
This week, the publication of detailed results of a phase 1, dose-escalation,
open-label trial (14 July) reminded us that the race for a vaccine is gaining
momentum. More encouraging results from competitor researchers are ex-
pected within days.
Meanwhile, the pandemic is gaining momentum, too, with sad records rec-
orded from all over the world. A new area of concern is Europe, where a sec-
ond wave may be building up (18 July). In contrast to what happened in
March, local epidemics seem now to be fueled by the infection of younger
people. Wearing face masks may soon be required in many European coun-
tries (16 July).
In the US, daily new SARS-CoV-2 cases are on track to go beyond 100,000. As
Rudolf Virchow, the great 19th century father of pathological anatomy, liked
to say: “An epidemic is a social phenomenon that has some medical aspects.”
(Cited by Bernard Henri-Lévy in Ce virus qui rend fou, Grasset, June 2020)

Sunday, 12 July
Fourteen renowned doctors (Antoine Pelissolo, Jimmy Mohamed Philippe
Amouyel, Francis Berenbaum, Eric Caumes, Robert Cohen, Anne-Claude
Crémieux, Gilbert Deray, Vianney Descroix, Philippe Juvin, Axel Kahn, Karine
Lacombe, Bruno Megarbane and Christine Rouzioux) demand “the wearing
of a mandatory mask in all enclosed public places” in order to prevent a
second COVID-19 wave (Le Parisien, Le Monde).
In Sydney, thousands of pub-goers have been asked to self-isolate for two
weeks after a hotel staff member and three other people became the latest
cases in an emerging coronavirus cluster (The Guardian).
Will COVID-19 help to cure over-tourism in the future? Many cities around
the world are searching for a new balance. Reflections about the current si-
tuation in Paris (Le Monde, Édition abonnés).
If you read Spanish, read Los delirios mortales del rey Donald, by Paul Krugman,
and Jornaleros de la pandemia, by Guillermo Abril.

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Monday, 13 July
California, 40 million people, return to the closure of all indoor operations
for restaurants wineries, movie theaters and family entertainment, zoos, mu-
seums and cardrooms bars. The state is one of the main SARS-CoV-2 foci in
the United States (more than 300,000 cases, 7,000 deaths).
A study examining data for 355 Dutch municipalities finds evidence of a posi-
tive relationship between air pollution and Covid-19 cases, hospital admis-
sions and deaths (Cole MA, Ozgen C, Strobl E (PDF); The Guardian).
The Guardian: 30-year-old dies after attending 'Covid party' in Texas | ‘I
think I made a mistake, I thought this was a hoax, but it’s not.’ See also the
video by Jane Appleby.
Do men without a mask look tough? (The Guardian)
Returning German tourists as superspreaders? The CEO of the World Medi-
cal Association Frank Ulrich Montgomery proposes a two-week quarantine
for holidaymakers returning from the Mallorca island (audio in German) after
hundreds of drunken tourists celebrate in a pre-COVID atmosphere.
No re-opening of discos in France as the French Council of State estimates
that the prolonged closing of the night clubs is not “disproportionate” (Le
Monde).

Tuesday, 14 July
Jackson et al. publish a preliminary report about 45 healthy adults, 18 to 55
years of age, who received two vaccinations, 28 days apart, with mRNA-1273
in a dose of 25 μg, 100 μg, or 250 μg. Read also the editorial by Editorial by
Penny M. Heaton: The Covid-19 Vaccine-Development Multiverse and the audio
interview Covid-19 Vaccine Development, by Rubin, Baden and Morrissey.
Israel, Uzbekistan, Melbourne, California – certain states, areas and cities en-
ter new lockdowns. Le Monde updates a non-exhaustive list of new pandemic
hotspots, classified by number of inhabitants concerned and by country.
Jeneen Interlandi publishes Why We’re Losing the Battle With Covid-19. (The New
York Times)
Michelle Goldberg publishes In Some Countries, Normal Life Is Back. Not Here.
(The New York Times)
Twitter comment on British tourists in Spain: “Parts of Spain in lockdown,
the elderly shut away in care homes, we all wear masks in the street, but in
Magaluf the antisocial and irresponsible Brits do whatever they please. It’s
shameful.” (The Guardian, text and video)

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Wednesday, 15 July
If you read Spanish, read Una sanitaria en L’Hospitalet de Llobregat: “El ambulato-
rio roza el colapso, peor que en abril”. (El País).
Matthew J. Belanger, Michael A. Hill, Angeliki M. Angelidi, Maria Dalamaga,
James R. Sowers, and Christos S. Mantzoros publish Covid-19 and Disparities in
Nutrition and Obesity. (The New England Journal of Medicine)
Renee N. Salas, James M. Shultz, and Caren G. Solomon publish The Climate
Crisis and Covid-19 — A Major Threat to the Pandemic Response. (The New England
Journal of Medicine)

