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CLINICAL UPDATE

BMJ: first published as 10.1136/bmj.m3862 on 23 October 2020. Downloaded from http://www.bmj.com/ on 3 January 2021 by guest. Protected by copyright.
1 Division of Infection and Global
Health Research, School of Medicine,
University of St Andrews, St
Andrews, UK Virology, transmission, and pathogenesis of SARS-CoV-2
2 Specialist Virology Laboratory, Royal
Muge Cevik, 1 , 2 Krutika Kuppalli, 3 Jason Kindrachuk, 4 Malik Peiris5
Infirmary of Edinburgh, Edinburgh, UK
and Regional Infectious Diseases Unit,
What you need to know viral response phase and an inflammatory second
Western General Hospital, Edinburgh, phase. Most clinical presentations are mild, and the
UK
• SARS-CoV-2 is genetically similar to SARS-CoV-1, but typical pattern of covid-19 more resembles an
3 Division of Infectious Diseases, characteristics of SARS-CoV-2—eg, structural influenza-like illness—which includes fever, cough,
Medical University of South Carolina, differences in its surface proteins and viral load malaise, myalgia, headache, and taste and smell
Charleston, SC, USA kinetics—may help explain its enhanced rate of disturbance—rather than severe pneumonia
transmission
4 Laboratory of Emerging and (although emerging evidence about long term
Re-Emerging Viruses, Department of • In the respiratory tract, peak SARS-CoV-2 load is consequences is yet to be understood in detail).1 In
Medical Microbiology, University of observed at the time of symptom onset or in the first this review, we provide a broad update on the
Manitoba, Winnipeg, MB, Canada week of illness, with subsequent decline thereafter,
emerging understanding of SARS-CoV-2
indicating the highest infectiousness potential just
5 School of Public Health, LKS Faculty
before or within the first five days of symptom onset
pathophysiology, including virology, transmission
of Medicine, The University of Hong dynamics, and the immune response to the virus.
Kong, Hong Kong Special • Reverse transcription polymerase chain reaction
Administrative Region, China
Any of the mechanisms and assumptions discussed
(RT-PCR) tests can detect viral SARS-CoV-2 RNA in the
in the article and in our understanding of covid-19
Correspondence to M Cevik mc349@st- upper respiratory tract for a mean of 17 days; however,
andrews.ac.uk detection of viral RNA does not necessarily equate to may be revised as further evidence emerges.
infectiousness, and viral culture from PCR positive
Cite this as: BMJ 2020;371:m3862 What we know about the virus
http://dx.doi.org/10.1136/bmj.m3862 upper respiratory tract samples has been rarely
Published: 23 October 2020 positive beyond nine days of illness SARS-CoV-2 is an enveloped β-coronavirus, with a
• Symptomatic and pre-symptomatic transmission (1-2 genetic sequence very similar to SARS-CoV-1 (80%)
days before symptom onset), is likely to play a greater and bat coronavirus RaTG13 (96.2%).2 The viral
role in the spread of SARS-CoV-2 than asymptomatic envelope is coated by spike (S) glycoprotein, envelope
transmission (E), and membrane (M) proteins (fig 1). Host cell
• A wide range of virus-neutralising antibodies have binding and entry are mediated by the S protein. The
been reported, and emerging evidence suggests that first step in infection is virus binding to a host cell
these may correlate with severity of illness but wane through its target receptor. The S1 sub-unit of the S
over time protein contains the receptor binding domain that
binds to the peptidase domain of
Since the emergence of SARS-CoV-2 in December angiotensin-converting enzyme 2 (ACE 2). In
2019, there has been an unparalleled global effort to SARS-CoV-2 the S2 sub-unit is highly preserved and
characterise the virus and the clinical course of is considered a potential antiviral target. The virus
disease. Coronavirus disease 2019 (covid-19), caused structure and replication cycle are described in figure
by SARS-CoV-2, follows a biphasic pattern of illness 1.
that likely results from the combination of an early

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BMJ: first published as 10.1136/bmj.m3862 on 23 October 2020. Downloaded from http://www.bmj.com/ on 3 January 2021 by guest. Protected by copyright.
Fig 1 | (1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s transmembrane serine protease 2 (cell surface protein), which is principally
expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7)
show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

