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.[36]

  • 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.[37][38] The full genome has been determined and published in GenBank. GenBank external link opens in a new window

com.bmj.content.model.Caption@7272773a[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].

Emerging SARS-CoV-2 variants

  • All viruses, including SARS-CoV-2, change over time. Over 394,000 variants of the virus have been sequenced by the COVID-19 Genomics UK Consortium (COG-UK) as of 6 April 2021. COG-UK: data external link opens in a new window

  • Noteworthy SARS-CoV-2 variants of concern (VOC) include the following.

    • VOC-20DEC-01 (B.1.1.7 lineage): first identified in Kent, South East of England in September 2020, and reported to the World Health Organization in December 2020. The origin is unclear. It is now the dominant variant in the UK. The variant has been reported in at least 130 countries, and community transmission has been reported in 31 of these countries (as of 31 March 2021). There is evidence that suggests this variant may be more transmissible. Secondary attack rates have been reported to be higher if the index case has this variant. The reported secondary attack rate is 10% in contacts of people without the variant, and 11% in contacts of people with the variant (who have not traveled). However, secondary attack rates for nonvariant forms are known to vary quite widely (see Secondary attack rate below). The variant does not appear to be associated with more severe disease compared with the wild-type virus.[39][40] There is consistent evidence of cross-neutralizing activity in convalescent sera (i.e., sera from individuals who have been infected with B.1.1.7 shows neutralizing activity against viruses from other lineages, and the converse is also true).[41][42][43] The variant has mutations that have been associated with attenuation in other variants.[44] 

    • VOC-21FEB-02 (B.1.1.7 cluster with E484K mutation): a small number of B.1.1.7 sequences have acquired the spike protein mutation E484K. A small cluster of cases has been reported, mostly in South West England. Only one death has been reported with this variant in the UK. International cases have been reported in three countries (as of 31 March 2021).[41] 

    • VOC-20DEC-02 (B.1.351 lineage): first detected in Nelson Mandela Bay, South Africa in October 2020. The variant has been reported in at least 89 countries, including the UK (as of 31 March 2021). The variant has similar spike protein mutations to the B.1.1.7 lineage. Sequence analysis reveals that the N501Y mutation reported in the UK and South Africa originated independently. These mutations may affect its transmissibility and antigenic profile; however, cases, hospitalizations, and deaths are currently decreasing in South Africa.[41]

    • VOC-21JAN-02 (P.1 lineage): a descendant of the B.1.1.28 lineage first detected in Japan in travelers from Brazil. The variant has been reported in at least 38 countries (as of 31 March 2021), including the UK and the US. All cases in the UK have been linked to international travel. Based on modeling and laboratory data, it is plausible that there is some degree of immune escape, or increased transmissibility, or both with this variant. However, the magnitude and clinical significance of these effects are yet to be determined.[41] 

    • B.1.427 and B.1.429 lineages: first detected in California in the US, these variants have been classified as variants of concern by the Centers for Disease Control and Prevention. They have an increased risk of transmission and may not be as responsive to certain treatments.[45]

    • Cluster 5 variant: detected in people in Denmark and associated with transmission from farmed minks. The clinical implications of this new variant are not yet well understood; however, mutations in the spike protein have been reported. No new human cases of the cluster 5 variant have been reported in Denmark since 20 November 2020, and the variant is no longer circulating in humans. All mink on affected mink farms, and farms within an assigned zone, were culled. Seven other countries have reported SARS-CoV-2 in farmed minks (Lithuania, Greece, Spain, Italy, the Netherlands, Sweden, and the US).[46][47]

  • Further investigations are required to more fully understand the impact of these variants. There are many other variants under investigation.

  • In a global study of over 12,000 mutations of the SARS-CoV-2 virus (which excluded the variants above), there was no evidence to suggest that any of the identified SARS-CoV-2 variants were associated with increased transmissibility.[48]

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.[49][50][51] 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.[51]

  • Some studies suggest that SARS-CoV-2 may be a recombinant virus between a bat coronavirus and an origin-unknown coronavirus.[37][38][52][53] Pangolins and minks have been suggested as possible intermediate hosts.[54][55][56][57] However, there is currently no evidence to demonstrate the possible route of transmission from a bat reservoir to human through one or several intermediary animal species.[58] 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.[59] 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.[60]

  • Airborne transmission can occur in healthcare settings during aerosol-generating procedures. There are also some outbreak reports that suggest aerosol transmission is possible in the community under certain conditions; however, these reports relate to enclosed indoor crowded spaces with poor ventilation where the infected person may have been breathing heavily (e.g., restaurants, choir practice, fitness classes). A detailed investigation of these clusters suggests that droplet and fomite transmission could also explain the transmission in these reports.[60][61] While the air close to, and distant from, patients has been found to frequently be contaminated with SARS-CoV-2 RNA, few of these samples contained viable virus.[62]

