Covid Reference 04

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Bernd Sebastian Kamps

Christian Hoffmann
COVID
reference
eng | 2020.4
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Christian Hoffmann
COVID Reference
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Fourth Edition 2020~4
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have received no support from third parties to realize this manual.
Christian Hoffmann
COVID Reference
www.CovidReference.com
Edition 2020.4
Steinhäuser Verlag
4 |
Bernd Sebastian Kamps, M.D.

www.Amedeo.com
Christian Hoffmann, M.D.

Infektionsmedizinisches Centrum
Hamburg MVZ PartG (ICH)
ICH Stadtmitte
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| 5
Preface
Six weeks after the third edition, the world has changed again.
The pandemic is raging in South America, particularly in Brazil,
Ecuador and Peru. SARS-CoV-2 is under control in China, but in
Iran it is not. And in Europe, where most countries have weath-
ered the first wave and open borders to save a compromised
tourist season, is now wondering if and for how long this biologi-
cal drôle de guerre could last.
Science has moved ahead, too. We have seen a more complex
picture of COVID-19 and new clinical syndromes; the first data
from vaccine trials; first results from randomized controlled
drug studies; encouraging publications on monoclonal neutraliz-
ing antibodies and serological evidence about the number of
people who have come into contact with SARS-CoV-2. Unfortu-
nately, we have also seen the first science scandal with fake data
published in highly ranked journals. And we face new challenges
like long-term effects of COVID-19 and a Kawasaki-like inflam-
matory multisystem syndrome in children.
For quite some time, prevention will continue to be the primary
pillar of pandemic control. In future waves of the SARS-CoV-2
pandemic, we will focus on the conditions under which SARS-
CoV-2 is best transmitted: crowded, closed (and noisy) places and
spaces. Although hospitals are not noisy, they are crowded and
closed, and the battle against the new coronavirus will be decid-
ed at the very center of our healthcare system. Over the next
months and maybe years, one of all of our top priorities will be
to give all healthcare workers and patients perfect personal pro-
tective equipment.
Bernd Sebastian Kamps & Christian Hoffmann

7 June 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 maga-
zine concluded that our SARS Reference
(www.SARSReference.com) was “not fancy”, but presented
“plenty of information”. When we became aware of the new
coronavirus epidemic in mid-January 2020, we immediately felt
that time had come to repeat our millenium 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 enforcing 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 life-
styles in what is the most disruptive event since World War II.
We believe that the current situation needs a new type of text-
book. Humanity is confronting an unknown and threatening dis-
ease 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 rumors and fake news. The
tedious work of screening the scientific literature and the scien-
tific data has to be done – regularly & constantly, like a Swiss
watch.
| 7
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
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
| 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
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
Türkçe
Zekeriya Temircan
Ph.D. in Health/Clinic Psychology
Neuropsychology Department
Turkey
Professor, Erciyes University Neurology Department/

Pediatric Neurology
Gevher Nesibe Genom and Stem Cell Institute Neuroscience Department
Turkey
Dilara Güngör
Turkey
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
| 11
Deutsch
Ulf Lüdeke
www.Sardinienintim.com
Art + Editor
Attilio Baghino
Cover
Félix Prudhomme
YouTube: IYENSS
Thomas Splettstösser
SciStyle (Figures)
Rob Camp
Copy editor
| 13
Content
0. Top 10 17
1. Epidemiology 19
Transmission Hotspots 20
The pandemic 33
Lockdown outcomes 37
Special Aspects of the Pandemic 45
Lockdown Exit 53
“COVID Pass” 56
The second wave 57
References 60
2. Transmission 71
The Virus 71
Person-to-Person Transmission 74
Routes of Transmission 75
Transmission Event 81
Outlook 89
References 90
3. Virology 105
4. Immunology 125
Protective antibodies 125
Cellular immune response 126
The quest for a vaccine 127
Outlook 136
References 137
5. Prevention 141
Prevention at the personal level 142
Prevention at the community/societal levels 145
Prevention at the institutional level 150
6. Diagnostic Tests and Procedures 155

Diagnosis 155
Radiology 172
References 176
7. Clinical Presentation 185

Incubation period 185
Asymptomatic cases 186
Symptoms 188
Laboratory findings 200
Clinical classification 205
Outcome 206
Kamps – Hoffmann
| 15
Outlook 218
References 218
8. Treatment 233
Inhibitors of the viral RNA synthesis 234
Antiviral entry inhibitors 243
Immunomodulators 248
Outlook 258
References 260
9. Severe COVID 271
10. Comorbidities 277

Hypertension and cardiovascular comorbidities 279
Diabetes mellitus 287
COPD and smoking 289
HIV infection 291
Immunosuppression (other than HIV) 296
Transplantation 298
Other comorbidities 300
11. Pediatrics 303

SARS-CoV-2 infection in children 303
Epidemiology of COVID-19 in children 305
Natural course and risk factors for complications 306
Pathophysiology and immunopathology 308
Transmission 310
Diagnosis and classification 311
Management 318
References 326
12. Timeline 333
Kamps – Hoffmann
Top 10 | 17
0. Top 10
Please bookmark www.CovidReference.com/Top10Papers and
come back at 19:00 CEST 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 004

Kamps – Hoffmann
Epidemiology | 19
1. Epidemiology
Stefano Lazzari
In December 2019, several patients from Wuhan, People’s Repub-

lic of China, developed pneumonia and respiratory failure remi-
niscent of the SARS epidemic in 2003 (WMHC 2019,
www.SARSReference.com). In early January 2020, a new virus
was isolated from bronchoalveolar lavage fluid samples and
found to be a betacoronavirus (Zhou 2020). Between then and
the time of this writing (7 June), the virus, later denominated
SARS-CoV-2, has spread to every corner of the world. Millions
have been diagnosed with SARS-CoV-2 infection and hundreds of
thousands of people have died of COVID-19, the disease caused
by SARS-CoV-2. SARS-CoV-2 has the potential to cause a long-
lasting pandemic with high fatality rates.
In this chapter, we will discuss:
Hotspots of SARS-CoV-2 infection
The natural course of the COVID-19 pandemic and its mitiga-
tion by “lockdown” measures
The effect of “lockdown” measures
Special aspects of the pandemic in selected places
A ‘COVID pass’
The second wave
The transmission of SARS-CoV-2 is discussed in a separate chap-
ter (page 71) which highlights that SARS-CoV-2 is easily trans-
missible both by symptomatic and asymptomatic individuals; it
thrives in closed and densely inhabited environments; and is
amplified by so-called ‘superspreader’ events. There is evidence

that in China, human-to-human transmission has occurred

among close contacts since the middle of December 2019 (Li Q
2020). In Italy and France, SARS-CoV-2 was circulating as early as
January among asymptomatic or paucisymptomatic people
(Cereda 2020, Gámbaro 2020). In the Greater Paris Region, after
retesting samples from 24 patients treated in December and Jan-
uary, one sample collected on December 27 was retrospectively
found to be positive for COVID (France 24, 5 May 2020). The sam-
ples had initially been collected to detect flu using PCR tests.
The mean incubation period of SARS-CoV-2 infection is around 5
days (Li 2020, Lauer 2020, Nie X 2020). The serial interval – de-
fined 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 infec-
tious period in a naïve, uninfected population.]
Transmission Hotspots
The probability of SARS-CoV-2 transmission is a function of time
and closeness of contact between infected and susceptible indi-
viduals. The following settings are catalyzers of local outbreaks:
Homes (+ intense social life with friend and colleagues)
Workplaces
Hospitals
Nursing facilities
Cruise ships
Aircraft carriers and other military vessels
Mass gatherings and religious gatherings
Kamps – Hoffmann
Epidemiology | 21
Schools
Prisons
Homeless shelters
Industrial meat-packing plants
Choirs
Homes
Infection rates at home varied widely (between 11% and 19%) in
three studies (Bi Q 2020, Jing QL 2020, Li W 2020). One group not-
ed 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 of that a 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 at-
tack 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 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);
however, this percentage relied on the assumption that all sec-
ondary cases were infected by the index case. In single house-
holds, the transmission rates may probably reach 75% or more
(Böhmer 2020).

Workplaces
As early as January 2020, SARS-CoV-2 was found to spread during
workshops and company meetings (Böhmer 2020). Later, an out-
break 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).
Recently, outbreaks with hundreds of infected individuals were
reported from meat-packing plants in Germany (DER SPIEGEL),
the US (The Guardian) and France (Le Monde).
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, refreshments were served in the
same 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 colleagues for about 45 min. The 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 im-
portant amplifiers of local outbreaks epidemics.
Hospitals and other health care centers

There is no doubt that transmission in hospitals and other health
care centers (including doctors offices) played a prominent role
in the origin and spread of local epidemics, especially in the be-
ginning when suspicion of the disease was low. This is reminis-
cent of the largest MERS outbreak outside of the Arabian penin-
sula which occurred in the Republic of Korea in 2015. Of the 186
Kamps – Hoffmann
Epidemiology | 23
cases, 184 were infected nosocomially (Korea Centers for Disease

Control and Prevention 2015).
Hospitals are a favorable environment for the propagation of
SARS-CoV-2 (Wison 2020). In some instances, hospitals could
have been even the main COVID-19 hub, as they were rapidly
populated by infected patients, facilitating transmission to
health workers and uninfected patients (Nacoti 2020). Within the
first 6 weeks of the epidemic in China, 1,716 cases among health
care workers were confirmed by nucleic acid testing, and at least
5 died (0.3%) (Wu 2020).
One hospital 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. Contamination was greater in ICUs. Virus was
found on floors, computer mice, trash cans, sickbed handrails,
and was detected in the air up to approximately 4 m from pa-
tients (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, most of these studies have evaluated only viral RNA. It
remains to be seen whether this translates into infectious virus.
Although nosocomial spread of the virus is well documented,
appropriate hospital infection control measures can prevent
nosocomial transmission of SARS-CoV-2 (Chen 2020). This was
nicely demonstrated by the case of a person in her 60s who trav-
elled to Wuhan on Dec 25, 2019, returned to Illinois 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 infected
(Ghinai 2020).
However, working in a high-risk department, longer duty hours,
and suboptimal hand hygiene after coming into contact with
patients, are all associated 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 and other health care workers. On 14 April,
the US CDC reported that 9,282 Health Care Personnel has been
infected with SARS-COV-2 in the USA.
The risk factors for SARS-CoV-2 infection in health care workers
has recently been summarized in a review. There is evidence
that more consistent and full use of recommended PPE measures
was associated with decreased risk for infection, suggesting a
dose–response relationship. Association was most consistent for
masks but was also observed for gloves, gowns, and eye protec-
tion, as well as hand hygiene. Some evidence was found that N95
respirators might be associated with higher reduction of risk for
infection than surgical masks. Evidence also indicated an associ-
ation between certain exposures (such as involvement in intuba-
tions, direct contact with infected patients, or contact with bodi-
ly fluids) (Chou 2020).
SARS-CoV-2 outbreaks can occur everywhere, not only in admis-
sion, infectious disease and intensive care units. In a pediatric
dialysis unit in Münster (Germany), a healthcare worker infected
7 colleagues, three young patients and one accompanying person
(Schwierzeck 2020). A Chinese study of 9,684 healthcare workers
(HCW) in Tongji Hospital confirmed 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). Those who work in clinical departments other than fever
clinics and wards may have neglected to adopt adequate protec-
tive measures.
In a well-documented report about nosocomial transmission re-
cently published, a man sought help for coronavirus symptoms
on March 9, spending only a few hours at the emergency de-
partment of a hospital in Durban, South Africa. He was kept sep-
arate in a triage area, but that room was reached through the
Kamps – Hoffmann
Epidemiology | 25
main resuscitation bay, where a stroke patient occupied a bed.

Both patients were seen by the same doctor. After being infect-
ed, the stroke patient caused a chain of transmission with 39
patients and 80 staff in 16 different departments being infected,
and 15 patients dying. The study found that patients infected few
other patients directly. Instead staff members spread the disease
from patient to patient and from department to department,
perhaps sometimes without becoming infected themselves
(Nordling 2020). Strictly enforcing infection control measures
and screening hospital staff will be important measures in future
waves of COVID-19.
Long-term care facilities

Long-term care facilities are high-risk settings for infectious
respiratory diseases. In a skilled nursing facility in King County,
Washington, US, 167 cases of COVID-19 were diagnosed within
less than three weeks from the identification of the first case:
101 residents, 50 health care personnel and 16 visitors
(McMichael 2020) (Table 1).
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 demonstrates that once intro-
duced 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.
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 3,045 residents who died between 1 February and 14
April were either diagnosed with COVID-19 or presented flu-like
symptoms, a death rate among residents of 6.7%. Among the 661
residents who were hospitalized during the same period, 199
(30%) were found positive by a PCR test. According to WHO esti-

mates, in countries in the European Region up to half of those

who have died from COVID-19 were residents in long-term care
facilities (see the statement to the press by Hans Henri P. Kluge,
WHO Regional Director for Europe). Excess mortality data sug-
gests 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 mortality
statistics.
Table 1. 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
SARS-CoV-2 continues to spread in US nursing homes where ap-

proximately 1.3 million Americans reside (CDC 200311). In mid-
April, more than 1,300 facilities had identified infected patients
(Cenziper 2020). As most residents have one or more chronic
underling condition such as hypertension, cardiac disease, renal
disease, diabetes mellitus, obesity and pulmonary disease,
COVID-19 puts them at high risk for premature death.
Kamps – Hoffmann
Epidemiology | 27
Cruise ships
Cruise ships carry many people in confined spaces. On 3 Febru-
ary 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 passen-
gers quarantined on board. Over time, more than 700 of 3,700
passengers and crew tested positive (around 20%). One study
suggested that without any intervention 2,920 individuals out of
the 3,700 (79%) would have been infected (Rocklov 2020). The
study also showed that an early evacuation of all passengers on 3
February would have been associated with only 76 infected.
For cruise ships, SARS-CoV-2 may spell disaster as carrying vil-
lage-loads of people from one place to another may not be a via-
ble business model until the global availability of a safe and effi-
cient vaccine.
Aircraft carriers and other military vessels

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, alt-
hough 95% had been appropriately vaccinated (Earhart 2001).
Since the beginning of the year, several outbreaks of COVID-19
on military 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 The-
odore 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 4,800 were infected with SARS-CoV-2
(see also the March 30 entry of the Timeline); around 60% re-
mained asymptomatic. One active duty sailor died (USNI News).
On the French aircraft carrier Charles-de-Gaulle, a massive epi-
demic was confirmed on 17 April. Among the 1,760 sailors, 1,046

(59%) were positive for SARS-CoV-2, 500 (28%) presented symp-

toms, 24 (1.3%) sailors were hospitalized, 8 on oxygen therapy
and one in intensive care.
Smaller clusters have also been reported on 5 other US military
vessels, and in one each from France, Taiwan, and Holland. How-
ever, given usual security policies and communication re-
strictions of national armies and navies, it is possible that other
unreported cluster of cases and even deaths might have oc-
curred.
For aircraft carriers, the potential for further outbreaks at any
time might well interfere with full operability.
Mass gatherings
Several mass gathering events have been associated with explo-
sive outbreaks of COVID-19. As of April 24, 2020, a total of 5,212
coronavirus cases were related to an outbreak at the Shincheonji
Church in South Korea, accounting for about 48.7% of all infec-
tions in the country.
A football match played in Milan, Italy on 19 February 2020 has
been described as “Game zero” or “a biological bomb”. The
match was attended by 40,000 fans from Bergamo and 2,500 from
Valencia and played just two days before the first positive case of
COVID-19 was confirmed in Italy. 35 percent of Valencia’s team
members tested positive for the coronavirus 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 COVID-19 outbreak in Italy. Va-
lencia also had 2,600 cases of the infection.
The annual gathering of the Christian Open Door Church held
between 17 and 24 February in Mulhouse, France, was attended
by about 2,500 people and became the first significant cluster in
Kamps – Hoffmann
Epidemiology | 29
France. After a parishioner and 18 family members tested posi-

tive 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 contributed to the start of the COVID-19 epidemic in
France. A large number of diagnosed cases and deaths in France
as well as Switzerland, Belgium and Germany were linked to this
gathering.
Religious celebrations
One report describes 35 confirmed COVID-19 cases among 92
attendees at church events during March 6–11. The estimated
attack rates 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 individu-
als were confirmed to be infected with SARS-CoV-2 (Frankfurter
Rundschau).
The bottom line: Going to church does not protect from SARS-
CoV-2.
Schools and schoolchildren

Schoolchildren usually play a major role in the spread of respira-
tory viruses, including influenza. However, while the SARS-CoV-
2 virus has been detected in many children, they generally expe-
rience milder symptoms than adults, need intensive care less
frequently and have a low death rate.
The possible role of children in SARS-COV-2 transmission is still
unclear. In a small COVID-19 cluster detected in the French Alps
at the end of January, one person 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 infections. Also, no virus was found
in the boy’s two siblings who were on the same Alpine vacation.
The researchers concluded that “because children are less likely
to become infected and symptoms are milder, they may play a
less important role in the spread of the new virus”.
A Norwegian Institute of Public Health review of the role of chil-
dren in the transmission of SARS-CoV-2 found five documented
cases of likely spread of disease from children, but concluded
that the evidence is sparse and it is too early to say if children
play an important role in the spread of the disease (Fretheim
2020). However, a pre-print study of SARS-CoV-2 viral load by
patient age conducted by the Institute of Virology, Charité-
Universitätsmedizin Berlin, did not find any statistical difference
in viral load in different age groups, concluding that children
may be as infectious as adults and suggesting to use caution in
the re-opening of schools and kindergartens in the present situa-
tion (Jones 2020). The debate continues.
Prisons
According to the WHO, people deprived of their liberty, such as
people in prisons and other places of detention, are more vul-
nerable to the coronavirus disease (COVID-19) outbreak (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 diseases 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).
The UN High Commissioner for Human Rights, Michelle Bach-
elet, has encouraged governments to release inmates who are
especially vulnerable to COVID-19, such as older people, as well
as low-risk offenders, and a number of countries are taking ac-
tion to try to reduce the prison population.
Kamps – Hoffmann
Epidemiology | 31
As of 21 April, SARS-CoV-2 was present in US correctional and

detention facilities. Aggregated data on cases from 37 of 54 state
and territorial health department jurisdictions revealed 4,893
cases and 88 deaths among incarcerated and detained persons
and 2,778 cases and 15 deaths among staff members (Wallace
2020).
Homeless shelters
Testing in 1,192 residents and 313 staff members in 19 homeless
shelters from 4 US cities (see table), initially triggered by the
identification of a COVID-19 cluster, found infection rates of up
to 66% (Mosites 2020).
In another report from Boston, Massachusetts, 147/408 (36%)
homeless shelter residents were positive. Of note, 88% had no
fever or other symptoms at the time of diagnosis (Baggett 2020).
Industrial meat-packing plants

On 5 May 2020, the German magazine DER SPIEGEL reported that
more than 600 employees were infected with SARS-CoV-2 at
meat processing plants in Germany. One week later, The Guardi-
an reported that almost half of the current COVID-19 hotspots in
the US were linked to meat processing plants where poultry, pigs
and cattle are slaughtered and packaged. At the same time,
around a hundred people tested positive in two meat processing
plants in France (Le Monde).
Promiscuity, cold and humid conditions are currently favored as
explanations for these unusual outbreaks.
Choirs
On 8 March 2020, the Amsterdam Mixed Choir gave a perfor-
mance of Bach’s St John Passion in the city’s Concertgebouw Au-
ditorium. 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 colleagues;
some singers required intensive care (The Guardian, 17 May).
On 9 March, members of the Berlin Cathedral Choir meet for
their weekly rehearsal. Three weeks later, 32 out of 74 choir
members were positive for SARS-CoV-2 (NDR 2020). All recov-
ered.
On 10 March 2020, 61 members of a Skagit County, Washington,
choir met for a 2.5-hour practice. A few weeks later, researchers
reported that 32 confirmed and 20 probable secondary COVID-19
cases 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 virus diffusion by the act of
singing (Hamner 2020).
These data suggest that any noisy, closed and stagnant air envi-
ronments (e,g, discos, pubs, birthday parties, restaurants, butch-
ering facilities, etc.) where people stand, sit or lie close together
and are required to shout for communication are ideal condi-
tions for generating large SARS-CoV-2 outbreaks.
SARS-COV-2 re-activation or re-infection?

In South Korea and elsewhere more than 100 people who had
recovered from COVID-19 were retested positive (Ye 2020) and
there was concern that patients who recover from COVID-19 may
be at risk of reinfection. However, there was no indication that
they were contagious. The most likely explanation is that the
‘infection had been reactivated’ in the patients or that the tests
picked up non-infective RNA of the virus. Very preliminary data
from an animal study (n=2) suggest that that immunity acquired
following primary infection may protect upon subsequent expo-
sure to the virus. Infection of rhesus macaques with SARS-CoV-2
and re-infection after recovery showed that there was no viral
Kamps – Hoffmann
Epidemiology | 33
replication in nasopharyngeal or anal swabs, nor any other signs

of COVID-19 disease recurrence (Bao 2020).
Blood Transfusion
After screening 2,430 donations (1,656 platelet and 774 whole
blood) with real-time PCR, authors from Wuhan only found
plasma samples positive for viral RNA from 4 asymptomatic do-
nors (Chang 2020). It remains unclear whether detectable RNA
signifies infectivity. A preliminary report of a study in Dutch
blood donors found that in April 2020 around 3% had detectable
antibodies against SARS-COV-2 (NLTimes.nl).
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). However, more data are still needed before we can
conclude that transmission through transfusion is unlikely.
The pandemic
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 main-
land China, to neighboring countries (in particular, South Korea,
Hong Kong and Singapore) and west to Iran, Europe and the
American continent. 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 quite different, with slower global spread but high burden
due to limited diagnostic and therapeutic capacities and no op-
tion of nation-wide lockdowns (see also a report of the influenza
pandemics in 1957 and 1968: Honigsbaum 2020). According 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 ap-
proximately 3 months after the beginning of local epidemics.
Another model predicted that 80% of the US population (around
260 million people) would have contracted the disease. Of those,
2.2 million Americans would have died, including 4% to 8% of
those over age 70 (Ferguson 2020).
Despite these dire predictions, some epidemiologists and senior
politicians seriously considered implementing only limited miti-
gating measures, based on two questionable arguments:
The country would not have to face the dramatic economic
downturn that seems unavoidable in countries and states
which opted for strict containment measures (China, Italy,
Spain, France, California, New York, to name a few). However,
most economists would argue that there would still be an
economic downturn due to self-imposed restrictions by the
population and businesses, as shown by the major economic
impact even in countries with less severe restrictions (e.g.,
Sweden).
After a few months, up to 70% of the population could be

naturally immunized (through infection with SARS-CoV-2)
and protected against further outbreaks, able to look ahead
to the next winter season with an even temper. (However, it
is still unclear how long such acquired immunity would last?
Maybe only a few months or few years? See the Immunology
chapter, page 125).
In mid-March 2020, the prime minister of a former EU country
proposed the approach of ‘letting the virus spread until we reach
herd immunity’ as the best solution to the epidemic his nation
was about to face. The shock treatment: accepting that a large
Kamps – Hoffmann
Epidemiology | 35
majority of the population would contract the virus, thus devel-

oping a collective immunity and preventing future coronavirus
epidemics. The estimated figures from simulation models were
dire. With a little over 66 million inhabitants, some 40 million
people would have been infected, 4 to 6 million could have be-
come seriously ill, 2 million requiring intensive care. Around
400,000 Britons may have died. The prime minister stated:
“Many more families are going to lose loved ones before their
time.” Faced with the rapid increase of cases and deaths and a
public uproar, the PM eventually made a U-turn, implementing
strict confinement measures as other countries were doing.
Only one European country, Sweden, has decided to pursue a
strategy of limited public health measures (e.g., protection of
older age groups, widespread testing, individual social distanc-
ing measures) without enforcing strict rules of confinement or
business shutdowns. The results will be briefly discussed below
on page 51.
Pandemic 2.0: 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 unemployment could surpass
the levels reached during the Great Depression in the 1930s, at
first, almost all governments considered saving hundreds of
thousands lives more important than avoiding a massive eco-
nomic recession. First in China, six weeks later in Italy and an-
other a week later in most Western European countries, more
recently in the US and in many other countries in the world, un-
precedented experiments of gigantic dimensions were started:
ordering entire regions or the whole nation to lockdown. In Italy
and Spain, people were ordered to stay home, except for con-
ducting “essential activities” (i.e., purchasing food, medicines,

and other basic supplies, going to hospital, or performing essen-

tial work). Italians were told to stay at home even on the popular
Pasquetta day, Easter Monday, where people usually flock to the
seaside or countryside to enjoy a picnic with family and friends.
Eventually, Italians were even restricted from moving from one
municipality to another.
While there are differences in the implementation of the lock-
down from one country to another, some common measures in-
clude:
Restrictions of movement from home, unless it is strict-
ly necessary (confinement or “stay-at-home” order)
Ban on all public mass gatherings, including concerts,
festivals, rallies, even religious events (Tian H 2020)
Closure of schools and universities
Closure of all retail shops, except for those serving pri-
mary needs (food, medicines, gas stations, newsstands,
etc)
Shutting down of all industries and factories, except
where providing essential products
Border closing with neighbouring countries, interna-
tional travel bans. In some cases, restrictions of travel
within the country outside the area or region of resi-
dence.
Lockdowns have been used in the past to control disease out-
breaks, usually in limited areas and for limited periods. China
was the first country to implement, on 23 January, a strict and
total lockdown in a city of 11 million people, later extended to
the whole Hubei province (WHO called this “unprecedented in
public health history”). The lockdown lasted 2 months.
Italy was the first country to implement a nationwide lockdown
to the whole country on 9 March, to be followed by Denmark (11
Kamps – Hoffmann
Epidemiology | 37
March), Ireland and Norway (12 March), Spain and Poland (13
March), Switzerland, France, Belgium (17 March) and then most
other European countries. By 26 March, 1.7 billion people
worldwide were under some form of lockdown, which increased
to 3.9 billion people by the first week of April — more than half
of the world’s population. Lockdowns in Europe were generely
less strict than in China, allowing the continuation of essential
services and industries and the circulation of people when justi-
fied.
Lockdown outcomes
The expected result of lockdown measures is the breaking of the
chain of SARS-CoV-2 transmission, leading to a reduction of the
number of new infections, hospitalization and ultimately deaths.
This can be measured in different ways, including by the number
of
SARS-CoV-2 newly infected people
Hospital admissions for COVID-19
Patients treated in intensive care units (ICU)
Deaths
Number of infections
Figure 1 proved as early as four weeks after the Wuhan lockdown
that strict containment measures are capable of curbing a SARS-
CoV-2 epidemic. The figure presents the Chinese COVID-19 epi-
demic curves of laboratory-confirmed cases, by symptom onset
(blue) and – separately – by date of report (orange). The data
were compiled on 20 February 2020, four weeks after the begin-
ning of the containment measures which included a lockdown on
nearly 60 million people in Hubei province as well as travel re-
strictions for hundreds of millions of Chinese citizens. The blue

columns show that (1) the epidemic rapidly grew from 10-22
January, (2) reported cases (by date of onset) peaked and plat-
eaued between 23 January and 28 January and (3) steadily de-
clined thereafter (apart from a spike reported on 1 February).
Based on these data, we would now expect a decline in reported
cases around three weeks after a general lockdown.
Figure 1. The Chinese outbreak in January/February 2020. Epidemic curves

by symptom 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 Disease 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)
However, the number of newly diagnosed SARS-CoV-2 cases is of

limited usefulness since, being closely related to the number of
tests being performed, do not reflect the true number of infections
that have occurred. To know the true number, the entire popula-
tion would need to be tested repeatedly which is, of course, im-
practical. PCR tests are usually performed in symptomatic pa-
tients or, in some cases, in close contacts and most asymptomat-
ic cases will be missed. Seroprevalence studies in population
Kamps – Hoffmann
Epidemiology | 39
samples that are being implemented can provide a better esti-

mate of the number of people who have been infected in the past
but will not directly measure the incidence (new infections). Best
incidence estimates can only be made by mathematical model-
ling. Not surprisingly, the first models of the European epidemic
revealed that reported COVID-19 cases represent only a fraction
of those truly infected. A model based on observed deaths in 11
European countries suggested that true infections were much
higher than reported cases (Flaxman 2020). According to the
model, as of 28 March, 5.9 million people in Italy and 7 million in
Spain could have been SARS-CoV-2-infected (Table 2). Germany,
Austria, Denmark, and Norway would have the lowest attack
rates (proportion of the population infected). If these assump-
tions are validated, the true number of cases would outnumber
the reported cases on March 28 (Italy: 92,472; Spain: 73,235;
France: 37,575) by up to two orders of magnitude
[The data provided by Flaxman et al. immediately invited us in
March to do some kitchen epidemiology. First: if on 28 March the
number of infected people in Italy was around 6 million (with a
credible interval of 2 to 15 million) and if we assumed that 18
days later the total number of deaths in Italy was around 30,000
(the official figure reported on 15 April was 21,645 deaths), the
mortality of COVID-19 infection in Italy could be in the range of
0.5% (0.19%-1.6%).

Table 2. Estimates of total population infected as of 28 March 2020
Country % of population Population infected*

Deaths on infected*
28 March
Austria 1.1% (0.36%-3.1%) 96,800
68 (31,680-272,800)
Belgium 3.7% (1.3%-9.7%) 425,500
353 (149,500-1,115,500)
Denmark 1.1% (0.40%-3.1%) 63,800
65 (23,200-179,800)
France 3.0% (1.1%-7.4%) 2,010,000
2,314 (737,000-4,958,000)
Germany 0.2% (0.28%-1.8%) 166,000
433 (232,400-1,494,000)
Italy 9.8% (3.2%-26%) 5,919,200
10,023 (1,932,800-15,704,000)
Norway 0.41% (0.09%-1.2%) 21,600
23 (4,860-64,800)
Spain 15% (3.7%-41%) 7,035,000
5,982 (1,735,300-19,229,000)
Sweden 3.1% (0.85%-8.4%) 316,200
105 (86,700-856,800)
Switzerland 3.2% (1.3%-7.6%) 275,200
264 (111,800-653,600)
UK 2.7% (1.2%-5.4%) 1,798,200
1,019 (799,200-3,596,400)
*mean (95% credible interval)
Data source: Flaxman S et al. (Imperial College COVID-19 Response
Team). Report 13: Estimating the number of infections and the impact of
non-pharmaceutical interventions on COVID-19 in 11 European
countries. 30 March 2020. DOI: https://doi.org/10.25561/77731
Second: if at the end of March, around 60% of all deaths in Italy

were reported from Lombardy, 60% of the 6 million projected
Italian SARS-CoV-2 infections – 3.6 million – would have oc-
curred in a region with a population of 10 million. Moreover,
Kamps – Hoffmann
Epidemiology | 41
20% of all deaths in Italy were reported from the province of

Bergamo alone which has a population of one 1.1 million.]
Seroprevalence studies underway in several European countries
and in the US will clarify these figures soon. Preliminary results
of a population survey in Los Angeles County released by USC on
20 April that tested 863 adults found that approximately 4.1%
had antibodies to the virus (USC News, 20 April 2020). Adjusting
for the statistical margin of error it suggested that between 2.8%
to 5.6% of the county’s adult population, approximately 221,000
to 442,000 adults, had been infected. That estimate is 28 to 55
times higher than the 7,994 confirmed cases of COVID-19 report-
ed to the county at the time of the study. The number of COVID-
related deaths in the county had then surpassed 600. On 13 May,
preliminary results from a nationwide coronavirus antibody
study showed that about 5% of the overall Spanish population
had contracted the virus, with spikes in prevalence of 11.3%. in
Madrid and 14.2% and 13.5% in the central regions of Castilla y
Leon and Castilla La Mancha. That is about 10 times more than
the number of diagnosed cases.
Hospital admissions for COVID-19

Hospitalizations for COVID-19 are usually recorded and reported
as part of the regular health care monitoring system. Several
countries are regularly reporting the daily number of COVID-19
hospital admissions as an indicator of the trend in the epidemic.
The advantage of monitoring hospital admission is that it can
detect changes in transmission dynamics more quickly than the
more lagged measures of (incidence of) ICU admissions and
deaths (mortality rates). However, hospital admissions have lim-
itations (hospital admission criteria 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 health
system collapse. In addition, many governments are not publicly

providing numbers of daily hospital admissions and discharges

(Garcia-Basteiro 2020).
Admissions into intensive care units

A more reliable indicator of the epidemic trend is the number of
people treated in intensive care units. In France, the number of
new hospital ICU admissions peaked on 1 April (Figure 2), while
the daily variation in people treated in ICU (the balance between
ICU entries and exits; Figure 3) started being negative one week
later. However, this indicator can be influenced by the number
of ICU beds and trained health personnel available for COVID-19
patients. If overwhelmed, hospitals might be forced to limit the
admission to patients with more chances of survival, or patients
might die at home (Grasselli 2020). In most developing coun-
tries, the very small number of ICUs will make this indicator of
limited use.
Figure 4 shows the daily number of COVID-19 patients treated in
ICU units in France.
Figure 2. Daily number of new hospital ICU admissions for COVID-19 (y-axis:
Nouvelles admissions en réanimation).
Source: Pandémie de Covid-19 en France, Wikipedia.
Kamps – Hoffmann
Epidemiology | 43
Figure 3. Daily variation in the number of people in ICU for COVID-19 (y-axis:
Variation des cas en réanimation).
Figure 4. Daily number of COVID-19 patients in ICU units (y-axis: Personnes

en réanimation).
Deaths
Asymptomatic infections go unnoticed; even mild to moderate
symptoms may go unnoticed; deaths do not. Consequently,
deaths reflect the reality of the COVID-19 epidemic better than
the number of SARS-CoV-2-infected people. They will, however,
only provide a picture of the number of infections that have oc-
curred 2-4 weeks before (given the median incubation period
and the period of hospitalization).