Coronaviruses have the capacity for proofreading during replication, transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially
and therefore mutation rates are lower than in other RNA viruses. interact with the angiotensin-converting enzyme 2 (ACE 2) receptor,
As SARS-CoV-2 has spread globally it has, like other viruses, SARS-CoV-2 has structural differences in its surface proteins that
accumulated some mutations in the viral genome, which contains enable stronger binding to the ACE 2 receptor4 and greater efficiency
geographic signatures. Researchers have examined these mutations at invading host cells.1 SARS-CoV-2 also has greater affinity (or
to study virus characterisation and understand epidemiology and bonding) for the upper respiratory tract and conjunctiva,5 thus can
transmission patterns. In general, the mutations have not been infect the upper respiratory tract and can conduct airways more
attributed to phenotypic changes affecting viral transmissibility or easily.6
pathogenicity. The G614 variant in the S protein has been postulated
Viral load dynamics and duration of infectiousness
to increase infectivity and transmissibility of the virus.3 Higher viral
loads were reported in clinical samples with virus containing G614 Viral load kinetics could also explain some of the differences
than previously circulating variant D614, although no association between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak
was made with severity of illness as measured by hospitalisation SARS-CoV-2 load is observed at the time of symptom onset or in the
outcomes.3 These findings have yet to be confirmed with regards first week of illness, with subsequent decline thereafter, which
to natural infection. indicates the highest infectiousness potential just before or within
the first five days of symptom onset (fig 2).7 In contrast, in
Why is SARS-CoV-2 more infectious than SARS-CoV-1? SARS-CoV-1 the highest viral loads were detected in the upper
SARS-CoV-2 has a higher reproductive number (R0) than respiratory tract in the second week of illness, which explains its
SARS-CoV-1, indicating much more efficient spread.1 Several minimal contagiousness in the first week after symptom onset,
characteristics of SARS-CoV-2 may help explain this enhanced enabling early case detection in the community.7

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BMJ: first published as 10.1136/bmj.m3862 on 23 October 2020. Downloaded from http://www.bmj.com/ on 3 January 2021 by guest. Protected by copyright.
Fig 2 | After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations,
ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the
infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines
thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/sci-
ence/article/pii/S009286742030475X; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext)

Quantitative reverse transcription polymerase chain reaction infection occurring by direct or indirect contact with nasal,
(qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper conjunctival, or oral mucosa, when respiratory particles are inhaled
respiratory tract for a mean of 17 days (maximum 83 days) after or deposited on these mucous membranes.6 Target host receptors
symptom onset.7 However, detection of viral RNA by qRT-PCR does are found mainly in the human respiratory tract epithelium,
not necessarily equate to infectiousness, and viral culture from PCR including the oropharynx and upper airway. The conjunctiva and
positive upper respiratory tract samples has been rarely positive gastrointestinal tracts are also susceptible to infection and may
beyond nine days of illness.5 This corresponds to what is known serve as transmission portals.6
about transmission based on contact tracing studies, which is that
Transmission risk depends on factors such as contact pattern,
transmission capacity is maximal in the first week of illness, and
environment, infectiousness of the host, and socioeconomic factors,
that transmission after this period has not been documented.8
as described elsewhere.12 Most transmission occurs through close
Severely ill or immune-compromised patients may have relatively
range contact (such as 15 minutes face to face and within 2 m),13
prolonged virus shedding, and some patients may have intermittent
and spread is especially efficient within households and through
RNA shedding; however, low level results close to the detection
gatherings of family and friends.12 Household secondary attack
limit may not constitute infectious viral particles. While
rates (the proportion of susceptible individuals who become infected
asymptomatic individuals (those with no symptoms throughout the
within a group of susceptible contacts with a primary case) ranges
infection) can transmit the infection, their relative degree of
from 4% to 35%.12 Sleeping in the same room as, or being a spouse
infectiousness seems to be limited.9 -11 People with mild symptoms
of an infected individual increases the risk of infection, but isolation
(paucisymptomatic) and those whose symptom have not yet
of the infected person away from the family is related to lower risk
appeared still carry large amounts of virus in the upper respiratory
of infection.12 Other activities identified as high risk include dining
tract, which might contribute to the easy and rapid spread of
in close proximity with the infected person, sharing food, and taking
SARS-CoV-2.7 Symptomatic and pre-symptomatic transmission (one
part in group activities 12 The risk of infection substantially increases
to two days before symptom onset) is likely to play a greater role in
in enclosed environments compared with outdoor settings.12 For
the spread of SARS-CoV-2.10 12 A combination of preventive
example, a systematic review of transmission clusters found that
measures, such as physical distancing and testing, tracing, and
most superspreading events occurred indoors.11 Aerosol
self-isolation, continue to be needed.
transmission can still factor during prolonged stay in crowded,
Route of transmission and transmission dynamics poorly ventilated indoor settings (meaning transmission could occur
at a distance >2 m).12 14 -17
Like other coronaviruses, the primary mechanism of transmission
of SARS-CoV-2 is via infected respiratory droplets, with viral

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The role of faecal shedding in SARS-CoV-2 transmission and the syndrome (MERS) and severe acute respiratory syndrome (SARS).26 27
extent of fomite (through inanimate surfaces) transmission also A distinctive feature of covid-19 is the presence of mucus plugs with

