Etiology

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.[27]

  • 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.[28][29] 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.[30]

com.bmj.content.model.Caption@6df37428[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]

  • 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.[28][29][34][35] Pangolins have been suggested as an intermediate host as they have been found to be a natural reservoir of SARS-CoV-2-like coronaviruses.[36][37] Over 5 months after the initial outbreak, the virus is yet to be identified in an animal host.[38]

Transmission dynamics

  • 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.[33]

  • 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. Transmission via fomites also appears to be likely. 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. Further research is required.[39]

  • Preliminary reports suggested that the reproductive number (R₀), the number of people who acquire the infection from an infected person, was estimated to be 2.2 to 3.3.[33][40] However, the R₀ may actually be lower in light of social distancing measures that have been instituted.[41]

  • 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).[42] In healthcare settings, the virus is widely distributed in the air and on object surfaces (e.g., floors, trash cans, sickbed handrails, and computer mice) in both general wards and intensive care units, with a greater risk of contamination in the intensive care unit.[43] While viral RNA has been detected on surfaces and air samples across a range of acute healthcare settings, no virus has been cultured from these samples indicating that the deposition may reflect nonviable viral RNA.[44]

  • The virus has been detected in feces. The pooled detection rate of fecal SARS-CoV-2 RNA in patients with COVID-19 is approximately 44%. The rate is higher in female patients, those with gastrointestinal symptoms, and patients with severe disease.[45] Observational and mechanistic evidence supports the hypothesis that SARS-CoV-2 can infect and be shed from the gastrointestinal tract.[46] While fecal-oral transmission (or respiratory transmission through aerosolized feces) may be possible, it has not been reported as yet.

  • The contribution to transmission by the presence of the virus in other body fluids is unknown; however, the virus has been detected in blood, cerebrospinal fluid, pericardial fluid, pleural fluid, placental tissue, urine, semen, saliva, tears, and conjunctival secretions.[47][48][49][50][51][52][53][54][55] The presence of virus or viral components in these fluids or viral RNA shedding does not necessarily equate with infectivity. Sexually transmitted infection has not yet been reported.[54] The SARS-CoV-2 virus has been detected in the middle ear and mastoid in a small number of patients.[56]

  • Nosocomial transmission in healthcare workers and patients has been reported in 44% of patients.[57] The nosocomial infection rate in a major London teaching hospital was around 15% during the peak of the outbreak, with a case fatality rate of 36% for this cohort.[58] Recent reports of healthcare workers exposed to index cases (not in the presence of aerosol-generating procedures) found no nosocomial transmission when contact and droplet precautions were used.[39]

  • Widespread transmission has been reported in long-term care facilities, homeless shelters, meat processing facilities, and prisons, and on cruise ships (19% of 3700 passengers and crew were infected aboard the Diamond Princess).[59][60][61][62][63][64][65] Approximately 16,000 cases have been reported in meat and poultry processing facility workers in the US across 23 states and 239 facilities, with 87% of cases occurring in racial or ethnic minorities.[66] There is a lack of evidence for transmission in the school setting.[67]

  • Clusters of cases originating from family gatherings, overnight youth camps, weddings, choir practices, fitness classes, religious gatherings, and churches have been reported.[68][69][70][71][72][73][74] Nonpharmaceutical interventions (e.g., arrival quarantine, social distancing, cloth face coverings, rapid isolation) may limit the incidence and spread in congregate settings according to a study at a US air force base.[75]

  • The secondary attack rate among all close contacts is approximately 0.45% to 0.7%.[76][77] The secondary attack rate among household members is higher and ranges from 4.6% to 30%.[76][77][78][79] The secondary attack rate is higher for spouse contacts of the index case. The rate lowered to 0% in one study where index patients were quarantined by themselves from the onset of symptoms.[79] The secondary attack rate in children is lower compared with adults. In one study, the secondary attack rate in children was 6.1%; children ages <5 years had lower rates of infection (1.3%) compared with older children following exposure to an infected household member. The risk of secondary infection in children was higher if the household index case was the mother.[80] The secondary attack rate in children exposed to a positive case in a childcare setting or school was 1.2% in one study.[81]