However, the current numbers of COVID-19 deaths are incom-

plete and will soon need to be corrected upwards. (By 10%, 30%,
50% or more? Nobody knows yet.) In Italy, especially in the most
hit Northern regions, a certain number of people died at home
and did not appear in the official reports. Data about overall
mortality in epidemic hot spots in Northen Italy (ISS 2020) and in
Spain (Madrid) suggests that excess mortality due to COVID-19
might be twice the officially reported figure. In France and the
UK, as in other countries, deaths from long-term care facilities
were initially not included in the official data. Figure 2 shows
that the number of daily deaths decreases about three weeks
after the implementation of lockdown measures (Italy: 8/10
March; Spain: 14 March).
Figure 5. Daily confirmed COVID-19 deaths, rolling 3-day average. Source:

www.ourworldindata.org
The data from Europe show that lockdown measures were effec-
tive but less so than in China, probably reflecting a less strict
lockdown in Europe. Daily updates are available from
www.ourworldindata.org (Figure 5).
Kamps – Hoffmann
Epidemiology | 45
To calculate COVID-19 excess mortality over 1 year, based on

age, sex, and underlying condition-specific estimates, an
online tool is now available (OurRisk.CoV). For the UK, 293,991
deaths would be expected in a “do-nothing scenario”. With miti-
gation (i.e., less rigorous and voluntary measures), authors pre-
dicted between 18,000 and 37,000 deaths (Banerjee 2020).
Special Aspects of the Pandemic

The COVID-19 pandemic has highlighted a number of specific
aspects and lessons learned that should be kept in mind during
the management of future pandemics (by coronaviruses, influ-
enza 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 of the COVID-19 outbreak – as any
other nation would have been – but “thanks” to the SARS out-
break in 2003 (Kamps-Hoffmann 2003), was prepared for it. At
first, the epidemic spread within Wuhan and Hubei Province
(December 2019) 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, with-

in 3 weeks from the identification of the identification of a new

virus, the government ordered the lockdown of more than 50
million in Wuhan and the surronding province Hubei as well as
travel restrictions for hundreds of millions of Chinese citizens.
This astonishing first in human history achieved what even spe-
cialists didn’t dare dream: curbing an epidemic caused by a high-
ly contagious virus (Lau 2020).
As early as four weeks after the Wuhan lockdown, there was evi-
dence that strict containment measures were capable of curbing
a SARS-CoV-2 epidemic as demonstrated in Figure 1 (page 38).
The lesson from China: it is possible to lockdown entire provinc-
es 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 diag-
nosis of the first autoctonous case), other governments didn’t.
Preparedness (Taiwan)
On 7 June, Taiwan (24 million people with a population density of
650/km2), had reported 443 cases and 7 deaths. Most SARS-CoV-
2 infections were not autochthonous. As of 6 April 2020, 321 cas-
es 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 experi-
ence to focus on protecting health care worker safety and
strengthening the pandemic response (Schwartz 2020 + The
Guardian, 13 March 2020). An early study suggested that identi-
fying and isolating symptomatic patients alone might not suffice
to contain the epidemic and recommended more generalized
measures such as social distancing (Cheng HY 2020). Big data
analytics 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
3000 passengers of a cruise ship. These passengers had disem-
Kamps – Hoffmann
Epidemiology | 47
barked at Keelung Harbor in Taiwan for a 1-day tour five days

before the COVID-19 outbreak on the Diamond Princess cruise
ship on February 5, 2020 (Chen CM 2020).
At the time of this writing, Taiwan is definitely one of the coun-
tries with the most successful management of COVID-19.
Surprise or unpreparedness (Italy)

Italy was the first European country struck by the pandemic.
Complete genome analysis of SARS-CoV-2 isolates suggests that
the virus was introduced on multiple occasions (Giovanetti
2020). Although the first local case was diagnosed only on 20
January, the force of the outbreak also 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. During the yearly flu season, COVID-19 deaths
in elderly people could easily be interpreted as flu deaths. On the
other end of the age spectrum, among the most active social age
group – young people crowded in bars, restaurants and discos –,
the rapid SARS-CoV-2 virus would not have caused life-
threatening symptoms. Before being detected, the epidemic had
time (at least a month) to grow.
There is one additional possible reason for the delay in recogniz-
ing the encroaching epidemic in Italy that is worth mentioning:
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 re-
questing 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 eventually happen eve-
rywhere after the first asymptomatic individuals had spread the
infection). The anesthesiologist who eventually requested the

PCR test for Italian patient #1, Mattia, did it “under her own re-
sponsibility and not in line with MOH guidelines”.
It is as yet unclear why the epidemic took such a dramatic turn
in the northern part of Italy, especially in Lombardy (Gedi Visual
2020), while other areas, especially the southern provinces, were
relative spared. Of note, healthcare in Italy is run by the regions
and for a long time, the Lombardy Region has favored the devel-
opment of a mostly private and hospital-centered system, with
great facilities but poor community-based services. This meant
that patients were quickly run to the hospital, even those with
minor symptoms, resulting in overcrowded emergency services
and major nosocomial spread. A more decentralized and com-
munity-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 addition, Italy had not updated nor implement-
ed 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 national response between the regions and
the central government.
Unwillingness to prepare/denial (UK, USA, Brazil)

In the UK, clumsy political maneuvering delayed the start of ef-
fective lockdown measures by a week or more. As the epidemic
doubles in size about every 7 days (Li 2020), around 50% and 75%
of all deaths might have been prevented had lockdown or social
distancing measures been ordered one or two weeks earlier, re-
spectively. Early data from Ireland and the United Kingdom
seem to confirm this assumption.
Like in Iran, where the regime covered up news of the corona-
virus for three days to avoid impacting turnout at parliamentary
elections on 21 February, domestic politics (or paranoia; BMJ,
Kamps – Hoffmann
Epidemiology | 49
6 March 2020) influenced the epidemic response in the United

States of America. Scientific advice from CDC and other national
public health institution was ignored (The Lancet 2020). The US
is now the country with the highest number of cases and deaths
(2 million and more than 110,000 on 7 June, respectively). With-
out this unprecedented vacuum in leadership in US, most of
these deaths would have been prevented.
Brazil, which is also not an example of good governance perfor-
mance, is on track to be the country with the second highest
number of deaths.
Partial preparedness (France)

France was partially prepared, partially not. During the first na-
tional outbreak near Mulhouse, 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 deci-
sion of the Hollande government to greatly reduce the expen-
sive stocks of 1.7 billion protective masks (surgical and FFP2)
available in 2009 to 145 million surgical masks in 2020 (“We are
not going to manage mask stocks, it is 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 were pouring into the hospitals of the Greater Par-
is Region, the number of available intensive care unit beds had
already increased from 1,400 to 2,000 during the preceding week.
Furthermore, two years before, in a simulation of a major terror-
ist attack, 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. 7It is
assumed that the main reason for this difference is simply test-
ing. While other countries were conducting a limited number of
tests of older patients with severe cases of the virus, Germany
was doing many more tests that included milder cases in young-
er people (Stafford 2020). The more people with no or mild
symptoms you test, the lower the fatality rate. Reliable PCR
methods had been developed by the end of January from the
Drosten group at Berlin’s Charité (Corman 2020).
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 conducted at quality-controlled laboratories
throughout the country. Within a few weeks, 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 Ger-
many might be age distribution. During the first weeks of the
epidemic, most people became 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 peo-
ple.
Kamps – Hoffmann
Epidemiology | 51
Herd immunity (Sweden)

Sweden has never really imposed a lockdown, counting on the
population to adopt individual social distancing and other pro-
tective measures to curb the transmission of SARS-CoV-2. As a
result, Sweden has today (7 June 2020) a death rate of 461 per
million population which compares unfavorably with Denmark
(101) and Norway (44), with most deaths occurring in care homes
and immigrant communities. Surprisingly, an initial antibody
survey in Stokholm found that only about 7% of residents had
been infected with SARS-COV-2 at the end of April. Still worse,
Sweden didn’t benefit economically of its no-lockdown approach
as its economical performance seems to contract at a similar rate
as countries in the rest of Europe (Financial Times, 10 May 2020).
For a detailed discussion of herd immunity, see Randolph 2020.
Deferred beginning (South America)

In the initial months of 2020, the number of cases were compara-
tively low in South America (Haider 2020). As a matter of fact,
the local epidemics took off roughly 4 weeks later than in Europe
(see www.worldometers.info/coronavirus). Whether this delay is
due only to a deferred import of SARS-CoV-2 from the initial
outbreak region in China or to other factors (sunshine intensity?
Guasp 2020) is unknown. However, according to WHO, South
America has not become the new epicenter of the coronavirus
pandemic, with Brazil (374,000 cases and more than 23,000
deaths as of 27 May) reporting more cases than any other coun-
try in South America.
Splendid isolation (New Zealand, Australia)

With 102 deaths in Australia, 21 in New Zealand and no deaths in
French Polynesia, Fiji, New Caledonia and Papua New Guinea,
Oceania is the least hit area in the world. The geographical isola-

tion may allow these countries to become the first non-COVID

zones in the world. International travel to New Zealand and Aus-
tralia is still banned and may be subject to quarantine measures
for quite a time.
The unknown outcome

The transmissibility of SARS-CoV-2, combined with the scarcity
of crucial health equipment and facilities and the challenges of
implementing widespread case isolation (Wells 2020), was sup-
posed to have a devastating impact on African countries. Until
now, these predictions have not come true. Although a few hun-
dred deaths have been reported from a small number of coun-
tries (<10), the African COVID-19 epidemic is in no way compara-
ble to the situation in Asia, Europe and the Americas.
However, caution should be used before hypothesizing an “Afri-
can exception” due to factors such as demographics (huge young
populations) or previous ‘exposure to more and different patho-
gens’. Some official figures may be underestimates, voluntary or
not, due to regional difficulties in reporting. In some cities, such
as Kano, Nigeria, major outbreaks may already be under way.
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 would be working
overtime. In Mogadishu, Somalia, officials say burials had tri-
pled, according to the same report. In Tanzania, the US embassy
has warned of the risk of “exponential growth” of COVID-19 cas-
es in the country, adding that hospitals were “overwhelmed”
(The Guardian, 19 May).
It is too soon to say, how COVID-19 will evolve in Africa. As the
situation in South America illustrates, on the scale of continents,
the pandemic can “be late” by some weeks or months and still
hit very hard.
Kamps – Hoffmann
Epidemiology | 53
Lockdown Exit
In the next months, all countries will have to find a balance be-
tween a maximum of economic activity and a still manageable
number of patients in ICUs. Lockdown exit strategies should al-
ways include
Strengthening of the national testing capacities to en-
sure access to PCR to all those in need;
Effective contact-tracing system;
Isolation capacities for positive people and close con-
tacts.
Not all countries are able to fulfill these essential requirements,
raising concerns about the possibility of new clusters and out-
breaks. To facilitate identifying contacts at risk, several coun-
tries are considering developing smartphone applications that
would record when other phones are coming into close contact
and send an alert message in case one of these would have tested
positive. However, opinions are still divided between centralized
systems, where individual data would be stored in a central gov-
ernment server, and a decentralized system, where data will be
stored in the mobile phone only. No common system has been
agreed upon and the feasibility and usefulness of these apps still
needs to be proven.
At the beginning of June 2020, most countries had started nor-
malizing and restoring economic and societal activities. Europe-
an borders will open again and tourism is expected to take off,
albeight at a much reduced level (–50%?) compared to previous
years.
Austria and Germany have eased lockdown measures for
around 6 weeks, and apart from a few clusters in Germany, there
is currently no indication of an imminent second “cataclysmic
wave of contagion”, as the authors feared in previous editions.
Italy started “Phase 2” on 4 May, with four million people re-

turning to their workplaces, shops opening and relaxed re-

striction on the movements of people, including visiting rela-
tives. The number of new cases and deaths continues to decline
everywhere except in Lombardy. However, schools will remain
closed until September. Spain also slightly relaxed the lockdown
measures on 2-4 May allowing greater movements and outdoor
sport activities. France partially ended the lockdown on 11 May,
with the country divided in a “red zone” where stricter re-
strictions will still apply, and “green zones” where they will be
gradually relaxed.
In the USA, states have set their own timetables for imposing
and easing lockdown measures, with a general trend in resuming
activities despite the ongoing spread of the virus and high mor-
tality from COVID-19. The government of the United Kingdom,
the latecomer in European lockdown, announced the easing of
the measures for 15 June.
Sweden has never really imposed a lockdown, counting on the
population to adopt individually social distancing and other pro-
tective measures. Given the observed high death rate compared
to neighbouring countries, there is now public pressure to im-
plement stricter lockdown measures.
In all countries, most activities will eventually resume, but the
tight-rope walk between maximising economic output and
avoiding a new COVID-19 outbreak will need careful evaluation
and considerations would include:
Recommend frequent handwashing, disinfection, dis-
tancing (shops) and face masks (transport and other
public places);
Order distancing in cinemas, theaters and operas, and
consider preventive contact tracing schemes in case an
attendent should later be found to be infected;
Kamps – Hoffmann
Epidemiology | 55
Ban events and activities that put people at less than

one meter of distance (sports events, concerts, disco,
festivals, pubs, etc.);
Implement mandatory requirements of wearing face
masks in public (Anfinrud 2020);
In the case of local outbreaks, recommend limitation in
the movement of people and consider applying special
restrictions to population groups at higher risk (e.g., el-
derly people, people with health conditions that put
them at risk of severe COVID-19).
Some activities might remain closed for an unknown period of
time, possibly until the availability of a vaccine.
In some countries, including the US, the epidemic is far from
over with many new cases and deaths being reported every day.
Therefore, it looks like the decision to exit the lockdown is more
driven by economic necessity than justified by a satisfactory epi-
demiological situation. In this “second half” of the match
“COVID vs. Humanity”, the economists are coming back and
scoring more goals that the public health officials.
The economic impact of the COVID-19 pandemic is certainly un-
precedented. The International Monetary Fund (IMF) forecasts a
contraction of 3% of the planet’s GDP in 2020. In a recession like
no other in peacetime for nearly a century, the countries of the
Euro zone, the United States and the United Kingdom might see
a contraction in activity of between 5.9% and 7.5%1. Economical-
1
The global CO2 emissions decreased by 17% by early April 2020
compared with the mean 2019 levels, just under half from
changes in surface transport (cars, truck, buses) (Le Quéré 2020).
More than one billion tons of carbon emissions less. At their
peak, emissions in individual countries decreased by an average
of 26%, admittedly extreme and probably unseen before, but just

ly, socially, and politically, protracted lockdown is unsustaina-

ble. What can be done once – self-isolation of the population for
months and months – can probably not be repeated.
“COVID Pass”
In countries with large COVID-19 outbreaks, tens of thousands of
people died. Those who survive severe or less severe illness, with
or without hospitalization, will have developed antibodies
against the SARS-CoV-2 virus (Zhang 2020, Okba 2020). Even
more people, those who were infected but developed no symp-
toms, will have antibodies, too. Already, millions of people in
China, Italy, Spain, France, and the US have developed SARS-
CoV-2 antibodies.
In early June 2020, we still cannot be sure if and for how long
these antibodies protect against a second infection. On 24 April,
WHO issued a Scientific Brief stating that “There is no evidence
yet that people who have had COVID-19 will not get a second
infection” (WHO 200424). However, recently, neutralizing anti-
bodies against SARS-CoV-2 were detected in virtually all hospital
staff sampled from 13 days after the onset of COVID-19 symp-
toms (n=160) (Fafi-Kremer 2020; see Le Monde, 27 May) and there
is no reason why they should not, since even symptomatic peo-
ple recover from the infection, and most researchers think,
based on our general knowledge of coronavirus infection, that
to the level of emissions in 2006. The impact on 2020 annual

emissions will depend on the duration of the confinement, with a
low estimate of –4% if pre-pandemic conditions return by mid-
June, and a high estimate of –7% if some restrictions remain
worldwide until the end of 2020. These figures are comparable to
the rates of decrease needed year-on-year over the next decades
to limit climate change to a 1.5°C warming.
Kamps – Hoffmann
Epidemiology | 57
neutralizing antibodies are likely to be protective. Though fur-

ther studies are needed to support this, it is very likely that once
people have recovered from SARS-CoV-2 infection, they would
not be vulnerable to a secondary infection and, even if they had
a mild infection, they would be unlikely to infect others.
This has led to speculations about the possible introduction of a
SARS-CoV-2 antibody passport, or a COVID Pass. People with neu-
tralizing antibodies – assumed to be protected following a symp-
tomatic or asymptomatic COVID-19 infection and therefore una-
ble to transmit the virus – would be allowed to freely move
around. Chile, Germany, and the UK, among others, considered
implementing certifications that a person has contracted and
recovered from COVID-19. These “licenses” would then allow
immune people to engage in economic activity and provide safer
care for vulnerable populations. The intention was to develop
population-level ‘shield immunity’ by amplifying the proportion
of interactions with recovered individuals relative to those of
individuals of unknown status (Weitz 2020).
Major concerns remain as community licensing could stigmatize
people, undermining the value of equal treatment. Immunity-
based licenses would require therefore careful implementation
to be ethical in practice (Persad 2020) and there are at least 10
good reasons why COVID (or immunity) passes are a bad idea
(Kofler 2020), foremost because restricting liberty on the basis of
biology threatens freedom, fairness and public health.
For the time being, a confirmed positive SARS-CoV-2 serological
positivity might be useful in health care settings to determine
who, among the health workers, should be allowed to work in
close contact with confirmed or suspected COVID-19 patients.
The second wave

For now, in June 2020, the second wave of the COVID pandemic,
as hypothesized in a study by Ferguson (Ferguson 2020; figure 7)

has not yet materialized. The study predicted that for as long as
most people had no immunity against SARS-CoV-2, the lifting of
strict “Stay at home” measures such as extreme social distancing
and home quarantines would inevitably make the epidemic
bounce back.
Figure 7. Impact of non-pharmaceutical interventions (NPIs) to reduce

COVID-19 mortality and healthcare demand (Source: Ferguson 2020).
However, the world has changed. Today, a fever, a cough, anos-

mia and many other more subtle COVID symptoms will usually
trigger an immediate cascade of action to prove or refute an
acute SARS-CoV-2 infection. An existing acute infection, for its
part, will trigger a similarly immediate cascade of contact trac-
ing, testing, and quarantining. In addition, many people, while
waiting for the coming episodes of the pandemic to unfold, have
changed their behavior and avoid mass gatherings. They have
understood that restrictive social-distancing measures will need
to be combined with widespread testing and contact tracing to
end the ongoing pandemic (Giordano 2020 + less realistic, Peto
2020).
Herd immunity, the notion introduced to a wider public by a
foolish politician, will not not be on the agenda for a long time.
As for now, not a single country is anywhere close to reaching
Kamps – Hoffmann
Epidemiology | 59
herd immunity. Even in past hotspots like Wuhan, the preva-

lence of SARS-CoV-2 IgG positivity was 9.6% among 1,021 people
applying for a permission (the SARS CoV 2 nucleic acid test
needed to be negative) (Wu X 2020). A French study projected 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 this low number may be biased because
symptomatic persons may have been more likely to participate.)
A recent nationwide coronavirus antibody study In Spain showed
that about 5% of the population had contracted the virus. These
infection rates are clearly insufficient to avoid a second wave of
a SARS-CoV-2 epidemic (Salje 2020).
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? How many years will
air traffic need to return to pre-COVID-19 levels? Will we be in-
clined to plan vacations nearer to home than at 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 drinking in any city of the world anytime soon?
The French have an exquisitely precise formula to express un-
willingness 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 now!) 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, 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 three years into the future and read the
story of COVID-19, we would not believe our eyes.
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Transmission | 71
2. Transmission
Christian Hoffmann
Viruses have substantially influenced human health, interac-

tions with the ecosphere, and societal history and structures
(Chappell 2019). In a highly connected world, microbial evolu-
tion is boosted and pathogens exploit human 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, tuberculo-
sis, avian H7N9 influenza virus – have emerged (Kamps-
Hoffmann 2006, Jassal 2009, Gao 2013).
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 rapid-
ly evolved into a pandemic (Google 2020). In most cases, the ill-
ness is asymptomatic or paucisymptomatic and self-limited. A
subset of infected individuals has severe symptoms and some-
times 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 coro-
navirus highjacks 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 coronaviruses
SARS-CoV and MERS-CoV, it manages to get transmitted to the
next individual before it develops symptoms in the first one (see
below, Asymptomatic Infection, page 83). There is no doubt that
SARS-CoV-2 has a bright future – at least until the scientific
community develops a safe and efficient vaccine (see the chapter
Immunology, page 125).
SARS-CoV-2 and its kin

SARS-CoV-2 is a coronavirus like
SARS-CoV (its cousin of the 2002/2003 epidemic),
MERS-CoV (Middle East Respiratory Syndrome corona-
virus),
and a group of so-called CAR coronoviruses (for Communi-
ty-Acquired Respiratory CoVs: 229E, OC43, NL63, HKU1)
which account for 15 to 30% of common colds.
The CAR group viruses are highly transmissible and produce
about 15 to 30% of the common colds, typically in the winter
Kamps – Hoffmann
Transmission | 73
months. On the contrary, SARS-CoV and MERS-CoV have case

fatality rates of 10% and 34%, respectively, but 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 mortali-
ty.
SARS-CoV-2 is a virus like other commonly known viruses that
cause human disease such as hepatitis C, hepatitic B, Ebola, in-
fluenza and human immunodeficiency viruses. (Note that the
differences between them are bigger than 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 dis-
ease, 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 secre-
tions can transmit the virus. Ideal infection environments 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 diseas-
es 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 to reduce mortality – despite tests on thousands of
patients. After 35 years of research, there is still no vaccine to
prevent HIV infection.

Ecology of SARS-CoV-2
SARS-CoV-2 is present at high concentrations in the upper and
lower respiratory 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 has been shown to be detectable 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). 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 patients’ rooms, includ-
ing 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 presymptomatic patients (He 2020).
A key factor in the transmissibility of SARS-CoV-2 is the high
level of virus shedding in the upper respiratory tract (Wolfel
2020), even among paucisymptomatic 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
occured mainly in the lower respiratory tract (Gandhi 2020);
Kamps – Hoffmann
Transmission | 75
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 symptoms and seroconversion is not always followed by a
rapid decline in viral load (Wolfel 2020). This contrasts with in-
fluenza where persons with asymptomatic 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).
Routes of Transmission
Respiratory droplets vs aerosol
SARS-CoV-2 is spread predominantly via virus-containing drop-
lets 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). Other people may come
into contact with these droplets and get infected when they
touch their nose, mouth or eyes.
SARS-CoV-2 was thought to be transmitted primarily through
larger droplet particles, >5-10 m in diameter, commonly re-
ferred to as respiratory droplets, which fall to the ground at-
tracted by gravity. In the beginning of the pandemic SARS-CoV-2
was NOT thought to be transmitted via smaller particles, <5 m in
diameter, which are referred to as droplet nuclei or aerosol.
Recently, however, some authors have voiced concern that
SARS-CoV-2 could also be spread via aerosol. They point to epi-
sodes during the 2003 SARS epidemic when an airborne route

of transmission 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 transmitted indirectly by
contact with fomites as the aerosol settled (WHO 2003). Other
authors suggest that ‘Heating, Ventilation and Air Conditioning
Systems’ (HVAC) when not adequately used may contribute to
the transmission of the virus, as suggested by descriptions from
Japan, Germany, and the Diamond Princess Cruise Ship (Correia
2020, Gormley 2020). As a matter of fact, SARS-CoV-2 has been
shown to be detectable as an aerosol (in the air) for up to three
hours (van Doremalen 2020) and in patients’ toilet areas (Liu Y
2020).
Figure 1. Transmission of a respiratory virus. 1) After coughing, sneezing,

shouting and even after speaking – particularly loud speaking–, large drop-
lets (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. Whether the second – aerosol – transmission is an
epidemiologically relevant transmission route in the SARS-CoV-2 pandemic,
is currently being discussed. Adapted from Morawska 2020. Art work: Félix
Prudhomme; YouTube: IYENSS. (This and the following illustration are under
free license if credited correctly.)
Kamps – Hoffmann
Transmission | 77
Experimental support for these concerns comes from studies

that visualize 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 show that the lifetime of a droplet can 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). Loud and
persistent shouting as would be usual in noisy, closed and stag-
nant 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 activ-
ities such as singing have also been shown to generate air parti-
cles, with the rate of emission corresponding to voice loudness
(Asadi 2019). Confined public spaces (e.g., restrooms or eleva-
tors) were discussed as a favorable environment in an outbreak
in Wenzhou, China (Cai J 2020). Of note, several outbreaks are
now linked to choir practices in the Netherlands, Germany and
the US (Hamner 2020) (see also the chapter Epidemiology, page
19).
The question of whether SARS-CoV-2 is transmitted only via res-
piratory droplets (see a recent transmission experiment among
hACE2 mice; Bao L 2020) or also via aerosol is crucial for the im-
plementing of future prevention measures. In the former case,
the current prevention recommendations of frequent hand-
washing and maintaining a distance of at least one meter (arm’s
length) (WHO 2020a) could be sufficient. In the case of proven
airborne transmission over several meters, however, current
distancing measures would need to be adapted, with far-
reaching implications for cultural and economic life (theaters,

cinemas, restaurants, pubs, shops, etc.). Some authors plead that

the international and national authorities acknowledge the reali-
ty that the virus spreads through air, and recommend that ade-
quate control measures be implemented to prevent further
spread of the SARS-CoV-2 virus (Morawska 2020), including
wearing suitable masks whenever infected persons may be near-
by and providing adequate ventilation of enclosed spaces
(Somsen 2020) where such persons are known to be or may re-
cently have been (Meselson 2020).
The current evidence for aerosol transmission and resulting rec-
ommendations for prevention have been sublimely summarized
by Prather et al. in five sentences: “Respiratory infections occur
through the transmission of virus-containing droplets (>5 to 10
m) and aerosols ( 5 m) exhaled from infected individuals dur-
ing 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. However, a large proportion of the spread
of coronavirus disease 2019 (COVID-19) appears to be occurring
through airborne transmission of aerosols produced by asymp-
tomatic individuals during breathing and speaking (Morawska
2020, Anderson 2020, Asadi 2019). Aerosols can accumulate, re-
main 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 implemented, including
universal masking and regular, widespread testing to identify
and isolate infected asymptomatic individuals (Prather 2020).”
Fomites
It is currently unclear whether and to which extent transmission
of via fomites (e.g., elevator buttons, hand rails, restroom taps) is
epidemiologically relevant (Cai J 2020). (A fomite is any inani-
mate object that, when contaminated with or exposed to infec-
Kamps – Hoffmann
Transmission | 79
tious agents such as a virus, can transfer a disease to another

person).
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 new-
born 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 operative delivery.
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 con-
clude that although post-partum infection cannot be excluded
with 100% certainty, vaginal delivery seems to be associated with
a low risk of intrapartum SARS-CoV-2 transmission (Ferrazzi
2020).
In at least two cases, SARS-CoV-2 has been found in breast milk
(Wu Y 2020, Groß 2020). As of May 2020, the Italian Society on
Neonatology (SIN), endorsed by the Union of European Neonatal
& Perinatal Societies (UENPS), recommended breastfeeding as
advisable if a mother previously identified as COVID-19-positive
or under investigation for COVID-19 was asymptomatic or pauci-
symptomatic 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 reported 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 remained positive for
SARS-CoV-2 RNA for a mean of 17 days and fecal samples re-
mained positive for a mean of 28 days after first symptom onset
(Wu Y 2020). In 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).
Until proof of the contrary, the possibility of fecal-oral transmis-
sion 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 disinfectants 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.
Blood products
SARS-CoV-2 is rarely detected in blood (Wang W 2020, Wolfel
2020). After screening of 2,430 donations in real-time (1,656
platelet and 774 whole blood), authors from Wuhan found plas-
ma samples positive for viral RNA from 4 asymptomatic donors
(Chang 2020). It remains unclear whether detectable RNA signi-
fies 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
Kamps – Hoffmann
Transmission | 81
(Kwon 2020). More data are needed before 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 drop-
lets during sexual intercourse would suppose remarkable acro-
batics many people might not be willing to perform.
Cats and dogs

SARS-CoV-2 can be transmitted to cats and dogs. When inoculat-
ed with SARS-CoV-2, three cats transmitted the virus to three
other cats. None of the cats showed symptoms, but all shedded
virus for 4 to 5 days and developed antibody titers by day 24
(Halfmann 2020). In another study, two out of fifteen dogs from
households with confirmed human cases of COVID-19 in Hong
Kong were found to be infected. The genetic sequences of viruses
from the two dogs were identical to the virus detected in the
respective human cases (Sit 2020). It is too early to know if cats
and dogs are potential intermediate hosts in chains of human–
pet–human transmission.
Transmission Event
Transmission of a virus from one person to another depends on
four variables:
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 series of challenges. They must attach to cells; fuse
with their membranes; release 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 hu-
man genetic code). That doesn’t prevent the virus from being
ferociously successful:
It attaches to the human angiotensin converting enzyme 2
(ACE2) receptor (Zhou 2020) which is present not only in na-
sopharyngeal and oropharyngeal mucosa, but also in lung
cells, such as in type II pneumocytes. SARS-CoV-2 thus com-
bines the high transmission rates of the common coronavirus
NL63 (infection of the upper respiratory tract) with the se-
verity of SARS in 2003 (lower respiratory tract);
It has a relatively long incubation time of around 5 days (in-
fluenza: 1-2 days), thus giving it more time to spread;
It is transmitted by asymptomatic individuals.
As mentioned above, SARS-CoV-2 can be viable for days (van
Doremalen 2020). Environmental factors that might influence
survival of the virus outside the human body will be discussed
below (page 87).
The virologic determinants of more or less successful SARS-CoV-
2 transmission are not yet fully understood.
Kamps – Hoffmann
Transmission | 83
Transmittor
Infectiousness seems to peak on or before symptom onset (He X
2020), with around half of secondary cases being possibly infect-
ed during the presymptomatic stage. The mean incubation is
around 5 days (Lauer 2020, Li 2020, Zhang J 2020, Pung 2020),
comparable to that of the coronaviruses causing SARS or MERS
(Virlogeux 2016). Almost all symptomatic individuals will devel-
op symptoms within 14 days of infection, beyond that only in
rare cases (Bai Y 2020).
It is currently unknown if SARS-CoV-2 transmission correlates
with the following characteristics of the index case (transmit-
tor):
Symptom severity;
Large concentrations of virus in the upper and lower respira-
tory tract;
SARS-CoV-2 RNA in plasma;
In the future: reduced viral load due to drug treatment (as in
people treated for HIV infection) [Cohen 2011, Cohen 2016,
LeMessurier 2018])
SARS-CoV-2 transmission certainly correlates with a still ill-
defined “super-spreader status” of the infected individual. For
unknown reasons, some individuals – so-called super-spreaders –
are remarkably contageous, capable of infecting dozens or hun-
dreds of people, possibly because they breathe out many more
particles than others when they talk (Asadi 2019), shout, cough
or sneeze.
Transmission is more likely when the infected individual has few
or no symptoms. Asymptomatic transmission 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
pandemic (Gandhi 2020). As shown during an outbreak in a

skilled nursing facility, the percentage of asymptomatic individ-

uals can be as high as 50% early (Arons 2020); note that most of
these individuals would later develop some symptoms. Im-
portantly, SARS-CoV-2 viral load was comparable in individuals
with typical and atypical symptoms, and in those who were pre-
symptomatic or asymptomatic. Seventeen of 24 specimens (71%)
from presymptomatic persons had viable virus by culture 1 to 6
days before the development of symptoms (Arons 2020), suggest-
ing that SARS-CoV-2 may be shed at high concentrations before
symptom development. It is assumed that about 50% of all infec-
tions occur through presymptomatic transmission (He X 2020).
To what extent children contribute to the spread of SARS-CoV-2
infection in a community is unknown. Infants and young chil-
dren are normally at high risk for respiratory tract infections.
The immaturity of the infant immune system may alter the out-
come 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, some-
thing that has perplexed clinicians, epidemiologists, and scien-
tists (Kelvin 2020). Although the discovery of a pediatric inflam-
matory multisystem syndrome (PIMS) in SARS-CoV-2 infection in
children (Verdoni 2020, Viner 2020, ECDC 15 May 2020) came as a
surprise, the fact that children are susceptible to SARS-CoV-2
infection but frequently do not have notable disease raises the
possibility that children could be an important source of viral
transmission and amplification in the community. There is an
urgent need for further investigation of the role children have in
SARS-CoV-2 transmission chains (Kelvin 2020).
SARS-CoV-2 is highly transmissible, but given the right circum-
stances and the right prevention precautions, zero transmis-
sion can be achieved. In one case report, there was no evidence
of transmission to 16 close contacts, among them 10 high-risk
Kamps – Hoffmann
Transmission | 85
contacts, from a patient with mild illness and positive tests for
up to 18 days after diagnosis (Scott 2020).
Transmittee
Upon exposure to SARS-CoV-2, the virus may come in contact
with cells of the upper or lower respiratory tract of an individu-
al. 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). (The
pathogenesis of COVID-19 will be discussed in an upcoming sepa-
rate COVID Reference chapter.) Susceptibility to SARS-CoV-2
infection is probably influenced by the host genotype (Williams
2020). This would explain the higher percentage of severe
COVID-19 in men (Piccininni 2020) and possibly the similar dis-
ease 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 expo-
sure to other coronaviruses (“common cold” coronaviruses)
which have proteins that are highly similar to those of SARS-
CoV-2. It is still unclear whether these cross-reactive T cells con-
fer some degree of protection, are inconsequential or even po-
tentially 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 exposure, 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 diseases 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 in-
fected patients, and frequent exposure to excretia with high vi-
ral load (Little 2020).

Transmission setting
The transmission setting, i.e., the actual place where the trans-
mission of SARS-CoV-2 occurs, is the final element in the succes-
sion of events that lead to the infection of an individual. High
population density which facilitates super-spreading events (see
also chapter Epidemiology, Transmission Hotspots, page 20) are
key to widespread transmission of SARS-CoV-2.
Super-spreading events
Transmission of SARS-CoV and MERS-CoV, too, occurred to a
large extent by means of super-spreading events (Peiris 2004,
Hui 2018). Super-spreading has been recognized 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 a small fraction of infectious individuals (around 10%). A val-
ue called the dispersion factor (k) describes this phenomenon.
The lower the k is, the more transmission comes from a small
number of people (Kupferschmidt 2020). While SARS was esti-
mated 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 influenza
(Endo 2020, Miller 2020, On Kwok 2020).
Examples of SARS-CoV-2 clusters have been linked to a wide
range of mostly indoor settings (Leclerc 2020). In 318 clusters of
three or more cases involving 1245 confirmed cases, only a single
outbreak originated in an outdoor environment (Qian H 2020). In
one study, the odds that a primary case transmitted COVID-19 in
a closed environment was around 20 times greater compared to
an open-air environment (Nishiura 2020).
Kamps – Hoffmann
Transmission | 87
Transmission clusters, partly linked to super-spreader events,

have been reported 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)
Advisory board meeting, Munich, Germany, 20-21 (Hijnen
2020)
Nursing facility, King County, Washington, 28 February
(McMichael 2020)
Aircraft carriers: Theodor Rossevelt (The Guardian) + Charles-
de-Gaulle, March (Le Monde)
Choir (Hamner 2020)
Homeless shelter, Boston, 28 March (Baggett 2020)
Temperature and climate

Another variable still poorly understood is ambient temperature
and humidity.
2003: SARS-CoV
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 Tai-
yuan suggested that the SARS outbreak in 2002/2003 was signifi-
cantly 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 environments (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
environment 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 countries in the tropics (such
as Malaysia, Indonesia or Thailand) with high temperature and
high relative humidity environment did not have major commu-
nity SARS outbreaks (Chan KH 2011).
2020: SARS-CoV-2
It is as yet unclear as to whether and to what extent climatic fac-
tors influence virus survival outside the human body and might
influence local epidemics. SARS-CoV-2 is not readily inactivated
at room temperature and by drying like other viruses, for exam-
ple 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
transmissibility of SARS-CoV-2 (Triplett 2020; Wang 2020b, To-
bías 2020) and that the arrival of summer in the northern hemi-
sphere could reduce the transmission of the COVID-19. A possi-
ble association of the incidence of COVID-19 and both reduced
solar irradiance and increased population density has been dis-
cussed (Guasp 2020). It was reported that simulated sunlight rap-
idly inactivated SARS-CoV-2 suspended in either simulated saliva
Kamps – Hoffmann
Transmission | 89
or culture media and dried on stainless steel plates while no sig-

nificant 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 – countries 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
Less than 6 months 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 sec-
ondary transmissions could be caused by a small fraction of in-
fectious 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.
It also appears that aerosol transmission might play an im-
portant 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 probabil-
ity of SARS-CoV-2 infection.
It finally appears that shouting and speaking loudly emits thou-
sands 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.

Over the coming months, the scientific community will try and
define more precisely the role of aerosols 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 community level;
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 re-
searchers are working around the clock, motivated by fame (be-
coming the next Dr. Salk?) and money (becoming the next
Scrooge McDuck?). However, despite these efforts, it is not even
certain that developing a COVID-19 vaccine is possible (Piot 2020,
cited by Draulens). Until the worldwide availability of a vaccine,
the only feasable prevention scheme is a potpourri of physical
distancing (Kissler 2020), intensive testing, case isolation, con-
tact tracing, quarantine (Ferretti 2020) and, as a last (but not
impossible) resort, local lockdowns.
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Virology | 105
3. Virology
This page is under construction.
The author will be disclosed soon.
Coronaviruses are found in a variety of animals and humans.