BMJ: first published as 10.1136/bmj.m3862 on 23 October 2020. Downloaded from http://www.bmj.com/ on 3 January 2021 by guest. Protected by copyright.
remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 fibrinous exudate in the respiratory tract, which may explain the
remain viable for many days on smooth surfaces (stainless steel, severity of covid-19 even in young adults.28 This is potentially caused
plastic, glass) and at lower temperature and humidity (eg, air by the overproduction of pro-inflammatory cytokines that
conditioned environments).18 19 Thus, transferring infection from accumulate in the lungs, eventually damaging the lung
contaminated surfaces to the mucosa of eyes, nose, and mouth via parenchyma.24
unwashed hands is a possible route of transmission. This route of
Some patients also experience septic shock and multi-organ
transmission may contribute especially in facilities with communal
dysfunction.24 For example, the cardiovascular system is often
areas, with increased likelihood of environmental contamination.
involved early in covid-19 disease and is reflected in the release of
However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated
highly sensitive troponin and natriuretic peptides.29 Consistent with
by commonly used disinfectants, emphasising the potential value
the clinical context of coagulopathy, focal intra-alveolar
of surface cleaning and handwashing. SARS-CoV-2 RNA has been
haemorrhage and presence of platelet-fibrin thrombi in small arterial
found in stool samples and RNA shedding often persists for longer
vessels is also seen.27 Cytokines normally mediate and regulate
than in respiratory samples7; however, virus isolation has rarely
immunity, inflammation, and haematopoiesis; however, further
been successful from the stool.5 7 No published reports describe
exacerbation of immune reaction and accumulation of cytokines
faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission
in other organs in some patients may cause extensive tissue damage,
was not considered to occur in most circumstances; but, one
or a cytokine release syndrome (cytokine storm), resulting in
explosive outbreak was attributed to aerosolisation and spread of
capillary leak, thrombus formation, and organ dysfunction.24 30
the virus across an apartment block via a faulty sewage system.20
It remains to be seen if similar transmission may occur with Mechanisms underlying the diverse clinical outcomes
SARS-CoV-2. Clinical outcomes are influenced by host factors such as older age,
Pathogenesis male sex, and underlying medical conditions,1 as well as factors
related to the virus (such as viral load kinetics), host-immune
Viral entry and interaction with target cells response, and potential cross-reactive immune memory from
SARS-CoV-2 binds to ACE 2, the host target cell receptor.1 Active previous exposure to seasonal coronaviruses (box 1).
replication and release of the virus in the lung cells lead to
non-specific symptoms such as fever, myalgia, headache, and Box 1: Risk factors associated with the development of severe disease,
admission to intensive care unit, and mortality
respiratory symptoms.1 In an experimental hamster model, the virus
causes transient damage to the cells in the olfactory epithelium, Underlying condition
leading to olfactory dysfunction, which may explain temporary loss • Older age
of taste and smell commonly seen in covid-19.21 The distribution of • Hypertension
ACE 2 receptors in different tissues may explain the sites of infection
• Cardiovascular disease
and patient symptoms. For example, the ACE 2 receptor is found
on the epithelium of other organs such as the intestine and • Chronic obstructive pulmonary disease
endothelial cells in the kidney and blood vessels, which may explain • Diabetes
gastrointestinal symptoms and cardiovascular complications.22 • Obesity
Lymphocytic endotheliitis has been observed in postmortem
• Malignancy
pathology examination of the lung, heart, kidney, and liver as well
as liver cell necrosis and myocardial infarction in patients who died Presentation
of covid-19.1 23 These findings indicate that the virus directly affects • Higher fever (≥39°C on admission)
many organs, as was seen in SARS-CoV-1 and influenzae. • Dyspnoea on admission
Much remains unknown. Are the pathological changes in the • Higher qSOFA score
respiratory tract or endothelial dysfunction the result of direct viral
Laboratory markers
infection, cytokine dysregulation, coagulopathy, or are they
multifactorial? And does direct viral invasion or coagulopathy • Neutrophilia/lymphopenia
directly contribute to some of the ischaemic complications such as • Raised lactate and lactate dehydrogenase
ischaemic infarcts? These and more, will require further work to • Raised C reactive protein
elucidate.
• Raised ferritin
Immune response and disease spectrum (figure 2) • Raised IL-6
After viral entry, the initial inflammatory response attracts • Raised ACE2
virus-specific T cells to the site of infection, where the infected cells • D-dimer >1 μg/mL
are eliminated before the virus spreads, leading to recovery in most
people.24 In patients who develop severe disease, SARS-CoV-2 elicits
Sex-related differences in immune response have been reported,
an aberrant host immune response.24 25 For example, postmortem
revealing that men had higher plasma innate immune cytokines
histology of lung tissues of patients who died of covid-19 have
and chemokines at baseline than women.31 In contrast, women had
confirmed the inflammatory nature of the injury, with features of
notably more robust T cell activation than men, and among male
bilateral diffuse alveolar damage, hyaline-membrane formation,
participants T cell activation declined with age, which was sustained
interstitial mononuclear inflammatory infiltrates, and desquamation
among female patients. These findings suggest that adaptive
consistent with acute respiratory distress syndrome (ARDS), and is
immune response may be important in defining the clinical outcome
similar to the lung pathology seen in severe Middle East respiratory