  • 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.[59] 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, but this does not reflect real-life conditions.[63] In healthcare settings, the virus is widely distributed in the air and on object surfaces in both general wards and intensive care units.[64] However, no virus has been cultured from these samples indicating that the deposition may reflect nonviable viral RNA.[65][66][67]

  • Fecal-oral transmission (or respiratory transmission through aerosolized feces) may be possible, but there is only limited circumstantial evidence to support this mode of transmission.[59] The pooled detection rate of fecal 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.[68] 

  • Transmission via other body fluids (including sexual transmission or bloodborne transmission) has not been reported.[59] While the virus has been detected in blood, cerebrospinal fluid, pericardial fluid, pleural fluid, urine, semen, saliva, ocular tissue including the cornea, 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.[69][70][71][72][73][74][75][76][77][78][79][80][81] SARS-CoV-2 is not sexually transmitted, but may have an effect on male fertility, although this is yet to be confirmed.[82]

  • Vertical transmission occurs rarely and transplacental transmission has been documented. There is limited evidence on the extent of vertical transmission and its timing.[83] Overall, 6.3% of infants born to mothers with COVID-19 tested positive for SARS-CoV-2 at birth. Transmission was reported in both preterm and full-term infants. There is also evidence for antibodies against SARS-CoV-2 among infants born to mothers with COVID-19 who tested negative for SARS-CoV-2.[84] The rate of infection appears to be no greater when the baby is born vaginally, breastfed, or allowed contact with the mother.[85] Viral fragments have been detected in breast milk; however, this finding is uncommon and, when it occurs, has been associated with mild symptoms in infants. Anti-SARS-CoV-2 antibodies are more prevalent in breast milk compared with viral fragments.[86] Vertical transmission is unlikely to occur if correct hygiene precautions are taken.[87]

  • 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.[88] Hospital-acquired infections (defined as patients diagnosed more than 7 days after hospital admission) accounted for approximately 17% of infections in the NHS England as of 26 October 2020, and rates have been as high as 25% in some areas.[89] Studies 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.[60][90]

Transmission dynamics in relation to symptoms

  • Symptomatic transmission

    • Transmission appears to mainly be spread via droplets and close contact with infected symptomatic cases. Transmissibility depends on the amount of viable virus being shed and expelled by a person (viral load is highest just before or around the time of symptom onset and during the first 5-7 days of illness), the type of contact, the setting, and what infection prevention and control measures are in place.[60][91]

  • Presymptomatic transmission

    • Transmission may occur during the incubation period, usually 1 to 3 days before symptom onset.[91] 

    • Presymptomatic transmission was reported in 12.6% of cases in China, and 6.4% of cases in Singapore.[92][93] 

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

  • Asymptomatic transmission

    • Transmission from asymptomatic cases (laboratory-confirmed cases who never develop symptoms) has been reported; however, most of the evidence is based on early data from China and has limitations (e.g., small number of cases, cases may have been presymptomatic).[94][95][96][97][98][99][100] The World Health Organization states that asymptomatic cases are not the major driver of the overall epidemic dynamics.[101] Numerous studies have reported no evidence of asymptomatic transmission from carriers of SARS-CoV-2.[102][103][104] In a post-lockdown screening study in nearly 10 million residents in Wuhan, there were no positive tests among 1174 close contacts of asymptomatic cases. In addition to this, virus culture was carried out on samples from asymptomatic positive cases and all cultures were negative, indicating that asymptomatic positive cases in the study were not infectious.[105]

    • 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 (range 2% to 75%), and nearly half developed symptoms later.[106] The overall estimate of the proportion of people who become infected and remain asymptomatic throughout infection has been estimated to be 17% to 33%.[107][108][109][110]

    • 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.[111] 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.[112]

    • Children are more likely to be asymptomatic.[106] The pooled proportion of asymptomatic cases in children was thought to be significant (around 40%).[113][114] However, recent studies have found that the rate of asymptomatic infection in children was very low (1% compared with 9% in adults in one study, and 0.6% compared with 1.8% in adults in another study), indicating that children appear not to be particular drivers of the pandemic.[115][116]

Superspreading events

  • Superspreading events have been reported. These events are associated with explosive growth early in an outbreak and sustained transmission in later stages.[117] 