These enveloped viruses contain a single strand of positive-sense
RNA. Virions are mostly spherical, with pronounced spiked gly-
coprotein (S) embedded in the envelope. Additional structural
proteins include envelope (E), matrix (M), and nucleocapsid (N).
The family Coronaviridae includes four genera, alpha-, beta-, del-
ta- and gammacoronavirus, as well as several subgenera and
species. Phylogenetic analysis on the coronavirus genomes has
revealed that SARS-CoV-2 is a new member of the betacorona-
virus genus, which includes severe acute respiratory syndrome-
related coronavirus (SARS-CoV), Middle East respiratory syn-
drome-related coronavirus (MERS-CoV), bat SARS-related coro-
naviruses (SARSr-CoV), as well as others identified in humans
and diverse animal species. Intra- and inter-species transmission
of CoVs, and genetic recombination events contribute to the
emergence of new CoV strains.
SARS-CoV-2 is taxonomically related to the subgenus Sarbe-
covirus together with SARS-CoV and bat SARS-like CoVs. Genomic
sequencing showed SARS-CoV-2 to be closely related to be-
tacoronaviruses detected in bats, but distinct from SARS-CoV.
The following sections includes some key papers on different
topics. Please check the comments on these studies.

Taxonomy
Coronaviridae Study Group of the International Committee on Taxonomy of
Viruses. The species severe acute respiratory syndrome-related coro-
navirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Micro-
biol. 2020 Apr;5(4):536-544. PubMed: https://pubmed.gov/32123347. Full-
text: https://doi.org/10.1038/s41564-020-0695-z
A consensus statement defining the place of SARS-CoV-2
(provisionally named 2019-nCoV) within the Coronaviridae
family.
Ceraolo C, Giorgi FM. Genomic variance of the 2019-nCoV coronavirus. J Med

Virol. 2020 May;92(5):522-528. PubMed: https://pubmed.gov/32027036.
Full-text: https://doi.org/10.1002/jmv.25700
Analysis of 56 genomic sequences from distinct patients,
showing high sequence similarity (>99%). A few variable ge-
nomic regions exist, mainly at the ORF8 locus (coding for
accessory proteins).
Full-length genome sequences from five patients at an early
stage of the outbreak, showing 79.6% sequence identity to
SARS-CoV and 96% to a bat coronavirus.
Genomic variation
MacLean O, Orton RJ, Singer JB, et al. No evidence for distinct types in the
evolution of SARS-CoV-2. Virus Evolution. Full-text:
https://doi.org/10.1093/ve/veaa034
Do not overinterpret genomic data! In this paper, authors
discuss the difficulty in demonstrating the existence or na-
ture of a functional effect of a viral mutation, and advise
against overinterpretation.
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Virology | 107
Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical
outcome of COVID-19. Nature (2020). Full-text:
Viral variants do not affect outcome. This important study
on 326 cases found at least two major lineages with differen-
tial exposure history during the early phase of the outbreak
in Wuhan. Patients infected with these different clades did
not exhibit significant differences in clinical features, muta-
tion rates or transmissibility.
Origin and hosts

Andersen KG, Rambaut A, Lipkin WA, Holmes EC, Garry RF. The proximal origin
of SARS-CoV-2. Nature Medicine. Published: 17 March 2020. Fulltext:
Review on notable genomic features of SARS-CoV-2, com-
pared to alpha- and beta-coronaviruses. Insights on the
origin, clearly showing that this virus is not a laboratory
construct or a purposefully manipulated virus.
Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev
Microbiol. 2019 Mar;17(3):181-192. PubMed: https://pubmed.gov/30531947.
Full-text: https://doi.org/10.1038/s41579-018-0118-9
SARS-CoV and MERS-CoV likely originated in bats, both
jumping species to infect humans through different inter-
mediate hosts.
Lam TT, Shum MH, Zhu HC, et al. Identifying SARS-CoV-2 related coronavirus-
es in Malayan pangolins. Nature. 2020 Mar 26. PubMed:
https://pubmed.gov/32218527. Fulltext: https://doi.org/10.1038/s41586-
020-2169-0
Do Malayan pangolins act as intermediate hosts? Meta-
genomic sequencing identified pangolin-associated corona-
viruses, 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 pangolins. Nature. 2020 May 7. PubMed:
020-2313-x
In a wildlife rescue center, authors found a coronavirus in
25 Malayan pangolins (some of them were very sick), show-
ing 90-100% amino acid identity with SARS-CoV-2 in differ-
ent genes. Comparative genomic analysis suggested that
SARS-CoV-2 might have originated from the recombination
of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like vi-
rus. 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 eco-
logical niches, which make pangolins the ideal intermediate
host. Stop the illegal pangolin trade!
Zhang T, Wu Q, Zhang Z. Probable Pangolin Origin of SARS-CoV-2 Associated

with the COVID-19 Outbreak. Curr Biol. 2020 Mar 13. PubMed:
https://doi.org/10.1016/j.cub.2020.03.022
This study suggests that pangolin species are a natural res-
ervoir of SARS-CoV-2-like CoVs. Pangolin-CoV was 91.0%
and 90.6% identical to SARS-CoV-2 and Bat-CoV RaTG13, re-
spectively.
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://doi.org/10.1016/j.cub.2020.05.023
A novel bat-derived coronavirus was identified from a met-
agenomics 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
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Virology | 109
date. However, RmYN02 showed low sequence identity

(61.3%) in the receptor binding 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 envi-
ronmental conditions.The Lancet Microbe 2020, April 02. Full-text:
https://www.thelancet.com/journals/lanmic/article/PIIS2666-
5247(20)30003-3/fulltext
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 also 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 plas-
tic on day 7. Strikingly, a detectable level of infectious virus
(<0·1% of the original inoculum) 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. Cell Host Microbe. 2020 Apr 5. PubMed:
https://doi.org/10.1016/j.chom.2020.03.023.
Ferrets shed the virus in nasal washes, saliva, urine, and fe-
ces up to 8 days post-infection. They may represent an in-
fection 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 masks. Nature Med 2020, April 3.
This study from Hong Kong (performed 2013-16) quantified
virus in respiratory droplets and aerosols in exhaled breath.
In total, 111 participants (infected with seasonal corona-
virus, 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
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 detected 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 partici-
pants who did not cough at all during the 30 min exhaled
breath collection, suggesting droplet and aerosol routes of
transmission from individuals with no obvious signs or
symptoms.
Shi J, Wen Z, Zhong G, et al. Susceptibility of ferrets, cats, dogs, and other
domesticated animals to SARS-coronavirus 2. Science. 2020 Apr 8. Pub-
SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and
ducks. However, 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.
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 virus can remain viable and
infectious in aerosols for hours and on surfaces up to days
(depending on the inoculum shed).
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Virology | 111
Cell tropism, ACE expression

Chu H, Chan JF, Yuen TT, et al. Comparative tropism, replication kinetics, and
cell damage profiling of SARS-CoV-2 and SARS-CoV with implications
for clinical manifestations, transmissibility, and laboratory studies of
COVID-19: an observational study. Lancet Microbe April 21, 2020. Full-
An elegant study, explaining distinct clinical features of
COVID-19 and SARS. Investigation of cell susceptibility, spe-
cies tropism, replication kinetics, and virus-induced cell
damage from both SARS-CoVs, using live infectious virus
particles. SARS-CoV-2 replicated more efficiently in human
pulmonary cells, indicating that SARS-CoV-2 has most likely
adapted better to humans. SARS-CoV-2 replicated signifi-
cantly less in intestinal cells (might explain lower diarrhea
frequency compared to SARS) but better in neuronal cells,
highlighting the potential for neurological 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: https://doi.org/10.1016/j.cell.2020.05.042
This study quantitated differences in ACE2 receptor expres-
sion 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 aspiration, these studies
argue for the widespread use of masks to prevent aerosol,
large droplet, and/or mechanical exposure to the nasal pas-
sages.
Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, replication competence,
and innate immune responses of the coronavirus SARS-CoV-2 in hu-
man respiratory tract and conjunctiva: an analysis in ex-vivo and in-
vitro cultures. Lancet Respir Med. 2020 May 7. PubMed:
2600(20)30193-4
More insights into the transmissibility and pathogenesis.
Using ex vivo cultures, the authors evaluated tissue and cel-

lular 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 replication
competence was higher than SARS-CoV. In the lung, it was
similar 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 coronaviruses. Compared to SARS-CoV and RaTG13
(isolated from bats), ACE2-binding affinity is higher. Func-
tionally important epitopes in SARS-CoV-2 RBM are de-
scribed that can potentially be targeted by neutralizing an-
tibody drugs.
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:
Another elegant paper, confirming the expression of ACE2
in multiple tissues shown in previous studies, with added in-
formation on tissues not previously investigated, including
nasal epithelium and cornea and its co-expression with
TMPRSS2. Potential tropism was analyzed by surveying ex-
pression of viral entry-associated genes in single-cell RNA-
sequencing data from multiple tissues from healthy human
donors. These transcripts were found in specific respirato-
ry, corneal and intestinal epithelial cells, potentially ex-
plaining the high efficiency of SARS-CoV-2 transmission.
Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through its

spike protein-mediated membrane fusion. Cell Mol Immunol. 2020 Apr 7.
Kamps – Hoffmann
Virology | 113
It remains unclear whether SARS-CoV-2 can also infect T

cells, resulting in lymphocytopenia. Using a model with
pseudoviruses, authors showed that SARS-CoV-2 infects (but
does not replicate in) T cells through S protein-mediated
membrane fusion. T-cell lines were significantly more sensi-
tive to SARS-CoV-2 infection when compared with SARS-
CoV. Of note, a very low expression level of hACE2 was
found, indicating that a novel receptor might mediate SARS-
CoV-2 entry into T cells.
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 antivi-
rals.
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:
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 ap-
proach, the authors reveal these glycan structures on a re-
combinant SARS-CoV-2 S immunogen.

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 resolution/atomic level, authors used X-ray crystal-
lography. Binding mode was very similar to SARS-CoV, ar-
guing 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 in-
sights into the future identification of cross-reactive anti-
bodies.
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:
Atomic details of the crystal structure of the C-terminal
domain of SARS-CoV-2 spike protein in complex with hu-
man ACE2 are presented. The hACE2 binding mode of SARS-
CoV-2 seems to be similar to SARS-CoV, but some key resi-
due substitutions slightly strengthen the interaction and
lead to higher affinity for receptor binding. Antibody ex-
periments indicated notable differences in antigenicity be-
tween SARS-CoV and SARS-CoV-2
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
Using cryo–electron microscopy, this paper shows how
SARS-CoV-2 binds to human cells. The first step in viral en-
try is the binding of the viral trimeric spike protein to the
human receptor angiotensin-converting enzyme 2 (ACE2).
The authors present the structure of human ACE2 in com-
Kamps – Hoffmann
Virology | 115
plex with a membrane protein that it chaperones, B0AT1.

The structures provide a basis for the development of ther-
apeutics targeting this crucial interaction.
Cell entry
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry De-
pends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven
Protease Inhibitor. Cell. 2020 Mar 4. PubMed:
This work shows how viral entry happens. SARS-CoV-2 uses
the SARS-CoV receptor ACE2 for entry and the serine prote-
ase TMPRSS2 for S protein priming. In addition, sera from
convalescent SARS patients cross-neutralized SARS-2-S-
driven entry.
Letko M, Marzi A, Munster V. Functional assessment of cell entry and recep-

tor 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 potential. Host protease pro-
cessing during viral entry is a significant barrier for several
lineage B viruses. However, bypassing this barrier allows
several coronaviruses to enter human cells through an un-
known receptor.
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 recep-
tor-binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020 Apr 3.
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:
Description of the X-ray structures of the main protease
(Mpro, 3CLpro) of SARS-CoV-2 which is essential for pro-
cessing the polyproteins that are translated from the viral
RNA. A complex of Mpro and an optimized protease -
ketoamide inhibitor is also described.
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, an-
other central enzyme of the viral replication machinery. It
is also shown how remdesivir and sofosbuvir 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.
Kamps – Hoffmann
Virology | 117
Hillen HS, Kokic G, Farnung L et al. Structure of replicating SARS-CoV-2 poly-

merase. 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 active form, mimicking the replicating enzyme.
Long helical extensions in nsp8 protrude along the exiting
RNA, forming positively charged ‘sliding poles’. These slid-
ing 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 replica-
tion machine.
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:
020-2312-y
In transgenic mice bearing human ACE2 and infected with
SARS-CoV-2, the pathogenicity of the virus was demonstrat-
ed. This mouse model will be valuable for evaluating antivi-
ral 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 Syri-
an hamster model: implications for disease pathogenesis and trans-
missibility. Clin Infect Dis. 2020 Mar 26. PubMed:
A readily available hamster model as an important tool for
studying transmission, pathogenesis, treatment, and vac-
cination 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:
No re-infection in macaques. Following initial viral clear-
ance, 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 observed in BAL on
day 1 after re-challenge, with no viral RNA detected at sub-
sequent timepoints. These data show that SARS-CoV-2 in-
fection induced 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:
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.abb731
4
Macaques may serve as a model to test therapeutic strate-
gies. Virus was excreted from nose and throat in the ab-
sence of clinical signs, and was detected in type I and II
pneumocytes in foci of diffuse alveolar damage and in ciliat-
ed epithelial cells of nasal, bronchial, and bronchiolar mu-
cosae. 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.
Munster VJ, Feldmann F, Williamson BN, et al. Respiratory disease in rhesus

macaques inoculated with SARS-CoV-2. Nature 2020. Full-text:
SARS-CoV-2 caused respiratory disease in 8 rhesus ma-
caques, lasting 8-16 days. High viral loads were detected in
swabs as well as in bronchoalveolar lavages. This “model”
Kamps – Hoffmann
Virology | 119
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 hamsters. Nature 2020. Full-text:
In most cases, you don’t need monkeys. Golden Syrian ham-
sters may also work. SARS-CoV-2 transmitted efficiently
from inoculated hamsters to naïve hamsters by direct con-
tact and via aerosols. Transmission via fomites in soiled
cages was less efficient. Inoculated and naturally-infected
hamsters showed apparent weight loss, and all animals re-
covered 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 re-
mained asymptomatic but later developed antibody re-
sponses detected using plaque reduction neutralization as-
says. Genetic analysis suggested that the dogs caught the vi-
rus from their owners. It still remains unclear whether in-
fected dogs can transmit the virus to other animals or back
to humans.
Vaccine (see also Immunology)

Le TT, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development land-
scape. 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 efforts are unprecedented in terms of scale and speed
and that there is an indication that vaccine could be availa-
ble by early 2021. As of 8 April 2020, the global vaccine land-

scape includes 115 candidates, of which the 5 most ad-

vanced candidates have already moved into clinical devel-
opment, including mRNA-1273 from Moderna, Ad5-nCoV
from CanSino Biologics, 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 scientists 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 understand, it explains different approaches such as
virus, viral-vector, nucleic-acid and protein-based vaccines.
Zhu FC, Li YH, Guan XH. Safety, tolerability, and immunogenicity of a recom-
binant adenovirus 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 vac-
cine, 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 follow 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 head-
ache (39%). Phase II studies are underway.
Kamps – Hoffmann
Virology | 121
Pathogenesis (see also Immunology)

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
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 consist-
ently revealed a unique and inappropriate inflammatory re-
sponse to SARS-CoV-2 which is imbalanced with regard to
controlling virus replication versus activation of the adap-
tive 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 authors propose that reduced
innate antiviral defenses coupled with exuberant inflamma-
tory cytokine production are the defining and driving fea-
tures of COVID-19. Given this dynamic, treatments for
COVID-19 have less to do with the IFN response and more to
do with controlling inflammation.
Bordoni V, Sacchi A, Cimini E. An inflammatory profile correlates with de-

creased frequency of cytotoxic cells in COVID-19. Clinical Infectious Dis-
eases 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 func-
tion. 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 immune cytotox-
ic arm as a pathogenic mechanism.
Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-

CoV-2 coronavirus 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 identified circulating SARS-CoV-
CD4 T cells in 70-100% of 20 COVID-19 convalescent patients,

respectively. CD4 T cell responses to spike protein were ro-

bust and correlated with the magnitude of IgG titers. Of
note, the authors detected SARS-CoV-
in 40-60% of unexposed individuals, suggesting cross-
reactive T cell recognition between circulating seasonal
coronaviruses and SARS-CoV-2.
Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hy-
potheses. Lancet. 2020 May 9;395(10235):1517-1520. PubMed:
6736(20)30920-X
Brief but nice review and several hypotheses about SARS-
CoV-2 pathogenesis. What happens during the second week
- when resident macrophages initiating lung inflammatory
responses are unable to contain the virus after SARS-CoV-2
infection and when both innate and adaptive immune re-
sponses are inefficient to curb the viral replication so that
the patient would recover quickly?
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 in-
fection. 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 plate-
let degranulation. It was found that 80 significantly changed
metabolites were also involved in the three biological pro-
cesses revealed in the proteomic analysis.
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Virology | 123
Tay MZ, Poh CM, Rénia L et al. The trinity of COVID-19: immunity, inflamma-
tion and intervention. Nat Rev Immunol (2020). Full-text:
Brilliant overview of the pathophysiology of SARS-CoV-2 in-
fection. How SARS-CoV-2 interacts with the immune sys-
tem, how dysfunctional immune 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 immune responses elicited by SARS-CoV-2 infec-
tion 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 transmis-
sion over 8 years in the HIVE cohort of households in Michigan. J Infect
Dis. 2020 Apr 4. PubMed: https://pubmed.gov/32246136. Full-text:
It’s not clear whether SARS-CoV-2 behaves like other hu-
man coronaviruses (hCoVs). A longitudinal surveillance co-
hort 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
after 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:
020-2294-9
An important technical advance, enabling the rapid genera-
tion and functional characterization of evolving RNA virus
variants. The authors show the functionality of a yeast-

based synthetic genomics platform to genetically recon-

struct 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.
Kamps – Hoffmann
Immunology | 125
4. Immunology
Thomas Kamradt
Rapid progress is being made in deciphering the immune re-

sponses to SARS-CoV-2. Nevertheless, some of the important and
most urgent questions remain unanswered including:
Is someone who has recovers from COVID-19 protected from
the disease?
If yes, how long does the immune protection last?
What are the correlates of protection?
Why is the disease so much more severe in the elderly?
How does the immune response against SARS-CoV-2 contrib-
ute to disease development? Are there pathogenic immune
responses?
Can we use immunological parameters to predict an individ-
ual patient’s risk in developing severe disease?
Can we develop a vaccine against SARS-CoV-2?
The current state of knowledge is beautifully summarised in a

recent extensive review (Vabret 2020).
Protective antibodies
In the absence of robust experimental or clinical data on SARS-
CoV-2-induced immune responses we can make some educated
guesses based on prior experiences with endemic coronaviruses
(e.g. 229E or OC43), the SARS-CoV and the MERS-CoV viruses.
Experimental, serological and sero-epidemiological studies
strongly suggest that coronaviruses, including SARS-CoV-2 in-
duce neutralizing and protective antibodies. These studies also

seem to indicate that antibody-mediated protection is short-

lived.
Cellular immune response

Less is known about cellular immune responses, i.e. T cell re-
sponses against coronaviruses. Experimental evidence from
studies in mice suggests that T cells residing in the mucosa of the
respiratory tract could be an important correlate of protection.
However, although mice can be infected with coronaviruses in-
cluding SARS-CoV, they do not develop the severe pulmonary
symptoms that are characteristic of SARS and COVID-19. There-
fore, these results have to be interpreted with caution. Human T
cells from the respiratory mucosa of ill recovering humans
would be necessary to clarify the issue but are difficult to come
by.
These questions are not simply of an academic nature. Rational
vaccine design is based on solid knowledge about protective im-
munity. As long as we do not know which protective immune
response we need to induce by vaccination, vaccine development
remains guesswork.
Important insights come from two recent studies on T cell re-
sponses against SARS-CoV-2 in healthy donors and COVID-19
patients. Alessandro Sette and coworkers examined T cell re-
sponses in COVID-19 patients and 11 healthy controls (Grifoni
2020). Using a pool of peptides from the SARS-CoV-2 S-, M-, N-
and nsp proteins, they detected CD4+ and CD8+ T cell responses
in 100% and 80% of the patients, respectively. Perhaps more sur-
prisingly they also found reactive CD4+ and CD8+ T cells in 50%
and 20% of unexposed healthy donors. In a similar study, Andre-
as Thiel and co-workers used large pools of overlapping peptides
spanning the entire sequence of the SARS-CoV-2 S protein and
detected S-reactive CD4+ T cells in 83% of the COVID-19 patients
and 34% of the seronegative healthy donors (Braun 2020). The
Kamps – Hoffmann
Immunology | 127
high percentage of seronegative healthy donors who have SARS-

CoV-2 reactive T cells is explained by previous exposure to other
coronaviruses (“common cold” coronaviruses) which have pro-
teins that are highly similar to those of SARS-CoV-2. Thiel and
coworkers went on to show that T cells targeting the C-terminus
of the S protein occur frequently in both patients and healthy
donors, indicating cross-reactivity, whereas T cells targeting the
N-terminus occur frequently in patients but not in healthy do-
nors. The important question posed by these results is whether
those frequently occuring cross-reactive T cells in healthy do-
nors confer some degree of protection, are inconsequential or
even potentially harmful if someone who possesses these cells
becomes infected with SARS-CoV-2. Longitudinal studies will be
needed to provide the answer and to determine how long after
infection the SARS-CoV-2-specific T cells remain detectable in
the blood of patients who have recovered from the disease.
The quest for a vaccine

The fundamentals:
Recovery from infection often induces long-term and some-
times life-long immunity against the causative pathogen.
Immunological memory protects against re-infection and is
mediated by specific antibodies and T cells.
Immunizations confer immunity without exposure to viru-
lent pathogens. Immunization can be passive or active.
In passive immunization protective antibodies are trans-
ferred from a donor to a recipient whereas active immuniza-
tion induces a protective immune response in the recipient.

Passive immunization against SARS-CoV-2

Passive immunization against COVID-19 can be achieved with
convalescent plasma, hyperimmune sera, or with neutralizing
monoclonal antibodies.
Convalescent Plasma
Treatment of patients with convalescent plasma is based on the
idea that someone who has recovered from an infection will
have antibodies against the causative pathogen in their blood.
Convalescent plasma is used for some infectious diseases includ-
ing Argentinian hemorrhagic fever (Casadevall 2004). Prior ex-
perience shows antibody transfer is most effective when given
prophylactically or early in the disease.
Convalescent plasma has been given to SARS patients. Regretta-
bly, this was not done in the context of controlled clinical stud-
ies. A meta-analysis could therefore only conclude that the
treatment was probably safe and perhaps helpful (Mair-Jenkins
2015). While drugs or vaccines against COVID-19 are still months
or years away, convalescent plasma is available now.
To date, we do not know if all patients who have recovered from
COVID-19 will harbor enough titers of neutralizing antibodies to
confer protection upon transfer of plasma. Even the assays to
determine the concentration of neutralizing antibodies are not
standardized nor widely available.
Currently, convalescent plasma is given to COVID-19 patients
(see Treatment chapter). Several randomized clinical studies are
underway. The multicenter CONCOR-1 trial in Canada id due to
start on April 27th with 1,200 participants planned and the CON-
COVID trial in The Netherlands with a target number of more
than 400 patients. These and similar studies will show if conva-
lescent plasma is safe and effective.
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Immunology | 129
Given the possibility of antibody-dependent disease enhance-

ment (ADE), safety is an important consideration in these trials.
One study on macaques found that passive transfer of anti-SARS-
CoV-S immunoglobulin from immunized monkeys into naïve
recipients resulted in acute lung injury after infection. The pro-
posed 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).
Taken together, these data stress the necessity to administer
convalescent plasma in controlled trials, which will determine
safety and efficacy.
Pooled immunoglobulin preparations

Hyperimmune globulin preparations, e.g. cytomegalovirus im-
munoglobulin (CMVIG), pooled from many different donors, are
currently the most frequently used form of passive antibody
transfer. These preparations contain higher concentrations of
pathogen-specific antibodies than convalescent plasma. Howev-
er, they are more difficult to produce and there are currently no
SARS-CoV-2 hyperimmune globulin preparations available.
Monoclonal antibodies
Neutralising monoclonal antibodies are a plausible therapeutic
option against infectious diseases (Marston 2018). For example, a
monoclonal antibody is licensed for prophylaxis against respira-
tory syncytial virus in at-risk infants. and mabs have been used
to treat Ebola-patients (Marston 2018). Monoclonal antibodies
against SARS-CoV have been tested in animal models and some
were found to be effective. It is likely that mabs against SARS-

CoV-2 will soon be developed and testet. As explained above (see

section on antibody dependent disease enhancement) the possi-
bility of antibody dependend disease enhancement needs to be
ruled out before such mabs can be applied in humans.
Active immunization against SARS-CoV-2

At the time of this writing, there are more than 100 COVID-19
vaccine candidates in different stages of preclinical develop-
ment. Five candidate vaccines are in phase I clinical trials
(Thanh Le 2020).
The speed of vaccine development is breathtaking. On 11 Janu-
ary, 2020 Chinese researches published the sequence of the
SARS-CoV-2 genome on the internet. Approximately 2 months
later, on 16 March, an mRNA-based vaccine entered a phase I
clinical trial. This was possible, thanks to knowledge gained in
efforts to develop vaccines against SARS and MERS and the
availability of innovative technologies.
Earlier work had identified the S protein of SARS-CoV and MERS-
CoV as a suitable vaccine target. The S protein binds to its cellu-
lar receptor, ACE2, to infect human cells. A high degree of ho-
mology between the S proteins of the three viruses was quickly
established after the discovery of SARS-CoV-2 and the interac-
tion of SARS-CoV-2 S protein with ACE2 was confirmed. Thus, a
vaccine target was identified in record time.
New technologies helped the rapid development of an mRNA-
based vaccine. The principle was first used in 2013. The Chinese
CDC had discovered H7N9, a novel avian influenza virus strain,
and immediately published the sequence of the relevant anti-
gens online. Synthetic biology approaches enabled the genera-
tion of a vaccine candidate within 8 days and that vaccine was
shown to induce antibodies in mice (Hekele 2013).
Kamps – Hoffmann
Immunology | 131
Why, then, do we still wait for an effective and safe vaccine

against SARS-CoV-2? There are still some obstacles to overcome.
Different strategies to develop a vaccine against

SARS-CoV-2
Many fundamentally different strategies are currently used to
develop a vaccine against COVID-19 (Amanat 2020).
The most traditional way to produce vaccines is the use of whole
viruses, which are either attenuated or inactivated. Currently li-
censed examples include the vaccines against measles and yellow
fever (attenuated virus) and influenza and polio (inactivated
viruses). Efforts are ongoing to develop attenuated or inactivated
SARS-CoV-2 as a vaccine.
Another approach is to use recombinant viral proteins as vac-
cine; licensed examples include the vaccines against hepatitis B
and human papilloma virus. Efforts are ongoing to develop re-
combinant SARS-CoV-2 S protein as an immunogen.
A more recent approach is to use recombinant viral vectors in
which a relevant antigen of the pathogenic virus is expressed.
The only currently licensed example is the vaccine against Ebola,
which is based on a modified vesicular stomatitis virus. An ade-
novirus-based recombinant vaccine against COVID-19 has en-
tered a clinical phase I trial in March 2020.
DNA vaccines targeting the S protein are also in preclinical de-
velopment. There are currently no licensed DNA vaccines, which
might make the licensing process slower as compared with e.g.
protein-based vaccines. A DNA vaccine against COVID-19 entered
a clinical phase I trial in April 2020.
An mRNA vaccine targeting the S protein has been used in a
clinical phase I trial that started on 16 March. There are current-
ly no licensed mRNA vaccines, which might make the licensing
process slower as compared with e.g. protein-based vaccines.

A vaccine based on genetically modified dendritic cells express-

ing a lentivirally encoded SARS-CoV-2 minigene and a study us-
ing genetically modified artificial antigen presenting cells en-
tered a clinical phase I trial in March. There are currently no
licensed vaccines based on genetically modified antigen-
presenting cells, which might again make the licensing process
slower as compared with e.g. protein-based vaccines.
While it is much too early to make any predictions on the safety,
immunogenicity and efficacy of the many vaccines currently
under development, it is useful to see what can be learned from
prior attempts to develop vaccines against coronaviruses.
Vaccines against coronaviruses can induce pathological im-

mune responses.
Rarely, vaccines can enhance disease rather than protect from
disease (Openshaw 2001). Vaccines are administered to healthy
people. SARS-CoV-2 causes a mild, if not clinically inapparent
disease in at least 80% of those who are infected. Therefore, safe-
ty considerations are of utmost importance. Unfortunately,
there is some data hinting at the possibility that the develop-
ment of a safe vaccine against COVID-19 might be unusually dif-
ficult.
Vaccine-induced immune response against FIPV is harmful

in kittens
Feline infectious peritonitis (FIP) is a severe and often fatal dis-
ease in cats. It is caused by a coronavirus, FIPV. Different at-
tempts at vaccine development have failed. In an early study
kittens that were vaccinated with an avirulent FIPV strain were
more susceptible to infection with virulent FIPV than the non-
vaccinated controls (Pedersen 1983). More worryingly were the
results of a later study in which cats were immunized with a re-
combinant vaccinia virus that expressed the FIPV S protein. Vac-
Kamps – Hoffmann
Immunology | 133
cination induced low titers of neutralizing antibodies. Upon

FIPV-challenge the previously immunized animals were not pro-
tected but died earlier than the controls (Vennema 1990). It is
thought that antibody-mediated infection of macrophages and
the deposition of immune complexes cause the more severe dis-
ease in immunized animals (Perlman 2005, Weiss 1981).
Immunopathology seen in experimental vaccines against

SARS
Immunopathological or disease-enhancing effects were reported
by many different research groups using different technologies
and different animal models in an effort to develop a vaccine
against SARS.
Immunization with recombinant modified vaccinia virus Ankara
(rMVA) expressing the SARS-CoV spike (S) protein causes severe
hepatitis in ferrets.
Ferrets are susceptible to SARS-CoV infection. Weingartl and
collegues immunized ferrets with recombinant modified vaccinia
virus Ankara (rMVA) expressing the SARS-CoV S protein
(Weingartl 2004). Upon challenge with the virus, high titers of
neutralizing antibodies were detectable more rapidly in the im-
munized animals than in the controls. However, the ferrets im-
munized with rMVA-S developed severe hepatitis which was not
the case in the control animals (Weingartl 2004). Ferrets are also
highly susceptible to SARS-CoV-2 infection (Kim 2020) and are
thus suitable for the evaluation of the safety of future vaccine
candidates.
Immunization of mice results in type 2 inflammatory re-

sponses in the lungs
A group from North Carolina, USA used inactivated virus with or
without adjuvant to immunize mice against SARS-CoV (Bolles
2011). The vaccine protected young and to a lesser extent, older

animals from morbidity and mortality following high-dose viral

challenge. However, challenge with a heterologous virus resulted
in inflammatory infiltrates and pulmonary eosinophilia that
were more severe in the vaccinated animals. Moreover, in old
mice the vaccine did not confer protection but still resulted in
inflammatory infiltrates in the lung. The occurrence of lung im-
munopathology with this vaccine was later confirmed and ex-
tended by another group (Tseng 2012). Eosinophilic lung infil-
trates were also observed when a recombinant baculovirus ex-
pressed S protein or coronavirus-like particles (VLPs) expressing
the SARS-CoV S protein were used to immunize mice
(Lokugamage 2008, Tseng 2012). It is important to note that
these were mainly histopathological findings and the vaccinated
mice had reduced viral titers upon challenge. However, these
histopathological findings are reminiscent of those that were
associated with vaccine-induced pathology in children that had
received a vaccine against respiratory syncytial virus (RSV) in
the 1960s (Castilow 2007). Moreover, lung pathology and even
pneumonia were reported when mice were immunized with re-
combinant vaccinia virus (VV) expressing SARS-CoV S and nu-
cleocapsid (N) proteins (Yasui 2008). Lung pathology was also
observed when Venezuelan equine encephalitis virus replicon
particles (VRP) expressing the N protein were used to immunize
mice (Deming 2006).
Unfortunately, if perhaps not surprisingly, similar findings were
reported for MERS-CoV vaccine candidates. An inactivated
MERS-CoV vaccine induced neutralizing antibodies in mice and
also resulted in an enhanced type 2 pathology in the lung, i.e.
eosinophilic infiltrates and increased concentrations of IL-5 and
IL-13 (Agrawal 2016).
Some studies suggest that this type 2 pathology may be amelio-
rated or prevented by using toll-like receptor agonists (Iwata-
Yoshikawa 2014) or delta inulin (Honda-Okubo 2015) as adju-
Kamps – Hoffmann
Immunology | 135
vants for inactivated whole virus or recombinant spike protein

vaccine candidates.
Together, these findings cause concern. Careful histopathologi-
cal evaluation of the lungs should be part of the pre-clinical de-
velopment of COVID-19 vaccines.
Immunization of non-human primates results in severe

acute lung injury
In a recent study Chinese macaques were vaccinated with a mod-
ified 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 anti-
bodies and reduced virus loads. However, the vaccinated mon-
keys had diffuse alveolar damage (DAD) (Liu 2019). An earlier
study had used inactivated SARS-CoV to vaccinate four ma-
caques. Three monkeys were protected upon challenge whereas
one macaque had lung-pathology consistent with antibody-
dependent disease enhancement (ADE) (Wang 2016). These au-
thors further suggested that ADE was mediated by antibodies
against certain epitopes of SARS-CoV S but not others (Wang
2016).
Anti-S antibodies enhance infection of human immune cells

Antibodies against SARS-CoV spike protein can enhance virus
entry into human cells by interaction with conformational
epitopes in the ACE2-binding domain (Yang 2005). Anti-Spike
immune serum was reported to promote the infection of human
hematopoietic cell lines by SARS-CoV. Virus entry was not medi-
ated via ACE2 but depended on Fc receptor II (Jaume 2011).
While the in vivo relevance of these findings remains to be de-
termined, they add to the list of concerns that need to be ad-
dressed in the development of safe and effective vaccines against
COVID-19.

