• 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.[31]

  • 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.[32][33] The full genome has been determined and published in GenBank. GenBank external link opens in a new window

  • See the Classification section below for information on SARS-CoV-2 variants.

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.[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 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.[36] More recent studies suggest that the virus may have emerged earlier than previously thought.[37]

  • Some studies suggest that SARS-CoV-2 may be a recombinant virus between a bat coronavirus and an origin-unknown coronavirus.[32][33][38][39] Pangolins and minks have been suggested as possible intermediate hosts.[40][41][42][43] 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.[44] 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.[45] 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.[46]

  • 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.[46][47] 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.[48] The risk of transmission is much lower outdoors compared with indoors, with a limited number of studies estimating a transmission rate of <1%.[49] Evidence that nebuliser treatments increase the risk of transmission of coronaviruses similar to SARS-CoV-2 is inconclusive, and there is minimal direct evidence about the risk for transmission of SARS-CoV-2.[50]

  • 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.[45] While the majority of studies report identification of the virus on inanimate surfaces, there is a lack of evidence to demonstrate recovery of viable virus.[51]

  • 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.[45] 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.[52]

  • Transmission via other body fluids (including sexual transmission or bloodborne transmission) has not been reported.[45] 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.[53][54][55][56][57][58][59][60][61][62][63][64][65] While SARS-CoV-2 is not sexually transmitted, it may have an effect on male fertility, although this is yet to be confirmed.[66]

  • Vertical transmission occurs rarely and transplacental transmission has been documented. There is limited evidence on the extent of vertical transmission and its timing.[67] 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.[68] The rate of infection appears to be no greater when the baby is born vaginally, breastfed, or allowed contact with the mother.[69] 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.[70] Vertical transmission is unlikely to occur if correct hygiene precautions are taken.[71]

  • 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.[72] Hospital-acquired infections accounted for approximately 11.3% of infections in the UK between February and August 2020. This peaked at 15.8% in the middle of May. Rates as high as 25% were reported in some areas in October 2020. Rates were notably higher in residential community care hospitals (61.9%) and mental health hospitals (67.5%) compared with acute and general care hospitals (9.7%).[73][74] 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.[46][75]

Transmission dynamics in relation to symptoms

  • Transmission is more likely if contacts are exposed shortly before or after symptom onset in the index patient. In one study, the risk of transmission to close contacts was higher if exposure occurred between -2 and 3 days from symptom onset in the index patient. Among contacts who became infected, asymptomatic infection was more common if they were exposed to an asymptomatic index patient, suggesting that disease severity in the index patient may be associated with the clinical presentation of disease.[76]

  • 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.[46][77]

  • Presymptomatic transmission

    • Transmission may occur during the incubation period, usually 1 to 3 days before symptom onset.[77]

    • Presymptomatic transmission was reported in 12.6% of cases in China, and 6.4% of cases in Singapore.[78][79]

    • 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).[80][81][82][83][84][85][86] The World Health Organization states that asymptomatic cases are not the major driver of the overall epidemic dynamics.[87] Numerous studies have reported no evidence of asymptomatic transmission from carriers of SARS-CoV-2.[88][89][90] 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.[91]

    • 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.[92] The overall estimate of the proportion of people who become infected and remain asymptomatic throughout infection has been estimated to be 17% to 33%.[93][94][95][96] Another meta-analysis found that 35.1% of patients were truly asymptomatic (i.e., never developed clinical symptoms). This analysis excluded index cases, thereby correcting a bias that may lead to underestimation of asymptomaticity in other analyses.[97]

    • 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.[98] 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.[99]

    • Some reports from early in the pandemic suggested that children were presenting with asymptomatic disease more commonly than adults. Although there is some evidence that older children have higher rates of asymptomatic disease than infants <1 year of age, the majority of children present with symptomatic disease and do not appear to be silent spreaders of infection.[13]

Superspreading events

  • Superspreading events have been reported. These events are associated with explosive growth early in an outbreak and sustained transmission in later stages.[100]

  • 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 centres.[45][101][102][103][104] Widespread transmission has also been reported in long-term care facilities, homeless shelters, prisons, immigration detention centres, and meat and poultry processing facilities, as well as on board cruise ships.[105][106][107][108][109][110][111][112][113]

