Aetiology

Virology

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a previously unknown betacoronavirus that was discovered in bronchoalveolar lavage samples taken from clusters of patients who presented with pneumonia of unknown cause in Wuhan City, Hubei Province, China, in December 2019.[26]

  • Coronaviruses are a large family of enveloped RNA viruses, some of which cause illness in people (e.g., common cold, severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]), and others that circulate among mammals and birds. Rarely, animal coronaviruses can spread to humans and subsequently spread between people, as was the case with SARS and MERS.

  • SARS-CoV-2 belongs to the Sarbecovirus subgenus of the Coronaviridae family, and is the seventh coronavirus known to infect humans. The virus has been found to be similar to SARS-like coronaviruses from bats, but it is distinct from SARS-CoV and MERS-CoV.[27][28] The full genome has been determined and published in GenBank. GenBank external link opens in a new window

  • A preliminary study suggests that there are two major types (or strains) of the SARS-CoV-2 virus in China, designated L and S. The L type was found to be more prevalent during the early stages of the outbreak in Wuhan City and may be more aggressive (although this is speculative), but its frequency decreased after early January. The relevance of this finding is unknown at this stage and further research is required.[29] Patients in Singapore infected with a SARS-CoV-2 variant with a 382-nucleotide deletion appeared to have a milder course compared with those infected with a wild-type virus.[30]

Illustration revealing ultrastructural morphology exhibited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when viewed with electron microscopically[Figure caption and citation for the preceding image starts]: Illustration revealing ultrastructural morphology exhibited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when viewed with electron microscopicallyCenters for Disease Control and Prevention [Citation ends].

Origin of virus

  • A majority of patients in the initial stages of this outbreak reported a link to the Huanan South China Seafood Market, a live animal or ‘wet’ market, suggesting a zoonotic origin of the virus.[31][32][33] An initial assessment of the transmission dynamics in the first 425 confirmed cases found that 55% of cases before 1 January 2020 were linked to the market, whereas only 8.6% of cases after this date were linked to the market. This suggests that person-to-person spread was occurring among close contacts since the middle of December 2019.[33]

  • Some studies suggest that SARS-CoV-2 may be a recombinant virus between a bat coronavirus and an origin-unknown coronavirus.[27][28][34][35] Pangolins have been suggested as a possible intermediate host; however, the virus has not been identified in an animal host as yet.[36][37][38] Further research is required to determine the origin of SARS-CoV-2.

Transmission dynamics

  • Respiratory transmission is the dominant mode of transmission, with proximity and ventilation being the key determinants of transmission risk.[39] Available evidence suggests that transmission between people occurs primarily through direct, indirect, or close contact with infected people through infected secretions such as saliva and respiratory secretions, or through their respiratory droplets, which are expelled when an infected person coughs, sneezes, talks, or sings.[40]

  • Airborne transmission can occur in healthcare settings during aerosol-generating procedures. There are some outbreak reports that suggest aerosol transmission is possible in the community; however, these reports relate to indoor crowded spaces with poor ventilation (e.g., restaurants, choir practice, fitness classes), and a detailed investigation of these clusters suggests that droplet and fomite transmission could also explain the transmission in these reports.[40]

  • Fomite transmission (from direct contact with fomites) may be possible, but there is currently no conclusive evidence for this mode of transmission. In the few cases where fomite transmission has been presumed, respiratory transmission has not been completely excluded.[39] The virus has been found to be more stable on plastic and stainless steel (up to 72 hours) compared with copper (up to 4 hours) and cardboard (up to 24 hours) under experimental conditions.[41]In healthcare settings, the virus is widely distributed in the air and on object surfaces in both general wards and intensive care units.[42] However, no virus has been cultured from these samples indicating that the deposition may reflect non-viable viral RNA.[43]

  • Faecal-oral transmission (or respiratory transmission through aerosolised faeces) may be possible, but there is only limited circumstantial evidence to support this mode of transmission.[39] The pooled detection rate of faecal SARS-CoV-2 RNA in patients with COVID-19 is approximately 51%, with 64% of samples remaining positive for a mean of 12.5 days (up to 33 days maximum) after respiratory samples became negative.[44]

  • Transmission via other body fluids (including sexual transmission or bloodborne transmission) has not been reported.[39] While the virus has been detected in blood, cerebrospinal fluid, pericardial fluid, pleural fluid, urine, semen, saliva, tears, and conjunctival secretions, as well as in the middle ear and mastoid, the presence of virus or viral components does not equate with infectivity.[45][46][47][48][49][50][51][52][53][54][55]