Outlook
Given the massive and diverse ongoing efforts to develop a vac-
cine against COVID-19, we can be optimistic that a safe and effec-
tive vaccine will be available in the not-too-distant future. The
development of a vaccine against Ebola took five years and there
is reason to believe that the COVID-19 vaccine(s) will be devel-
oped even faster than that. We need to keep in mind that vaccine
discovery and early development only require 30% of all the
work and time required to bring a vaccine to the end user.
One challenge for the developers of COVID-19 vaccine(s) is that
the elderly are most susceptible to the infection and carry a par-
ticularly high risk for severe or lethal disease. Due to immunose-
nescence, the elderly are notoriously difficult to immunize, re-
quiring higher doses or particular immunization schemes in or-
der to generate a protective immune response. Studies in mice
indicate that older animals are also more likely to develop im-
munopathology upon vaccination.
A lesson that should have been learned already following the
SARS outbreak is that more enzootic viruses will jump from their
animal reservoirs to humans. Given the fact that not too many
different viruses can cause severe and potentially deadly respira-
tory infections we should not stop our efforts once a SARS-CoV-2
specific vaccine is available. Instead, efforts should be made to
develop a vaccine platform that can quickly be adapted to newly
emerging coronaviruses. We do not know the date of the next
outbreak, but we can be sure that SARS-CoV-2 is not the last
coronavirus humankind will confront.
Kamps – Hoffmann
Immunology | 137
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Prevention | 141
5. Prevention
A thorough discussion of SARS-CoV-2 prevention will be pre-
sented in the 5th edition of COVID Reference by Stefano Lazzari.
In the meantime, please find this outline with key topics and
references. At present, based on the current understanding of
SARS-COV-2 transmission presented in Chapter 2, several pre-
vention measures can be considered at the personal, institution-
al, community and societal levels:
1. Personal infection prevention measures

Hand hygiene (washing or disinfecting)
Practice good respiratory hygiene/cough etiquette.
Use of face masks
Physical and social distancing. Avoid crowded places
Speak quietly, don’t shout (or sing)!
Strengthen overall personal health and immunity
Household hygiene
Self-quarantine at home
Physical distancing
Use chemoprophylaxis (not yet available)
2. Preventive measures at community and social levels

Mandatory face masks
Ban mass gatherings (sports events, discos, crowded
bars, religious celebrations etc.)
Localized and nationwide lockdowns
Travel bans/border closures
Widespread testing, intensive contact tracing (with or
without smartphone apps)
Quarantine and isolation of suspected or confirmed cas-
es

Environmental hygiene and disinfection

Vaccinate for seasonal influenza and for COVID-19 (not
yet available)
3. Preventive measures at institutional level

Hospitals
Nursing facilities
Long-term Care Institutions
Workplaces
Schools
Prisons
Homeless shelters
Prevention at the personal level

Good respiratory hygiene/cough etiquette.
Chavis S, Ganesh N. Respiratory Hygiene and Cough Eti-
quette. Infection Control in the Dental Office. 2019;91-103. Pub-
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030-30085-2_7
Hand Hygiene
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WHO Interim recommendations on obligatory hand hy-
giene against transmission of COVID-19. 1 April 2020
Kamps – Hoffmann
Prevention | 143
Guide to Local Production: WHO-recommended Handrub

Formulations. WHO 2020.
Face masks
Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ.
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and eye protection to prevent person-to-person transmis-
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WHO Advice on the use of masks in the context of COVID-
19. Interim guidance, 5 June 2020

Physical/Social distancing and avoiding crowded

conditions
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Speak quietly, don’t shout (or sing)!

Asadi S, Wexler AS, Cappa CD, Barreda S, Bouvier NM, Ris-
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Household hygiene
Radhika Gharpure; Candis M. Hunter; Amy H. Schnall; Cathe-
rine E. Barrett; Amy E. Kirby; Jasen Kunz; Kirsten Berling;
Jeffrey W. Mercante; Jennifer L. Murphy; Amanda G. Garcia-
Williams. Knowledge and Practices Regarding Safe
Household Cleaning and Disinfection for COVID-19 Pre-
vention — United States, MMWR Morb Mortal Wkly Rep.
May 2020 Early Release, June 5, 2020/9. Full-text:
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m
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Prevention | 145
Chang A, Schnall AH, Law R, et al. Cleaning and Disinfect-

ant Chemical Exposures and Temporal Associations with
COVID-19 - National Poison Data System, United States,
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Chin AWH, Chu JTS, Perera MRA, et al. Stability of SARS-
CoV-2 in different environmental conditions. Lancet
2020: April 02, 2020. Full-text:
Chemoprophylaxis
Post-exposure prophylaxis (PEP) with antiviral drugs after doc-
umented exposure can reduce the risk of infection. In the future,
SARS-CoV-2-PEP could be used to reduce viral shedding in sus-
pected cases and as a prophylactic treatment of contacts.
Prevention at the community/societal levels

Mandatory face masks
Recommendation Regarding the Use of Cloth Face Cover-
ings, Especially in Areas of Significant Community-Based
Transmission, US CDC 2020
WHO Advice on the use of masks in the context of COVID-
19, Interim guidance, 5 June 2020
European Centre for Disease Prevention and Control.
Using face masks in the community. Stockholm: ECDC
2020

Ban on mass gatherings

McCloskey B, Zumla A, Ippolito G, et al. Mass gathering
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4;395(10230):1096-1099. PubMed:
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Localized and nationwide Lockdowns

Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of
non-pharmaceutical interventions against coronavirus
disease 2019 and influenza in Hong Kong: an observa-
tional study. Lancet Public Health. 2020 May;5(5):e279-e288.
Travel bans/border closures

#COVID19 Government Measures Dataset, ACAPS, 2020
Updated WHO recommendations for international traffic
in relation to COVID-19 outbreak, WHO 29 February 2020
Habibi R, Burci GL, de Campos TC, et al. Do not violate
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COVID-19 outbreak. Lancet. 2020 Feb
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Devi S. Travel restrictions hampering COVID-19 re-

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Test. Treat. Track.

Contact tracing for COVID-19: current evidence, options
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ECDC, April 2020
Contact tracing in the context of COVID-19: Interim
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Steinbrook R. Contact Tracing, Testing, and Control of
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Cheng HY, Jian SW, Liu DP, Ng TC, Huang WT, Lin HH; Tai-
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Salathé M, Althaus CL, Neher R, et al. COVID-19 epidemic in
Switzerland: on the importance of testing, contact trac-
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Tracking apps
Jia JS, Lu X, Yuan Y, Xu G, Jia J, Christakis NA. Population
flow drives spatio-temporal distribution of COVID-19 in
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Oliver N, Lepri B, Sterly H, et al. Mobile phone data for in-
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Ferretti L, Wymant C, Kendall M, et al. Quantifying SARS-
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Quarantine and isolation of suspected or con-

firmed cases
Little P, Read RC, Amlôt R, et al. Reducing risks from coro-
navirus transmission in the home-the role of viral load.
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Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of
COVID-19 in 391 cases and 1286 of their close contacts in
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Wu J, Huang Y, Tu C, et al. Household Transmission of

SARS-CoV-2, Zhuhai, China, 2020. Clin Infect Dis. 2020 May
Environmental hygiene and disinfection

Cleaning and disinfection of environmental surfaces in
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Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of
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Disinfection of environments in healthcare and non-
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Vaccinate for seasonal influenza and for COVID-19

(not yet available)
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Singer BD. COVID-19 and the next influenza season. Sci-
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Prevention at the institutional level

Hospitals and other health care settings
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus
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US CDC Interim Infection Prevention and Control Rec-
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Coronavirus Disease 2019 (COVID-19) in Healthcare Set-
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Hoe Gan W, Wah Lim J, Koh D. Preventing intra-hospital
infection and transmission of COVID-19 in healthcare
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son-to-person transmission of severe acute respiratory
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Diagnostic Tests and Procedures | 155
6. Diagnostic Tests and Procedures

Christian Hoffmann
Diagnosis
Rapid identification and isolation of infected individuals is cru-
cial. 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 nucle-
ic acid-based polymerase chain reaction (PCR), amplifying a spe-
cific genetic sequence in the virus. Within 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 capacity achieved through coordination of
academic and public laboratories in national and European re-
search networks.
There is an interim guidance for laboratory testing for corona-
virus disease (COVID-19) suspected human cases, published by
WHO on March 19, 2020 (WHO 2020). Several comprehensive up-
to-date reviews of laboratory techniques in diagnosing SARS-
CoV-2 have been published recently (Chen 2020, Loeffelholz
2020).
In settings with limited resources, no testing capacity should be
wasted. Importantly, patients should only be tested if a positive
test results in imperative action. This is not the case in the fol-
lowing examples:
Young people who had contact with an infected person a few
days earlier, have mild or moderate symptoms and live alone.
They do not need PCR testing, even if they get fever. They’ll
remain in at-home quarantine, on sick leave if necessary, un-
til at least 14 days after the onset of symptoms. A test would

only be useful to clarify whether they can work in a hospital

or other health care facilities after quarantine. Some authori-
ties require at least one negative test (nasopharyngeal) be-
fore starting work again (in addition to at least 48 hours of
being symptom-free).
A couple returning from an epidemic hotspot and feel a slight
scratch in their throats. As they should remain in quarantine
anyway, again, no testing is needed.
A family of four with typical COVID-19 symptoms. Testing
only one (symptomatic) person is sufficient. If the test is posi-
tive, it is not necessary to test the other household contacts –
as long as they stay at home.
These decisions are not easy to commnicate, particularly to fear-
ful and worried patients.
In other situations, however, a test must be immediately carried
out and repeated if necessary, especially for medical profession-
als with symptoms, but also, for example, in nursing homes, in
order to detect an outbreak as quickly as possible.
Even though there are constantly updated recommendations by
authorities and institutions of the country’s health system about
who should be tested by whom and when: they are constantly
changing and have to be constantly adapted to the local epide-
miological situation. With decreasing infection rates and in-
creasing test capacities, more patients will certainly be able to be
tested in the future, and the indication for a test will be expand-
ed.
Specimen collection
SARS-CoV-2 can be detected in different tissues and body fluids.
In a study on 1,070 specimens collected from 205 patients with
COVID-19, bronchoalveolar lavage fluid specimens showed the
highest positive rates (14 of 15; 93%), followed by sputum (72 of
Kamps – Hoffmann
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%). None of the 72 urine
specimens tested positive (Wang X 2020). The virus was also not
found in the vaginal fluid of 10 women with COVID-19 (Saito
2020).
It was also not found in two early studies on sperm and breast
milk (Song 2020, Scorzolini 2020). However, in a recent case re-
an infected mother on 4 consecutive days. Detection of viral RNA
born (Groß 2020).

On rare occasions, however, the virus may be also detected in
tears and conjunctival secretions (Xia 2020).
Besides nasopharyngeal swabs, samples can be taken from spu-
tum (if producible), endotracheal aspirate, or bronchoalveolar
lavage. It is likely that lower respiratory samples are more sensi-
tive than nasopharyngeal swabs. Especially in seriously ill pa-
tients, 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 be-
come infected.
However, viral replication 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 (nasopharyngeal
and oropharyngeal swab or wash) in ambulatory patients (WHO
2020). It is preferred to collect specimens from both nasopha-
ryngeal and oropharyngeal swabs which can be combined in the
same tube.

Nasopharyngeal swabs – practical issues

It is important to carry out the swab correctly. Both nasophar-
ynx 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! Respiratory protec-
tion, protective glasses, gowns and gloves are required. The cor-
rect putting on and taking off of the protective clothing should
be practiced! Many mistakes occur even when a protective mask
is removed. There is a very useful video on protection, prepara-
tion, equipment, handling, removing personal protective equip-
ment, 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 posi-
tion in order to avoid a possible cough drop. Tell the patient that
it can 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. “Nose popules” is
not enough! Touching the teeth and tongue should be avoided
when taking 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 swabs. After appropriate instruc-
tion, many patients can perform the swabs themselves.
We have established swabs for patients who are able to do this
(most of them!) at home. A courier with the tubes is sent directly
to the patient's home, and the courier places the tubes in front
of the door. Direct contact between patient and courier should
be avoided. The swab tubes should not be touched by the courier
Kamps – Hoffmann
(either put them directly in a bag or collect them with an invert-

ed bag) and should be brought back directly (no mailing!). This
requires prior, precise instruction, but is usually quite feasible.
The swabs can be stored dry or in a small amount of NaCl solu-
tion; if necessary, this should be clarified with the laboratory
beforehand. Quick PCR examination is important, preferably on
the same day if possible. Heat is not favorable. In a small study,
samples were inactivated by incubation in a water bath at 56°C
for 30 minutes. 7/15 samples with low viral values converted to
false negative. Longer storage also led to false negative results
(Pan 2020).
Lower respiratory specimens may include sputum (if produced)
and/or endotracheal aspirate or bronchoalveolar lavage in pa-
tients with more severe respiratory disease. However, a high risk
of aerosolization should be considered (adhere strictly to infec-
tion prevention and control procedures). Additional clinical
specimens may be collected as COVID-19 virus has been detected
in blood and stool (see below).
Gathering specimens from nasopharyngeal and throat swabs can
cause discomfort for patients and put health-care workers at
risk. In contrast to many respiratory viruses, SARS-CoV-2 is pre-
sent in saliva and several studies have shown that posterior oro-
pharyngeal (deep throat) saliva samples are feasible and more
acceptable to patients and healthcare workers (To 2020, Yu
2020). Throat washing may be used for monitoring due to its
non-invasiveness and reliability. Throat washing was harvested
by asking patients to oscillate over the posterior pharyngeal wall
with 20 ml sterile normal saline. After 5-10 seconds, they spit out
the normal saline from their throat to a sterile container. In 24
paired throat washings and nasopharyngeal swabs specimens,
the positive testing rate of throat washing was much higher than
that of swabs (Guo WL 2020).

Fecal shedding
Although no cases of transmission via fecal-oral route have yet
been reported, there is also increasing evidence that SARS-CoV-2
is actively replicating in the gastrointestinal tract. Several stud-
ies 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).
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 finding remains unclear and there is one study that did
not detect infectious virus from stool samples, despite having
high virus RNA concentrations (Wolfel 2020). Therefore, the
presence of nucleic acid alone cannot be used to define viral
shedding or infection 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 infec-
tious virus.
Blood
SARS-CoV-2 is rarely detected in blood (Wang W 2020, Wolfel
2020). What about transmission risk associated with transfu-
sions? In a screening study of 7,425 blood donations in Wuhan,
plasma samples were found positive for viral RNA from 2 asymp-
tomatic donors (Chang 2020).
Another study from Korea found seven asymptomatic blood do-
nors 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. Transfusion transmission of
SARS-CoV-2 was considered to be unlikely (Kwon 2020). As with
Kamps – Hoffmann
feces, it remains unclear whether detectable RNA in the blood

signifies infectivity.
PCR
Several different qPCR-based detection kits are available as labs
worldwide have customized their PCR tests for SARS-CoV-2, us-
ing 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).
If not, the limits of detection of six commercial kits differ sub-
stantially (up to 16-fold difference), with the poorest limits likely
leading to false-negative results when RT–PCR were used to de-
tect SARS-CoV-2 infection (Wang X 2020). According to the au-
thors, manufacturers should analyze the existing problems ac-
cording to the clinical application and further improve their
products.
Qualitative PCR
A qualitative PCR (“positive or negative”) is usually sufficient in
routine diagnostics. Quantification of viral RNA is currently
(still) only of academic interest.

False positive results are rare. However, they do occur. Though

the analytical specificity of these tests is usually 100%, the clini-
cal specificity is less, due to contamination (a significant prob-
lem for NAT procedures) and/or human error in the handling of
samples or data (very hard to eliminate entirely). As seen with
serology (see below), these false positive results will have sub-
stantial-to-large effects when prevalence is low (Andrew Cohen,
personal communication).
Another problem of any qualitative PCR is false negative results
which have many causes. Incorrect smears are particularly
common, but laboratory errors also occur. In a review of 7 stud-
ies with a total of 1,330 respiratory samples the authors estimat-
ed 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%,
decreased to 20% (day 8) and then began 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 lowest 3 days after onset of symptoms, or ap-
proximately 8 days after exposure (Kucirka 2020). Figure 1 illus-
trates PCR and antibody detection during SARS
Several studies have shown that asymptomatic patients also
have positive PCR results and can transmit the virus (Bai 2020,
Cereda 2020, Rothe 2020). Viral shedding may begin 2 to 3 days
before the appearance 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 symptom onset. Infectiousness
started from 2.3 days (95% CI, 0.8–3.0 days) before symptom on-
set and peaked at 0.7 days before symptom onset (He 2020). In-
fectiousness was estimated to decline quickly within 7 days.
Kamps – Hoffmann
Figure 1. Timeline of diagnostic markers for detection of SARS-CoV-2. AB =

Antibody.
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,
the PCR was positive even longer: male gender and a severe
course (invasive mechanical ventilation) were independent risk
factors for prolonged shedding (Xu K 2020).
Recent reports from patients have repeatedly gained much me-
dia attraction, showing positive results after repeated negative
PCR and clinical recovery (Lan 2020, Xiao AT 2020, Yuan 2020).
These studies raise the question of re-activation or re-infection
of COVID-19 (see below, clinical chapter). Currently, the results
are much more likely due to methodological problems (Li 2020).
At low virus levels, especially during the last days of an infec-
tion, the viral load can fluctuate and sometimes be detectable,
sometimes not (Wolfel 2020). Reactivation, and also a rapid rein-
fection would be very unusual for coronaviruses.

Quantification of viral load

Several studies have evaluated the SARS-CoV-2 viral load in dif-
ferent specimens. 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 the asymptomatic pa-
tients was similar to that in the symptomatic patients, which
suggests the transmission potential of asymptomatic or minimal-
ly symptomatic patients.
In another study on 82 infected individuals, the viral loads in
throat swab and sputum samples peaked at around 5–6 days af-
ter symptom onset, ranging from around 79,900 copies/ml in the
throat to 752,000 copies per mL in sputum (Pan 2020). In a study
on oropharyngeal saliva samples, unlike SARS, patients 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 specimens 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 copies) and
nasal swabs (651 copies). Viral load was higher in the early and
progressive stages than in the recovery stage (Yu 2020). Accord-
ing to a recently published study, viral shedding may already
begin 2-3 days before the appearance of the first symptoms and
the infectiousness profile may more closely resemble that of in-
fluenza than of SARS (He 2020).
Higher viral loads might be associated with severe clinical out-
comes. In a study evaluating serial samples from 21 mild and 10
severe cases (Liu 2020), mild cases were found to have an early
viral clearance, with 90% of these patients repeatedly testing
negative on RT-PCR by day 10 post-onset. By contrast, all severe
cases still tested positive at or beyond day 10 post-onset. Howev-
Kamps – Hoffmann
er, large and 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 the viral load? Probably yes. It may be help-
ful in clinical practice. A positive RT-qPCR result may not neces-
sarily 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.
RT-qPCR provides quantification by first reverse transcribing
RNA into DNA, and then performing qPCR where a fluorescence
signal increases proportionally to the amount of amplified nucle-
ic acid. The test is positive if the fluorescence reaches a specified
threshold within a certain number of PCR cycles (Ct value, in-
versely 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 calcu-
late viral load which can help refine decision-making (shorter
isolation etc). Unfortunately, there is still wide heterogeneity
and inconsistency of the standard curves calculated from studies
that provided Ct values from serial dilution samples and the es-
timated 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 misunderstand-
ing of viral load kinetics for comparison across different studies
(Han 2020).
Test systems other than PCR

Point-of-care tests
Point-of-care tests are easy-to-use devices to facilitate testing
outside of laboratory settings (Joung 2020). They are eagerly
awaited. On May 6, the FDA granted an emergency use authori-
zation for a clustered regularly interspaced short palindromic
repeats (CRISPR)-based SARS-CoV-2 fluorescent assay marketed

by Sherlock Biosciences. This method gives results in an hour

and has successfully diagnosed 12 positive and 5 negative COVID-
19 patients, with at least 2 of 3 replicates scoring positive in in-
fected persons. However, its use still remains limited to labora-
tories certified to perform high-complexity tests. On May 6, FDA
has also authorized Quidel’s Sofia 2 SARS Antigen Fluorescent
Immunoassay. This test must be read on a dedicated analyzer
and detects SARS-CoV-2 nucleocapsid protein from nasopharyn-
geal swabs in 15 min. According to the manufacturer, the assay
demonstrated acceptable clinical sensitivity and detected 47/59
infections (80%). Unfortunately, no peer-reviewed papers have
been published to date. Given the low sensitivity, these tests may
mainly serve as an early tool to identify infectious individuals
very rapidly, i.e. in the emergency unit. They will not work as a
general diagnostic test.
Diagnosis in the setting of 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 not meet the need of a growing infected
population. Thus, pooled samples are often used to save materi-
al. Several samples are examined together. Only when such a
pooled sample is positive, will the samples be examined individ-
ually.
Some studies have also investigated whether the diagnosis in
high prevalence periods and countries cannot 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 findings and tests can identify subjects at
high risk of COVID-19. Low leukocytes, low lymphocytes, higher
Kamps – Hoffmann
body temperature, higher respiratory rate, gastrointestinal

symptoms and decreased sputum production were strongly asso-
ciated with a positive SARS-CoV-2 test. However, those prelimi-
nary prediction models are sensitive to the local epidemiological
context and phase of the global outbreak. They make only 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 in-
cidence is lower, 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. Whenever 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 test-
ing is multipurpose: these serological assays are of critical im-
portance to determine seroprevalence, previous exposure and
identify highly reactive human donors for the generation of con-
valescent serum as therapeutic. They will support contact trac-
ing 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 diagnosis, and for what
reasons, how many patients are asymptomatic, and what is the
real mortality rate in a defined population? Only with compre-
hensive serology testing (and well-planned epidemiological stud-
ies) will we be able to answer these questions and reduce the
ubiquitous undisclosed number in the current calculations. Sev-
eral 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 several days, antibodies may be helpful and enhance
diagnostic sensitivity.
However, antibody testing is not trivial. The molecular hetero-
geneity of SARS-CoV-2 subtypes, imperfect performance of
available tests and cross-reactivity with seasonal CoVs have to be
considered (reviews: Krammer 2020, Torres 2020).
Tests
Several groups are working towards producing these tests
(Amanat 2020), some of them are already commercially available.
A nice overview of the different platforms, including binding
assays such as enzyme-linked immunosorbent assays (ELISAs),
lateral flow assays, or Western blot–based assays is given by
Krammer 2020. In addition, functional assays that test for virus
neutralization, enzyme inhibition, or bactericidal assays can also
inform on antibody-mediated immune responses. Many caveats
and open questions with regard to antibody testing are also dis-
cussed.
Antibody testing usually focuses on antigens (proteins). In the
case of SARS-CoV-2, different Enzyme-Linked Immunosorbent
Assay (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 coronaviruses—
Kamps – Hoffmann
false positives resulting from immunity to other coronaviruses.

Cross reactivity to other coronaviruses can be challenging. So
called confirmation tests (usually neutralization tests) can be
used to reduce false positive testings.
Even with a very high specificity of 99% and above, especially in
low-prevalence areas, the informative value is limited and a high
rate of false positive tests can be assumed. An example: With a
specificity of 99%, it is expected that one test out of 100 is posi-
tive. In a high prevalence 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 val-
ue, 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 popula-
tion, still have shown a relatively constant rate of around 0.8% in
March 2020 (Gudbjartsson 2020). Even in apparently more se-
verely affected countries, the infection rates are only slightly
higher. If we assume an infection number of 183,000 (May 30) for
Germany, a country with one of the world's largest number of
infections, and assume that the number of undetected infections
is about 5 times as high, then the prevalence in Germany is over-
all still around 1%. Almost every hundredth is infected, every
second positive test would be false positive, even with a specifici-
ty of 99%. General antibody screening in the population will
therefore produce a fairly high rate of false positive 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).

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. However, it can still be done if, for example,
you want to validate a test. In addition 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 antibodies when the testing result has consequences.
Patients should be informed 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, virtually
everybody is still seronegative. If positive, the predictive value is
too low.
Kinetics of antibodies
Serologic responses to coronaviruses are only transient. Anti-
bodies to other human, seasonal coronaviruses may disappear
even after a few months. Preliminary data suggest that the pro-
file 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 dramatically 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 de-
tected on day 15 and rapidly reached a peak, then declined grad-
ually 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 relatively
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 to the diagnosis
of COVID-19, including subclinical cases (Guo 2020). In this study,
Kamps – Hoffmann
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 positive 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
another study of 173 patients, the seroconversion rates (median
time) for IgM and IgG were 83% (12 days) and 65% (14 days), re-
spectively. A higher titer of antibodies was independently asso-
ciated with severe diseases (Zhao 2020).
In some patients, IgG occurs even faster than IgM. In a study on
seroconversion patterns of IgM and IgG antibodies, the serocon-
version time of IgG antibody 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 se-
quentially. Both IgG and IgM titers plateaued within 6 days after
seroconversion. The median day of seroconversion for both IgG
and IgM was 13 days post-symptom onset. No association be-
tween plateau IgG levels and clinical characteristics was found
(Long 2020).
Do all asymptomatic individuals develop antibodies? Probably
not. Among five asymptomatic cases, only one generated SARS-
CoV-2 specific antibody responses within the first 4 weeks
(Yongchen 2020).
Taken together, antibody testing is not only an epidemiological
tool. It also may help in the diagnosis. It will be seen in the com-
ing 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 patients (e.g.
those with immunodeficiency), the antibody response remains
reduced.
Radiology
Chest computed tomography
Computed tomography (CT) can play a role in both diagnosing
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 cur-
rent pandemic that a considerable proportion of subclinical pa-
tients (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 pneumo-
nia PCR in nasopharyngeal swabs was still negative (Xu 2020). On
the other hand, half of the patients who later develop CT mor-
phologically 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
recommendation 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 Chi-
nese studies have been exposed to significant errors and short-
comings. In view of the high effort and also because of the risk of
infection for the staff, many experts strictly reject the general
CT screening in SARS-CoV-2 infected patients or in those with
suspicion (Hope 2020, Raptis 2020). According to the recommen-
dation of the British Radiology Society, which made attempts to
incorporate CT into diagnostic algorithms for COVID-19 diagnos-
Kamps – Hoffmann
tics, 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 attempted 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 sensi-
tivity but low specificity (Kim 2020). The sensitivity of CT was
affected by the distribution of disease severity, the proportion of
patients with comorbidities, and the proportion of asymptomatic
patients. In areas with low prevalence, chest CT had a low posi-
tive 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 multiple bilateral lobes. Lesions may display sig-
nificant overlap with those of SARS and MERS (Hosseiny 2020).
A systematic review of imaging findings in 919 patients found
bilateral multilobar GGO with a peripheral or posterior distribu-
tion, 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, lymphadenopathy, cavita-
tion, 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, including consolidation, bilateral
and peripheral disease, greater total lung involvement, linear

opacities, “crazy-paving” pattern and the “reverse halo” sign

(Bernheim 2020). Some experts have proposed that imaging can
be sorted 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 en-
large, developing into multiple GGOs as well as infiltrating con-
solidation in both lungs. In the severe phase, massive pulmonary
consolidations and “white lungs” are seen, but pleural effusion is
rare. In the dissipative phase, the GGOs and pulmonary consoli-
dations were completely absorbed, and the lesions began to
change into fibrosis.
In a longitudinal study analyzing 366 serial CT scans in 90 pa-
tients with COVID-19 pneumonia, the extent of lung abnormali-
ties 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 eval-
uate 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 recov-
ery. 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 symptomatic times (< 2 days). In case of COVID-
19, a large number of patients with infection or suspected infec-
Kamps – Hoffmann
tion swarm into the hospital. Consequently, the examination

workload of the radiology department increases sharply. Be-
cause the transmission route of SARS-CoV-2 is through respira-
tory droplets and close contact transmission, unnecessary CT
scan should be avoided. An overview of the prevention and con-
trol 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 in-
clude portability, bedside evaluation, safety and possibility of
repeating the examination during follow-up. Experience espe-
cially from Italy with lung ultrasound as a bedside tool has im-
proved 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 cases also remains unclear (Deng 2020, Qin
2020).
In patients with neurological symptoms, brain MRI is often per-
formed. In 27 patients, the most common imaging finding was
cortical signal abnormalities on FLAIR images (37%), accompa-
nied by cortical diffusion restriction or leptomeningeal en-
hancement (Kandemirli 2020). However, the complex clinical
course including comorbidities, long ICU stay with multidrug
regimens, respiratory distress with hypoxia episodes can all act
as confounding factors and a clear cause-effect relationship be-

tween COVID-19 infection and MRI findings will be hard to estab-

lish.
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Kamps – Hoffmann
Clinical Presentation | 185
7. Clinical Presentation
Christian Hoffmann
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 comorbidities. The clinical pic-
ture ranges from completely asymptomatic to rapidly devastat-
ing courses.
In this chapter we discuss clinical presentation, including incu-
bation period and asymptomatic patients, frequent and rare
symptoms, laboratory findings and risk factors for severe dis-
ease. Radiological findings are described in the diagnostic chap-
ter.
Incubation period
A pooled analysis of 181 confirmed COVID-19 cases with identifi-
able exposure and symptom onset windows estimated the medi-
an 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
symptoms 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 very similar median incubation period of 5.0
days (95 % CI, 4.4 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
period) may be shorter. There is little doubt that transmission of
SARS-CoV-2 during 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 Nature
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 very im-
portant for assessing disease dynamics. It is important to distin-
guish those patients who will remain asymptomatic 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. The probably best data
come from 3,600 people on board the cruise ship Diamond Prin-
cess (Mizumoto 2020) who became involuntary actors in a “well-
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controlled experiment” where passengers and crew comprised

an environmentally homogeneous cohort. Due to insufficient
hygienic conditions, >700 people became infected while the ship
was quarantined in the port of Yokohama, Japan. After systemat-
ic testing, 328 (51.7%) of the first 634 confirmed cases were found
to be asymptomatic. Considering the varying of the incubation
period between 5.5 and 9.5 days, the authors calculated the true
asymptomatic proportion at 17.9% (Mizumoto 2020).
From a total of 565 Japanese citizens evacuated from Wuhan, the
asymptomatic ratio was estimated to be 42% (Nishiura 2020). Of
279 close contacts to COVID-19 patients who became PCR posi-
tive, 63 (23%) remained asymptomatic throughout their infec-
tions. Of note, 29 patients had abnormal CT findings (Wang Y
2020). In a screening study conducted in Iceland, the number of
patients testing positive for SARS-CoV-2 but without symptoms
was 44%, although some of these may have been pre-
symptomatic (Gudbjartsson 2020). In an observational cohort
study of 199 infected patients in a residential treatment center
in South Korea, the rate of asymptomatic patients was 26% (Noh
2020). The range of true asymptomatic patients in the studies
published to date is still broad and may depend on the popula-
tion which was analyzed.
Asymptomatic patients may transmit the virus (Bai 2020, Rothe
2020). In a study from Northern Italy viral loads in nasal swabs
between asymptomatic and symptomatic subjects did not differ
significantly, suggesting the same potential for transmitting the
virus (Cereda 2020). Of 63 asymptomatic patients in Chongquing,
9 (14%) transmitted the virus to others (Wang Y 2020). In an out-
break in a long-term care facility, 13/23 residents who tested
positive were asymptomatic or presymptomatic on the day of
testing (Kimball 2020). In another skilled nursing facility, of 48
residents, 27 (56%) were asymptomatic at the time of testing pos-
itive. Of these, 24 subsequently developed symptoms, with medi-

an time to onset of 4 days (Arons 2020). There is some evidence

that shedding of RNA and viral load is somewhat shorter in
asymptomatic (not presymptomatic!) patients (Noh 2020, Yang
2020).
Taken together, these preliminary studies indicate that around
20-40% of all COVID-19 infected subjects may remain asympto-
matic during their infection. But it may well be that we are still
quite wrong. Only large-scale field studies on seroprevalence will
be able to clarify the exact proportion.
Symptoms
A plethora of symptoms have been described in the past months,
clearly indicating 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 diseases. Howev-
er, different clusters can be distinguished in COVID-19. The most
common symptom cluster encompasses the respiratory system:
cough, sputum, shortness of breath, and fever. Other clusters
encompass musculoskeletal symptoms (myalgia, joint pain,
headache, and fatigue), enteric symptoms (abdominal pain, vom-
iting, and diarrhoea); and less commonly, a mucocutaneous clus-
ter.
Fever, cough, shortness of breath

Symptoms occur in the majority of cases (for asymptomatic pa-
tients, see below). 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 temperature 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
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symptom was cough, occurring in about two thirds of all pa-

tients. 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). In a meta-analysis of COVID-19 in
papers published until February 23, fever (88.7%), cough (57.6%)
and dyspnea (45.6%) were the most prevalent clinical manifesta-
tions (Rodriguez-Morales 2020). In another review, the corre-
sponding percentages were 88.5%, 68.6% and 21.9%, respectively
(Li 2020).
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 contrast, shortness of breath has been
identified as a strong predictor of severe disease in larger stud-
ies. In a cohort of 1,590 patients, dyspnea was assocoiated with
an almost two-fold risk for critical disease (Liang 2020) and mor-
tality (Chen 2020). Others found higher rates of shortness of
breath, and temperature of > 39.0 in older patients compared
with younger patients (Lian 2020). In the Wuhan study on pa-
tients with severe COVID-19, multivariate analysis revealed that
a respiratory rate of > 24 breaths per minute at admission was
higher in non-survivors (63% versus 16%).
Within the last weeks, huge cohort data from countries outside
China have been published. However, almost all data applies to
patients who were admitted to hospitals, indicating selection
bias towards more severe and symptomatic 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 common 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 fever of > 38 C. 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-
Presbyterian/Columbia University (Argenziano 2019), 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 2019, Docherty
2020, Guan 2020). Although subjectively 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 prac-
tice, and headache 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 presenting symptom. Significant features are moderate-
severe, bilateral headache with pulsating or pressing quality in
the temporo-parietal, forehead or periorbital region. The most
striking features are sudden to gradual onset and poor response
to common analgesics. Possible pathophysiological mechanisms
include activation of peripheral trigeminal nerve endings by the
SARS-CoV-2 directly or through the vasculopathy and/or in-
creased circulating pro-inflammatory cytokines and hypoxia.
Gastrointestinal symptoms
Cell experiments have shown that SARS-CoV and SARS-CoV-2 are
able to infect enterocytes (Lamers 2020). Active replication has
been shown in both bats and human intestinal organoids (Zhou
2020). Fecal calprotectin as a reliable fecal biomarker allowing
Kamps – Hoffmann
detection of intestinal inflammation in inflammatory bowel dis-

eases and infectious colitis, was found in some patients, provides
evidence that SARS-CoV-2 infection instigates an inflammatory
response in the gut (Effenberger 2020). These findings explain
why gastrointestinal symptoms are observed in a subset of pa-
tients and why viral RNA can be found in rectal swabs, even after
nasopharyngeal testing has turned negative. In patients with
diarrhea, stool viral RNA was detected at higher frequency
(Cheung 2020).
In the early Chinese studies, however, gastrointestinal symptoms
were rarely seen. In a meta-analysis of 60 early studies compris-
ing 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 otolaryngeal
symptoms, it remains unclear whether this difference reflects
geographic 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 complained of en-
teric symptoms on admission, mostly in association with respira-
tory symptoms; however, 4% of all patients described enteric
symptoms alone (Docherty 2020).
Otolaryngeal symptoms (including anosmia)

Although upper respiratory tract symptoms such as rhinorrhea,
nasal congestion, sneezing and sore throat are relatively unusu-
al, it has become clear within a few weeks that anosmia and hy-
posmia are important signs of the disease (Luers 2020). Interest-
ingly, 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 in
the initial phase in China were not recorded well enough. 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 symp-
toms (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 characterized 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 pa-
tients (n=59), compared to only 16% in negative patients (n=203).
Smell and taste impairment were independently and strongly
associated with positivity (anosmia: adjusted odds ratio 11,
95%CI: 5-24). Conversely, sore throat was independently associ-
ated with negativity (Yan 2020).
Among a total of 18,401 participants from the US and UK who
reported potential symptoms on a smartphone app and had un-
dergone a SARS-CoV-2 test, the proportion of participants who
reported loss of smell and taste was higher in those with a posi-
tive test result (65 vs 22%). A combination of symptoms, includ-
ing anosmia, fatigue, persistent cough and loss of appetite was
appropriate to identify individuals with COVID-19 (Menni 2020).
Taken together, otolarnygeal symptoms do not indicate severity
but are important indicators for SARS-CoV-2 infection.
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
Kamps – Hoffmann
diseases (Bonow 2020). SARS-CoV-2 has the potential to infect

cardiomyocytes, pericytes and fibroblasts via the ACE2 pathway
leading to direct myocardial injury, but that pathophysiological
sequence remains unproven (Hendren 2020). A second hypothe-
sis to explain COVID-19-related myocardial injury centers on
cytokine excess and/or antibody mediated mechanisms. It has
been also shown that the ACE2 receptor is widely expressed on
endothelial cells and that direct SARS-CoV-2 infection of the en-
dothelial cell is possible, leading to diffuse endothelial inflamma-
tion (Varga 2020). Post-mortem examination cases indicating a
strong virus-induced vascular dysfunction (Menter 2020).
Clinically, COVID-19 can manifest with an acute cardiovascular
syndrome (termed “ACovCS”). Numerous cases with ACovCS
have been described, not only with typical thoracic complaints,
but also with very diverse cardiovascular manifestations. Tro-
ponin 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 nonobstructive
disease, and a poor prognosis. 6/9 patients undergoing coronary
angiography had obstructive disease. Of note, all 18 patients had
elevated D-dimer levels (Bangalore 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.
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 thrombo-
embolism (VTE), especially in those with severe COVID-19. The
initial coagulopathy of COVID-19 presents with prominent eleva-
tion of D-dimer and fibrin/fibrinogen degradation products,

while abnormalities in prothrombin time, partial thromboplastin

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 pulmo-
nary embolism with or without deep venous thrombosis, as well
as presence of recent thrombi in prostatic venous plexus, in pa-
tients with no history of VTE, suggesting de novo coagulopathy in
these patients with COVID-19. Others have highlighted changes
consistent with thrombosis occurring within the pulmonary ar-
terial circulation, in the absence of apparent embolism (nice re-
view: Deshpande 2020). Some studies have indicated severe hy-
percoagulability rather than consumptive coagulopathy (Spiezia
2020).
Some of the key studies are listed here:
Of 240 patients (109 critically ill) admitted to US hospitals,
VTE was diagnosed in 31 patients (28%) 8 ± 7 days after ad-
mission. The authors conclude that routine chemical VTE
prophylaxis may be inadequate (Maatman 2020).
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. Authors rec-
ommend performing screening compression ultrasound in
the ICU every 5 days (Middeldorp 2020).
Of 143 patients hospitalized with COVID-19, 66 patients de-
veloped lower extremity deep venous thrombosis (46%),
among them 23 with proximal DVT (Zhang L 2020). Patients
with DVT were older and had a lower oxygenation index, a
higher rate of cardiac injury, and worse prognosis. Multivari-
ate analysis found CURB-65 score 3-5 (OR 6.1), Padua predic-
Kamps – Hoffmann
tion sc -dimer >1.0 g/ml (OR 5.8) to be

associated with DVT.
Among the first 107 COVID-19 patients admitted to the ICU
for pneumonia in Lille, France, the authors identified 22
(21%) cases of pulmonary embolism (PE). At the time of diag-
nosis, 20/22 were receiving prophylactic antithrombotic
treatment (UFH or LWMH) according to the current guide-
lines in critically ill patients.
In 100 patients with severe COVID-19, a high prevalence of
23% was found for pulmonary embolus (PE) (Grillet 2020). PE
was diagnosed at a mean of 12 days from symptom onset. In
multivariable analysis, requirement for mechanical ventila-
tion remained associated with acute pulmonary embolus.
In a prospective study from France, 64/150 (43%) patients
were diagnosed with clinically relevant thrombotic complica-
tions. The authors argue for higher anticoagulation targets in
critically ill patients (Helms 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).
Careful examination of the lungs from deceased COVID-19
patients with lungs from 7 patients who died from ARDS sec-
ondary to influenza A showed distinctive vascular features.
COVID-19 lungs displayed severe endothelial injury associat-
ed with the presence of intracellular virus and disrupted cell
membranes. Histologic analysis of pulmonary vessels showed
widespread thrombosis with microangiopathy. Alveolar ca-
pillary 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 pa-
tients (age 33-49, 2 without any risk factors) (Oxley 2020).