  • Reported events include church/religious gatherings, family or social gatherings, weddings, choir practices, overnight youth camps or high school retreats, fitness classes, indoor recreational sporting activities, business conferences, and working in call centers.[59][118][119][120][121] Widespread transmission has also been reported in long-term care facilities, homeless shelters, prisons, immigration detention centers, and meat and poultry processing facilities, as well as on board cruise ships.[122][123][124][125][126][127][128][129][130] 

  • Limited transmission has been reported in childcare, school, and university settings, and infected cases may transmit the infection to their household members.[131][132][133] There is limited high-quality evidence to quantify the extent of transmission in schools, or to compare it with community transmission. However, emerging evidence suggests a lower overall infection attack rate in students (0.15%) compared with school staff (0.7%).[134]

  • 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 behavioral, host, and environmental factors.[135]

Viral transmission factors

  • Incubation period

    • The incubation period is estimated to be between 1 and 14 days, with a median of 5 to 7 days.[2][136] Viable virus is relatively short lived; infectiousness peaks around 1 day before symptom onset and declines within 7 days.[59]

    • The pooled mean incubation period is 9.6 days in children.[9]

  • Reproduction number (R₀)

    • Reports suggest that the reproduction number, the number of people who acquire the infection from an infected person, is estimated to be 2.2 to 3.3. However, there is very high heterogeneity across studies and the number varies between countries.[51][137][138][139] The Centers for Disease Control and Prevention gives a current best estimate of 2.5 (as of 19 March 2021).[140]

    • The R₀ decreases when public health measures (e.g., social distancing) are put in place.[141]

  • Serial interval

    • The time between the start of symptoms in the primary patient and the onset of symptoms in the patient being infected in a chain of transmission has been estimated to be approximately 5.45 days (range 4.2 to 6.7 days).[142]

  • Secondary attack rate

    • The secondary attack rate is the proportion of people exposed to an index (or primary) case that go on to develop the disease as a result of the exposure.

    • The pooled secondary attack rate among all close contacts of an index case has been estimated to be 7%.[143]

    • The secondary attack rate differs between contact settings. More familiar prolonged contact increases the potential for transmission. Pooled estimates of the secondary attack rate range from 1.2% to 5.9% in social settings (depending on level of contact and whether contact is with strangers or family and friends), 1.9% in workplaces (based on limited data), 3.6% in healthcare facilities, and 21.1% for household settings (increases with exposure >5 days).[144]

    • Another systematic review and meta-analysis of household transmission estimates the pooled household secondary attack rate to be slightly lower at 16.6%. The rate is higher for symptomatic index cases (18%) compared with asymptomatic cases (0.7%), and adults have a higher susceptibility to infection compared with children. Spouses of the index case are more likely to be infected compared with other household members.[145] 

    • 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.[101]

    • The secondary attack rate for close contacts of presymptomatic people has been estimated to be approximately 7%, compared with 1% in asymptomatic people and 6% in symptomatic people.[146]

    • Children ages <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.[147] The secondary attack rate was 1.2% in children in a childcare setting or school.[148]

    • Secondary attack rates for SARS-CoV-2 variants may differ (see Emerging SARS-CoV-2 variants above).

  • Viral load

    • Viral load is highest in the upper respiratory tract (nasopharynx and oropharynx) early in the course of infection (usually peaks in the first week of illness), and then increases in the lower respiratory tract (sputum). Viral load decreases after symptom onset. Patients with severe disease have higher viral loads compared with those with mild disease. Viral load in the upper respiratory tract is comparable in asymptomatic and symptomatic patients; however, most studies demonstrate faster viral clearance among asymptomatic people compared with symptomatic people.[149]

    • Viral load appears to be a leading driver of virus transmission. In one cohort study, the secondary attack rate was 17% among 753 contacts of index cases, with a variation from 12% when the index case had a viral load lower than 1x10⁶ copies/mL to 24% when the index case had a viral load of 1x10¹⁰ copies/mL or higher (in nasopharyngeal swabs). Higher viral loads in swabs of asymptomatic contacts were associated with a higher risk of developing symptomatic disease, and these contacts had shorter incubation periods than those with a lower viral load.[150]

  • Viral shedding

    • The mean duration of shedding was 17 days in the upper respiratory tract, 14.6 days in the lower respiratory tract, 17.2 days in stool, and 16.6 days in serum samples. The maximum duration of shedding was 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stool, and 60 days in serum samples. However, no live virus was detected beyond day 9 of symptoms, despite persistently high viral loads. Duration of viral shedding was longer in symptomatic patients compared with asymptomatic patients, and in patients with severe illness compared with those with nonsevere illness.[149]

    • 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.[59] There is no convincing evidence that duration of viral shedding correlates with duration of infectivity.[151] 

    • 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.[152] Immunocompromised patients may shed for at least 2 months.[153]

Pathophysiology

The pathophysiology is not yet fully understood; however, details are emerging.[154] 

com.bmj.content.model.Caption@6ab3a85c[Figure caption and citation for the preceding image starts]: Virus replication cycleBMJ. 2020;371:m3862 [Citation ends].