  • Vertical transmission occurs rarely and transplacental transmission has been documented.[39] Vertical transmission has been reported in approximately 3.2% of patients, usually in the third trimester.[56]The rate of infection appears to be no greater when the baby is born vaginally, breastfed, or allowed contact with the mother.[57]Viral fragments have been detected in breast milk; however, no replication-competent virus has been detected, suggesting that transmission via breast milk is unlikely.[58][59][60]Vertical transmission is unlikely to occur if correct hygiene precautions are taken.[61]

  • Nosocomial transmission was reported in 44% of patients in one systematic review; however, this review was limited to case series conducted early in the outbreak in Wuhan before the institution of appropriate infection prevention and control measures.[62] The nosocomial infection rate in a major London teaching hospital was around 15% during the peak of the outbreak.[63] More recent reports of healthcare workers exposed to index cases (not in the presence of aerosol-generating procedures) found little to no nosocomial transmission when contact and droplet precautions were used.[40][64]

Transmission dynamics in relation to symptoms

  • Symptomatic transmission

    • Transmission appears to be greatest when people are symptomatic, especially around the time of symptom onset.[2][65][66][67][68][69][70][71]

  • Presymptomatic transmission

    • Transmission may occur during the incubation period, usually 1 to 3 days before symptom onset.[2]

    • Presymptomatic transmission was reported in 12.6% of cases in China, and 6.4% of cases in Singapore.[72][73]

    • People without symptoms may be presymptomatic, or they may remain persistently asymptomatic.

  • Asymptomatic transmission

    • Transmission from asymptomatic cases (laboratory-confirmed cases who do not develop symptoms) has been documented.[74][75]However, evidence is limited, and the World Health Organization states that asymptomatic cases are much less likely to transmit the virus than those who develop symptoms, and asymptomatic cases are not the major driver of the overall epidemic dynamics.[76][77]Numerous studies have reported no evidence of asymptomatic transmission from carriers of SARS-CoV-2.[78][79][80]

    • Estimating the prevalence of asymptomatic cases in the population is difficult. A meta-analysis of over 50,000 people found that 15.6% of confirmed cases were asymptomatic at the time of testing, and nearly half developed symptoms later.[81]However, estimates of the proportion of asymptomatic cases vary widely from between 1.2% to 80%, depending on the study population.[82][83][84][85][86][87][88]

    • Healthcare workers may play a role in asymptomatic transmission. About 7.6% of healthcare workers who worked in hospital units with infected patients tested positive for SARS-CoV-2 antibodies; however, only 58% of these workers reported prior symptoms.[89]A cross-sectional study of nearly 2800 healthcare workers found that 5.4% of COVID-19-facing asymptomatic healthcare workers tested positive, compared with 0.6% of non-COVID-19-facing asymptomatic healthcare workers.[90]

    • Children are more likely to be asymptomatic.[81]The pooled proportion of asymptomatic cases in children was thought to be significant (around 40%).[91][92]However, a recent study found that the rate of asymptomatic infection in children was 1% compared with 9% in adults.[93]

Superspreading events

  • Superspreading events have been reported. These events are associated with explosive growth early in an outbreak and sustained transmission in later stages.[94]

  • Reported events include church/religious gatherings, weddings, choir practices, overnight youth camps, fitness classes, business conferences, and working in call centres.[39] Widespread transmission has also been reported in long-term care facilities, homeless shelters, prisons, and meat and poultry processing facilities, as well as on board cruise ships.[95][96][97][98][99][100][101] There is a lack of evidence for transmission in the school setting.[102]

  • Some individuals are supershedders of virus, but the reasons underlying superspreader events are often more complex than just excess virus shedding and can include a variety of behavioural, host, and environmental factors.[103]

Viral transmission factors

  • Incubation period

    • The incubation period is estimated to be between 1 and 14 days, with a median of 5 to 6 days.[2][104]Infectiousness peaks around 1 day before symptom onset and declines within 7 days.[39]

  • Reproduction number (R₀)

    • Preliminary reports suggested that the reproduction number, the number of people who acquire the infection from an infected person, was estimated to be 2.2 to 3.3.[33][105][106]The Centers for Disease Control and Prevention gives a current best estimate of 2.5 (as of 10 September 2020).[107]

    • The R₀ decreases when public health measures (e.g., social distancing) are put in place.[108]