Thursday, 16 July
The French government decides that wearing mask will be compulsory in
closed public places from next week. They describe the situation as “prob-
lematic” in Mayenne, “worrying” in New Aquitaine, and increasing number of
cases in Paris and in Finistère. (Le Monde)
In Spain, 40% of recent outbreaks might have been associated with family
events (“...a wedding in Tudela, a celebration of San Juan in a neighborhood
of Castellón, a meal with friends in Alcanar (Tarragona).” (El País).
In a response to the paper by Jackson et al. (see 14 July), British researchers
working on another Covid-19 vaccine at the University of Oxford spread the
word that their vaccine, too, triggers two types of immune response: the pro-
duction of antibodies – proteins that can bind to the virus, preventing it from
entering cells and flagging it to immune cells – but it also seems to result in
the production of “killer” T cells – immune cells that attack infected human
cells. (The Guardian)
Danielle Renwick publishes How quickly will there be a vaccine? And what if people
refuse to get it? (The Guardian)
Merlin Chowkwanyun and Adolph L. Reed publish Racial Health Disparities and
Covid-19 — Caution and Context. (The New England Journal of Medicine)
If you read Spanish, read Miguel Ángel Criado: Más de la mitad de los españoles
ingresados por coronavirus han desarrollado problemas neurológicos (El País)

Friday, 17 July
Israel returns to partial lockdown. All indoor gatherings of 10 or more people
are banned. Restaurants return to takeaways and deliveries only. During the
weekend, all shops, hairdressers and attractions are closed. All gyms and fit-
ness studios are closed at all times.

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Saturday, 18 July
Spain seems on the brink of a second COVID-19 wave. In the last 7 days, the
country had 10 times more new cases than a month ago (El País). Four mil-
lion residents of Barcelona and 12 municipalities around the city have been
urged to stay at home. The regional Government announces that the re-
strictions also include the reduction of capacity in bars and restaurants and
closure of nightlife venues, cultural activities and gyms, and a ban on gather-
ings of more than 10 people from Saturday.
In France, which already announced plans to make mask wearing mandatory
in enclosed public spaces, authorities reported a sharp rise in the infection
rate in Brittany. According to data released on Friday, the disease’s reproduc-
tion rate in Brittany has risen from 0.92 to 2.62 between 10-14 July.
Infections in India pass one million.
Tom McCarthy publishes ‘The virus doesn’t care about excuses’: US faces terrifying
autumn as Covid-19 surges (The Guardian).

Week 30
This week may be recalled as the timid beginning of the second European
COVID-19 wave. At the beginning of the week, bars in Barcelona were ordered
to limit the number of clients. On Saturday, Norway and the UK imposed a 10
(UK: 14) day quarantine on all people coming back from Spain, mostly holi-
daymakers, and Barcelona ordered the closure of discos, dance halls, etc. All
over the continent, outbreaks are linked to seasonal farm laborers, family
meetings and night life. 2020 tourism was severely affected by the continent-
wide spring lockdowns. It is now doubtful that the holiday season will contin-
ue to summer’s end.
The daily new cases in Australia:

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 The First Eight Months | 479

Figure 30.1. Daily new cases in Australia (blue line: 7-day monthly average).

Monday, 20 July
This is vaccine day. Andrew Pollard and colleagues report their phase 1/2
randomized trial of a chimpanzee adenovirus-vectored vaccine (ChAdOx1
nCoV-19); and Wei Chen and colleagues report results from a randomized
phase 2 trial of an Ad5-vectored COVID-19 vaccine. Read also the comment by
Naor Bar-Zeev and William John Moss.
In Sao Paulo, 900 health professionals will participate in a phase 3 trial of a
vaccine developed by the Chinese Sinovac Biotech laboratory. In total, the
vaccine will be offered to 9,000 volunteers in six Brazilian states.
In France, the wearing of a mask becomes compulsory in closed places which
are open to the public.
In Barcelona, the capacity in bars is limited to 50%. Visits to nursing homes
are prohibited.

Tuesday, 21 July
Historic pact of the European Union to overcome the COVID-19 crisis: for the
first time in its history, the EU member states will borrow money to finance
an extraordinary economic stimulus with 390,000 million in grants and
360,000 million in credits, sending a strong message that they will continue to
stay together. Presidents in the east and in the west will have taken notice
(see also The Guardian).
Indian authorities claim that SARS-CoV-2 antibody testing of people living in
the Delhi region showed that 23.5% had antibodies against the virus. Samples

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from 21,387 people were examined. This percentage would be 50 times higher
than the officially reported figures. Delhi, with a population of 29 million, has
reported only 123,747 infections.
Jennifer Steinhauer and Thomas Gibbons-Neff explain how American military
officials are trying to contain the spread of the SARS-Cov-2 in its ranks (The
New York Times).
See also the feature by The Guardian: How coronavirus is reshaping Europe's
tourism hotspots. An opportunity to rethink their business model?
Barcelona reduces the capacity of its beaches (El País).