Symptomatic transmission

  • Transmission mainly occurs from symptomatic people to others by close contact through respiratory droplets, by direct contact with infected people, or by contact with contaminated objects and surfaces.[2]

Presymptomatic transmission

  • The incubation period is estimated to be between 1 and 14 days, with a median of 5 to 6 days. Some patients may be contagious during the incubation period, usually 1 to 3 days before symptom onset. Presymptomatic transmission still requires the virus to be spread by infectious droplets or by direct or indirect contact with bodily fluids from an infected person.[2]

  • Presymptomatic transmission has been reported in 12.6% of cases in China.[82] A study in Singapore identified 6.4% of patients among seven clusters of cases in which presymptomatic transmission was likely to have occurred 1 to 3 days before symptom onset.[83]

  • The overall 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.[84]

Asymptomatic transmission

  • An asymptomatic case is a laboratory-confirmed case who does not develop symptoms. There is some evidence that spread from asymptomatic carriers is possible, although it is thought that transmission is greatest when people are symptomatic (especially around the time of symptom onset).[85][86][87][88][89][90][91] According to the World Health Organization, asymptomatic individuals are much less likely to transmit the virus than those who develop symptoms.[92] A case of an asymptomatic patient with 455 contacts found that none of the contacts (which included other patients, family members, and healthcare workers) became infected.[93] The majority of asymptomatically infected people remained asymptomatic throughout the course of infection in one cohort study.[94] Another small retrospective cohort study found no evidence of asymptomatic transmission from nine carriers to any close contacts over an average of 85 days.[95] Despite the reassuring data, there is some limited evidence for suspected asymptomatic transmission.[96]

  • Estimating the prevalence of asymptomatic cases in the population is difficult. A meta-analysis of over 50,000 patients found that approximately 15.6% of confirmed COVID-19 patients are asymptomatic, and nearly half of these patients will develop symptoms later. Children are more likely to have asymptomatic infection.[97] Studies with a large sample size (>1000) estimate that 1.2% to 12.9% of people who contract COVID-19 are likely to be asymptomatic.[98] 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 modeling study found that approximately 700 people with confirmed infection (18%) were asymptomatic.[99] However, a Japanese study of citizens evacuated from Wuhan City estimates the rate to be closer to 31%.[100] Early data from an isolated village of 3000 people in Italy estimates the figure to be higher at 50% to 75%.[101] Other studies ranged from 4% to 80%.[102] A narrative review of 16 cohorts found that the asymptomatic infection rate could be as high as 40% to 45%.[103]

  • Data from a long-term care facility in the US found that 30% of patients with positive test results were asymptomatic (or presymptomatic) on the day of testing.[104] In a skilled nursing facility, 64% of residents tested positive 3 days after one resident tested positive; 56% of the residents who tested positive and participated in point-prevalence surveys were asymptomatic at the time of testing, although most went on to develop symptoms.[105]

  • Asymptomatic transmission from healthcare workers may be a source of transmission. Among 249 healthcare workers who worked in hospital units with COVID-19 patients for 1 month, 7.6% tested positive for SARS-CoV-2 antibodies; however, only 58% of those with positive serology reported symptoms of a prior viral illness.[106] 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.[107]

  • Asymptomatic (or paucisymptomatic) transmission has been reported in family clusters.[108]

  • The proportion of asymptomatic cases in children is thought to be significant, and children may play a role in community spread.[109] However, there is a case report of an asymptomatic child who did not transmit the disease to 172 close contacts, despite close interactions within schools. This suggests that there may be different transmission dynamics in children.[110]

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.[111] 

  • 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.[112][113]