  • Limited transmission has been reported in childcare, school, and university settings, and infected cases may transmit the infection to their household members.[114][115][116] 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%).[117] In one study, infection in close contacts in secondary schools and colleges in England was uncommon (approximately 2%).[118]

  • 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.[119]

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.[120][121] Viable virus is relatively short lived; infectiousness peaks around 1 day before symptom onset and declines within 7 days.[45]

    • The pooled mean incubation period is 9.6 days in children.[122]

  • 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.[36][123][124][125][126] The US Centers for Disease Control and Prevention gives a current best estimate of 2.5.[127]

    • The R₀ decreases when public health measures (e.g., social distancing) are put in place.[128]

  • 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).[129]

    • Emerging evidence does not support a significant difference in serial interval between the Delta and wild-type variants.[130]

  • 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%.[131]

    • 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).[132]

    • Another systematic review and meta-analysis of household transmission estimates the pooled household secondary attack rate to be slightly lower at 18.9%. The rate is higher for symptomatic index cases compared with asymptomatic cases, contacts with comorbidities compared with contacts without comorbidities, and adults compared with children. Spouses of the index case are more likely to be infected compared with other household members.[133]

    • 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.[87]

    • 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.[134]

    • There is some evidence that children may be less infectious, as measured by secondary attack rates, than adolescents and adults.[13] 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.[135] The secondary attack rate was 1.2% in children in a childcare setting or school.[136] Among households with paediatric index cases, 27% of households experienced secondary transmission, and children aged 0 to 3 years of age were more likely to transmit the infection compared with older children.[137]

    • Secondary attack rates for SARS-CoV-2 variants may differ (see the Classification section below).

  • 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.[138]

    • 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.[139]

  • 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 non-severe illness.[138]

    • 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.[45] There is no convincing evidence that duration of viral shedding correlates with duration of infectivity.[140]

    • 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.[141] Immunocompromised patients may shed for at least 2 months.[142]


The pathophysiology resembles that of other coronavirus infections. However, emerging evidence indicates that COVID-19 has distinctive pathophysiological features that set it apart from respiratory failure of other origins.[143]

SARS-CoV-2 attaches to the angiotensin-converting enzyme-2 (ACE2) receptor on target host cells, followed by internalisation and replication of the virus. ACE2 receptors are highly expressed in the upper and lower respiratory tract cells, but are also expressed in myocardial cells, renal epithelial cells, enterocytes, and endothelial cells in multiple organs, which may explain the extrapulmonary manifestations associated with the disease.[144]

Multi-organ complications of COVID-19 and long COVID. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor[Figure caption and citation for the preceding image starts]: Multi-organ complications of COVID-19 and long COVID. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptorBMJ. 2021;374:n1648 [Citation ends].

The virus uses host transmembrane protease serine 2 (TMPRSS2) for viral spike protein priming and fusion of viral and host cell membranes.[145] The SARS-CoV-2 spike protein plays a key role in the recognition of the ACE2 receptor and cell membrane fusion process. A unique structural feature of the spike glycoprotein receptor-binding domain confers potentially higher binding affinity for ACE2 on host cells compared with SARS-CoV-1.[146] This furin-like cleavage site does not appear to exist in other coronaviruses.[147] The binding energy between the spike protein and ACE2 was highest for humans out of all species tested in one study, suggesting that the spike protein is uniquely evolved to bind to and infect human cells expressing ACE2.[148] Emerging evidence suggests that the spike protein alone may damage endothelial cells by downregulating ACE2 and consequently inhibiting mitochondrial function. Further research is required on whether the spike protein can by itself trigger cell signalling that could lead to various biological processes.[149][150] SARS-CoV-2 variants may be more transmissible, at least in part, due to enhanced spike protein binding affinity for the ACE2 receptor.[151]

Virus replication cycle[Figure caption and citation for the preceding image starts]: Virus replication cycleBMJ. 2020;371:m3862 [Citation ends].

In addition to direct cytopathic viral injury, severe disease is frequently complicated by an infection-induced microangiopathy or hypercoagulable state that causes capillary, venous, and/or arterial thrombosis, which may lead to end-organ damage due to distant thrombotic or embolic disease. The predominant pathological findings in fatal cases were diffuse alveolar damage, coagulopathy, and haemodynamic compromise. Involvement of non-pulmonary organs was limited to mild parenchymal inflammation (e.g., myocarditis, hepatitis, encephalitis). Direct viral cytopathic injury of extrapulmonary organs in general was not regarded as the cause of organ failure.[144] SARS-CoV-2-induced endotheliitis may play a role in both the respiratory and non-respiratory manifestations.[152]


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant classification

All viruses, including SARS-CoV-2, change over time. Most changes have little to no impact on the virus’ properties; however, some changes may affect virus transmission, disease severity, and performance of diagnostic tests, therapeutics, or vaccines.