Five cases with profound hemodynamic instability due to the

development of acute cor pulmonale, among them 4 younger
than 65 years of age (Creel-Bulos 2020).
There is a very controversial debate about a possible correlation
between the use of ibuprofen and the increased risk of VTE de-
velopment. According to a recent review (Arjomandi 2020), the
causation between the effects 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 migration across the
blood-brain barrier (review: Zubair 2020). With regard to
SARS-CoV-2, early occurrences such as olfactory symptoms (see
above) should be further evaluated for CNS involvement. Poten-
tial late neurological complications in cured COVID-19 patients
are possible (Baig 2020). A retrospective, observational case se-
ries found 78/214 patients (36%) with neurologic manifestations,
ranging from fairly specific symptoms (loss of sense of smell or
taste, myopathy, and stroke) to more non-specific symptoms
(headache, low consciousness, dizziness, or seizure). Whether
these more non-specific symptoms are manifestations of the
disease itself remains to be seen (Mao 2020).
There are several observational series of specific neurological
features such as Guillain–Barré syndrome (Toscano 2020) or Mil-
Kamps – Hoffmann
ler Fisher Syndrome and polyneuritis cranialis (Gutierrez-Ortiz

2020).
Especially in patients with severe COVID-19, neurological symp-
toms are common. In an observational series of 58 patients,
ARDS due to SARS-CoV-2 infection was associated with encepha-
lopathy, prominent agitation and confusion, and corticospinal
tract signs. Patients with COVID-19 might experience delirium,
confusion, agitation, and altered consciousness, as well as symp-
toms of depression, anxiety, and insomnia (review: Rogers 2020).
It remains unclear which of these features are due to critical ill-
ness–related encephalopathy, cytokines, or the effect or with-
drawal of medication, and which features are specific to SARS-
CoV-2 infection (Helms 2020).
Dermatological symptoms
Numerous studies have reported on cutaneous manifestations
seen in the context of COVID-19. The most prominent phenome-
non, the so-called “COVID toes”, are chilblain-like lesions which
mainly occur at acral areas. These lesions can be painful (some-
times itchy, sometimes asymptomatic) and may represent the
only symptom or late manifestations of SARS-CoV-2 infection. Of
note, in most patients with “COVID toes”, the disease is only mild
to moderate. It is speculated that the lesions are caused by in-
flammation in the walls of blood vessels, or by small micro-clots
in the blood. However, whether “COVID toes” represent a coagu-
lation disorder or a hypersensitivity reaction is not yet known.
In addition, in many patients, SARS-CoV-2 PCR was negative (or
not done) and serology testings (to prove the relationship) are
still pending. Key studies:
Two different patterns of acute acro-ischemic lesions can
overlap (Fernandez-Nieto 2020). The chilblain-like pattern
was present in 95 patients (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 pat-

tern was present in 37 patients (28.0%).
Five clinical cutaneous of lesions are described (Galvan 2020):
acral areas of erythema with vesicles or pustules (pseudo-
chilblain) (19%), other vesicular eruptions (9%), urticarial le-
sions (19%), maculopapular eruptions (47%) and livedo or ne-
crosis (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
the 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 in-
volvement, usually scattered distribution and mild/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 Car-
reras-Presas 2020).
Other case reports include digitate papulosquamous eruption
(Sanchez 2020), petechial skin rash (Diaz-Guimaraens 2020, Quin-
tana-Castanedo 2020). However, it should be kept in mind that
not all rashes or cutaneous manifestations seen in patients with
COVID-19 can be attributed to the virus. Coinfections or medical
complications have to be considered. Comprehensive mucocuta-
neous examinations, analysis of other systemic clinical features
or host characteristics, and histopathologic correlation, will be
vital to understanding the pathophysiologic mechanisms of what
we are seeing on the skin (Review: Madigan 2020).
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Kidneys and liver

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 compart-
ments obtained with the use of tissue microdissection 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 glo-
merular cells. Renal tropism is a potential explanation of com-
monly reported new 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. Of
the first 1,000 patients presenting at the NewYork-Presbyterian-
Columbia University, 236 were admitted or transferred to inten-
sive care units (Argenziano 2019). Of these, 78.0% (184/236) de-
veloped acute kidney injury and 35.2% (83/236) needed dialysis.
Concomitantly, 13.8% of all patients and 35.2% of patients in in-
tensive care units required in-patient dialysis, leading to a
shortage of equipment needed for dialysis and continuous renal
replacement therapy.
One of the largest studies, evaluating liver injury in 2,273 SARS-
CoV-2 positive patients, found that 45% had mild, 21% moderate,
and 6.4% severe liver injury. In multivariable analysis, severe
acute liver injury was significantly associated with elevated in-
flammatory 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, intubation, and renal replacement therapy
(Phipps 2020).

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 consistent with conjunctivitis, including
conjunctival hyperemia, chemosis, epiphora, or increased secre-
tions. 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 sub-
clinical retinal changes. Twelve adult patients showed hyper-
reflective lesions at the level of the ganglion cell and inner plexi-
form layers more prominently at the papillomacular bundle in
both eyes (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 extensive testing in the
current pandemic (Nickel 2020).
Laboratory findings
The most evident laboratory findings in the first large cohort
study from China (Guan 2020) are shown in Table 1. On admis-
sion, 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; less
common were elevated levels of alanine aminotransferase, and
D-dimer. Most patients have normal procalcitonin on admission.
Kamps – Hoffmann
Table 2. Percentage of symptoms in first larger 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- 60.7 81.5 56.4
41.0 58.1 37.1
AST >40 U/L,% 22.2 39.4 18.2
D- 46.6 59.6 43.2
Inflammation
Parameters indicating inflammation such as elevated CRP and
procalcitonin are very frequent findings. They have been pro-
posed to be important risk factors for disease severity and mor-
tality (Chen 2020). For example in a multivariate analysis of a
retrospective cohort of 1,590 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 better than other parameters (age, neutrophil
count, platelet count) in predicting adverse outcome. Besides,
admission serum CRP level was identified as a moderate discrim-
inator of disease severity (Lu 2020). Of 5,279 cases confirmed in a
large medical center in New York, 52% of them admitted to hos-
pital, a CRP > 200 was more strongly associated (odds ratio 5.1)
with critical illness than age or comorbidities (Petrilli 2019).
In a retrospective observational study of 69 patients with severe
COVID-19, the decrease of interleukin-6 (IL-6) levels was closely
related to treatment effectiveness, while the increase of IL-6 in-
dicated disease exacerbation. The authors concluded that the
dynamic change of IL-6 levels can be used as a marker in disease
monitoring in patients with severe COVID-19 (Liu 2020). High
levels of IL-6 and IL-8 during treatment were observed in pa-
tients with severe or critical disease and correlated with de-
creased lymphocyte count in another study on 326 patients from
China (Zhang 2020). The determinants of disease severity seemed
to stem mostly from host factors such as age, lymphocytopenia,
and its associated cytokine storm.
Hematological: Lymphocytes, platelets

Lymphocytopenia and transient but severe T cell depletion is a
well-known feature of SARS (He 2005). In COVID-19, lymphope-
nia is also among the most prominent hematological features.
Lymphopenia may be predictive for progression (Ji 2020) and
patients with severe COVID-19 present with lymphocytopenia of
less than 1500/µl in almost 100% (Guan 2020). It’s not only the
total lymphocyte count. There is growing evidence for a transi-
ent depletion of T cells. Especially the reduced CD4+ and CD8+ T
cell counts upon admission was predictive of disease progression
in a larger study (Zhang 2020). In another large study on COVID-
Kamps – Hoffmann
19 patients, CD3+, CD4+ and CD8+ T cells but also NK cells were
significantly decreased in COVID-19 patients and related to the
severity of the disease. According to the authors, CD8+ T and
CD4+ T cell counts can be used as diagnostic markers of COVID-19
and predictors of disease severity (Jiang 2020).
Another common hematological finding is low platelet counts
that may have different causes (Review: Xu 2020). Cases of hem-
orrhagic manifestation and severe thrombocytopenia respond-
ing to immunoglobulins fairly quickly with a sustained response
over weeks have been reported (Ahmed 2020).
Cardiac: Troponin
Given the cardiac involvement especially in severe cases (see
above), it is not surprising that cardiac parameters are frequent-
ly 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
Du 2020). In
a huge cohort study from New York, troponin was strongly asso-
ciated with critical illness (Petrilli 2019). 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 was recently published (Chapman
2020).
Coagulation: D-Dimer, aPTT

Several studies have evaluated the coagulation parameter D-
dimer in the progression of COVID-19. Among 279 patients in
whom D-dimer was measured for ten consecutive days after ad-
mission, dynamicly changes positively correlated with the prog-
nosis (Li 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 patients 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 anticoagulation therapies in the prevention and
treatment of venous thrombosis (Bowles 2020). Another case
series of 22 patients with acute respiratory failure present a se-
vere hypercoagulability rather than consumptive coagulopathy.
Fibrin formation and polymerization may predispose to throm-
bosis 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 prominent 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, leuko-
cytosis
Elevated D-dimer and troponin
Elevated LDH
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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 Diag-
nosis and Treatment Guidelines for Adults with Community-
acquired Pneumonia, published by the American Thoracic Socie-
ty 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, mul-
tilobar infiltrates, confusion/disorientation, uremia, leukopenia,
low platelet count, hypothermia, hypotension requiring aggres-
sive 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
manifestation through image results
2. Ordinary cases: having fever and other respiratory symptoms
with pneumonia manifestation through image results
3. Severe cases: meeting any one of the following: respiratory
(PaO2 < 60mmHg, PaCO2 > 50mmHg)

4. Critical cases: meeting any one of the following: Respiratory
failure which requires mechanical ventilation, shock, accom-
panied by other organ failure 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 overestimate 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 older
65 of age, reaching 6.9–16.0% (CDC 2020).
Outcome
We are facing rapidly increasing numbers of severe and fatal
cases in the current 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. However,
it will be important that these studies are carefully designed and
carried out, especially to avoid bias and confounding.
Case fatality rates

The case fatality rates (CFR) or infection fatality rates (IFR) are
both difficult to assess in such a dynamic pandemic. CFR can be
biased upwards by underreporting of cases and downwards by
insufficient follow up or unknown outcome. A downward trend
may also indicate improvements in epidemiological surveillance.
COVID-19 fatality is likely overestimated and especially early
estimates are susceptible to uncertainty about asymptomatic or
subclinical infections and several biases, including biases in de-
tection, selection or reporting (Niforatos 2020).
Dividing the number of deaths by the number of total confirmed
cases is not appropriate. For example, on May 30, the CFR be-
tween the 30 most affected countries (in terms of absolute num-
bers) ranged from 0.07 (Singapore) to 16.7 (Belgium). Within the
Kamps – Hoffmann
10 most affected countries, the range was 1.15 (Russia) to 15.3

(France).
The picture is much more complex and these simple calculations
certainly do not reflect the true mortality in each country with-
out taking into factor three other issues:
1. The testing policies (and capacities) in a country. This is the
most important factor. The fewer people you test (all people,
only symptomatic patients, only those with severe symp-
toms) the higher the mortality. In Germany, testing systems
and high lab capacities were established rapidly (Stafford
2020).
2. Age of the infected population and especially of the popula-
tion which is affected first. For example, in Italy, higher per-
centages of older people became infected during the first
weeks, compared to Germany (where many people acquired
SARS-CoV during ski holidays or carnival sessions). Especial-
ly if high-risk sites (such as retirement homes) are affected,
death cases in the country will increase considerably. For
example, a single outbreak in Washington has led to 34
deaths among 101 residents of a long-term care facility
(McMichael 2020) – this is exactly the same number of death
cases which Australia has reported as whole country on
April 4, among a total of 5,635 confirmed COVID-19 cases.
3. Stage of the epidemic. Some countries have experienced
their epidemic grow early, some are still a few days or weeks
behind. Death rates only reflect the infection rate of 2-3
weeks previously. In the large retrospective study from Wu-
han, the time from illness onset to death was 18.5 days (IQR
15-22 days).
The “death rates” for some selected countries, based on the
number of deaths and tests, is shown in Figure 1. These curves
reflect test readiness and test capacities. A country such as Swe-
den, which initially relied on “herd immunity”, differs signifi-

cantly from countries in which a lot has been tested from the
beginning of the epidemic, such as Germany. The USA is still at
the beginning, in Korea the outbreak was stopped relatively
quickly by intensive tracking measures.
Figure 1. People who tested positive (among 1 million inhabitants, dashed)

and deaths (among 10 million inhabitants). "Mortality" reaches 10% at the
point where the curves intersect. This has happened for countries such as
UK, Italy or Sweden, but is unlikely for others like Germany, Switzerland or
USA.
CFR among health care workers and among well-

defined populations
In well-monitored populations in which underreporting is un-
likely or can be largely determined, the mortality rates may bet-
ter reflect the “true” CFR of COVID-19. This applies to healthcare
workers (HCW) but also to populations of “well-defined” (lim-
Kamps – Hoffmann
ited) outbreaks. The low mortality rates in these populations are

remarkable.
In large study of 3,387 HCW from China infected with SARS-CoV-
2, only 23 have died, corresponding to a mortality of 0.68%. The
median age was 55 years (range, 29 to 72), and 11 of the 23 de-
ceased HCW had been reactivated from retirement (Zhan 2020).
Current studies in the USA have found similar rates, mortality
estimates were 0.3-0.6% (CDC 2020). Of the 27 HCW who have
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 frequently.
We will also learn more from limited outbreaks affecting homo-
geneous populations, such as cruise ships and aircraft carriers.
Outbreaks on these floating microcosms are unfortunate but
informative experiments, they tell us a lot about transmission
and the natural course of the disease in well-defined populations.
Two large “involuntary field studies” are currently taking place:
around 1,140 sailors were infected on the US aircraft carrier
Theodore Roosevelt (one soldier has already died, nine were
hospitalized), and more than 1,080 COVID-19 patients on the
French aircraft carrier Charles de Gaulle. These populations are
probably young, healthy and correspond more to the general
population. Detailled investigations will follow.
The most valid data seem to come from the Diamond Princess. As
of May 31, the total number of infected reached 712, and 13 pa-
tients have died from the disease leading to a CFR of 1.8%. How-
ever, this rate may yet increase, as at least 4 patients were in
serious condition (Moriarty 2020). Of note, around 75% of the
patients on the Diamond Princess were of 60 years or older,
many of them in their eighties. Projecting the Diamond Princess
case fatality rate onto the age structure of the general popula-
tion, it is obvious that the mortality rate may be much lower in

other broader populations. Mortality would be in a range of 0.2-

0.4 %.
Older Age
From the beginning of the epidemic, older age has been identi-
fied as an important risk factor for disease severity (Huang 2020,
Guan 2020). In Wuhan, there was a clear and considerable age
dependency in symptomatic infections (susceptibility) and out-
come (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 1,023 among 44,672 confirmed cases
(Wu 2020). Mortality increased markedly in older people. In the
cases aged 70 to 79 years, CFR was 8.0% and cases in those aged
80 years older had a 14.8% CFR.
In recent weeks, this has been seen and confirmed by almost all
studies published throughout the world. In almost all countries,
age groups of 80 years of 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 5,165 patients (26%) who died
in hospital from COVID-19 was 80 years (Docherty 2020).
Among 1,591 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 anal-
ysis of the first 2,003 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 sports
showed that the deviation in all-cause deaths compared to
previous years during epidemic peaks was largely driven by
Kamps – Hoffmann
the increase in deaths among older people, especially in men

(Piccininni 2020, Michelozzi 2020).
In 5,700 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).
In an outbreak reported from King County, Washington, a
total of 167 confirmed cases were 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 visi-
tors. The case fatality rate for residents was 33.7% (34/101)
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 Swe-
den) are facing higher CFR, while those without many older pa-
tients infected by SARS-CoV-2 (such as the Republic of Korea,
Singapore, Australia) have markedly lower rates.
Other risk factors for severe disease

Besides older age, 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 dis-
ease 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 of 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, their clinical relevance remains limited.
During recent weeks, several studies conducted outside China
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) or in Singapore,
especially in younger patients (Ong 2020). Smoking as a risk fac-
tor is under discussion, as well as COPD, kidney diseases and
many others (see comorbidity chapter). Among 1,150 adults who
were 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 hitherto largest registry data from different parts of the
world are shown in Table 3. A striking finding of these studies is
the lower mortality in female patients, running through almost
all available data. There is some evidence that there are sex-
specific differences 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 systemic inflamma-
tion, blunted immune system, down-regulation of ACE2 and ac-
celerated biological aging (Bonafè 2020).
The main problem of all studies published to date is that their
uncontrolled data is subject to confounding and that 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 hyper-
tension or a severe cardiomyopathy? The clinical manifestation
and the relevance of a certain comorbidity may be very hetero-
geneous (see also the comorbidity chapter).
Kamps – Hoffmann
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 3,481 patients in Louisiana, public insurance
(Medicare or Medicaid), residence in a low-income area, and
obesity were associated with increased odds of hospital admis-
sion (Price-Haywood 2020). A careful investigation of the NYC
epidemic revealed that the Bronx, which has the highest propor-
tion of racial/ethnic minorities, the most persons living in pov-
erty, and the lowest levels of educational attainment, had higher
rates (almost two-fold) of hospitalization and death related to
COVID-19 than the other 4 NYC boroughs Brooklyn, Manhattan,
Queens and Staten Island (Wadhera 2020).
Taken together, large registry studies have found slightly elevat-
ed Hazard Ratios of mortality for multiple comorbidities (Table
3). It seems, however, that most patients with preexisting condi-
tions are able to control and eradicate the virus. Comorbidities
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, heart and kidneys (nice review: Wadman 2020), it seems
plausible that a decreased cardiovascular and pulmonary capaci-
ty ameliorate clinical outcome in these patients.
However, at this time, we can only speculate about the precise
role of comorbidities and their mechanisms to contribute to dis-
ease 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 (hyperten-
sion, coronary heart disease, heart failure, and chronic kidney
disease). The incidence was also increased in patients with pre-
vious hospitalizations for cardiovascular or noncardiovascular
diseases (Mancia 2020). A large UK study found some evidence of

potential sociodemographic 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 comorbidities
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 hospitalization rates.
Table 3. Age and comorbidities 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)
Kamps – Hoffmann
Predisposition
COVID-19 shows an extremely variable course, from completely
asymptomatic to fulminantly fatal. In some cases it affects young
and apparently healthy people, for whom the severity of the dis-
ease 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 Timeline). So far, only assump-
tions can be made. The remarkable heterogeneity of disease pat-
terns from a clinical, radiological, and histopathological point of
view has led to the speculation that the idiosyncratic responses
of individual patients may be in part related to underlying ge-
netic variations (von der Thusen 2020). Some preliminary re-
ports suggest that this is the case.
For example, 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).
In a post-mortem examination of 21 COVID-19 cases, 65% of
the deceased patients had blood group A. Blood group A may
be associated with the failure of pulmonary microcirculation
and coagulopathies. Another explanation could be the direct
interaction between antigen A and the viral S protein, thus
facilitating virus entry via ACE2 (Menter 2020).
Researchers from UK have investigated the associations be-
tween ApoEe4 alleles and COVID-19 severity, using the UK Bi-
obank 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 al-
lele increased risks of severe COVID-19 infection, independ-
ent of pre-existing dementia, cardiovascular disease, and
type 2 diabetes. This interesting observation needs to be con-
firmed (and explained).

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 previous viral
diseases. If you inhale large numbers of virus deeply, leading
rapidly to a high number of virus in the pulmonary system, this
may be much worse than smearing a small amount of virus on
your hand to the nose. In this case, the immune system in the
upper respiratory tract may have much more time to limit fur-
ther spread into the lungs and other organs. But this is still
speculation and will have to be investigated in the coming
months.
Overburdened health care systems

Mortality may be also higher in situations where hospitals are
unable to provide 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 this is likely to be related to the rapid escalation
in the number of infections around the epicenter of the out-
break, which has resulted in an insufficiency of health-care re-
sources, thereby negatively affecting patient outcomes in Hubei,
while this has not yet been the situation 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).
The nightmare of insufficient ressources is currently the reality
in Northern Italy. In Italy, on March 15, the cumulative death
numbers exceeded for the first time those of admissions to in-
Kamps – Hoffmann
tensive care units – a clear sign for a collapsing health care sys-
tem. Other countries or regions will face the same situation soon.
Reactivations, reinfections
There are several reports of patients who become positive again
after negative PCR tests (Lan 2020, Xiao 2020, Yuan 2020). These
reports have gained much attention, because this could indicate
both reactivations as well as reinfections. After closer inspection
of these reports, however, there is no good evidence for reactiva-
tions 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 ma-
terial collection or storage are just two examples of many prob-
lems with PCR. Even if everything is done correctly, it can be
expected that a PCR could fluctuate between positive and nega-
tive at times when the values are low and the viral load drops at
the end of an infection (Wölfel 2020). It also depends on the as-
say used, the detection limit is between a few hundred and sev-
eral thousand virus copies/mL (Wang 2020).
The largest study to date found a total of 25 (14.5%) of 172 dis-
charged 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 ex-
pected.
In addition, animal studies suggest that re-infection is very un-
likely (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 uti-
lized for the primary infection. Very limited viral RNA was ob-
served 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.
Reactivations as well as rapid new infections would be very unu-
sual, especially 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.
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 disease, in order to adapt pre-
vention strategies. Older age is the main but not the only risk
factor. Recently, a 106-year-old COVID-19 patient recently recov-
ered in the UK. The precise mechanisms how comorbidities (and
comedications) may contribute to an increased risk for a severe
disease course have to be elucidated. Genetic and immunological
studies have to reveal susceptibility and predisposition for both
severe and mild courses. Who is really at risk, who is not? Quar-
antining only the old is too easy.
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Treatment | 233
8. Treatment
Christian Hoffmann
The number of people infected with SARS-CoV-2 is increasing

rapidly. Because up to 5-10% can have a severe, potentially life-
threatening course, there is an urgent need for effective drugs.
No proven effective therapy for this virus currently exists. The
time in this pandemic is too short for the development of new,
specific agents; a vaccine will also be a long time coming. Thus,
existing antivirals or immune modulators with known safety
profiles will gain traction as the fastest route to fight COVID-19.
Those compounds that have already been tested in other indica-
tions now have priority, in particular those that have been
shown to be effective in other beta-coronaviruses such as SARS
and MERS.
Many current suggestions have emerged from animal models,
cell lines or even virtual screening models. While some ap-
proaches have at least some evidence for clinical benefit, for
others this remains highly speculative. A brief look at Clinical-
Trials.gov may illustrate the intensive research efforts that are
underway: on April 18, the platform listed 657 studies, with 284
recruiting, among them 121 in Phase III randomized clinical tri-
als (RCTs, assessed on April 19). On May 31, these numbers have
increased to 1844, 926 and 126.
Several very different therapeutic approaches are in the treat-
ment pipeline for COVID-19: antiviral compounds that inhibit
enzyme systems, those inhibiting the entry of SARS-CoV-2 into
the cell and, finally, immunomodulators that are supposed to
reduce the cytokine storm and associated pulmonary damage
that is seen in severe case. In an interim guidance, the WHO stat-
ed on March 13, that “there is no current evidence to recom-
mend any specific anti-COVID-19 treatment” and that use of in-

vestigational therapeutics “should be done under ethically ap-

proved, randomized, controlled trials”. Of note, this has not
changed during recent weeks. There is no agent that shows a
decreased mortality.
However, performing clinical trials remains challenging during a
public health crisis (Rome 2020) and enrolling patients in clinical
trials will not be possible everywhere. For these, this chapter
may support in decision-making. The following agents will be
discussed here:
1. Inhibitors of viral RNA synthesis

RdRp Inhibitors Remdesivir, Favipiravir
(and Ribavirin, Sofosbuvir)
Protease Inhibitors Lopinavir/r

2. Antiviral Entry Inhibitors
TMPRSS2 Inhibitors Camostat

Fusion Inhibitors Umifenovir
Others Hydroxy/chloroquine,
Oseltamivir, Baricitinib
3. Immunomodulators and
other immune therapies
Corticosteroids
IL-6 targeting therapies Tocilizumab, Siltuximab
Immune modulation Interferon, Anakinra
Passive immunization Convalescent plasma,
monoclonal antibodies
Inhibitors of the viral RNA synthesis

SARS-CoV-2 is a single-stranded RNA beta-coronavirus. Potential
targets are some non-structural proteins such as protease, RNA-
dependent RNA polymerase (RdRp) and helicase, but also acces-
Kamps – Hoffmann
Treatment | 235
sory 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%
(Morse 2020), suggests that substances effective for SARS may
also be effective for COVID-19.
RdRp inhibitors
Remdesivir
Remdesivir (RDV) is a nucleotide analogue and the prodrug of an
adenosine C nucleoside which incorporates into nascent viral
RNA chains, resulting in premature termination. From WHO,
remdesivir has been ranked as the most promising candidate for
the treatment of COVID-19. In vitro experiments have shown that
remdesivir has a broad anti-CoV activity by inhibiting RdRp in
airway epithelial cell cultures, even at submicromolar concen-
trations (Sheahan 2017). This RdRp inhibition also applies to
SARS-CoV-2 (Wang 2020). The substance is very similar to
tenofovir alafenamide, another nucleotide analogue used in HIV
therapy. Remdesivir was originally developed by Gilead Sciences
for the treatment of the Ebola virus but was subsequently aban-
doned, after disappointing results in a large randomized clinical
trial (Mulangu 2019). Experimental data from mouse models
showed better prophylactic and therapeutic efficacy in MERS
than a combination of lopinavir/ritonavir (see below) and inter-
feron beta. Remdesivir improved lung function and reduced viral
load and pulmonary damage (Sheahan 2020). Resistance to
remdesivir in SARS was generated in cell cultures, but was diffi-
cult to select and seemingly impaired viral fitness and virulence
(Agostini 2018). The same is seen with MERS viruses (Cockrell
2016). Animal models suggest that a once-daily infusion of 10
mg/kg remdesivir may be sufficient for treatment; pharmacoki-
netic data for humans are still lacking. Gilead is currently “in the

process” of opening expanded access programs in Europe (refer

to gilead.com). In the US, this program is already in place.
Clinical data: Safety was shown in the Ebola trial. Remdesivir is
currently being tested in several RCTs in > 1,000 patients with
both mild-to-moderate and with severe COVID-19 disease.
Remdesivir is also among four treatment options being tested in
the large WHO SOLIDARITY RCT (see below). In the Phase III
studies on COVID-19, an initial dose of 200 mg is started on day 1,
similar to the Ebola studies, followed by 100 mg for another 4-9
days. The key trials are listed here:
Compassionate Use Program: this was a fragmentary case
series (Grein 2020) on some patients (only 53/61 patients
were analyzed) with various disease severity. Some im-
proved, some didn’t: random noise. We believe, for a number
of reasons, that this case series published in the New England
Journal of Medicine is a cautionary tale for “science in a hur-
ry”, arousing false expectations. It might have been preferab-
le to postpone the publication.
NCT04257656: This multicentre trial was conducted between
Feb 6 and March 12 at ten hospitals in Hubei (Wang 2020). A
total of 237 patients with pneumonia, oxygen saturation of
94% or lower on room air and within 12 days of symptom on-
set were randomized 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 clin-
ical scale (from 1 = discharged to 6 = death) or discharged
alive from hospital, whichever came first. Patients were 65
years old (IQR 56–71), more male (56%) and many were co-
treated with lopinavir (28%) and corticosteroids. The trial did
not attain the predetermined sample size because the out-
break was brought under control in China. However,
remdesivir was not associated with a difference in time to
clinical improvement (hazard ratio 1.23, 95% CI 0.87–1.75).
Kamps – Hoffmann
Treatment | 237
Clinical improvement rates were 27% versus 23% at day 14

and 65% versus 58% at day 28. Day 28 mortality was 14% ver-
sus 13%. Of note, the viral load decreased similarly in both
groups. Some patients with remdesivir had dosing prema-
turely 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 than the
control group, particularly in those treated within 10 days of
symptom onset.
SIMPLE 1: in this randomized, open-label, Phase III trial in
397 hospitalized patients with severe COVID-19 and not re-
quiring IMV, clinical improvement at day 14 was 64% with 5
days remdesivir and 54% with 10 days (Goldman 2020). After
adjustment for (significant) baseline imbalances in disease
severity, 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 additional
5,600 (!) patients around the world.
ACTT (Adaptive COVID-19 Treatment Trial): The conclusion
of this double-blinded Phase III study that randomized 1,063
COVID-19 patients throughout the world to the drug or to
placebo, was remarkably short: “Remdesivir was superior to
placebo in shortening the time to recovery in adults hospital-
ized with Covid-19 and evidence of lower respiratory tract in-
fection” (Beigel 2020). Median recovery time was 11 versus 15
days. The benefit was most apparent in patients with a base-
line ordinal score of 5 (requiring oxygen but not high-flow
oxygen). In patients requiring mechanical ventilation or
ECMO, there was no effect at all (although the numbers were
low). Gender, ethnicity, age or symptom duration had no im-

pact. The Kaplan-Meier estimates of mortality by 14 days

were 7.1% and somewhat (not significantly) lower with
remdesivir compared to 11.9% with placebo (hazard ratio for
death, 0.70; 95% CI, 0.47 to 1.04). These results are prelimi-
nary. The full analysis of the entire trial population is ex-
pected to be published soon.
What comes next? Several additional trials are ongoing. Some
have been suspended such as NCT04252664, a trial in adults with
mild and moderate COVID-19, as during the last few weeks no
eligible patients could be recruited. The second SIMPLE trial,
NCT04292730 (GS-US-540-5774) is probably the most interesting
study, evaluating the efficacy of two remdesivir regimens com-
pared to standard of care in 600 patients with moderate COVID-
19, with respect to clinical status assessed by a 7-point ordinal
scale on day 11. Estimated study completion date is May 2020.
INSERM in France has initiated a study evaluating remdesivir
and other potential treatments, using a master protocol (SOLI-
DARITY) developed by WHO. This study (NCT04315948) is a mul-
ti-centre, adaptive, randomized, open clinical trial of the safety
and efficacy of treatments of COVID-19 in hospitalized adults.
Adults hospitalized for severe COVID-19 will be randomized to
one of 4 treatment arms, including standard of care, remdesivir,
lopinavir/r plus interferon ß-1a and hydroxychloroquine.
In the meantime, EMA’s human medicines committee (CHMP)
has started a ‘rolling review’ of data. This speeds up the assess-
ment of a promising investigational medicine during a public
health emergency but does not imply that its benefits outweigh
its risks. The EUA allows for the distribution and emergency use
of remdesivir only for the treatment of COVID-19; remdesivir
remains an investigational drug and has not been approved by
FDA. The fact sheet for health care providers is found here: FDA
2020.
Kamps – Hoffmann
Treatment | 239
Favipiravir
Favipiravir is another broad antiviral RdRp inhibitor that has
been approved for influenza in Japan (but was never brought to
the market) and other countries (Shiraki 2020). Favipiravir is
converted into an active form intracellularly and recognized as a
substrate by the viral RNA polymerase, acting like a chain termi-
nator and thus inhibiting RNA polymerase activity (Delang 2018).
In an in vitro study, this compound showed no strong activity
against a clinical isolate of SARS-CoV-2 (Wang 2020). On Febru-
ary 14, however, a press release with promising results was pub-
lished in Shenzhen (PR). In the absence of scientific data, favipi-
ravir 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, following a maintenance dose of
1200-1800 mg QD. 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). ncluding foetal abnormal-
ities in pregnant women
Clinical data: Uncontrolled data (Cai 2020) and preliminary re-
sults (press release) on encouraging results in 340 COVID-19 pa-
tients were reported from Wuhan and Shenzhen. With favipi-
ravir, patients showed shorter periods of fever (2.5 versus 4.2
days), faster viral clearance (4 versus 11 days) and improvement
in radiological findings (Bryner 2020). A first open-label random-
ized trial (RCT) was posted on March 26 (Chen 2020). This RCT
was conducted in 3 hospitals from China, comparing arbidol and
favipiravir in 236 patients with COVID-19 pneumonia. Primary
outcome was the 7-day clinical recovery rate (recovery of fever,
respiratory rate, oxygen saturation and cough relief). In “ordi-
nary” COVID-19 patients (not critical), recovery rates were 56%
with arbidol (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 evident. Many cases were not confirmed by PCR. There were
also imbalances between subgroups of “ordinary” patients. On
May 26, the Japanse government postponed approving, after an
interim analysis covering 40 patients by a third-party organiza-
tion stated that it was “too soon to evaluate effectiveness”.
Other RdRp inhibitors

