How is COVID-19 different from other coronavirus infections?
The pace of COVID-19 spread has been unprecedented and far outstripped
that of the other novel coronaviruses. COVID-19 was first identified in
Wuhan, China in December 2019 and only 4 months later was declared a
pandemic by WHO 2. At time of writing, there are
722,646 confirmed cases of COVID-19 in over 190 countries, with 33,983
deaths 3. By comparison, the 2002-2003 SARS outbreak
infected 8096 people before it was brought under control, with 774
deaths 4. The SARS-COV and SARS-COV2 viruses show a
high degree of sequence homology within their genetic material (82%)
and initial studies suggested that their molecular biology is similar5. Both viruses are predominantly spread by
respiratory droplets and contact with contaminated surfaces (fomites).
So why is it that quarantine measures which were so effective against
SARS 6 have struggled to contain COVID-19?.
There are several possible explanations. COVID-19 appears to have a
higher transmissibility than SARS 7, with peak viral
shedding earlier in the course of the illness when patients exhibit
fewer symptoms 8. In addition, COVID-19 is generally a
milder illness than SARS and may even be asymptomatic. These
asymptomatic cases still shed virus, however, and may account for the
majority of transmissions 9, 10. This combination of
factors allowed COVID-19 to spread quickly through communities before
severe cases were identified, making public health measures much more
difficult to implement 11.
What is the pathogenesis of
COVID-19?
All coronaviruses enter the host cell by binding to a cell surface
receptor with peptidase activity. In the case of SARS-COV-2, the entry
receptor is angiotensin converting enzyme 2 (ACE2) 12.
The physiological function of this is to convert angiotensin II to
angiotensin I, which is a vasodilator, and is an essential control
mechanism within the renin-angiotensin-aldosterone system to control
blood pressure by mediating salt and water homeostasis. It may also have
a significant role in mediating amino acid transport across the
intestinal epithelium 13. ACE2 is present in abundance
on type 2 alveolar cells of the lungs, as well as stratified epithelial
cells of the GI tract, cardiac myocytes, kidney proximal tubules and
bladder urothelium, which may all be at risk of infection14. The spike proteins of SARS-COV-2 bind to ACE2,
resulting in enzymatic activity and a conformational change of the spike
that allows fusion of the viral and host cell membranes and entry of the
nucleocapsid to the cell.
On entry to the host cell, the RNA genome is translated into a single
long polypeptide by the host ribosome, then cleaved by viral-specific
proteases to form many non-structural proteins. A number of these viral
proteins will then coalesce to form a multi-protein
replicase-transcriptase complex, which results in further replication
and transcription of the viral genome 1. The function
of most of the viral proteins remains unknown, however it is likely that
these interfere with normal host cell processing.
The exact pathogenic mechanisms of COVID-19 are not yet understood but
are thought to be similar to SARS. Examination of lung tissue from a
patient who died of severe COVID-19 showed diffuse alveolar damage with
pneumocyte desquamation and hyaline membrane formation, indicative of
ARDS (Acute Respiratory Distress Syndrome). Pneumocytes showing viral
cytopathic changes were also seen, suggesting direct viral damage15. Severe COVID-19 disease is associated with a
dramatic increase in secretion of pro-inflammatory cytokines, including
IL-2, IL-10 and TNF α 16. This cytokine storm is very
similar to that seen in secondary haemophagocytic lymphohistiocytosis
(sHLH), a high-mortality hyperinflammatory syndrome, suggesting that
death in severe COVID-19 may be partially immune-mediated17.
What is the clinical picture of
COVID-19?
COVID-19 generally presents with fever (77-98%), cough (46-82%) and
myalgia or fatigue (11-52%) in those who show symptoms and require
hospital admission. The mean incubation period is thought to be 4 days,
estimated range from 2-14 days 18. Of those patients
who require admission, approximately 19% enter a severe or critical
condition, with 5% requiring intensive therapy unit admission and
intubation 19. This is generally due to pneumonia. In
these patients, a deterioration of symptoms occurs from day 8 onwards,
with patients developing shortness of breath indicative of acute
respiratory distress syndrome (ARDS).
On admission to hospital, blood tests often show mild lymphopenia (83%)
and thrombocytopaenia (36%). Liver transaminases may be mildly
deranged. C-reactive protein (CRP) is slightly elevated in non-severe
disease (<40mg/L) but predictably rises to 60-160 mg/L in
severe and fatal cases 20. A raised D-dimer also
appears to be associated with severe disease 20.
Computer tomography (CT) imaging of the chest tends to show bilateral
infection with ground-glass opacities and multiple areas of
consolidation. The diagnosis of COVID-19 is confirmed by RT-PCR of nose
and throat swabs or respiratory secretions.
Of those who become seriously ill, estimates suggest a mortality rate of
50-80%, generally due to acute respiratory failure secondary to ARDS,
secondary infection or cardiac events (including COVID-19 myocarditis)16, 20, 21. Those who become seriously ill are more
likely to be older, have underlying medical conditions or immune
suppression. Pregnancy has also been suggested as a risk factor for
severe COVID-19 disease.