  • Secondary attack rate

    • The secondary attack rate, the proportion of people exposed to a primary case that go on to develop the disease as a result of the exposure, among all close contacts ranges from 0.45% to 3.7%. The rate among household members, particularly spouses, is higher and ranges from 4.6% to 30%. The rate lowered to 0% when index patients were quarantined by themselves from the onset of symptoms.[76][109][110][111][112]

    • The secondary attack rate increases with the severity of the index case (i.e., 0.3% for asymptomatic cases to 6.2% for severe/critical cases) according to a study of 3410 close contacts of 391 index cases.[76]

    • The secondary attack rate for close contacts of presymptomatic people is approximately 3.3%, with a rate of 16.1% for household contacts, 1.1% for social contacts, and 0% for work contacts.[113]

    • Children aged <5 years had lower secondary attack rates compared with older children, and the risk of infection was higher if the household index case was the mother.[114]The secondary attack rate was 1.2% in children in a childcare setting or school.[115]

  • Viral load

    • Viral load is highest in the upper respiratory tract (nasopharynx and oropharynx) early in the course of infection, and then increases in the lower respiratory tract (sputum). Viral load rapidly decreases after symptom onset. Patients with severe disease have higher viral loads compared with those with mild disease.[39]

    • Viral load in the upper respiratory tract is comparable in asymptomatic patients and those with mild symptoms.[116]

  • Viral shedding

    • The median duration of viral shedding has been estimated to be between 8 and 20 days after symptoms resolve. However, shedding has been detected for up to 60 days in various samples, and for 104 days in one pregnant woman.[117][118][119][120][121][122][123]

    • Duration of viral shedding was longer in symptomatic patients compared with asymptomatic patients (25.2 days versus 22.6 days), and in patients with severe illness compared with those with mild illness (21 days versus 14 days).[124][125]

    • The period of infectiousness is far shorter than the duration of detectable viral shedding. No viable virus has been isolated in patients with mild or moderate disease after 10 days of symptoms, or after 20 days in those with severe or critical disease, despite ongoing viral shedding. Data about the dynamics of viral shedding in people with persistent asymptomatic infection are inconsistent.[39] There is no convincing evidence that duration of viral shedding correlates with duration of infectivity.[126]

    • Factors associated with prolonged viral shedding include male sex, older age, comorbid hypertension, delayed admission to hospital after symptom onset or severe illness on admission, and use of invasive mechanical ventilation or corticosteroids.[127]

Pathophysiology

The pathophysiology of COVID-19 is not fully understood; however, it has been confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme-2 (ACE2) receptor in humans, which suggests a similar pathogenesis to SARS.[28][128] A unique structural feature of the spike glycoprotein receptor binding domain of SARS-CoV-2 (which is responsible for the entry of the virus into host cells) confers potentially higher binding affinity for ACE2 on host cells compared with SARS-CoV.[129] Mechanistic evidence from other coronaviruses suggests that SARS-CoV-2 may downregulate ACE2, leading to a toxic overaccumulation of plasma angiotensin-II, which may induce acute respiratory distress syndrome and fulminant myocarditis.[130][131]

Based on an analysis of single-cell RNA sequencing datasets derived from major human physiological systems, the organs considered more vulnerable to SARS-CoV-2 infection due to their ACE2 expression levels include the lungs, heart, oesophagus, kidneys, bladder, and ileum.[132]This may explain the extrapulmonary manifestations associated with infection. Lower expression of ACE2 in the nasal epithelium of children ages <10 years compared with adults may explain why COVID-19 is less prevalent in children; however, further research on this is required.[133]

The virus uses the host transmembrane protease serine 2 (TMPRSS2) for S protein priming and fusion of viral and host cell membranes.[134]Higher expression of TMPRSS2 has been noted in the nasal epithelium of Black people compared with Asian people, Latin people, White people, and people of mixed race/ethnicity, which may be a contributing factor to the higher burden of infection among Black people.[135]

A furin-like cleavage site has been identified in the spike protein of the virus; this does not exist in other SARS-like coronaviruses.[136]

Autopsy studies have revealed that patients who died of respiratory failure had evidence of exudative diffuse alveolar damage with massive capillary congestion, often accompanied by microthrombi. Hyaline membrane formation and pneumocyte atypical hyperplasia are common. Pulmonary artery obstruction by thrombotic material at both the macroscopic and microscopic levels has been identified. Patients also had signs of generalised thrombotic microangiopathy. Severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes has been noted. Other findings include bronchopneumonia, pulmonary embolism, alveolar haemorrhage, and vasculitis. Significant new blood vessel growth through intussusceptive angiogenesis distinguishes the pulmonary pathology of COVID-19 from severe influenza infection.[137][138][139][140][141][142]