Some other compounds inhibiting RdRp have been discussed.
Ribavirin is a guanosine analogue and RNA synthesis inhibitor
that was used for many years for hepatitis C infection and is also
thought to inhibit RdRp (Elfiky 2020). In SARS and MERS, ribavi-
rin was mostly combined with lopinavir/ritonavir or interferon;
however, a clinical effect has never been shown (Arabi 2017).
Ribavirin is now available generically. Its use is limited by con-
siderable side effects, especially anemia. Sofosbuvir is a poly-
merase inhibitor which is also used as a direct-acting agent in
hepatitis C. It is usually very well tolerated. Modelling studies
have shown that sofosbuvir could also inhibit RdRp by compet-
ing with physiological nucleotides for RdRp active site (Elfiky
2020). Sofosbuvir could be combined with HCV PIs. Among these,
the fixed antiviral combinations with ledipasvir or velpatasvir
could be particularly attractive as they may inhibit the both
RdRp and protrease of SARS-CoV-2 (Chen 2020). Studies are
planned but not yet officially registered (assessed May 31).
Protease inhibitors
Lopinavir
This HIV protease inhibitor (PI) is thought to inhibit the 3-
chymotrypsin-like protease of coronaviruses. Lopinavir/r is ad-
ministered orally. To achieve appropriate plasma levels, it has to
Kamps – Hoffmann
Treatment | 241
be boosted with another HIV PI called ritonavir (usually indicat-

ed by “/r”: lopinavir/r). At least two case-control studies on
SARS (Chan 2003, Chu 2004) and one prophylactic study on MERS
(Park 2019) have indicated a beneficial effect, but the evidence
remains poor. A small substudy indicated that SARS-CoV viral
load seems to decrease more quickly with lopinavir than without
(Chu 2004). However, all studies were small and non-
randomized. It therefore remained unclear, whether all prognos-
tic factors were matched appropriately. As with all HIV PIs, one
should be always aware of drug-drug interactions. Ritonavir is a
strong pharmacoenhancer. For example, tacrolimus has to be
reduced by 10-100 fold to maintain concentration within the
therapeutical range. In a case report, a woman with kidney
transplantation was treated with lopinavir/r for COVID-19 while
receiving full dose tacrolimus. Levels went incredibly high and
were still above the therapeutical range 9 days after stopping
both lopinavir/r and tacrolimus (Bartiromo 2020).
From the beginning of the pandemic, lopinavir/r has been wide-
ly used in clinical practice, despite the lack of any evidence
(Chen 2020). For example, of all patients in the remdesivir trial
NCT04257656, 18% were on lopinavir/r at baseline (Wang 2020 ).
Clinical data: In an early retrospective study on 280 cases, early
initiation of lopinavir/r and/or ribavirin showed some benefits
(Wu 2020). However, in a small study from Singapore study, lop-
inavir/r did not affect SARS-CoV-2 clearance in nasal swabs
(Young 2020). There are two randomized clinical trials (RCT)
published to date:
The first open-lable RCT in 199 adults hospitalized with se-
vere COVID-19 did not find any clinical benefit with lop-
inavir/r treatment beyond standard care in patients receiv-
ing the drug 10 to 17 days after onset of illness (Cao 2020).
The percentages of patients with detectable viral RNA at var-

ious time points were similar, suggesting no discernible effect

on viral shedding.
A Phase 2, multicentre, open-label RCT from Hong Kong ran-
domized 127 patients with mild-to-moderate COVID-19 (me-
dian 5 days from symptom onset) to receive lopinavir/r only
or a triple combination consisting lopinavir/r, ribavirin and
interferon (Hung 2020). The results indicate that the triple
combination can be beneficial when started early (see below,
interferon). As there was no lopinavir/r-free control group,
this trial does not prove lopinavir/r efficacy.
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 ob-
served, exceeding those in HIV-infected patients by 2-3 fold
(Schoergenhofer 2020, Gregoire 2020). However, concentrations
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 levels will be sufficient for (earlier)
treatment of mild cases or as post-exposure prophylaxis. More
than 30 clinical trials are ongoing. Lopinavir/r will be tested in
WHO’s huge SOLIDARITY trial.
Other PIs
For another HIV PI, the manufacturer Janssen-Cilag published a
letter to the European Medical Agency on March 13, pointing out
that “based on preliminary, unpublished results from a previous-
ly reported in vitro experiment, it is not likely darunavir will
have significant activity against SARS-CoV-2 when administered
at the approved safe and efficacious dose for the treatment of
HIV-1 infection.” There is no evidence from both cell experi-
ments or clinical observations that the drug has any prophylac-
tic effect (De Meyer 2020, Härter 2020).
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Treatment | 243
It is hoped that the recently published pharmacokinetic charac-

terization of crystal structure of the main protease SARS-CoV-2
may lead to the design of optimized protease inhibitors (Zhang
2020). Virtual drug screening to identify new drug leads that
target protease which plays a pivotal role in mediating viral rep-
lication and transcription, have already identified several com-
pounds. Six compounds inhibited M(pro) with IC50 values rang-
ing from 0.67 to 21.4 muM, among them with disulfiram and
carmofur (a pyrimidine analogue used as an antineoplastic
agent) two approved drugs (Jin 2020).
Antiviral entry inhibitors

Most coronaviruses attach to cellular receptors by their spike (S)
protein. Within a few weeks, several groups have elucidated the
entry of SARS-CoV-2 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 epithe-
lial cells. The affinity for this ACE-2 receptor appears to be high-
er with SARS-CoV-2 than with other coronaviruses. The hypoth-
esis that ACE inhibitors promote severe COVID-19 courses
through increased expression of the ACE2 receptor remains un-
proven (see clinical chapter).
Camostat
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 cellular membranes. SARS-CoV-2 uses the
cellular protease transmembrane protease serine 2 (TMPRSS2).
Compounds inhibiting this protease may therefore inhibit viral
entry (Kawase 2012). The TMPRSS2 inhibitor camostat, which
was 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: pending. At least five trials are ongoing. A Phase
III study in the UK (named SPIKE1) in patients who exhibit symp-
toms but do not require hospitalization was announced at the
end of May. Another Phase II study is underway in Denmark. A
German study (CLOCC trial) which has been planned to start in
June, comparing camostat and hydroxychloroquine, will have to
deal with the disappointing results of HCQ (see below).
Umifenovir
Umifenovir (Arbidol®) is a broad-spectrum antiviral drug which
is approved as a membrane fusion inhibitor in Russia and China
for the prophylaxis and treatment of influenza. Chinese guide-
lines recommend it for COVID-19, according to a Chinese press
release it is able to inhibit the replication of SARS-CoV-2 in low
concentrations of 10-30 M (PR 2020).
Clinical data: 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 nasopharyngeal specimens became negative
in 75% (94%), compared to 35% (53%) with lopinavir/r mono-
therapy. Chest CT scans were improving for 69% versus 29%, re-
spectively. Similar results were seen in another retrospective
analysis (Zhu 2020). However, a clear explanation for this re-
markable 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 prelimi-
nary report of a randomized study indicating a weaker effect of
umifenovir compared to favipiravir (Chen 2020).
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Treatment | 245
Hydroxychloroquine (HCQ) and Chloroquine (CQ)

Chloroquine is used for prevention and treatment of malaria and
is effective (but not approved) as an anti-inflammatory agent for
rheumatoid arthritis and lupus erythematosus. Hydroxychloro-
quine is approved for malaria and certain autoimmune diseases
and is also better tolerated. Some lab experiments had suggested
that HCQ and CQ might have some antiviral effects against SARS-
CoV-2, due to an increase in the endosomal pH value, which dis-
rupts the virus-cell fusion and some post-entry steps (Wang
2020, Yao 2020). An early enthusiastic mini-review stated that
“results from more than 100 patients” showed that chloroquine
phosphate would be able to alleviate the course of the disease
(Gao 2020). Other experts, however, raised doubts (Touret 2020).
A benefit of chloroquine would be the first positive signal, after
decades of unsuccessfully studies conducted in a huge number of
acute viral diseases. On March 17, a preliminary report from
Marseille, France appeared to show some benefit in a small non-
randomized study on 36 patients (Gautret 2020). Although this
work lacked essential standards of data generation and interpre-
tation (Kim 2020), someone’s swanky tweet on March 21 claiming
that the combination of HCQ and azithromycin has “a real
chance to be one of the biggest game changers in the history of
medicine”, attracted world-wide attention and led to ten thou-
sands of uncontrolled treatments. Moreover, many patients
turned away from clinical trials of other therapies that would
require them to give up chloroquine treatments. This has al-
ready prompted serious delays in trial enrolment, muddled ef-
forts 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 ap-
proved clinical indications. Only a few weeks later, we are now
facing an overwhelming amount of data strongly arguing against
any use of both HCQ and CQ.

Clinical data: There are no large RCT, comparing HCQ or CQ

with placebo as treatment. However, growing data indicates that
there is only low efficacy. If there is any. Some key studies argu-
ing against HCQ during recent weeks
In an observational study from New York City (Geleris 2020)
of 1,376 consecutive hospitalized patients, 811 received HCQ
(60% received also azithromycin). After adjusting for several
confounders (HCQ patients were more severely ill at base-
line), there was no significant association between HCQ use
and intubation or death.
Another retrospective cohort of 1,438 patients from 25 hospi-
tals in the New York metropolitan region looked at 1,438 pa-
tients (Rosenberg 2020). In adjusted Cox models, compared
with patients receiving neither drug, there were no signifi-
cant differences in mortality for patients receiving HCQ +
azithromycin, HCQ alone, or azithromycin alone. Cardiac ar-
rest was significantly more likely seen with HCQ + azithromy-
cin (adjusted OR 2.13).
A randomized, Phase IIb clinical trial in Brazil allocated se-
vere COVID-19 patients to receive high-dosage CQ (600 mg
BID for 10 days) or low-dosage CQ (450 mg BID on day 1, QD
for 4 days). The DSMB terminated the trial after 81/440 indi-
viduals had been enrolled (Borba 2020). By day 13 of enrol-
ment, 6/40 patients (15%) in the low-dose group had died,
compared with 16/41 (39%) in the high-dose group. Viral RNA
was detected in 78% and 76%, respectively.
In a retrospective study of 251 patients receiving HCQ plus
azithromycin, extreme new QTc prolongation to > 500 ms, a
known marker of high risk for torsade de pointes, had devel-
oped in 23% (Chorin 2020).
In 150 patients with mainly persistent mild to moderate
COVID-19, the probability of negative PCR conversion by 28
was 85.4% with HCQ, similar to that in the standard of care
Kamps – Hoffmann
Treatment | 247
group (81.3%) (Tang W 2020). Adverse events were recorded

more frequently with HCQ (30% vs 9%, mainly diarrhea).
Free plasma HCQ concentration achieved with HCQ doses tol-
erable for humans are probably too low to have any antiviral
effects (Fan 2020).
HCQ does not work as a prophylaxis. In total, 821 asympto-
matic participants were randomized to receive hydroxychlo-
roquine or placebo within 4 days after exposure (88% with a
high-risk exposure). Incidence of confirmed SARS-CoV-2 was
11.8% with CQ and 14.3% with placebo. Side effects were more
common with hydroxychloroquine than with placebo (40.1%
vs. 16.8%), but no serious adverse reactions were reported
(Boulware 2020).
The main conclusion of a recent review was that “there is insuf-
ficient and often conflicting evidence on the benefits and harms
of using hydroxychloroquine or chloroquine to treat COVID-19.
As such, it is impossible to determine the balance of benefits to
harms”. There are no assessments of hydroxychloroquine or
chloroquine for prophylaxis against COVID-19 (Hernandez 2020).
No. 45 may continue to take it, but for other patients, there is no
rationale outside of clinical trials.
Others
Baricitinib (Olumiant®) is a Janus-associated kinase (JAK) inhib-
itor 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 inhibi-
tion may also reduce 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 the fact that baricitinib

causes lymphocytopenia, neutropenia and viral reactivation

(Praveen 2020). However, several studies are underway in Italy
and the US, among them a huge trial (ACTT-II), comparing bari-
citinib and remdesivir to remdesivir alone in more than 1,000
patients.
Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is also
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 may be
crucial immediately after the onset of symptoms. Oseltamivir is
best indicated for accompanying influenza coinfection, 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 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.
Immunomodulators
While antiviral drugs are most likely to prevent mild COVID-19
cases from becoming severe, adjuvant strategies will be particu-
larly necessary in severe cases. Coronavirus infections may in-
duce excessive and aberrant, ultimately ineffective host immune
responses that are associated with severe lung damage
(Channappanavar 2017). Similar to SARS and MERS, some pa-
tients with COVID-19 develop acute respiratory distress syn-
drome (ARDS), often associated with a cytokine storm (Mehta
2020). This is characterized by increased plasma concentrations
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, inter-
leukin-1 blocking agents such as anakinra or JAK-2 inhibitors are
also an option (Mehta 2020). These therapies may potentially act
Kamps – Hoffmann
Treatment | 249
synergistically when combined with antivirals. Numerous drugs

are discussed, including those for lowering cholesterol, for dia-
betes, 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 in-
clude bevacizumab, brilacidin, cyclosporin, fedratinib (Wu 2020),
fingolimod, lenadilomide and thalidomide, sildenafil, teicoplanin
(Baron 2020), monoclonal antibodies (Shanmugaraj 2020) and
many more. However, convincing clinical data is pending for
most strategies.
Interferon
The interferon (IFN) response constitutes the major first line of
defense against viruses. This complex host defense strategy can,
with accurate understanding of its biology, be translated into
safe and effective antiviral therapies. In a recent comprehensive
review, the recent progress in our understanding of both type I
and type III IFN-mediated innate antiviral responses against hu-
man coronaviruses is described (Park 2020).
In patients with coronaviruses such as MERS, however, interfer-
on studies were disappointing. Despite impressive antiviral ef-
fects in cell cultures (Falzarano 2013), no convincing benefit was
shown in clinical studies in combination with ribavirin (Omrani
2014, Shalhoub 2015, Arabi 2017).
Nevertheless, inhalation of interferon is still recommended as an
option in Chinese COVID-19 treatment guidelines.
Clinical data: A Phase 2, 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 lopinavir/r, ribavirin and in-
terferon (Hung 2020). This trial indicates that the triple combi-
nation can be beneficial when started early. Combination thera-

py was given only in patients with less than 7 days from symp-
tom onset and consisted of lopinavir/r, ribavirin (400 mg BID),
and interferon beta-1b (1-3 doses of 8 Mio IE per week). Combi-
nation therapy led to a significantly shorter median time to neg-
ative 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. Up to now, this is the only larger RCT show-
ing a virological response of a specific drug regimen.
Corticosteroids
Corticosteroids are often used, especially in severe cases. In the
largest uncontrolled cohort study to date of 1,099 patients with
COVID-19, a total of 19% were treated with corticosteroids, in
severe cases almost half of all patients (Guan 2020). However,
according to current WHO guidelines, steroids are not recom-
mended outside clinical trials.
A systematic review of several observational SARS studies
(Stockman 2006) yielded no benefit and various side effects
(avascular necrosis, psychosis, diabetes). However, the use of
corticosteroids COVID-19 is still very controversial (R Russell
2020, Shang 2020). In a retrospective study of 401 patients with
SARS, it was found that low doses reduce mortality and are able
to shorten the length of hospital stay for critically ill patients,
without causing secondary infection and/or other complications
(Chen 2006).
In another retrospective study involving a total of 201 COVID-19
patients, methylprednisolone reduced mortality in patients with
ARDS (Wu 2020). One group, after reviewing 213 patients, postu-
lated that an early short course of methylprednisolone in pa-
Kamps – Hoffmann
Treatment | 251
tients with moderate to severe COVID-19 may reduce escalation

of care and improved clinical outcomes (Fadel 2020).
On the other hand, there is strong evidence of a delayed viral
clearance (Ling 2020), which has also been observed with SARS
(Stockman 2006). In a consensus statement by the Chinese Tho-
racic Society on February 8, corticosteroids should only be used
–1
mg/kg methylprednisolone or equivalent per day) and, last but
ays) (Zhao 2020).
Famotidine
Famotidine is a histamine-2 receptor antagonist that suppresses
gastric acid production. It has an excellent safety profile. Initial-
ly it was thought to inhibit the 3-chymotrypsin-like protease
(3CLpro), but it seems to act rather as an immune modulator, via
its antagonism or inverse-agonism of histamine signalling. A
retrospective study looked at 1,620 patients, including 84 pa-
tients (5.1%) who received different doses of famotidine within
24 hours of hospital admission (Freedberg 2020). After adjusting
for baseline patient characteristics, use of famotidine remained
independently associated with risk for death or intubation (ad-
justed hazard ratio 0.42, 95% CI 0.21-0.85) and this remained un-
changed after careful propensity score matching to further bal-
ance the co-variables. Of note, there was no protective effect
associated with use of PPIs. The maximum plasma ferritin value
during the hospitalization was lower with famotidine, indicating
that the drug blocks viral replication and reduces cytokine
storm. Randomized clincial trials are underway.
Cytokine Blockers
The hypothesis that quelling the cytokine storm with anti-
inflammatory therapies directed at reducing interleukin-6 (IL-6),
IL-1, or even tumour necrosis factor TNF alpha, might be benefi-

cial has led to several ongoing trials. It is suggestive that inter-

leukin blocking strategies might improve the hyperinflammato-
ry state seen in severe COVID-19. A recent review on this strate-
gy, 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 suc-
cessful and, in some cases, have worsened outcomes. Moreover,
there is concern that suppressing the innate and adaptive im-
mune system to address increased cytokine concentrations,
could enable unfettered viral replication, suppress adaptive im-
munity, and delay recovery processes. There is growing recogni-
tion that potent immunosuppressive mechanisms are also preva-
lent in such patients. Following, we will briefly discuss the evi-
dence on cytokine blockers.
Anakinra
Anakinra 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 immune response in hy-
perinflammatory COVID-19 and is currently being investigated
in clinical trials.
Clinical data: Some case series have reported on encouraging
results.
A study from Paris, comparing 52 “consecutive” patients
treated with anakinra with 44 historical patients. Admission
to the ICU for invasive mechanical ventilation or death oc-
curred in 25% of patients in the anakinra group and 73% of
patients in the historical group. The treatment effect of ana-
kinra remained significant in the multivariate analysis. Con-
trolled trials are needed.
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Treatment | 253
A retrospective cohort study at the San Raffaele Hospital in

Milan, Italy, including 29 patients with moderate-to-severe
ARDS and hyperinflammation (serum C-reactive protein, CRP
-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 sec-
ondary hemophagocytic lymphohistocytosis (sHLH) charac-
terized by pancytopenia, hyper-coagulation, acute kidney in-
jury and hepatobiliary dysfunction. At the end of treatment,
ICU patients had less need for vasopressors and significantly
improved respiratory function. Although 3/8 patients died,
the mortality was lower than historical series of patients with
sHLH in sepsis (Dimopoulos 2020).
Clinical improvement in three patients with acute leukaemia
and confirmed or suspected COVID-19 pneumonia with a life-
threatening hyperinflammatory syndrome (Day 2020).
Tocilizumab
Tocilizumab (TCZ) is a monoclonal antibody that targets the in-
terleukin-6 receptor. Tocilizumab (RoActemra® or Actemra®) is
used for rheumatic arthritis and has a good safety profile. There
is no doubt that TCZ should be reserved for patients with severe
disease who have failed other therapies. However, some case
reports have suggested that IL-6-blocking treatment given for
chronic autoimmune diseases may even prevent the develop-
ment of severe COVID-19 (Mihai 2020). The initial dose should be
4-8 mg/kg, with the recommended dosage being 400 mg (infu-
sion over more than 1 hour). Controlled trials are underway (as
of May 31, 46 trials at clinicaltrials.gov were listed, among them

14 Phase III studies) as well as for sarilumab (Kevzara®), another

IL-6 receptor antagonist.
Clinical data: Some uncontrolled case series exist, many show-
ing rapid relief of respiratory symptoms in some patients, as well
as a resolution of fever and reduction in CRP following TCZ ad-
ministration.
62 consecutive patients admitted to the Montichiari Hospital
(Italy) with COVID-19 related pneumonia and respiratory
failure (but not needing mechanical ventilation) received to-
cilizumab when the drug became available on March 12
(Capra 2020). Patients were compared with 23 “control” pa-
tients admitted before March 13th who were prescribed the
standard therapy (HCQ, lopinavir/r). Patients receiving TCZ
showed significantly greater survival rate, even after adjust-
ing for baseline clinical characteristics. Only two out of 62 pa-
tients of the TCZ group and 11 out of 23 in the control group
died. The respiratory function resulted improved in 64.8% of
the observations in tocilizumab patients who were still hospi-
talized, whereas 100% of controls worsened and needed me-
chanical ventilation.
Among 58 patients who received TCZ at a center in Barcelona,
8 (14%) died. Almost all (98%) received intravenous pulse
therapy with steroids. There was a trend towards lower mor-
tality when steroids were given before TCZ (Campins 2020).
In a risk-adjusted Cox regression analysis of 31 hyperglyce-
mic and 47 normoglycemic patients with severe COVID-19,
TCZ in hyperglycemic patients failed to attenuate the risk of
severe outcomes as it did in normoglycemic patients
(Marfella 2020).
Off-label use in 45 patients (most requiring high-flow oxygen
supplementation or invasive ventilation) from Milan (Morena
2020). 14 died (27%). From baseline to day 7 after TCZ, how-
ever, a dramatic drop of body temperature and CRP value
Kamps – Hoffmann
Treatment | 255
with a significant increase in lymphocyte count was seen

(Morena 2020).
Siltuximab
Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. How-
ever, this chimeric monoclonal antibody targets interleukin-6
directly and not the receptor. Siltuximab has been approved for
idiopathic multicentric Castleman’s disease (iMCD). In these pa-
tients it is well tolerated.
Clinical data: 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).
Passive immunization
A meta-analysis of observational studies on passive immuno-
therapy for SARS and severe influenza indicates a decrease in
mortality, but the studies were commonly of low or very low
quality and lacked control groups (Mair-Jenkins 2015). In MERS,
fresh frozen convalescent plasma or immunoglobulin from re-
covered patients have been discussed (Zumla 2015, Arabi 2017).
Recovered SARS patients develop a neutralizing antibody re-
sponse against the viral spike protein (Liu 2006). Preliminary
data indicate that this response also extends to SARS-CoV-2
(Hoffmann 2020), but the effect on SARS-CoV-2 was somewhat
weaker. Others have argued that human convalescent serum
could be an option for prevention and treatment of COVID-19
disease to be rapidly available when there are sufficient numbers
of people who have recovered and can donate immunoglobulin-

containing serum (Casadevall 2020). Recently, an overview on

current evidence of benefit, regulatory considerations, logistical
work flow (recruitment of donors etc) and proposed clinical tri-
als has been published (Bloch 2020). Passive immune therapy
appears to be relatively safe. However, an unintended conse-
quence of receiving convalescent plasma or globulins may be
that recipients won’t develop their own immunity, putting them
at risk for reinfection. Other issues that have to be addressed in
clinical practice (Kupferschmidt 2020) are plasma supply (may
become a challenge), consistency (concentration differs) and
rare but relevant risks (transfusion-related acute lung injury, in
which transferred antibodies damage pulmonary blood vessels,
or transfusion-associated circulatory overload).
Clinical data: Up to now, no larger controlled clinical trials in
COVID-19 have been published. There are small case series:
In 5 critically ill patients with COVID-19 and ARDS, admin-
istration of convalescent plasma was followed by improve-
ment in their clinical status (Shen 2020). All 5 patients were
receiving mechanical ventilation at the time of treatment
and all had received antiviral agents and methylpredniso-
lone.
In another pilot study, a single dose (200 mL) of convalescent
plasma was given to 10 patients (9 treated with umifenovir, 6
with methylprednisolone, 1 with remdesivir). In all 7 patients
with viremia, serum SARS-CoV-2 RNA decreased to an unde-
tectable level within 2-6 days (Duan 2020). Meanwhile, clini-
cal symptoms and paraclinical criteria rapidly improved -
within three days.
In 25 patients with severe and/or life-threatening COVID-19
disease enrolled at Houston, convalescent plasma was safe.
By day 14 post-transfusion, 19 (76%) patients had at least a 1-
point improvement in clinical status and 11 were discharged
(Salazar 2020).
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Treatment | 257
Don’t be too late: Of 6 patients with respiratory failure receiv-

ing convalescent plasma at a median of 21 days after first de-
tection of viral shedding, all tested RNA negative by 3 days af-
ter infusion. However, 5 eventually died (Zeng 2020).
On March 26, the FDA has approved the use of plasma from re-
covered patients to treat people who are critically ill with
COVID-19 (Tanne 2020). It’s now time for larger and controlled
studies.
Monoclonal antibodies
As long as all other therapies fail or have only modest effects,
monoclonal neutralizing 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 also have to go through all phases of clinical
trial testing programs, which will take time. Safety and tolerabil-
ity in particular is an important issue. The production of larger
quantities is also likely to cause problems. No antibody has been
tested in humans to date. However, some are very promising.
Key papers:
The first report of a human monoclonal antibody that neu-
tralizes 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 anti-
body could be useful for development of antigen detection
tests and serological assays targeting SARS-CoV-2.
Fantastic study identifying 14 potent neutralizing antibodies
by high-throughput single B cell RNA-sequencing from 60
convalescent patients (Cao 2020). The most potent one, BD-
368-2, exhibited an IC50 of 15 ng/mL against SARS-CoV-2.

This antibody displayed strong therapeutic and prophylactic

efficacy in mice, the epitope overlaps with the ACE2 binding
site. Time to go into the clinic!
Isolation and characterization of 206 RBD-specific monoclo-
nal 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).
Four human-origin monoclonal antibodies were isolated from
a convalescent patient, all of which display neutralization
abilities. B38 and H4 blocked the binding between virus S-
protein RBD and cellular receptor ACE2. A competition assay
indicates their different epitopes on the RBD. In a mouse
model, both antibodies reduced virus titers in infected lungs.
The RBD-B38 complex structure revealed that most residues
on the epitope overlap with the RBD-ACE2 binding interface,
explaining the blocking effect and neutralizing capacity (Wu
2020).
Outlook
It is hoped that at least some of the options given in this over-
view will show positive results over time. It is also important
that in this difficult situation, despite the immense pressure, the
basic principles of drug development and research including
repurposing are not abandoned.
Four different options, namely lopinavir/r, alone and in combi-
nation with interferon, remdesivir and (hydroxy) chloroquine
will be tested in the SOLIDARITY study launched on March 18 by
the WHO. Results of this large-scale, pragmatic trial will generate
the robust data we need, to show which treatments are the most
effective (Sayburn 2020).
Kamps – Hoffmann
Treatment | 259
So in the present dark times, which are the best options to offer
patients? There is currently no evidence from controlled clinical
trials to recommend a specific treatment for SARS-CoV-2 coro-
navirus infection. Guidelines do not help, especially those con-
cluding that evidence is insufficient and that “all patients should
be treated in controlled randomized trials”. Moreover, on the
day of their publication, many guidelines are outdated. However,
after reviewing all these studies until May 31, we would recom-
mend reviewing the following treatment options, considering
the severity of the disease:
Hospital, severe COVID-19
In the clinic, use remdesivir if available and as soon as
possible
In patients with severe COVID-19, consider tocilizumab,
anakinra and corticosteroids (short)
Outpatient, mild to moderate COVID-18
Daily infusions of remdesivir are not feasible (and will
not be approved)
HCQ and CQ should no longer be used (too many side ef-
fects)
Lopinavir is still an (useless) option, but interactions
and gastrointestinal side effects have to be considered
Famotidin: why not? Potential harm seems to be limited
Interferon may work, if given early (optimal usage is
unclear)

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Zhu Z, Lu Z, Xu T, et al. Arbidol Monotherapy is Superior to Lop-
inavir/ritonavir in Treating COVID-19. J Infect. 2020 Apr 10. PubMed:
Zumla A, Azhar EI, Arabi Y, et al. Host-directed therapies for improving poor
treatment outcomes associated with the middle east respiratory syn-
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Kamps – Hoffmann
Severe COVID | 271
9. Severe COVID
This chapter about severe COVID-19 in the hospital/ICU will be
published soon. In the meantime, please find the following rec-
ommendations and key papers.
Checklists for hospitals

European Centre for Disease Prevention and Control. Checklist for hospitals
preparing for the reception and care of coronavirus 2019 (COVID-19)
patients. ECDC: Stockholm; 2020.
https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-
checklist-hospitals-preparing-reception-care-coronavirus-patients.pdf
Patient admission to ICUs

Swiss Society Of Intensive Care Medicine. Recommendations for the admission
of patients with COVID-19 to intensive care and intermediate care
units (ICUs and IMCUs). Swiss Med Wkly. 2020 Mar 24. Fulltext:
https://doi.org/10.4414/smw.2020.20227
Management of critically ill patients
Thomas-Ruddel D, Winning J, Dickmann P, et al. Coronavirus disease 2019

(COVID-19): update for anesthesiologists and intensivists March 2020.
Anaesthesist. 2020 Mar 24. Fulltext: https://doi.org/10.1007/s00101-020-
00760-3
Outstanding update for anesthesiologists and those working in
intensive care.
Sorbello M, El-Boghdadly K, Di Giacinto I, et al. The Italian COVID-19 outbreak:

experiences and recommendations from clinical practice. Anaesthesia.
2020 Mar 27. PubMed: https://pubmed.gov/32221973. Fulltext:
Detailed practical recommendations, based on experiences in
Italy. Key elements of clinical management, airway management,
personal protective equipment and non-technical aspects.

Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With
COVID-19. JAMA. 2020 Mar 26. Fulltext:
Short recommendations, made by the Surviving Sepsis Cam-
paign.
More reviews, overviews of specific issues of criti-

cally ill patients
Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. May 15, 2020. DOI:
10.1056/NEJMcp2009575. Full-text:
https://www.nejm.org/doi/full/10.1056/NEJMcp2009575?query=featured_
home
Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory
distress syndrome from COVID-19. Lancet Respir Med. 2020 Mar 20.
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 17
Apr 2020: eabb8925. DOI: 10.1126/science.abb8925. Fulltext:
https://science.sciencemag.org/content/early
/2020/04/16/science.abb8925
Smereka J, Puslecki M, Ruetzler K, et al. Extracorporeal membrane oxygena-
tion in COVID-19. Cardiol J. 2020 Apr 14. PubMed:
https://doi.org/10.5603/CJ.a2020.0053.
Stam HJ, Stucki G, Bickenbach J. Covid-19 and Post Intensive Care Syndrome:
A Call for Action. J Rehabil Med. 2020 Apr 14. PubMed:
https://doi.org/10.2340/16501977-2677.
Telias I, Katira BH, Brochard L, et al. Is the Prone Position Helpful During
Spontaneous Breathing in Patients With COVID-19? JAMA. Published
online May 15, 2020. doi:10.1001/jama.2020.8539.
Wadman M, Couzin-Frankel J, Kaiser J, et al. A rampage through the body. Sci-
ence 24 Apr 2020: Vol. 368, Issue 6489, pp. 356-360. DOI:
10.1126/science.368.6489.356. Full-text:
https://science.sciencemag.org/content/368/6489/356
Kamps – Hoffmann
Severe COVID | 273
Endotracheal intubation, bronchoscopy, airway

management and staff safety
Cheung JC, Ho LT, Cheng JV, Cham EYK, Lam KN. Staff safety during emergency
airway management for COVID-19 in Hong Kong. Lancet Respir Med.
2020 Feb 24. Fulltext: https://doi.org/10.1016/S2213-2600(20)30084-9
Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A, Higgs A. Consensus
guidelines for managing the airway in patients with COVID-19. Anaes-
thesia. 2020 Mar 27. PubMed: https://pubmed.gov/32221970. Fulltext:
Lentz RJ, Colt H. Summarizing societal guidelines regarding bronchoscopy
during the COVID-19 pandemic. Respirology. 2020 Apr 11. PubMed:
https://doi.org/10.1111/resp.13824.
Loftus RW, Dexter F, Parra MC, Brown JR. Importance of oral and nasal decon-
tamination for patients undergoing anesthetics during the COVID-19
era. Anesth Analg. 2020 Apr 3. PubMed: https://pubmed.gov/32250978.
Full-text: https://doi.org/10.1213/ANE.0000000000004854.
Luo M, Cao S, Wei L, et al. Precautions for Intubating Patients with COVID-19.
Anesthesiology. 2020 Mar 19. PubMed: https://pubmed.gov/32195703.
Fulltext: https://doi.org/10.1097/ALN.0000000000003288
Lyons C, Callaghan M. The use of high-flow nasal oxygen in COVID-19. Anaes-
thesia. 2020 Apr 4. PubMed: https://pubmed.gov/32246843. Full-text:
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2020 Apr 24. pii: 2765302. PubMed: https://pubmed.gov/32329799. Full-
Schünemann HJ, Khabsa J, Solo K, et al. Ventilation Techniques and Risk for
Transmission of Coronavirus Disease, Including COVID-19. A Living
Systematic Review of Multiple Streams of Evidence. Ann Int Med 2020,
May 22. https://doi.org/10.7326/M20-2306. Full-text:
Triage for intensive-care treatment

Swiss Academy Of Medical Sciences. COVID-19 pandemic: triage for intensive-
care treatment under resource scarcity. Swiss Med Wkly. 2020 Mar
24;150:w20229. PubMed: https://pubmed.gov/32208495.

