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.[1] Coronaviruses are a large family of enveloped RNA viruses, some of which cause illness in people (e.g., common cold, SARS, MERS), and others that circulate among mammals (e.g., bats, camels) 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 severe acute respiratory syndrome (SARS)-like coronaviruses from bats, but it is distinct from SARS-CoV and Middle East respiratory syndrome (MERS)-CoV.[17][18] 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.[19]

com.bmj.content.model.Caption@64130413[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.[20][21][22]

  • While the potential animal reservoir and intermediary host(s) are unknown at this point, studies suggest they may derive from a recombinant virus between the bat coronavirus and an origin-unknown coronavirus; however, this is yet to be confirmed.[17][18][23][24] Pangolins have been suggested as an intermediate host as they have been found to be a natural reservoir of SARS-CoV-2-like coronaviruses.[25][26]

Transmission dynamics

  • Transmission dynamics of the virus are currently unknown and the situation is rapidly evolving. Person-to-person spread has been confirmed in community and healthcare settings, with local transmission reported in many countries around the world.

  • It is uncertain how easily the virus spreads between people, but transmission in chains involving several links is increasingly recognised. Available evidence indicates that human transmission occurs via close contact with respiratory droplets produced when a person exhales, sneezes, or coughs, or via contact with fomites. Airborne transmission has not been reported; however, it may be possible during aerosol-generating procedures performed in clinical care.[20][22][27][28]

  • 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).[29] This study also found that the virus was viable in aerosol particles for up to 3 hours; however, aerosols were generated using high-powered apparatus that do not reflect normal human cough conditions or a clinical setting where aerosol-generating procedures are performed. The World Health Organization has confirmed that there have been no reports of airborne transmission.[30]

  • The contribution to transmission by the presence of the virus in other body fluids is unknown; however, the virus has been detected in blood, saliva, tears, cerebrospinal fluid, and conjunctival secretions. Faecal-oral transmission may be possible, although it has not been reported yet.[31][32][33][34][35][36]

  • 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 Huanan South China Seafood Market, whereas only 8.6% of cases after this date were linked to the market. This confirms that person-to-person spread occurred among close contacts since the middle of December 2019, including infections in healthcare workers. One study of a family cluster of five patients in Shenzhen who had a history of travel to Wuhan City (with one other family member who did not travel to Wuhan City) found that person-to-person spread is possible in both hospital and family settings.[22]

  • Nosocomial transmission in healthcare workers and patients has been reported in 41% of patients in one case series.[37]

  • Widespread transmission has been reported in long-term care facilities and on cruise ships (19% of 3700 passengers and crew were infected aboard the Diamond Princess).[38][39]

Asymptomatic transmission

  • Estimating the prevalence of asymptomatic cases in the population is difficult. The best evidence so far comes from the Diamond Princess cruise ship, which was quarantined with all passengers and crew members repeatedly tested and closely monitored. A modelling study found that approximately 700 people with confirmed infection (18%) were asymptomatic.[40] However, a Japanese study of citizens evacuated from Wuhan City estimates the rate to be closer to 31%.[41] Early data from an isolated village of 3000 people in Italy estimates the figure to be higher at 50% to 75%.[42]

  • The proportion of asymptomatic cases in children is thought to be significant, and children may play a role in community spread.[43]

  • There is mounting evidence that spread from asymptomatic carriers can occur and this has been observed in endemic areas.[44][45][46][47][48][49] Presymptomatic transmission has been reported in 12.6% of cases in one study.[50]

Superspreading events

  • Multiple superspreading events have been reported with COVID-19. These events are associated with explosive growth early in an outbreak and sustained transmission in later stages.[51]

  • Superspreaders can pass the infection on to large numbers of contacts, including healthcare workers. This phenomenon is well documented for infections such as severe acute respiratory syndrome (SARS), Ebola virus infection, and MERS.[52][53]

  • Some of these individuals are also 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 and environmental factors.[52]

Perinatal transmission

  • It is unknown whether perinatal transmission (including transmission via breastfeeding) is possible. Retrospective reviews of pregnant women with COVID-19 found that there is no evidence for intrauterine infection in women with COVID-19.[54][55] However, vertical transmission cannot be ruled out. There have been case reports of infection in neonates born to mothers with COVID-19, and virus-specific antibodies have also been detected in neonatal serum samples.[56][57][58][59][60]

Pathophysiology

Incubation period

  • Current estimates of the incubation period range from 1 to 14 days, according to the World Health Organization and the US Centers for Disease Control and Prevention.[61][62]

  • The median incubation period has been estimated to be approximately 5 days.[22][63] However, a pre-print study (not peer reviewed) suggests that the median incubation period may be longer (7 days in adults and 9 days in children with a range of 0 to 33 days).[64]

  • Transmission may be possible during the incubation period.[65]

Reproductive number

  • Preliminary reports suggest that the reproductive number (R₀), the number of people who acquire the infection from an infected person, is approximately 2.2.[22][66] However, as the situation is still evolving, the R₀ may actually be higher or lower.

  • The secondary attack rate for SARS-CoV-2 is estimated to be 0.45% for close contacts of US patients.[28]

Angiotensin-converting enzyme-2 receptor

  • While the pathophysiology of this condition is currently unknown, it is thought that the virus binds to the angiotensin-converting enzyme-2 (ACE2) receptor in humans, which suggests that it may have a similar pathogenesis to SARS.[18][67] However, 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.[68] A furin-like cleavage site has been identified in the spike protein of the virus; this does not exist in other SARS-like coronaviruses.[69]

  • 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.[70]

  • Mechanistic evidence from other coronaviruses suggests that SARS-CoV-2 may downregulate ACE2, leading to a toxic overaccumulation of angiotensin-II, which may induce acute respiratory distress syndrome and fulminant myocarditis.[71]

Viral load and shedding

  • High viral loads have been detected in nasal and throat swabs soon after symptom onset, and it is thought that the viral shedding pattern may be similar to that of patients with influenza. An asymptomatic patient was found to have a similar viral load compared with symptomatic patients.[72][73]

  • The median duration of viral shedding is approximately 20 days in survivors.[74]

Classification

World Health Organization: clinical classification of COVID-19[5]

Mild illness

  • Patients with uncomplicated upper respiratory tract viral infection may have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnoea, nasal congestion, or headache. Rarely, patients may also present with diarrhoea, nausea, and vomiting.

  • Older and/or immunosuppressed patients may present with atypical symptoms.

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

Pneumonia

  • Adults: pneumonia with no signs of severe pneumonia (see below) and no need for supplemental oxygen.

  • Children: pneumonia with cough or difficulty breathing plus fast breathing (i.e., <2 months of age: ≥60 breaths/minute; 2-11 months of age: ≥50 breaths/minute; 1-5 years years of age: ≥40 breaths/minute) and no signs of severe pneumonia (see below).

Severe pneumonia in adults and adolescents

  • Fever or suspected respiratory infection plus one of the following:

    • Respiratory rate >30 breaths/minute

    • Severe respiratory distress

    • SpO₂ ≤93% on room air.

Severe pneumonia in children

  • Cough or difficulty breathing plus at least one of the following:

    • Central cyanosis or SpO₂ <90%

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

    • Signs of pneumonia with a general danger sign (i.e., inability to breastfeed or drink, lethargy or unconsciousness, or convulsions).

  • Other signs of pneumonia may be present in children including chest indrawing or fast breathing (i.e., <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 is made on clinical grounds, chest imaging may identify or exclude some pulmonary complications.

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