  • 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 behavioral and environmental factors.[112]

Perinatal transmission

  • Vertical transmission is possible but appears to occur in a minority of cases (3.2%) in the third trimester.[114] Suspected intrauterine transmission and transplacental transmission have been reported.[115][116] The rate of infection is not greater when the baby is born vaginally, breastfed, or allowed contact with the mother.[117] Viral fragments have been detected in breast milk, but the significance of this is unknown.[118][119][120]

  • Perinatal transmission is unlikely to occur if correct hygiene precautions are taken. In a study of 1481 deliveries, 8% of mothers tested positive for SARS-CoV-2. About 83% of neonates roomed in with their mother and were breastfed. All neonates who were tested with reverse-transcription polymerase chain reaction (RT-PCR) at 5 to 7 days and 14 days of life tested negative for SARS-CoV-2.[121]

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.[122][123] High viral load at baseline may be associated with more severe disease and risk of disease progression.[124]

  • Pharyngeal viral shedding is high during the first week of symptoms when symptoms are mild or prodromal, peaking on day 4. This suggests active virus replication in upper respiratory tract tissues.[125] 

  • The median duration of viral shedding has been estimated to be between 8 and 20 days after symptoms resolve. However, the virus has been detected for up to 60 days in various samples, and for 104 days in one pregnant woman.[126][127][128][129][130][131][132] Viral shedding continued until death in nonsurvivors.[126]

  • Duration of viral shedding was longer in symptomatic patients compared with asymptomatic patients (25.2 days versus 22.6 days).[133] The median duration of shedding was lower in mild illness compared with severe illness (14 days versus 21 days).[134] 

  • Viral shedding in stool has been detected in 41% of patients.[135] The duration of viral shedding is significantly longer in stool samples than in respiratory and serum samples. The median duration of viral shedding in stool samples was 22 days, compared with 18 days in respiratory samples and 16 days in serum samples.[134]

  • 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.[136]

  • There is no convincing evidence that duration of viral shedding correlates with duration of infectivity.[137]

Pathophysiology

The pathophysiology of COVID-19 is not fully understood; however, it has been confirmed that SARS-CoV-2 binds to the angiotensin-converting enzyme-2 (ACE2) receptor in humans, which suggests a similar pathogenesis to SARS.[29][138] 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.[139] 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.[140][141]

Based on an analysis of single-cell RNA sequencing datasets derived from major human physiologic systems, the organs considered more vulnerable to SARS-CoV-2 infection due to their ACE2 expression levels include the lungs, heart, esophagus, kidneys, bladder, and ileum.[142] 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.[143]

The virus uses the host transmembrane protease serine 2 (TMPRSS2) for S protein priming and fusion of viral and host cell membranes.[144] A furin-like cleavage site has been identified in the spike protein of the virus; this does not exist in other SARS-like coronaviruses.[145] 

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 generalized 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 hemorrhage, and vasculitis. Significant new blood vessel growth through intussusceptive angiogenesis distinguishes the pulmonary pathology of COVID-19 from severe influenza infection.[146][147][148][149][150][151]

Histopathologic 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.[152] The virus has also been frequently detected in the myocardium in autopsy studies.[153]

There is a hypothesis that COVID-19 is a disease of the endothelium.[154][155][156] Endotheliopathy and platelet activation appear to be important features of COVID-19 in hospitalized patients and are likely to be associated with coagulopathy, critical illness, and death.[157] 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.[158]

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.[159]

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, dyspnea, and myalgia. Other nonspecific symptoms include sore throat, nasal congestion, headache, diarrhea, nausea/vomiting, and loss of smell/taste.

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

  • Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events (e.g., dyspnea, 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, dyspnea, fast breathing) but no signs of severe pneumonia, including blood oxygen saturation levels (SpO₂) ≥90% on room air.

  • Children: clinical signs of nonsevere 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, dyspnea, 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, dyspnea, 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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