Procedures
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coronavirus (COVID-19) pneumonia in the radiology department: a
Chinese experience. Diagn Interv Radiol. 2020 Mar 25. PubMed:
https://doi.org/10.5152/dir.2020.20167
Pragmatic recommendations for patient care in the radiology
department
Zhang Y, Zhang X, Liu L, Wang H, Zhao Q. Suggestions for infection prevention

and control in digestive endoscopy during current 2019-nCoV pneu-
monia outbreak in Wuhan, Hubei province, China. Endoscopy. 2020
Apr;52(4):312-314. PubMed: https://pubmed.gov/32212122. Full-text:
https://doi.org/10.1055/a-1128-4313
Brief workflow to prevent SARS-CoV-2 transmission in the en-
doscopy center
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atory monitoring for in-hospital patients with Covid-19 - a Swiss con-
sensus statement by the Working Party Hemostasis. Swiss Med Wkly.
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Thromboprophylaxis and laboratory monitoring
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the COVID-19 PandemicLessons Learned From the Severe Acute Res-
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lished online March 31, 2020. Full-text:
https://doi.org/10.1001/jamaoto.2020.0764
How to perform a tracheostomy
Kamps – Hoffmann
Severe COVID | 275
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cases. J Clin Pathol. 2020 Mar 20. PubMed: https://pubmed.gov/32198191.
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European Centre for Disease Prevention and Control. Considerations related to
the safe handling of bodies of deceased persons with suspected or con-
firmed COVID-19. Stockholm: ECDC; 2020.
https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-
safe-handling-of-bodies-or-persons-dying-from-COVID19.pdf.
Recommendations for conducting autopsies

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Comorbidities | 277
10. Comorbidities
Hundreds of articles have been published over the last few
weeks, making well-meaning attempts to determine whether
patients with different comorbidities are more susceptible for
SARS-CoV-2 infection or at higher risk for severe disease. This
deluge of scientific publications has resulted in worldwide un-
certainty. For a number of reasons, many studies must be inter-
preted with extreme caution.
First, in many articles, the number of patients with specific
comorbidities is low. Small sample sizes preclude accurate com-
parison of COVID-19 risk between these patients and the general
population. They may also overestimate mortality, especially if
the observations were made in-hospital (reporting bias). Moreo-
ver, 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 surgi-
cal 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 policies

vary widely between countries. The control group (with or with-
out 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 distribu-
tion, 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.
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. Hun-
dreds of guidelines or position papers have been published in
recent weeks, 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 guide-
lines 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 dyspho-
nia and voice rehabilitation (Mattei 2020: can be postponed),
infantile hemangiomas (Frieden 2020: use telehealth), ocular
allergy (Leonardi 2020: very controversial), high resolution anos-
copy (Mistrangelo 2020: also controversial), migraine manage-
ment (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 over-
whelmed health care systems in Wuhan, Bergamo, Madrid or
New York. In other cities or even a few weeks later, proposed
algorithms are already outdated. And nobody needs a 60-page
Kamps – Hoffmann
Comorbidities | 279
recommendation, concluding that “clinical judgment and deci-

sion making should be exercised on a case-by-case basis”. How-
ever, 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 comorbidi-

ties
From the beginning of the pandemic, hypertension and/or car-
diovascular disease (CVD) have been identified as potential risk
factors for severe disease and death (at least two studies had
performed a multivariate analysis (Table 1)). However, all studies
were retrospective, included only hospitalized patients and did
not distinguish between uncontrolled and controlled hyperten-
sion or used different definitions for CVD. Multivariate analyses
adjusting for confounders were performed in only a few studies.
Moreover, different outcomes and patient groups were analyzed.
According to some experts, current data do not necessarily im-
ply a causal relationship between hypertension and severity of
COVID-19. It is also “unclear whether uncontrolled blood pres-
sure is a risk factor for acquiring COVID-19, or whether con-
trolled blood pressure among patients with hypertension is or is
not less 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 very plausi-
ble 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.

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 death at ICU: 40 vs
Italy 63%
Guan 1,099 hospitalized Non-severe disease vs Not done
2020 pts, 522 hospitals severe: 13 vs 24%
in China
Zhou 191 hospitalized Survivors vs Non- Not done
2020 pts from Jinyintan Survivors: 23 vs 48%
and Wuhan
Shi 487 hospitalized Non-severe disease at OR 2.7 (1.3-5.6) for
2020 pts admission vs severe: severe disease at
in Zhejing 17 vs 53% admission
Province
Guan 1,590 hospitalized Non-severe vs severe HR 1.6 (1.1-2.3) for
2020 pts, 575 hospitals courses: 13 vs 33% severe course (ICU,
in China IMV, death)
Goyal 393 hospitalized No IMV vs IMV during Not done
2020 pts, stay: 48 vs 54%
2 hospitals in New
York
IMV invasive mechanical ventilation, ICU intensive care units
Various cardiac manifestations of COVID-19 do occur contempo-

rarily in many patients (see chapter Clinical Manifestations).
Infection may lead to cardiac muscle damage, blood vessel con-
striction and to elevated levels of inflammation-inducing cyto-
kines. These direct and indirect adverse effects of the virus may
be especially deleterious in those with already established heart
disease. During the next months, we will learn a lot more about
the role and contributions of arteriosclerosis in the pathogenesis
of COVID-19.
Kamps – Hoffmann
Comorbidities | 281
Treatment of hypertension during the pandemic

There has hardly been a topic in the last months that has kept
doctors and their patients as busy as the question of whether
antihypertensive drugs such as ACE inhibitors (ACEIs) or angio-
tensin-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 con-
cerns. These conditions share underlying renin-angiotensin-
aldosterone system pathophysiology that may be clinically in-
sightful. 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 plas-
ma ACE2 concentrations and the use of ACEIs/ARBs does 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 administration 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 dis-
continuation of these drugs. This is remarkable as clinical data
actually points in the opposite direction. Some small retrospec-
tive studies from China have shown no negative effect (Meng
2020, Yang 2020). In the largest study, 188 patients taking
ACEI/ARBs were compared with 940 patients who did not use
them. Of note, unadjusted mortality rate was lower in the

ACEI/ARB group (3.7% vs. 9.8%) and a lower risk was also found
in a multivariate Cox model (Zhang 2020).
By early May, two large studies were published in the NEJM (a
third was later retracted). Although both were observational
(with the possibility of confounding), their message was con-
sistent - none showed any evidence of harm (Jarcho 2020). One
study analyzed 2,573 COVID-19 patients with hypertension from
New York City, among them 25% with severe disease (Reynolds
2020). After looking at different classes of antihypertensive med-
ications – ACE inhibitors, ARBs, beta-blockers, calcium-channel
blockers, and thiazide diuretics, the authors ruled out any sub-
stantial difference in the likelihood of severe COVID-19, with at
least 97.5% certainty for all medication classes.
The second study looked at a possible independent relationship
between ACEI/ARBs and the susceptibility to COVID-19 (Mancia
2020). The authors matched 6,272 Italian cases (positive for
SARS-CoV-2) with 30,759 beneficiaries of the Regional Health
Service (controls) according to sex, age, and municipality of res-
idence. There was no evidence that ACE inhibitors or ARBs modi-
fy susceptibility to COVID-19. The results applied to both sexes as
well as to younger and older persons.
In conclusion, ACE inhibitors and/or ARBs should not be discon-
tinued (Bavishi 2020, Sriram 2020, Vaduganathan 2020). At least
four registered randomized trials plan to evaluate ACEIs and
ARBs for treatment of COVID-19 (Mackey 2020). According to a
brief review, adjuvant treatment and continuation of pre-
existing statin therapy could improve the clinical course of pa-
tients with COVID-19, either by their immunomodulatory action
or by preventing cardiovascular damage (Castiglion 2020).
Kamps – Hoffmann
Comorbidities | 283
Treatment of coronary heart disease during the

pandemic
Myocardial injury, evidenced by elevated cardiac biomarkers,
was recognized among early cases and myocardial infarction
(STEMI or NSTEMI) and may represent the first clinical manifes-
tation of COVID-19 (Reviews: Bonow 2020, Valente 2020). 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 prelim-
inary reports on a significant decline of 32% in the number of
percutaneous coronary interventions for acute coronary syn-
dromes (Piccolo 2020). Other authors have suggested that, in
settings with limited resources to protect the work force, fibri-
nolytic therapies may be prefered over primary percutaneous
coronary interventions (Daniels 2020).
Of note, several studies have found a spectacular drop in admis-
sions 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 caregiv-
ers, especially in the case of mild STEMI clinical presentation.
Other hypothetical reasons are reduced air pollution, better ad-
herence to treatment, limited physical activity or absence of oc-
cupational stress during lockdown. However, there is some evi-
dence that the lower incidence does not reflect a true decline but
just one more collateral damage of the pandemic. For example,
Italian researchers have found a 58% increase of out-of-hospital

cardiac arrests in March 2020 compared to the same period in

2019 (Baldi 2020).
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angiotensin-converting enzyme 2 in men and women with heart fail-
ure and effects of renin–angiotensin–aldosterone inhibitors. European
Heart Journal 2020, May 10. Full-text:
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article/doi/10.1093/eurheartj/ehaa373/5834647
Schiffrin EL, Flack J, Ito S, Muntner P, Webb C. Hypertension and COVID-19. Am
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Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe
COVID-19 and establishment of a host risk score: findings of 487 cases
outside Wuhan. Crit Care. 2020 Mar 18;24(1):108. PubMed:
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Solomon MD, McNulty EJ, Rana JS, et al. The Covid-19 Pandemic and the Inci-
dence of Acute Myocardial Infarction. NEJM 2020, May 19. DOI:
10.1056/NEJMc2015630 . Full-text:
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Sriram K, Insel PA. Risks of ACE inhibitor and ARB usage in COVID-19: evalu-
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Clinical Pearls and Plea to Insurers. Headache. 2020 May;60(5):833-842.
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Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD.
Renin-Angiotensin-Aldosterone System Inhibitors in Patients with
Covid-19. N Engl J Med. 2020 Mar 30. PubMed:
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Valente S, Anselmi F, Cameli M. Acute coronary syndromes during COVID-19.
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Wang Y, Lu X, Chen H, et al. Clinical Course and Outcomes of 344 Intensive
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Yang G, Tan Z, Zhou L, et al. Effects Of ARBs And ACEIs On Virus Infection,
Inflammatory Status And Clinical Outcomes In COVID-19 Patients With
Hypertension: A Single Center Retrospective Study. Hypertension. 2020
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Zhang P, Zhu L, Cai J, et al. Association of Inpatient Use of Angiotensin Con-
verting Enzyme Inhibitors and Angiotensin II Receptor Blockers with
Mortality Among Patients With Hypertension Hospitalized With
COVID-19. Circ Res. 2020 Apr 17. PubMed: https://pubmed.gov/32302265 .
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Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult
inpatients with COVID-19 in Wuhan, China: a retrospective cohort
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Diabetes mellitus
Diabetes mellitus is a chronic inflammatory condition character-
ized by several 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. 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 compared to non-
diabetics. In a meta-analysis of 33 studies and 16,003 patients

(Kumar 2020), diabetes was found to be significantly associated

with mortality of 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 whether diabetes is
acting as an independent factor responsible for COVID severity
and mortality or if it is just a confounding factor.
The hitherto by far largest retrospective study on the impact of
typ 2 diabetes (T2D) has carefully analyzed 7,337 cases of COVID-
19 in Hubei Province, China, among them 952 with pre-existing
T2D (Zhu 2020). The authors found that subjects with T2D re-
quired more medical interventions and had a significantly high-
er 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 associated with markedly low-
er mortality (in-hospital death rate 1.1% versus 11.0%) compared
to individuals with poorly controlled blood glucose.
A recent review has made some suggestions on the possible
pathophysiological mechanisms of the relationship between dia-
betes and COVID-19, and its management (Hussain 2020). Rigor-
ous glucose monitoring and careful consideration of drug inter-
actions might attenuate worsening of symptoms and adverse
outcomes. Some treatment strategies for COVID-19 such as ster-
oids and lopinavir/r bear a risk for hyperglycemia. On the other
hand, hydroxychloroquine may improve glycemic control in de-
compensated, 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 have to be different from those without dia-
betes. It is also unclear whether specific diabetes drugs such as
DPP4 inhibitors increase or decrease the susceptibility or severi-
ty of SARS-CoV-2 infection.
Kamps – Hoffmann
Comorbidities | 289
References
Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hy-
droxychloroquine in patients with type 2 diabetes mellitus who are re-
fractory to sulfonylureas--a randomized 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
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://doi.org/10.1016/j.diabres.2020.10814
Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortal-
ity 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 Metabo-
lism, 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 ex-
posure to noxious gases and particulates over a long period. A
meta-analysis of 15 studies, including a total of 2,473 confirmed
COVID-19 cases showed that COPD patients were at a higher risk
of more severe 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 1,399 patients ob-
served 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 compli-
cations compared to former and never smokers. Current smok-
ers also had a higher mortality rate (Alqahtani 2020).
Ever-smoking significantly and substantially increased pulmo-
nary 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 in lungs of smok-
ers. Cigarette smoke triggers an increase in ACE2 positive cells
by driving secretory cell expansion (Smith 2020). The overabun-
dance 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 correlations to the above cell experiments. Within a sur-
veillance centre 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 smok-
ing was associated with decreased odds (yes, decreased: adjusted
OR 0.49, 95% CI 0.34–0.71). According to the authors, their find-
ings should not be used to conclude that smoking prevents SARS-
CoV-2 infection, or to encourage ongoing smoking. Several ex-
planations 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
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Comorbidities | 291
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 corona-
virus disease 2019 (COVID-19). Eur J Intern Med. 2020 Mar 16. PubMed:
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 primary care network: a cross-sectional
study. Lancet Inf Dis 2020, May 15. Full-text:
Smith JC, Sauswille EL, Girish V, et al. Cigarette smoke exposure and inflam-
matory signaling increase the expression of the SARS-CoV-2 receptor
ACE2 in the respiratory tract. Development 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 patients take antiretroviral therapies that are thought to
have some effect against SARS-CoV-2. Second, HIV serves as a
model of cellular immune deficiency. 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.
Inexplicably, information on the HIV population is still scarce.
However, 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). Similar findings
were reported from Chicago (Ridgeway 2020). In Barcelona
where a local protocol included HIV serology for all hospitalized
COVID-19 patients, 32/2102 (1.5%) were HIV-infected, among

them only one single new HIV diagnosis (Miro 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” fac-
tors (i.e., antiviral therapies or immune activation). Moreover, a
defective cellular immunity could paradoxically 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 conclusions on the effect of COVID-19 are still lacking.
However, our own retrospective analysis of 33 confirmed SARS-
CoV-2 infections between March 11 and April 17 in 12 participat-
ing German HIV centers revealed no excess morbidity or mortal-
ity (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 recovered. 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 observa-
tion was made in Milan, Italy, where 45/47 patients with HIV and
COVID-19 (only 28 with confirmed SARS-CoV-2 infection) recov-
ered (Gervasoni 2020). In another single center study from Ma-
drid on 51 HIV patients 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. The last median CD4 count was 670/µl (range, 69 to 1715)
and in 30/32 cases in our cohort, the latest HIV RNA was below
50 copies/mL (Härter 2020). It remains to be seen whether HIV+
patients with uncontrolled viremia and/or low CD4 cells are at
higher risk for severe disease. It is also unclear whether immuni-
ty after infection remains impaired. However, there are case re-
ports on delayed antibody response in HIV+ patients (Zhao 2020).
Kamps – Hoffmann
Comorbidities | 293
Another issue making HIV+ patients an interesting population is

a potential effect of antiretroviral therapies against SARS-CoV-2.
For lopinavir/r, some reports on beneficial effects in patients
with SARS, MERS and COVID-19 exist, but the evidence remains
poor. Several studies on lopinavir are still underway (see Treat-
ment chapter). According to both the US DHHS and EACS state-
ment, an ART regimen should not be changed to include a PI to
prevent or treat COVID-19 (EACS 2020, US 2020). In our cohort,
4/33 (12%) patients were on darunavir when they developed
COVID-19 symptoms. In the Milan Cohort, the rate of patients on
a PI was 11% (Gervasoni 2020). Both studies indicate that PIs do
not protect from SARS-CoV-2 infection. Beside the PI, we did not
find any clear evidence for a protective effect of tenofovir.
Tenofovir alafenamide has some chemical similarities to
remdesivir and has been shown to bind to SARS-CoV-2 RNA pol-
ymerase (RdRp) with binding energies comparable to those of
native nucleotides, similar to remdesivir. Consequently, tenofo-
vir has recently been suggested as a potential 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/emtricitabine, hy-
droxychloroquine or the combination of both versus placebo as
prophylaxis for COVID-19 in healthcare workers. Our observa-
tion that the majority (22/33) of HIV+ patients 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) affected COVID-19 susceptibility
or severity (Gervasoni 2020, Vizcarra 2020).
The most serious concern regarding HIV, however, is the collat-
eral 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 having 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
African settings could well lead to adverse consequences beyond
those from COVID-19 itself. Lockdown, transport restrictions and
fear of coronavirus infection have already led to a dramatic drop
in HIV and TB patients collecting medication in several African
countries (Adepoju 2020). Using five different existing mathe-
matical models of HIV epidemiology and intervention pro-
grammes in sub-Saharan Africa, investigations have already es-
timated the impact of different disruptions to HIV prevention
and treatment services. Predicted average relative excess in HIV-
related deaths and new HIV infections (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 con-
tinuity and preventing treatment interruptions due to COVID-19
restrictions in sub-Saharan Africa.
References
Adepoju P. Tuberculosis and HIV responses threatened by COVID-19. Lancet
HIV. 2020 May;7(5):e319-e320. PubMed: https://pubmed.gov/32277870.
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 molec-
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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:
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immunodeficiency virus: a case series of 33 patients. Infection 2020,
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Immunosuppression (other than HIV)

Immunosuppression may bear a higher risk for SARS-CoV-2 in-
fection and severe COVID-19. But the story is not that simple.
Neither is it clear what immunosuppression actually means, nor
are the available data sufficient to 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 sys-
tematic review and meta-analysis on 8 studies and 4,007 patients
came to the conclusion that “immunosuppression and immuno-
deficiency were associated with increased risk of severe COVID-
19 disease, although the statistical differences were not signifi-
cant” (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 immunosuppres-
sion in the study was 39 (without HIV: 11!), with 6/8 studies de-
scribing less than 4 patients with different modalities of immu-
nosuppression.
Despite the large absence of data, numerous viewpoints and
guidelines have been published on how to manage immunosup-
pressed patients that may be more susceptible to acquire COVID-
19 infection and develop severe courses. There are recommenda-
tions for intranasal corticosteroids in allergic rhinitis (Bousquet
2020), immunosuppressants for psoriasis and other cutaneous
diseases (Conforti 2020, Torres 2020)), rheumatic diseases
(Favalli 2020, Figueroa-Parra 2020) or inflammatory bowel dis-
eases (Kennedy 2020, Pasha 2020). The bottom line of these hero-
ic 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 im-
portant.
Kamps – Hoffmann
Comorbidities | 297
However, two studies have indeed found evidence for deleterious

effects of glucocorticoids, indicating that these drugs should be
given with particular caution these days. The largest study pub-
lished to date, analysed 525 patients with inflammatory bowel
disease (IBD) from 33 countries (Brenner 2020). Thirty-seven
patients (7%) had severe COVID-19, and 16 patients died (3% case
fatality rate). Risk factors for severe COVID-19 among IBD pa-
i-
costeroids (adjusted odds ratio 6.9, 95% CI 2.3-20.5), and sulfasal-
azine or 5-aminosalicylate use (aOR 3.1, 95% CI 1.3-7.7). Notably,
TNF antagonist treatment was not associated with severe COVID-
19. Another larger case series looked at 86 patients with im-
mune-mediated inflammatory disease and symptomatic COVID-
19, among them 62 receiving biologics or Janus kinase (JAK) in-
hibitors (Haberman 2020). The percentage of patients who were
receiving biologics or JAK inhibitors at baseline was higher
among the ambulatory than among the hospitalized patients. In
contrast, hospitalization rates were higher in patients treated
with oral glucocorticoids, hydroxychloroquine and methotrex-
ate.
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Pasha SB, Fatima H, Ghouri YA. Management of Inflammatory Bowel Diseases
in the Wake of COVID-19 Pandemic. J Gastroenterol Hepatol. 2020 Apr 4.
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.
Transplantation
During a health crisis such as the COVID pandemic, it is crucial to
carefully balance cost and benefits in performing a transplanta-
tion (Andrea 2020). There is no doubt that the current situation
has deeply affected organ donation and that this represents an
important collateral damage of the pandemic. All Eurotransplant
countries have implemented preventive screenings policies for
potential organ donors. For detailed information on the national
policy, please visit
https://www.eurotransplant.org/2020/04/07/covid-19-and-
Kamps – Hoffmann
Comorbidities | 299
organ-donation/. Preliminary data indicate a significant reduc-

tion in transplantation 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 donor trans-
plantations 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 seen for heart, lung, and liver trans-
plants, 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 influ-
enza), due to their chronic immunosuppressive regimen, and
this may hold particularly true for SARS-CoV-2 infection. The
first larger cohort of COVID-19 in transplant recipients from the
US indeed indicated that transplant recipients appear to have
more severe outcomes (Pereira 2020). Of 90 patients (median age
of 57 years), 46 were kidney recipients, 17 lung, 13 liver, 9 heart
and 5 dual-organ transplants. Sixteen patients died (18% overall,
24% of hospitalized, 52% of ICU). It remains unclear whether
these high mortality and morbidity rates derived from reporting
or selection bias. However, a single center experience with 36
kidney transplant recipients found even higher rates. After 21
days, 10/36 had died (Akalin 2020). Patients appear to have less
fever as an initial symptom, lower CD3/4/8 cell counts and more
rapid clinical progression. In a case series of 28 patients who had
received heart transplant in a large academic center in New
York, 22 patients (79%) were hospitalized. At the end of the fol-
low-up, 4 remained hospitalized and 7 (25%) had died (Latif
2020).
Preliminary data from Switzerland, however, were more hopeful
(Tschopp 2020). Overall, 21 patients were included with a median

age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and

3 combined transplantations). Ninety-five percent and 24% of
patients required hospital and ICU admission, respectively. After
a median of 33 days of follow-up, 16 patients were discharged, 3
were still hospitalized and only 2 patients died.
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:
Andrea G, Daniele D, Barbara A, et al. Coronavirus Disease 2019 and Trans-
plantation: a view from the inside. Am J Transplant. 2020 Mar 17. Pub-
Med: https://pubmed.gov/32181969 . Fulltext:
https://doi.org/10.1111/ajt.15853
Latif F, Farr MA, Clerkin KJ, et al. Characteristics and Outcomes of Recipients
of Heart Transplant With Coronavirus Disease 2019. JAMA Cardiol. Pub-
lished online May 13, 2020. Full-text:
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during the COVID-19 pandemic. Lancet May 11, 2020. Full-text:
6736(20)31040-0/fulltext
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
https://doi.org/10.1111/ajt.15941
Tschopp J, L´Huillier AG, Mombelli M, et al. First experience of SARS-CoV-2
infections in solid organ transplant recipients in the Swiss Transplant
Cohort Study. Am J Transplant 2020 May 15. PubMed:
https://pubmed.gov/32412159. Full-text: https://doi.org/10.1111/ajt.16062
Other comorbidities
Ultimately, the current situation might lead to substantial
changes in how research and medicine are practiced in the fu-
ture. The SARS-CoV-2 pandemic has created major dilemmas in
almost all areas of health care. Scheduled operations, numerous
types of treatment and appointments have been cancelled world-
wide or postponed to prioritise hospital beds and care for those
Kamps – Hoffmann
Comorbidities | 301
who are seriously ill with COVID-19. Throughout the world,

health systems had to consider rapidly changing responses while
relying on inadequate information. 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 exacer-
bate this issue. During the next months, we will learn more and
provide more information on the consequences of this crisis on
various diseases. In the meantime, please refere to the key pa-
pers listed below.
Oncology
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 Ra-
diol). 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
Francesco C, Pettke A, Michele B, Fabio P, Helleday T. Managing COVID-19 in
the oncology clinic and avoiding the distraction effect. Ann Oncol. 2020
Mar 19. Fulltext: https://doi.org/10.1016/j.annonc.2020.03.286
Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on pa-
tients with cancer (CCC19): a cohort study. Lancet. 2020 May 28:S0140-
Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a
nationwide analysis in China. Lancet Oncol. 2020 Mar;21(3):335-337.
Fulltext: https://doi.org/10.1016/S1470-2045(20)30096-6
Paul S, Rausch CR, Jain N, et al. Treating Leukemia in the Time of COVID-19.
Acta Haematol. 2020 May 11:1-13. PubMed: https://pubmed.gov/32392559.
Full-text: https://doi.org/10.1159/000508199
The Lancet Oncology. COVID-19: global consequences for oncology. Lancet
Oncol. 2020 Apr;21(4):467. PubMed: https://pubmed.gov/32240603. Full-
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, Chi-
na: a multicentre, retrospective, cohort study. Lancet Oncol. 2020 May

29:S1470-2045(20)30309-0. PubMed: https://pubmed.gov/32479790. Full-

Ueda M, Martins R, Hendrie PC, et al. Managing Cancer Care During the
COVID-19 Pandemic: Agility and Collaboration Toward a Common
Goal. J Natl Compr Canc Netw. 2020 Mar 20:1-4. PubMed:
https://doi.org/10.6004/jnccn.2020.7560
Xia Y, Jin R, Zhao J, Li W, Shen H. Risk of COVID-19 for patients with cancer.
Lancet Oncol. 2020 Apr;21(4):e180. PubMed: https://pubmed.gov/32142622.
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 centres. Nephrol Dial Transplant. 2020 Mar
20. pii: 5810637. PubMed: https://pubmed.gov/32196116. Fulltext:
https://doi.org/10.1093/ndt/gfaa069
Xiong F, Tang H, Liu L, et al. Clinical Characteristics of and Medical Interventions
for COVID-19 in Hemodialysis Patients in Wuhan, China. J Am Soc Nephrol.
https://doi.org/10.1681/ASN.2020030354
Various
Dave M, Seoudi N, Coulthard P. Urgent dental care for patients during the
COVID-19 pandemic. Lancet. 2020 Apr 3. PubMed:
6736(20)30806-0
French JA, Brodie MJ, Caraballo R, et al. Keeping people with epilepsy safe
during the Covid-19 pandemic. Neurology. 2020 Apr 23. PubMed:
https://doi.org/10.1212/WNL.0000000000009632
Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ. 2020 Mar
27;368:m1185. PubMed: https://pubmed.gov/32220865. Fulltext:
Wang H, Li T, Barbarino P, et al. Dementia care during COVID-19. Lancet. 2020
Apr 11; 395(10231):1190-1191. PubMed: https://pubmed.gov/32240625 .
Yao H, Chen JH, Xu YF. Patients with mental health disorders in the COVID-19
epidemic. Lancet Psychiatry. 2020 Apr;7(4):e21. Full-text:
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Pediatrics | 303
11. Pediatrics
Tim Niehues
Jennifer Neubert
Acknowledgements: Without the skillful help of Andrea

Groth (Helios Klinikum Krefeld), the preparation of this
manuscript would not have been possible. We thank cand.
med. Lars Dinkelbach (Heinrich Heine Universität Düssel-
dorf) for critically reading the manuscript.
SARS-CoV-2 infection in children

Studies on the risk of acquiring SARS-CoV-2 infection in children
in comparison 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 under-
stood. Population based studies performed so far indicate that
children might not play a major factor in the spreading of
COVID-19 (Gudbjartsson 2020). Seropravalence studies are lack-
ing.
Children often have an asymptomatic or less severe COVID-19
disease course than adults (Zimmermann 2020, Parri 2020,
Ludvigsson 2020). In this regard COVID is strikingly different
from other virus-induced respiratory diseases, which can be fatal
(e.g. RSV in infants). The CoV-2 pandemic causes a large collat-
eral damage to children because they are taken out of their nor-
mal social environment (kindergartens, schools etc.), and be-
cause of parents anxiety to seek medical care despite need e.g.
for vaccination (Bramer 2020) or even if their children are hav-
ing an emergency (Lazzerini 2020).

Commonly circulating 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 coronavirus, HCoV2229E, was known to be asso-
ciated with the common cold (Weiss 2020). Commonly circulat-
ing human coronaviruses can be isolated from 4-8% of all chil-
dren with acute respiratory tract infections, which tend to be
mild, unless the child is immunocompromised (Ogimi 2019). Sev-
en coronaviruses circulate among humans: -Coronaviruses
HCoV2-229e, -HKU1; -Coronaviruses HCoV2-NL63, -OC43; MERS-
CoV, SARS-CoV and SARS-CoV-2 that have originally derived
from bats (NL63, 229e, SARS-CoV), dromedary camels (229e,
MERS-CoV), cattle (OC43), pangolins (SARS-CoV-2) (Zimmermann
2020). There appear to be re-infections with the earlier described
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 virus. There seems to be a cyclic
pattern with seasonal outbreaks between December and May or
March to November in the southern hemisphere.
A characteristic of the single-strand RNA coronaviruses is the
capability of rapid 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). Because 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-
Kamps – Hoffmann
Pediatrics | 305
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 chil-
dren were reported 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
r-
centage (15-62%) of hospitalization (CDC 2020). The Chinese CDC
report (Dong 2020) comprises 2,143 pediatric patients from Janu-
ary 16 to February 8 2020. Only 731 children (34.1%) were labora-
tory 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. One Chinese 10 month-old child who had been infected
with CoV-2 was reported to have died with intussuception and
multi-organ failure (Lu X 2020). 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 Dis-
ease 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 Span-
ish cohort from Madrid (2 March to 16 March) (Livingstone 2020,
Tagarro 2020).

The European Surveillance System (TESSy) collects data from

EU/EEA countries 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).
Natural course and risk factors for complica-

tions
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 P 2020, Parri
2020). Among a total of 100 children with SARS-CoV-2 from Italy,
21% were asymptomatic, 58% had mild disease, 19% had moder-
ate disease, 1% had severe disease, and 1% were in critical condi-
tion (Parri 2020).
At 10 days after onset of symptoms hyperinflammation may set
in and cause a more severe and potentially fatal disease, espe-
cially in high risk groups. The clinical manifestation is believed
to last for 1-2 weeks, longer in complicated cases. 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. chil-
dren with underlying chronic pulmonary or cardiac disease, se-
vere neurologic deficits, immunosuppressed or critically ill chil-
dren etc. Analogous to influenza there might be genetic suscep-
tibility in some children (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).
In the European surveillance System (TESSy) deaths among chil-
dren aged below 15 years are rare, 4 out of 44,695 (0.009%) were
reported in the TESSy. The rate of hospitalization was higher in
Kamps – Hoffmann
Pediatrics | 307
children under the age of five especially in infants compared to

persons aged 5-29. It is believed that the threshold for admission
is lower in young children. A severe course requiring admission
to ICU was not more likely in the younger children. The likeli-
hood of being hospitalised was higher when children had an un-
derlying condition, 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 preexisting comorbidities 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 Wash-
ington, 44 were hospitalized and 9 were critically ill. Of these,
6/9 were adolescents and young adults > 15 years of age. Alt-
hough asthma was the most prevalent underlying condition
overall, it was not more common among patients with severe
disease (DeBiasi 2020).
As of 11 May, 74 centers in Germany reported 137 pediatric hos-
pital admissions, 15% were admitted to the ICU. 55.6% of the pa-
tients admitted to the ICU had an underlying disease, mostly
pulmonary or cardiac diseases (www.dgpi.de).

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 angio-
tensin converting enzyme (ACE2) and the transmembrane serine
protease TMPRSS2 (essential for CoV-2 cell entry) as well as the
tissue tropism of CoV-2 in childhood are unknown. ACE2 is ex-
pressed on cells of the airways, the lungs, mucosal cells (lids,
eyelids, nasal cavities), intestines and on immune cells (mono-
cytes, lymphocytes, neutrophils) (Molloy 2020, reviewed in Bro-
din 2020). It needs to be clarified whether there is neurotropism
(e.g. affecting the developing brain of newborns).
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 respirato-
ry 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 pneumo-
nia is the macrophage activation syndrome (MAS)-like hyperin-
flammatory phase with a cytokine storm and acute respiratory
distress syndrome ARDS, usually within 10-12 days after symp-
tom onset. In general, children are not less prone to develop
ARDS during respiratory tract infections than adults. In the
H1N1 flu pandemic in 2009, being under the age of 1 year was a
significant risk factor for developing a severe form of the infec-
tion and ARDS (Bautista 2010). Why ARDS is less common in chil-
dren compared to adults with COVID-19 is unclear.
Regarding childhood immunity, an explanation for the milder
disease course in children could be age-related differences in
immune responses to CoV-2 between adults and children. To
Kamps – Hoffmann
Pediatrics | 309
what extent previous infections with non-SARS coronaviruses

may have led to protective cross-reactive antibodies is unclear.
In the innate immune response damaged lung cells induce in-
flammation by macrophages and granulocytes. Based on influen-
za animal models it has been proposed that BCG vaccination (for
tuberculosis prevention, done in the first week of life in some
countries) may enhance non-specific innate immunity in chil-
dren 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 com-
pared to countries with universal and long-standing BCG policies
and that BCG vaccination also reduced the number of reported
COVID-19 cases in a country (Miller 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-
vaccinated. Data on the effect of BCG vaccination on COVID-19
disease severity are unavailable (Hamiel 2020).
In the adaptive response 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 cyto-
toxic effector function of CD8 T cells in viral infection in children
may be less detrimental compared to adults. Immune dysregula-
tion 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 an-
tibodies, if the mother is naïve to CoV-2 or infected late in preg-
nancy. In mothers with COVID-19 pneumonia serum and throat
swabs of their newborns were negative for CoV-2 but virus-
specific IgG antibodies were detected (Zeng H 2020). Thus, neo-

nates 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 neutralizing IgM (within
days) and IgG antibodies (within 1-3 weeks) to one of the immu-
nodominant epitopes, e.g. the crown-like spike proteins giving
the coronaviruses their name.
Data regarding IgG and IgM seroprevalence and quality of the
immune response in children are lacking. No human reinfections
with CoV-2 have been demonstrated yet but overall it is not clear
whether children mount a durable memory immune response to
CoV-2.
Transmission
Contraction of COVID-19 in a pregnant woman may have an im-
pact on fetal outcome, namely fetal distress, potential preterm
birth or respiratory distress if the mother gets very sick. As of
yet there is no evidence that SARS-CoV-2 can be transmitted
vertically from mother to child. Amniotic fluid, cord blood, neo-
natal throat swabs all tested negative in a small cohort (Chen
2020). 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). Transmission by breastfeeding has not yet been
reported and there are no case reports of detection of CoV-2 in
breast milk.
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 transmis-
sion seems to be uncommon (Danis 2019). Prolonged exposure to
high concentrations of aerosols may facilitate transmission (She
2020).
Kamps – Hoffmann
Pediatrics | 311
SARS-CoV-2 may 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 fe-
ces 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.
Diagnosis and classification

Testing for the virus is only necessary in clinically suspect chil-
dren. 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 possible
in critically ill patients and in young children.
Diagnosis is usually made by real-time polymerase chain reac-
tion RT-PCR on respiratory secretions. For SARS-CoV, MERS-CoV
and SARS-CoV-2, higher viral loads have been detected in sam-
ples from lower respiratory tract compared with upper respira-
tory tract.
In some patients, SARS-CoV-2 RNA is negative in respiratory
samples while stool samples are still positive indicating that the
viral gastrointestinal infection 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 deter-
mined). Interestingly, asymptomatic seroconversion has been
hypothesized in a very small series of health workers (mean age

40 years) exposed to a child with COVID-19 in a pediatric dialysis

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 inflammatory multisystem syndrome temporarily
associated with SARS-CoV-2 (PIMS-TS). In case serology indicates
protective immunity, this will be extremely important from a
public health perspective, e.g. it will allow for strategic staffing
in medical care and for the assessment of CoV-2 epidemiology
(herd immunity).
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 hos-
pital the white blood cell count is usually normal. In a minority
of children decreased lymphocyte counts have been document-
ed. In contrast, adults (with hyperinflammation and cytokine
release syndrome) often have an increase in neutrophils and
lymphopenia. The inflammation parameters C-reactive protein
and procalcitonin can be slightly elevated or normal while there
are elevated liver enzymes, creatine kinase CK-MB and D-dimers
Kamps – Hoffmann
Pediatrics | 313
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 ex-
posure for the child and should only be done in complicated or
high-risk cases. In the beginning of the pandemic in China, chil-
dren all received CT scans even when they were asymptomatic
and oligosymptomatic; surprisingly, they displayed very severe
changes. On chest radiography there are bilateral patchy air-
space consolidations and so-called ground-glass opacities. CT
scans were more impressive 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
The clinical presentation of the disease appears somewhat simi-
lar to influenza. In the largest 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 only in less than 10% of the children (Lu
2020). In the case series 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).
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 radiolog-
ical signs of pneumonia. In one child disseminated intravascular

coagulation was described but eventually all children had stable

vital signs three weeks after the infection when the report was
published (26 March 2020) (Zeng L 020). In a second cohort, 9
infants aged 1 month to 9 months were described without any
severe complications (Wei 2020). Whether there may be compli-
cations of COVID-19 in newborns and infants long-term cannot
be judged at this stage of the pandemic. At present it is not rec-
ommended to separate healthy newborns from mothers with
suspicion of COVID-19 (CDC-2 2020). Clearly a preterm or new-
born that has been exposed to CoV-2 needs to be closely moni-
tored by the hospital and/or the primary care pediatrician. If
there are signs of COVID (e.g. poor feeding, unstable tempera-
ture, 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 a strict hygiene as much as possible in this mother-
child setting.
Pediatric inflammatory multisystem syndrome temporarily

associated with SARS-CoV-2 (PIMS-TS) (or synonym Multi-
system Inflammatory Syndrome in Children (MIS-C) or Ka-
wasaki-like 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 had not. Prior to this, Jones had de-
scribed the case of a six-month-old baby girl with fever, rash and
swelling characteristic of a rare pediatric inflammatory condi-
tion, Kawasaki syndrome (Jones 2020).
Eight patients from the UK and 10 patients from Bergamo in Italy
with features of Kawasaki disease have been published including
one death in a 14-year-old boy in the UK during the SARS-CoV-2
epidemic (Riphagen 2020, Verdoni 2020). In Bergamo, the region
Kamps – Hoffmann
Pediatrics | 315
with the highest infection rate in Italy, a 30-fold increased inci-

dence of Kawasaki disease has been reported following the SARS-
CoV-2 epidemic (Verdoni 2020).
Currently, the pathophysiological overlap between COVID-19
associated inflammation and Kawasaki disease is not yet clear,
their features are summarized in Table 2. asdf
Table 2. Features of Kawasaki Disease and pediatric inflammatory

multisystem syndrome temporarily associated with SARS-CoV-2
Kawasaki (Hedrich 2017, PIMS-TS (pediatric inflammatory

ECDC 2020) (previously multisystem syndrome
called mucocutaneous lymph temporarily associated with
-node syndrome) SARS-CoV-2 or MIS-C
(multisystem inflammatory
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
(EU, US), in north-east Asia
temporally associated with
higher; seasonal increase in
COVID-19 reported to ECDC
winter/spring, geographic
by May 15th (EU/EEA, UK).
wave-like spread of illness
More common in afro-
during epidemics (Rowley
caribbean descent, obesity?
2018)
(Riphagen 2020)
Age, sex >90% < 5 years of age, more 5-15 years of age, sex
males distribution unclear


Etiology Unknown, hypothesis: Unknown, no working

infection with common hypothesis yet.
pathogens, e.g. bacteria, Hyperinflammation/shock
fungi and viruses which associates with immune
cause immune-mediated response to SARS-CoV-2. In
damage (Dietz 2017) CoV-1 antibody-dependent
(Jordan-Villegas 2010, Kim enhancement (ADE):
2012, Turnier 2015). Genetic presence of antibodies can be
factors (increased frequency detrimental, enable the virus
in Asia and among family to spread (demonstrated in
members of an index case) SARS-CoV)
Case definition 1. Persistent fever, inflammation

with at least 4 of the 5 (neutrophilia, elevated CRP and
following items lymphopenia) and single or multi-
organ dysfunction (shock,
1.Bilateral bulbar
cardiac, respiratory, renal,
conjunctival injection
gastrointestinal or neurological
2. Oral mucous membrane disorder) with other additional
changes, including injected clinical, laboratory or imagining
or fissured lips, injected and ECG features. Children
pharynx, or strawberry fulfilling full or partial criteria for
tongue Kawasaki disease may be
included
3. Peripheral extremity
changes, including erythema 2. Exclusion of any other
of palms or soles, edema of microbial cause, including
hands or feet (acute phase) bacterial sepsis, staphylococcal
or periungual desquamation or streptococcal shock
(convalescent phase) syndromes, infections associated
with myocarditis such as
4. Polymorphous rash enterovirus
5. Cervical lymphadenopathy
3. SARS-CoV-2 PCR testing
(McCrindle 2017) positive or negative. (Royal
College of Paediatrics and Child
Health)
Children suspected of having
KD who do not fulfill
diagnostic criteria may have
incomplete or atypical KD
(Cimaz 2009)
Kamps – Hoffmann
Pediatrics | 317

CoV-2 status CoV-2 Ag (PCR); Abs (Elisa) CoV-2 Ag (PCR) negative and
in most cases negative Abs (Elisa) positive
Typical Lab Marked Elevation of acute- Marked elevation of acute phase

phase reactants (eg, C- reactants 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

Complications syndrome (KSSS) (rare), macrophage activation syndrome
features of macrophage (common), myocardial
activation syndrom, MAS involvement evidenced by
(rare), coronary artery markedly elevated cardiac
abnormalities, mitral enzymes (common), myocardial
regurgitation, prolonged infarction, aneurysms,
myocardial dysfunction, disseminated intravascular
disseminated intravascular coagulation
coagulation (Kanegaye
Gastrointestinal complications
2009)
(Ileitis, vomiting, abdominal pain)
Gastrointestinal are very common
complications (Ileitis,
vomiting, abdominal pain)
rare
Long term Artery abnormalities Unknown; aneurysms?