Wednesday, 22 July
Belgium is recording a significant increase in Covid-19 cases. During the peri-
od July 12-18, the number of new infections rose 89% with an average of 184
cases diagnosed per day, up from 98 the week before. Most cases are among
people between 20 and 59 years old who were infected during parties or gath-
erings.
On the eve of a four-day long weekend in Japan, the governor of Tokyo calls
on her constituents to stay at home, as the number of new daily cases of
Covid-19 is sharply increasing in the region. As Covid-19 infections appear to
be spreading widely, the Japanese capital is on its maximum alert level.
In Spain, 40% of people newly infected with SARS-CoV-2 are under 40 years of
age and most do not know where they have been infected.

Thursday, 23 July
The Spanish newspaper El País sounds the alarm: The virus rebounds in
Spain: data from 10 communities show more infections and more hospitaliza-
tions.
In the U.S., SARS-CoV2 testing laboratories struggle to find the chemicals and
plastic pieces they need to carry out coronavirus tests (The New York Times).
Lazaro Gamio, Sarah Mervosh and Keith Collins show Where the Virus Is Sending
People to Hospitals.

Friday, 24 July
Authorities order the closure of nightlife (discos, dance halls, etc.) in Catalo-
nia for at least 15 days. The hours of activity in casinos and game rooms are
limited until midnight (El País + El País).
Norway reinstates mandatory 10-day quarantine for travelers coming back
from Spain.

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 The First Eight Months | 481

The U.K. makes wearing masks compulsory in stores.

The New York Times and El País ask “Who will receive the first COVID vac-
cines?”
Lauren Leatherby publishes How the U.S. compares With the world’s worst
coronavirus hot spots.

Saturday, 25 July
Catalonia exceeds 50 hospitalized daily, 10 times more than the figures re-
ported by the Ministry of Health (El País).
In Belgium, wearing masks is now compulsory on markets, in shopping
streets, in hotels, cafes and restaurants (except at the table).
With immediate effect, the UK re-quarantines travelers from Spain. Those
who come back home must isolate themselves for 14 days. This measure will
affect Spain’s tourism industry. But not only Spain is suffering.
If you read Spanish, read El coronavirus ha repuntado en 30 provincias: el
mapa con la situación de los contagios en cada una | En el último mes han
aumentado los casos y las hospitalizaciones en media España (El País).

Sunday, 26 July
A tsunami of fake news hurts Latin America’s effort to fight SARS-CoV-2. A re-
port by Tom Phillips in São Paulo, David Agren in Mexico City, Dan Collyns in
Lima and Uki Goñi in Buenos Aires (The Guardian).
A surge in COVID-19 cases has forced a hospital in rural Texas to set up
“death panels” to decide which patients it can save and which ones will be
sent home to die. By Michael Sainato.
Victoria, Australia, reports a national record of 10 Covid-19 deaths.
North Korea reports the first COVID-19 case (...) and declares a state of emer-
gency (The Guardian).
How Hawaii avoided a coronavirus spike, but severely damaged its economy. Lau-
ren Aratani explains.
If you read Spanish, read this: Un verano con virus: qué hacer | Viajar con
amigos o ir a visitar a la familia unos días entraña riesgos. ¿Se comparte el
salón? ¿Y el coche? ¿Se puede ligar? Los expertos explican cómo minimizar la
exposición.
The true number of excess deaths due to COVID-19 is probably more than 50%
higher than the officially reported data. See the analysis by El País.

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Monday, 27 July
If you understand German, meet Dr Camilla Rothe (6 minutes) who detected
the first SARS-CoV-2 positive patient in Germany at the end of January. With-
in days, it became clear that asymptomatic transmission would play an im-
portant role in the pandemic. In the video interview, Dr Rothe looks back -
and forward.

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 www.CovidReference.com

Bernd Sebastian Kamps

Christian Hoffmann

COVID
reference
eng | 2020.5

eng | 2020.5
covidreference.com

Second waves, third waves, never ending waves –

as the world is about to enter the second year of the
SARS-CoV-2 pandemic, people realize that they are
just at the beginning of a global health and economic
crisis. In the Northern Hemisphere, the 6 dark autumn
and winter months have begun and the world is holding
its breath: will the new coronavirus follow the track
of the 1918 flu epidemic, relatively mild in spring and
devastating in autumn and winter?
There is no doubt that the immense resources of
medicine and biotechnology will soon produce a safe
and effective vaccine; however, only fools expect mass
vaccinations before the middle of 2021 and a measurable
impact on the pandemic before 2022.
In the meantime, people around the globe will
reduce their contacts with other people and perfect their
skills of social distancing. They will continue to wear
face masks next year, the year after and maybe beyond.
It isn’t fun but it must be done.