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as older age and male sex is associated with increased risk of severe response.34 In the same study many interferons, cytokines, and
disease and mortality. chemokines were elevated early in disease for patients who had

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severe disease and higher viral loads. This emphasises that viral
Increased levels of pro-inflammatory cytokines correlate with severe
load may drive these cytokines and the possible pathological roles
pneumonia and increased ground glass opacities within the
associated with the host defence factors. This is in keeping with the
lungs.30 32 In people with severe illness, increased plasma
pathogenesis of influenza, SARS, and MERS whereby prolonged
concentrations of inflammatory cytokines and biomarkers were
viral shedding was also associated with severity of illness.7 35
observed compared with people with non-severe illness.30 33 34
Given the substantial role of the immune response in determining
Emerging evidence suggests a correlation between viral dynamics,
clinical outcomes, several immunosuppressive therapies aimed at
the severity of illness, and disease outcome.7 Longitudinal
limiting immune-mediated damage are currently in various phases
characteristics of immune response show a correlation between the
of development (table 1).
severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α

Table 1 | Therapeutics currently under investigation

Entry to the cell Viral replication Host immune response
ACE receptor inhibitors RNA polymerase inhibitors Immunomodulators
Angiotensin II receptor blockers Remdesivir Tocilizumab
Fusion inhibitors Ribavirin Sarilumab
Uminefovir Favipiravir Adalimumab (TNF inhibitor)
Baricitinib Protease inhibitors IFN
Monoclonal antibodies Lopinavir Corticosteroids
Darunavir

Immune response to the virus and its role in protection Questions for future research
Covid-19 leads to an antibody response to a range of viral proteins, • What is the role of the cytokine storm and how could it inform the
but the spike (S) protein and nucleocapsid are those most often
development of therapeutics, vaccines, and supportive care
used in serological diagnosis. Few antibodies are detectable in the modalities?
first four days of illness, but patients progressively develop them,
• What is the window period when patients are most infectious?
with most achieving a detectable response after four weeks.36 A
wide range of virus-neutralising antibodies have been reported, • Why do some patients develop severe disease while others, especially
and emerging evidence suggests that these may correlate with children, remain mildly symptomatic or do not develop symptoms?
severity but wane over time.37 The duration and protectivity of • What are the determinants of healthy versus dysfunctional response,
antibody and T cell responses remain to be defined through studies and the biomarkers to define immune correlates of protection and
with longer follow-up. CD-4 T cell responses to endemic human disease severity for the effective triage of patients?
coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, • What is the protective role of T cell immunity and duration of both
but their role in protection remains unclear.38 antibody and T cell responses, and how would you define the
correlates of protection?
Unanswered questions
Further understanding of the pathogenesis for SARS-CoV-2 will be How patients were involved in the creation of this article
vital in developing therapeutics, vaccines, and supportive care
modalities in the treatment of covid-19. More data are needed to No patients were directly involved in the creation of this article.
understand the determinants of healthy versus dysfunctional
response and immune markers for protection and the severity of How this article was created
disease. Neutralising antibodies are potential correlates of
We searched PubMed from 2000 to 18 September 2020, limited to
protection, but other protective antibody mechanisms may exist. publications in English. Our search strategy used a combination of key
Similarly, the protective role of T cell immunity and duration of words including “COVID-19,” “SARS-CoV-2,” “SARS”, “MERS,”
both antibody and T cell responses and the correlates of protection “Coronavirus,” “Novel Coronavirus,” “Pathogenesis,” “Transmission,”
need to be defined. In addition, we need optimal testing systems “Cytokine Release,” “immune response,” “antibody response.” These
and technologies to support and inform early detection and clinical sources were supplemented with systematic reviews. We also reviewed
management of infection. Greater understanding is needed technical documents produced by the Centers for Disease Control and
regarding the long term consequences following acute illness and Prevention and World Health Organization technical documents.
multisystem inflammatory disease, especially in children.
Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and
all authors provided critical feedback and contributed to the manuscript.
Education into practice
How would you describe SARS-CoV-2 transmission routes and ways to Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial
companies. The authors declare the following other interests: none.
prevent infection?
How would you describe to a patient why cough, anosmia, and fever Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/re-
occur in covid-19? sources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned; externally peer reviewed.

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6 the bmj | BMJ 2020;371:m3862 | doi: 10.1136/bmj.m3862