Complications (aneurysms of mid-sized
arteries, giant coronary
artery aneurysms CAAs)


Management High-dose intravenous So far, most patients published

immunoglobulin (IVIG) were treated with high dose IVIG,
(2g/kg) first-line treatment; glucocorticoids, ASS (Verdoni
effective in reducing the risk 2020, Riphagen 2020)
of coronary artery disease
IVIG resistance requiring
when administered within 10
adjunctive steroid treatment is
days of onset of fever. In
common (Verdoni 2020,)
addition, acetylsalicylic acid,
glucocorticoids and anti-TNF Management on the pediatric
monoclonal antibodies have intensive care unit is often
been used necessary: progression to
vasoplegic shock is common
Hemodynamic support,
treatment with 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
in particular aneurysms, can cases
occur in up to 25% of
children
Management
Infection control
Early identification of COVID-19 and quarantine of contacts is
imperative. In the in- and out-patient setting it is advised to sep-
arate children who have infectious diseases from healthy non-
infectious children. Nosocomial outbreaks have played a role in
the clustering of COVID-19. Thus it is advised to admit children
with COVID-19 to the hospital only if an experienced pediatri-
cian feels it is medically necessary (e.g. tachypnea, dyspnea, ox-
ygen levels below 92%). In the hospital the child with COVID-19
Kamps – Hoffmann
Pediatrics | 319
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 maintains distance as well (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 reasons as well as for
help in nursing of the child.
During the peak phase of the COVID-19 epidemic, precautions in
the outpatient and hospital setting include entrance control,
strict hand and respiratory hygiene, daily cleaning and disinfec-
tion 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 inten-
sive care units (NICU), negative pressure rooms and filtering of
exhaust would be ideal (Lu Q 2020). Respirators with closed cir-
cuit and filter systems should be used. Aerosol generating proce-
dures, e.g. intubation, bronchoscopy, humidified inhala-
tions/nebulization should be avoided as much as possible.
Supportive treatment (respiratory support, bron-

chodilatation therapy, fever, superinfection, psy-
chosocial 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 cannula will be important to children as it
will increase lung ventilation and perfusion. In neonates, high
flow nasal cannula (HFNC) has been utilized widely due to its
superiority over other non-invasive respiratory support tech-
niques.
The clinical use and safety of inhaling different substances in
COVID-19 is unclear. In other common obstructive and infectious
childhood lung diseases, e.g. in bronchiolitis, the American
Academy of Pediatrics is now recommending against the use of

bronchodilators (Dunn 2020). Regarding the inhalation of ster-

oids 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 af-
fected by high-degree fever, 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 paracetamol
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 according 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 medication to treat COVID-19. The drugs
Kamps – Hoffmann
Pediatrics | 321
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 wheth-
er to try a drug or not. If initiation of a drug treatment is decid-
ed, children should be included into clinical trials
(https://www.clinicaltrialsregister.eu) if anyhow possible. How-
ever, there are only very few, if any, studies open for recruit-
ment in children.
When to treat with drugs

Under the lead of the German Society for Pediatric Infectiology
(DGPI) an expert panel has proposed a consensus on when to
start antiviral or immunomodulatory treatment in children (Ta-
ble 3, https://dgpi.de/stellungnahme-medikamentoese-
behandlung-von-kindern-mit-covid-19/).
A panel of pediatric infectious diseases physicians and pharma-
cists from North American institutions published an initial guid-
ance on use of antivirals for children with SARS. It is advised to
limit antiviral therapy to children in whom the possibility for
benefit outweighs risk of toxicity and remdesvir is the preferred
agent (Chiotos 2020).
Inhibitors of viral RNA synthesis

Remdesivir (GS-5734) 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
Remdesivir is an adenosine nucleotide analogue with broad-

spectrum antiviral activity against various RNA viruses. The
compound undergoes a metabolic mechanism, activating nucleo-
side triphosphate metabolites for inhibiting viral RNA polymer-

ases. Remdesivir has demonstrated in vitro and in vivo activity in

animal models against MERS and SARS-CoV. Remdesivir showed
good tolerability and a potential positive effect in regard to de-
crease of the viral load and mortality in Ebola in Congo in 2018
(Mulangu 2019). In Europe this drug has rarely been used in chil-
dren 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 No need for antiviral or
infection, no need for oxygen immunomodulatory treatment
More severe disease and risk Treat symptomatically

groups* consider antiviral therapy
pCAP, need for oxygen
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 en-
hancer (booster). LPV/r is an HIV-1 protease inhibitor success-
fully used in HIV-infected children as part of highly active an-
tiretroviral combination therapy (PENTA Group, 2015). In the
SARS epidemics, LPV/r had been recommended as a treatment. A
recent study in adult COVID-19 patients did not show an effect
Kamps – Hoffmann
Pediatrics | 323
regarding the primary end point in a controlled clinical trial.

Despite the fact that there is a large experience with LPV/r in
HIV, it is not advised to use it in children with COVID-19 as it
does not appear to be effective at all (see Treatment chapter,
page 233).
Inhibitors of viral entry

Hydroxychloroquine (HCQ, Quensyl®), Chloroquine (CQ, Reso-
chin junior®, Resochin®) The experience among pediatricians
with HCQ/CQ (except pediatriciancs 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 chapter Treatment, page 233).
Immunomodulatory drug treatment

The rational for immunomodulation in COVID-19 patients comes
from a high expression of pro-inflammatory cytokines (Interleu-
kin-1 (IL1) and interleukin-6 (IL6)), chemokines (“cytokine
storm”) and the consumption of regulatory T cells resulting in
damage of the lung tissue as reported in patients with a poor
outcome. Blocking IL-1 or IL-6 can be successful in children
with (auto) inflammatory disease (reviewed in Niehues 2019).
However, both interleukins are also key to the physiological im-
mune response and severe side effects of immunomodulators
have been reported. In adults with COVID-19, blocking interleu-
kin-1/6 might be helpful (see the Treatment chapter). In the rare
situation that the condition of the child deteriorates due to hy-
perinflammation and that they are resistant to other therapies,
tocilizumab or anakinra may be an option.
Steroids (e.g. prednisone, prednisolone) are available as oral
solution, tablets or different vials for intravenous application.

Dosage in children is 0.5 to 1 mg/kg i.v. or oral BID. Short term

use of steroids has few adverse events. Administration of ster-
oids will affect inflammation by inhibiting the transcription of
some of the pro-inflammatory cytokines and various other ef-
fects. The use of corticosteroids in children and adults with CoV-
induced ARDS is controversial (Lee 2004, Arabi 2018, Russell
2020). The corticosteroid-induced decrease of antiviral immunity
(e.g. to eliminate CoV-2 viruses) might be disadvantageous in
patients with COVID-19. The use of low-dose hydrocortisone may
be of advantage in adults with ARDS, whereas its use is contro-
versial in pediatric ARDS. Most patients with pediatric inflamma-
tory 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 common, requiring adjunctive steroid treatment
(Verdoni 2020).
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
Adverse events (deriving largely from long term use in chronic

inflammatory diseases and use in combination with other im-
munomodulatory drugs): severe bacterial or opportunistic infec-
tions, immune dysregulation (anaphylactic reaction, fatal mac-
rophage activation), psoriasis, vasculitis, pneumothorax, fatal
pulmonary hypertension, heart failure, gastrointestinal bleed-
ing, 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 s.c. QD daily as long as hyperinflam-
mation persists. Thereafter, dose reduction by 10-30% per day.
Kamps – Hoffmann
Pediatrics | 325
Adverse events (deriving largely from long-term use in chronic

inflammatory diseases and use in combination with other im-
munomodulatory drugs): severe bacterial or opportunistic Infec-
tions, fatal myocarditis, immune dysregulation, pneumonitis,
colitis, hepatitis, endocrinopathies, nephritis, dermatitis, en-
cephalitis, psoriasis, vitiligo, neutropenia (reviewed in Niehues
2019).
Immunotherapy
Engineering monoclonal antibodies against the CoV spike pro-
teins or against its receptor ACE2 or specific neutralizing anti-
bodies against CoV-2 present in convalescent plasma may pro-
vide protection but are not generally available yet.
Interferon has been inhaled by children with COVID-19 in the
original cohorts but there are no data on its effect (Qiu 2020).
Type-1 interferons (e.g. interferon-a) are central to antiviral
immunity. When coronaviruses (or other viruses) invade the
host, viral nucleic acid activates interferon-regulating factors
like IRF3 and IRF7 which promote the synthesis of type I inter-
ferons (IFNs).
PIMS / MIS-C / Kawasaki-like disease

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 de-
termine the optimal treatment strategies for patients with MIS-
C.
DOI: Tim Niehues has received authorship fees from uptodate.com (Wellesley, Massa-
chusetts, 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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Timeline | 333
12. Timeline
Sunday, 1 December
According to a retrospective study published in The Lancet on 24
January 20202, the earliest laboratory confirmed case of COVID-
19 in Wuhan was in a man whose symptoms began on 1 Decem-
ber 2019. No epidemiological link could be found with other ear-
ly cases. None of his family became ill.
Thursday, 12 December
In Wuhan, health officials start investigating a cluster of pa-
tients with viral pneumonia. They eventually find that most pa-
tients 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
ophthalmologist 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 patients have symptoms
similar to SARS and are in quarantine. Li askes his friends to in-
form their families and advises his colleagues to wear protective
equipment.
2
Huang, Chaolin et al., Clinical features of patients infected with
2019 novel coronavirus in Wuhan, China January 24, 2020
6736(20)30183-5/fulltext#%20

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 December).
The Wuhan Municipal Health Commission reports 27 patients
with viral pneumonia and a history of exposure to the Huanan
Seafood Wholesale Market. Seven patients are critically ill. The
clinical manifestations of the cases were mainly fever, a few pa-
tients had difficulty breathing, and chest radiographs showed
bilateral lung infiltrative lesions. The report says that the
“disease is preventable and controllable”. WHO is informed
about the outbreak.
Thursday, 1 January
The Huanan Seafood Wholesale Market is shut down.
Friday, 3 January
While examining bronchoalveolar lavage fluid collected from
hospital patients between 24 and 29 December, Chinese scientists
at the National Institute of Viral Disease Control and Prevention
ruled out the infection with 26 common respiratory viruses,
determined the genetic sequence of a novel -genus corona-
viruses (naming it '2019-nCoV') and identified three distinct
strains.3
Li Wenliang is summoned to a local public security office in Wu-
han for “spreading false rumours”. He is forced to sign a docu-
3
Notes from the Field: An Outbreak of NCIP (2019-nCoV) Infec-
tion in China —
Weekly, 2020, 2(5): 79-80
http://weekly.chinacdc.cn/en/article/id/e3c63ca9-dedb-4fb6-
9c1c-d057adb77b57
Kamps – Hoffmann
Timeline | 335
ment where he admits having made “false comments” and “dis-

rupted social order.” Li signs a statement 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 negative impact on society”. The following
day, the information is taken up by CCTV, the state television.
CCTV does not specify that the eight people accused of “spread-
ing false rumors” are doctors.
Sunday, 5 January
WHO issues an alert that 44 patients with pneumonia of un-
known etiology have been reported by the national authorities
in China. Of the 44 cases reported, 11 are severely ill while the
remaining 33 patients are in stable condition.
https://www.who.int/csr/don/05-january-2020-pneumonia-of-
unkown-cause-china/en/
Tuesday, 7 January
Chinese officials announce that they have identified a new coro-
navirus (CoV) from patients in Wuhan (pre-published 17 days
later: https://doi.org/10.1056/NEJMoa2001017). Coronaviruses
are a group of viruses that cause diseases in mammals and birds.
In humans, the most common coronaviruses (HCoV-229E, -NL63,
-OC43, and -HKU1) continuously circulate in the human popula-
tion; 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 Viro-
logical.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 contracted the coronavirus
and were admitted to the hospital with him. Wenliang tested
negative several times until finally testing positive for the coro-
navirus on 30 January 2020.
Sunday, 12 January
Using the genetic sequence of the new coronavirus made availa-
ble 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, Malay-
sia, Singapore, South Korea, Vietnam, Taiwan, and South Korea
report cases over the following 10 days.
Tuesday, 14 January
WHO tweeted that “preliminary investigations conducted by the
Chinese authorities have found no clear evidence of human-to-
human transmission of the novel coronavirus (2019-nCoV) iden-
tified in Wuhan, China”. On the same day, WHO’s Maria Van
Kerkhove said that there had been “limited human-to-human
Kamps – Hoffmann
Timeline | 337
transmission” of the coronavirus, mainly small clusters in fami-

lies, adding that “it is very clear right now that we have no sus-
tained human-to-human transmission”4
Saturday, 18 January
The Medical Literature Guide Amedeo (www.amedeo.com) draws
the attention of 50,000+ subscribers to a study from Imperial Col-
lege London, Estimating the potential total number of novel Corona-
virus cases in Wuhan City, China, by Imai et al. The authors esti-
mate 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, Shang-
hai and Shenzhen). Asian countries begin to introduce mandato-
ry screenings at airports of all arrivals from high-risk areas of
China.
After two medical staff were infected in Guangdong, the investi-
gation team from China's National Health Commission confirmed
for the first time that the coronavirus can be transmitted be-
tween humans. 5
4 WHO says new China coronavirus could spread, warns hospitals worldwide".
Reuters. 14 January 2020.
5 https://www.theguardian.com/world/2020/jan/20/coronavirus-spreads-to-
beijing-as-china-confirms-new-cases

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.6
Thursday, 23 January
In a bold and unprecedented move, the Chinese government puts
tens of millions of people in quarantine. Nothing comparable
has ever been done in human history. Nobody knows how effi-
cient 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 preliminary 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 decided that it was still too early to declare a Public
Health Emergency of International Concern (PHEIC) and agreed
to reconvene in approximately ten days’ time. 7
A scientific preprint from the Wuhan institute of Virology, later
published in Nature, announced that a bat virus with 96% similar-
ity had been sequenced in a Yunnan cave in 2013. The sequence
6 https://www.who.int/china/news/detail/22-01-2020-field-visit-wuhan-china-
jan-2020
7
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)
Kamps – Hoffmann
Timeline | 339
is posted the next day on public databases.8 It is confirmed that

the novel coronavirus uses this same entry receptor as SARS-
CoV.
Friday, 24 January
At least 830 cases have been diagnosed in nine countries: China,
Japan, Thailand, South Korea, Singapore, Vietnam, Taiwan, Ne-
pal, and the United States.
The first confirmed evidence of human-to-human transmission
outside of China was documented by the WHO in Vietnam.9
France reported its first three confirmed imported cases, the
first occurrences in the EU.10
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:
https://doi.org/10.1056/NEJMoa2001017). They describe sensi-
tive 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 fore-
warning signs during the incubation period and suggested a
“pandemic potential” for the new virus.
8 Zhou, Peng et al. "A pneumonia outbreak associated with a new coronavirus of
probable bat origin". Nature. 579 (7798): 270–273
9 "Novel Coronavirus (2019-nCoV) SITUATION REPORT - 4" WHO 24 January
2020.
10 "Coronavirus : un troisième cas d'infection confirmé en France". Le Monde.fr
(in French). 24 January 2020.

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 re-
ported. The source of infection was an individual from Shanghai
visiting a company in Bavaria11. She developed 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. Au-
thors state that “The fact that asymptomatic persons are poten-
tial sources of 2019-nCoV infection may warrant a reassessment
of transmission dynamics of the current outbreak.”12
11
Böhmer MM, Buchholz U, Cormann VM: Investigation of a COVID-19 out-
break 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
12
Kamps – Hoffmann
Timeline | 341
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 con-
trol. The WHO delegation highly appreciated the actions China
has implemented in response to the outbreak, its speed in identi-
fying the virus and openness to sharing information with WHO
and other countries.13
Thursday, 30 January
On the advice of the IHR Emergency Committee, WHO DG de-
clared a Public Health Emergency of International Concern and
advised “all countries should be prepared for containment, in-
cluding 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 transmis-
sion in 3 countries.
China reports 7,711 cases and 170 deaths. The virus has now
spread to all Chinese provinces.
Giuseppe Conte, Italy’s Prime Minister, confirms the first two
COVID-19 imported cases in Italy.
Friday, 31 January
Li Wenliang publishes his experience with Wuhan police station
(see 3 January) with the letter of admonition on social media. His
post goes viral.
13
https://www.who.int/news-room/detail/28-01-2020-who-
china-leaders-discuss-next-steps-in-battle-against-coronavirus-
outbreak

India, the Philippines, Russia, Spain, Sweden, the United King-

dom, 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 coronavirus, 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.
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 cha-
let in Contamines-Montjoie, in Haute-Savoie. He tested positive
upon return to England. Four contacts in the same chalet tested
positive, 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.
Kamps – Hoffmann
Timeline | 343
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 Yoko-
hama, Japan, 175 people are infected with the virus. Over the
following days and weeks, almost 700 people will be infected
onboard.
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 dou-
bled to 242. WHO indicated that for consistency it would report
only the number of laboratory-confirmed cases.14
14
https://www.who.int/docs/default-
source/coronaviruse/situation-reports/20200213-sitrep-24-
covid-19.pdf

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 innumerable bars
have been considered by some observers as a coronavirus ‘bio-
logical bomb’.
A patient in his 30s tested positive for SARS-CoV-2 and was ad-
mitted to the intensive care unit (ICU) in Codogno Hospital (Lo-
di, Lombardy, Italy). The symptomatic patient had visited the
hospital the day before but was not tested 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 corona-
virus infection, raising concerns about a potential “super
spreader” who has already infected 14 people in a church in the
south-eastern city of Daegu.
Kamps – Hoffmann
Timeline | 345
Sunday, 23 February
Italy confirms 73 new cases, bringing the total to 152, and a third
death, making 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 municipal 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.
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 sev-
eral 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 declined steadily
thereafter (Table 1).
https://www.who.int/publications-detail/report-of-the-who-
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 follow-
ing the Chinese example.

Figure 1. COVID-19 cases in China, January/February 2020. Epidemic

curves by symptom onset and date of report on 20 February 2020 for labora-
tory confirmed COVID-19 cases for all of China. Modified from Report of the
WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 16-24
February 2020. https://www.who.int/publications-detail/report-of-the-who-
A president, fearing for his chances to be re-elected, downplays
the threat from the coronavirus pandemic, twittering: “Low Rat-
ings Fake News...are doing everything possible to make the Ca-
ronavirus [sic] look as bad as possible, including panicking mar-
kets, if possible.”
Two days later, the same individual invokes magic: “It’s going to
disappear. One day, it’s like a miracle, it will disappear.”
P.S. On 28 March, The Guardian would ask why
this person failed the biggest test of his life.
Kamps – Hoffmann
Timeline | 347
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 credit 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
entire country of 60 million people, declaring the Italian territo-
ry 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 CoronaVirus, with 22 deaths.
Think about that!” (The Guardian)

Iran releases 70,000 prisoners because of the corona-

virus outbreak in the country.
Tuesday, 10 March
Xi Jinping tours the city of Wuhan and claims a provisional vic-
tory 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 pan-
demic.
All schools in and around Madrid, from kindergartens to univer-
sities, 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 municipalities are quarantined for at least 14 days. This is
the first time Spain adopts measures of isolation for entire mu-
nicipalities.
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.
Kamps – Hoffmann
Timeline | 349
Friday, 13 March
The prime minister of an ex-EU country introduces the notion
of ‘herd immunity’ 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 col-
lective 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, going to hospital, going to work or other
emergencies.
The French government announces the closure of all “non-
essential” public places (bars, restaurants, cafes, cinemas, night-
clubs) after midnight. Only food stores, pharmacies, banks, to-
bacconists, and petrol stations may remain open.
Sunday, 15 March
France calls 47 million voters to the poll. Both government and
opposition leaders seem to be in favor of maintaining the munic-
ipal elections. Is this a textbook example of unacceptable inter-
ference of party politics with the sound management of a deadly
epidemic? Future historians will have to investigate.

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 in-
dividual 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 Americans 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 supres-
sion. 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 virus. 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, restaurants (for takeout
and delivery only), hospitals, gas stations, banks.
Kamps – Hoffmann
Timeline | 351
Thursday, 19 March
For the first time since the beginning of the coronavirus out-
break, there have been no new cases in Wuhan and in the Hubei
province.
Californian Governor Gavin Newsom orders the entire popula-
tion of California (40 million people) to “stay at home”. Resi-
dents can only leave their homes to meet basic needs like buying
food, going to the pharmacy or to the doctor, visiting relatives,
exercising.
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 consecu-
tive days. Restrictions are eased, normal life resumes. The en-
tire 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 es-
sential businesses (grocers, restaurants 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 maña-
na (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 con-
tainment 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 peo-
ple are now in lockdown.
Wednesday, 25 March
After weeks of stringent containment measures, Chinese author-
ities 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
America First: the US is now the country with most known coro-
navirus cases in the world.
For fear of reactivating the epidemic, China bans most foreigners
from entering the country.
Kamps – Hoffmann
Timeline | 353
Friday, 27 March
The Prime Minister and the Ministre of Health of an ex-EU coun-
try tests positive 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). Ger-
many, Austria, Denmark and Norway would have the lowest in-
fection 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 lead-
ers to consider legislation giving them extraordinary powers. In
one case, a law was passed extending a state of emergency indef-
initely.
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, rec-

ommending that he be given permission to evacuate all non-
essential sailors, to quarantine known COVID-19 cases, and sani-
tize 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 generates several headlines. Three days later, 2 April,
Captain Crozier is sacked.
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.
Wednesday, 1 April
The United Nations chief warns that the coronavirus pandem-
ic 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 governments 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
Kamps – Hoffmann
Timeline | 355
predicts that “after two months, 90% of blondes will have disap-
peared 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 epidem-
ic 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.
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
Lombardy decides that as of Sunday 5 April, people must wear

masks or scarves. Supermarkets must provide gloves and hy-
droalcoholic 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.
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 retrospec-
tive analysis of the current lockdown reveal fewer cases of asth-
ma, 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: “Corona-
virus: 100 days that changed the world.”
Kamps – Hoffmann
Timeline | 357
Thursday, 9 April
EU finance ministers agree to a common emergency plan to limit
the impact of the coronavirus pandemic on the European econ-
omy. 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 cur-
rent interruption of global air travel shape our future travel be-
haviors?
The epidemic is devastating the US economy. More than 16 mil-
lion 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 an-
nounce 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 contact-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?

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, Etablissement d’Hébergement pour Personnes Agées Dépen-
dantes) in the greater Paris region (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
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 before.
Kamps – Hoffmann
Timeline | 359
Figure 4. Daily number of COVID-19 deaths in Italy (red) and Spain (blue).
The United Kingdom records its highest daily death toll of al-
most 1,000. The number of reported COVID-19-linked fatalities
now exceeds 10,000. As in many other countries, the true num-
bers may be slightly higher due to underreporting of people dy-
ing 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, isola-
tionism and short-term vision in the face of the greatest health
challenge in recent decades. The culprit?
Emmanuel Macron announces announces a month-long exten-
sion to France’s lockdown. Only on Monday, May 11, nurseries,

primary and high schools would gradually reopen, but not high-
er education. Cafés, restaurants, hotels, cinemas and other lei-
sure 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 cen-
ters (regardless of size) as well as smaller dealers with a custom-
er 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 reo-
pen (see also the April 3 entry, page 354).
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.
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 eco-
nomic downturn since the Great Depression 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 activi-
Kamps – Hoffmann
Timeline | 361
ty 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) re-
ports 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
65 years.
Wednesday, 15 April
Philip Anfinrud and Valentyn Stadnytsky from the National In-
stitutes of Health, Bethesda, report a laser light-scattering ex-
periment in which speech-generated droplets and their trajecto-
ries 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 mes-
sage for billions of people caught in the COVID-19 epidemic: low-
er your voice!
Friday, 17 April
Luiz Inácio Lula da Silva, the former Brazilian president says
that the current president is leading Brazil to “the slaughter-
house” with his irresponsible handling of coronavirus. In an in-
terview with The Guardian, Lula says that Brazil’s “troglodyte”
leader risks repeating the devastating scenes playing out in Ec-
uador 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%) 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 seriously.”
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 anoth-
er 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).
Kamps – Hoffmann
Timeline | 363
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 benchmark price for US oil, drops below $0. On certain spe-
cific contracts, it plunged down to minus 37 US dollars (-34 eu-
ros). After nearly two months of continuous 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 con-
tinue 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, col-
loquially 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 wood-
en 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 symptoms are no longer examined. Screening examina-
tions for breast and uterine cancer of over 200,000 women per
week have been cancelled. According to The British Heart Foun-
dation, 50 percent fewer people suspected of having a heart at-
tack 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 diseas-
es?
Thursday, 23 April
Pandemic hilarity, as a president known for his poor science rec-
ord 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 (fever, diarrhea,
delirium and loss of taste and smell)15. It is as yet unclear wheth-
er and to what extent reported deaths of identical twins can be
attributed to genetic factors.
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 Guardi-
an. The blood-based test would be able to detect the virus’s pres-
15
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:
Kamps – Hoffmann
Timeline | 365
ence as early as 24 hours after infection – before people show

symptoms and several days before a carrier is considered capa-
ble 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 jog-
ging 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 discovers 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 Ger-
man town which was exposed to a super-spreading event (carni-
val festivities). 15.5% were infected, with an estimated infection
fatality rate of 0.36%. 22% of infected individuals were asympto-
matic.
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 con-

finement (which he himself had contributed to establishing!) by

receiving at least twice a 38-year-old woman at his home.
Anthony Fauci, the director of the United States National Insti-
tute of Allergy and Infectious Diseases, says that there is no sci-
entific evidence to back the 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 million 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, Kiri-
bati, Marshall Islands, Micronesia, Samoa, Salomon Island, Tonga,
Tuvalu, Vanuatu, Cook Island, Nauru, Niue, Palau and Lesotho.
(We know North Korea is cheating, and Turkmenistan and Leso-
tho 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: élucubra-
tions; Italian: visioni; Spanish: fantasías) about hydroxychloro-
qine and injecting desinfectants, today is the day where COVID-
19 will “go away without vaccine”. The sad developments of the
coronavirus pandemic have now accumulated sufficient evidence
that the individual doesn’t believe himself what he is saying. The
Kamps – Hoffmann
Timeline | 367
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 individu-
al? 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.
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 Amer-
ica are the world’s biggest coronavirus losers?
Everything you always wanted to know about false negatives and
false positives* (*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 negatives 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 newspaper Le Monde reports that according to official fig-
ures 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 confine-

ment.
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 Analytics data of two dozen websites, both medical
(Amedeo, Free Medical Journals, FreeBooks4Doctors) and non-
medical (TheWordBrain, Ear2Memory, GigaSardinian, GigaMar-
tinique, 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 someone standing on the data line be-
tween COVID Reference and China (Figure 6)?
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.
Kamps – Hoffmann
Timeline | 369
Friday, 15 May
In a memorable blog entry for the British Medical Journal, Paul
Garner, professor of infectious diseases at Liverpool School of
Tropical Medicine, discusses 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
demonstrates 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 de-
tected in Germany: 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 extremists,
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 reconstruction 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 recovered from SARS-CoV-2
infection (The Guardian).

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 compatible with existing legislation about pri-
vacy.
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.
Kamps – Hoffmann
Timeline | 371
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 establishments, the closures of which
have led to food shortage among rodents, especially in dense
commercial areas. CDC warns of unusual or aggressive rodent
behavior.
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 Re-
combinant Adenovirus 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 neutralizing 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 dou-
ble as coffins (The Guardian).

Andrzej Krauze publishes a cartoon on the fallout from the

COVID-19 pandemic.
Sunday, 31 May
More than 50 million people across the US could go hungry
without help from food banks or other aid (Feeding America).
Wednesday, 3 June
In the hope of saving its tourist industry, Italy reopens its bor-
ders.
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 hospital-
ised 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 Spanish:
https://elpais.com/ciencia/2020-06-06/radiografia-de-tres-
brotes-asi-se-contagiaron-y-asi-podemos-evitarlo.html.
Kamps – Hoffmann
Timeline | 373
Notes

Notes
Kamps – Hoffmann
Timeline | 375
Notes

Notes
Kamps – Hoffmann

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www.CovidReference.

Bernd Sebastian Kamps

Editors, authors, publishing house and translators

Bernd Sebastian Kamps, M.D.

Christian Hoffmann, M.D.

Bernd Sebastian Kamps & Christian Hoffmann

Preface to the First Edition

Over the coming months, COVID Reference will be presenting

Stefano Lazzari, M.D.

Jennifer Neubert, M.D.

Tim Niehues, M.D.

COVID Reference International

Professor, Erciyes University Neurology Department/

Khanh Phan Nguyen Quoc

6. Diagnostic Tests and Procedures 155

7. Clinical Presentation 185

9. Severe COVID 271

10. Comorbidities 277

11. Pediatrics 303

12. Timeline 333

COVID Reference ENG 004

In December 2019, several patients from Wuhan, People’s Repub-

COVID Reference ENG 004

that in China, human-to-human transmission has occurred

COVID Reference ENG 004

Hospitals and other health care centers

cases, 184 were infected nosocomially (Korea Centers for Disease

COVID Reference ENG 004

main resuscitation bay, where a stroke patient occupied a bed.

Long-term care facilities

COVID Reference ENG 004

mates, in countries in the European Region up to half of those

Table 1. COVID outbreak in a long-term care facility

Residents Healthcare Visitors

SARS-CoV-2 continues to spread in US nursing homes where ap-

Aircraft carriers and other military vessels

COVID Reference ENG 004

(59%) were positive for SARS-CoV-2, 500 (28%) presented symp-

France. After a parishioner and 18 family members tested posi-

Schools and schoolchildren

COVID Reference ENG 004

contacts. No one was found positive to the coronavirus, though

As of 21 April, SARS-CoV-2 was present in US correctional and

Industrial meat-packing plants

COVID Reference ENG 004

in the end 102 of 130 choristers were confirmed to have COVID-

SARS-COV-2 re-activation or re-infection?

replication in nasopharyngeal or anal swabs, nor any other signs

COVID Reference ENG 004

and with a mortality rate of around 0.5%, without interventions

After a few months, up to 70% of the population could be

majority of the population would contract the virus, thus devel-

Pandemic 2.0: Lockdowns

COVID Reference ENG 004

and other basic supplies, going to hospital, or performing essen-

Hospital admissions for COVID-19

Patients treated in intensive care units (ICU)

COVID Reference ENG 004

Figure 1. The Chinese outbreak in January/February 2020. Epidemic curves