Angiotensin-converting enzyme-2 (ACE2) receptor

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor in humans, which suggests a similar pathogenesis to SARS.[38][155]

  • 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-1.[156] This furin-like cleavage site does not exist in other SARS-like coronaviruses.[157] The binding energy between the SARS-CoV-2 spike protein and ACE2 was highest for humans out of all species tested, suggesting that the SARS-CoV-2 spike protein is uniquely evolved to bind to and infect human cells expressing ACE2.[158]

  • 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.[159][160]

  • 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.[161] This may explain the extrapulmonary manifestations associated with infection. ACE2 expression has also been identified in the diaphragm, which may lead to diaphragm fibrosis and myopathy.[162]

  • 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.[163]

Transmembrane protease serine 2 (TMPRSS2)

  • SARS-CoV-2 uses host TMPRSS2 for S protein priming and fusion of viral and host cell membranes.[164] 

  • 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.[165]

Autopsy studies

  • Pulmonary: 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.[166][167][168][169][170][171] Some patients with severe disease may develop fibrotic lung disease for which lung transplantation may be the only treatment option.[172]

  • Neurologic: 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.[173] Another study found mild neuropathologic changes, with pronounced neuroinflammatory changes in the brainstem being the most common finding.[174]

  • Cardiac: SARS-CoV-2 has been frequently detected in the myocardium in autopsy studies. While cardiac pathologic findings are prevalent, acute myocarditis is uncommon. The most frequent findings were cardiac dilatation, myocardial ischemia, and thrombosis.[175] The virus, along with inflammatory changes, has been reported in the cardiac tissue of a child with pediatric inflammatory multisystem syndrome.[176]

  • Immunology: the mechanisms contributing to increased thrombosis involve extensive cross-talk between the immune system and hemostasis.[177] Evaluation of immune infiltrate has revealed a notable presence of aggregated neutrophils in the lungs and several other organs. Neutrophilic plugs, composed of neutrophils with neutrophil extracellular traps (NETs) or as aggregates of NETs and platelets, were present in the heart, kidney, liver, and brain. NETs may therefore play a role in coagulopathy associated with SARS-CoV-2 infection. The disproportionate presence of aggregate neutrophils and NETs in comparison with the sporadic presence of virus suggests an autonomous maladaptive immune response.[178] NETs appear to play a role in the pathogenesis of ST-elevation myocardial infarction in COVID-19 patients based on a small case series of patients with COVID-19 and myocardial infarction.[179]

  • Hepatic: a high prevalence of hepatic steatosis, congestion of hepatic sinuses, vascular thrombosis, and fibrosis have been noted, along with portal and lobular inflammation and Kupffer cell hyperplasia or proliferation.[180]

  • Other: other novel findings at autopsy include pancreatitis, pericarditis, adrenal microinfarction, secondary disseminated mucormycosis, and brain microglial activation.[181]

Endothelial dysfunction

  • There is a hypothesis that COVID-19 is a disease of the endothelium.[182][183][184] 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.[185]

  • 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.[186]

Genetic factors

  • Genetic factors are thought to play a role. 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.[187]

  • A novel susceptibility locus has been detected at a chromosome 3p21.31 gene cluster in patients with respiratory failure, which may confirm the involvement of the ABO blood-group system.[188]

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. Additional neurologic manifestations reported include dizziness, agitation, weakness, seizures, or findings suggestive of stroke. Children may not report fever or cough as frequently as adults.

  • 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 signs: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions

    • Fast breathing (<2 months: ≥60 breaths per minute; 2-11 months: ≥50 breaths per minute; 1-5 years: ≥40 breaths per minute).

  • 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, septic shock, acute thrombosis, or multisystem inflammatory syndrome in children.

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) using a virologic test but have no symptoms consistent with COVID-19.

Mild illness

  • People who have any of various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) without shortness of breath, dyspnea, or abnormal chest imaging.

Moderate illness

  • People who have evidence of lower respiratory disease by clinical assessment or imaging and an oxygen saturation (SpO₂) ≥94% on room air at sea level.

Severe illness

  • People who have respiratory frequency >30 breaths per minute, SpO₂ <94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <300 mmHg, or lung infiltrates >50%.

Critical illness

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

Persistent symptoms or organ dysfunction after acute COVID-19

  • People who experience persistent symptoms and/or organ dysfunction after acute disease. Also known as post-acute COVID-19 syndrome or long COVID. See the Complications section for more information.

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