Histopathological examination of brain specimens showed hypoxic changes but no encephalitis or other specific brain changes due to the virus in one autopsy study. The virus was detected at low levels in brain tissue.[143]

SARS-CoV-2 has been frequently detected in the myocardium in autopsy studies.[144] The virus, along with inflammatory changes, has been reported in the cardiac tissue of a child with paediatric inflammatory multisystem syndrome.[145]

Other novel findings at autopsy include pancreatitis, pericarditis, adrenal microinfarction, secondary disseminated mucormycosis, and brain microglial activation.[146]

There is a hypothesis that COVID-19 is a disease of the endothelium.[147][148][149] Endotheliopathy and platelet activation appear to be important features of COVID-19 in hospitalised patients and are likely to be associated with coagulopathy, critical illness, and death.[150] Hyperviscosity has been reported in patients. It is known to damage the endothelium, and is a known risk factor for thrombosis. The potential link between hyperviscosity and thrombotic complications warrants further investigation.[151]

Genetic factors are thought to play a role in the pathogenesis. In a case series of four male patients with severe disease, rare putative loss-of-function variants of X-chromosomal TLR7 were identified, and this was associated with impairment of interferon responses.[152]

Classification

World Health Organization: COVID-19 disease severity[2]

Mild illness

  • Symptomatic patients meeting the case definition for COVID-19 without evidence of hypoxia or pneumonia.

  • Common symptoms include fever, cough, fatigue, anorexia, dyspnoea, and myalgia. Other non-specific symptoms include sore throat, nasal congestion, headache, diarrhoea, nausea/vomiting, and loss of smell/taste.

  • Older people and immunosuppressed people may present with atypical symptoms (e.g., fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium, absence of fever).

  • Symptoms due to physiological adaptations of pregnancy or adverse pregnancy events (e.g., dyspnoea, fever, gastrointestinal symptoms, fatigue) or other diseases (e.g., malaria) may overlap with COVID-19 symptoms.

Moderate disease

  • Adolescent or adult: clinical signs of pneumonia (i.e., fever, cough, dyspnoea, fast breathing) but no signs of severe pneumonia, including blood oxygen saturation levels (SpO₂) ≥90% on room air.

  • Children: clinical signs of non-severe pneumonia (i.e., cough or difficulty breathing plus fast breathing and/or chest indrawing) and no signs of severe pneumonia. Fast breathing is defined as:

    • <2 months of age: ≥60 breaths/minute

    • 2-11 months of age: ≥50 breaths/minute

    • 1-5 years years of age: ≥40 breaths/minute.

  • While the diagnosis can be made on clinical grounds, chest imaging may assist in diagnosis and identify or exclude pulmonary complications.

Severe disease

  • Adolescent or adult: clinical signs of pneumonia (i.e., fever, cough, dyspnoea, fast breathing) plus one of the following:

    • Respiratory rate >30 breaths/minute

    • Severe respiratory distress

    • SpO₂ <90% on room air.

  • Children: clinical signs of pneumonia (i.e., cough or difficulty in breathing) plus at least one of the following:

    • Central cyanosis or SpO₂ <90%

    • Severe respiratory distress (e.g., fast breathing, grunting, very severe chest indrawing)

    • General danger sign

    • Inability to breastfeed or drink, lethargy or unconsciousness, or convulsions.

  • While the diagnosis can be made on clinical grounds, chest imaging may assist in diagnosis and identify or exclude pulmonary complications.

Critical disease

  • Presence of acute respiratory distress syndrome (ARDS), sepsis, or septic shock.

  • Other complications include acute pulmonary embolism, acute coronary syndrome, acute stroke, and delirium.

National Institutes of Health: clinical classification of COVID-19[3]

Asymptomatic or presymptomatic infection

  • People who test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but have no symptoms.

Mild illness

  • People who have any of various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnoea, or abnormal imaging.

Moderate illness

  • People who have evidence of lower respiratory disease by clinical assessment or imaging and an oxygen saturation (SpO₂) >93% on room air at sea level.

Severe illness

  • People who have respiratory frequency >30 breaths per minute, SpO₂ ≤93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <300, or lung infiltrates >50%.

Critical illness

  • People who have respiratory failure, septic shock, and/or multiple organ dysfunction.

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