These variants have been emerging and circulating around the world since the beginning of the pandemic, and are routinely monitored and classified as either variants under monitoring, variants of interest, or variants of concern.[2] These classification systems may vary between countries. For example, in the UK, variants are classified as variants in monitoring, variants under investigation, or variants of concern.[3] In the US, variants are classified as variants being monitored, variants of interest, variants of concern, or variants of high consequence.[4]

The World Health Organization (WHO) has assigned simple labels for key variants using letters of the Greek alphabet. This does not replace existing scientific names (e.g., Pango, Nextstrain, GISAID), which continue to be used in research.[2]

Variant of interest

  • The WHO defines a variant of interest as a variant with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, disease severity, immune escape, or diagnostic or therapeutic escape; and that has been identified to cause significant community transmission or multiple case clusters, in multiple countries with increasing relative prevalence alongside increasing number of cases over time, or other apparent epidemiological impacts to suggest an emerging risk to global public health.[2]

  • Current variants of interest (as designated by WHO) include the Lambda variant (C.37, first identified in Peru in December 2020) and the Mu variant (B.1.621, first identified in Colombia in January 2021).[2] There may be other variants of interest in other countries.

Variant of concern

  • The WHO defines a variant of concern as a variant that has been demonstrated to be associated with one or more of the following changes at a degree of global public health significance:[2]

    • Increase in transmissibility or detrimental change in epidemiology

    • Increased virulence or change in clinical disease presentation

    • Decrease in effectiveness of public health and social measures, or available diagnostics, therapeutics, or vaccines.

  • Current variants of concern (as designated by WHO) are detailed below.[2] These variants may not be variants of concern in some countries, or may have been downgraded from a variant of concern in other countries.

Alpha variant

The Alpha variant is classified as a variant of concern by the WHO and the UK Health Security Agency, but has been downgraded to a variant being monitored in the US.[2][3][4]

  • Pango lineage: B.1.1.7.

  • Earliest documented samples: UK (September 2020).

  • Transmissibility: appears greater than the wild type virus.[3]

  • Disease severity: appears to be associated with an increased risk of hospitalization and intensive care unit admission (suggesting more severe disease), but not mortality, compared with the wild-type virus, although data are conflicting. Not associated with changes in the symptoms reported or their duration.[5][6][7][8]

Beta variant

The Beta variant is classified as a variant of concern by the WHO and the UK Health Security Agency, but has been downgraded to a variant being monitored in the US.[2][3][4]

  • Pango lineage: B.1.351.

  • Earliest documented samples: South Africa (May 2020).

  • Transmissibility: no more transmissible than Alpha.[3]

  • Disease severity: insufficient information available.[3]

Gamma variant

The Gamma variant is classified as a variant of concern by the WHO and the UK Health Security Agency, but has been downgraded to a variant being monitored in the US.[2][3][4]

  • Pango lineage: P.1.

  • Earliest documented samples: Brazil (November 2020).

  • Transmissibility: appears greater than the wild type virus.[3]

  • Disease severity: insufficient information available.[3]

Delta variant

The Delta variant is classified as a variant of concern by the WHO, the UK Health Security Agency, and the US Centers for Disease Control and Prevention.[2][3][4] It is currently the dominant variant in many countries around the world including the UK and the US.

  • Pango lineage: B.1.617.2 (including all AY sublineages).

  • Earliest documented samples: India (October 2020).

  • Transmissibility: appears greater than the wild type virus and Alpha. In the UK, the secondary attack rate among household contacts of cases that have not travelled is 10.6%, compared with 10.2% with Alpha (as of 28 September).[3]

  • Disease severity: appears to be associated with an increased risk of hospitalisation (suggesting more severe disease) compared with contemporaneous Alpha cases; however, there is a high level of uncertainty in these findings. The crude case fatality rate is estimated to be 0.4%, considerably less than the Alpha variant (as of 1 October 2021).[3]


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