COVID-19: Clinical features

INTRODUCTION — Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries throughout the world. In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019 [1]. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); previously, it was referred to as 2019-nCoV.

Understanding of COVID-19 is evolving. Interim guidance has been issued by the World Health Organization and by the United States Centers for Disease Control and Prevention [2,3]. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

This topic will discuss the clinical features of COVID-19. The epidemiology, virology, prevention, and diagnosis of COVID-19 are discussed elsewhere. (See "COVID-19: Epidemiology, virology, and prevention" and "COVID-19: Diagnosis".)

The management of COVID-19 is also discussed in detail elsewhere:

●(See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

Issues related to COVID-19 in pregnant women and children are discussed elsewhere:

●(See "COVID-19: Overview of pregnancy issues".)

●(See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

See specific topic reviews for details on complications of COVID-19 and issues related to COVID-19 in other patient populations.

Common cold coronaviruses, severe acute respiratory syndrome (SARS) coronavirus, and Middle East respiratory syndrome (MERS) coronavirus are discussed separately. (See "Coronaviruses" and "Severe acute respiratory syndrome (SARS)" and "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology".)

ASYMPTOMATIC INFECTIONS — Asymptomatic infections have been well documented [4-10]. One review performed prior to the introduction of COVID-19 vaccination estimated that 33 percent of people with SARS-CoV-2 infection never develop symptoms [11]. This estimate was based on four large population-based, cross-sectional surveys, among which the median proportion of individuals who had no symptoms at the time of a positive test was 46 percent (range 43 to 77 percent), and on 14 longitudinal studies, among which a median of 73 percent of initially asymptomatic individuals remained so on follow-up. A metanalysis of 95 Chinese and American studies covering almost 30 million tested individuals (including some children) found that 40.5 percent (95% CI 33.5-47.5 percent) of SARS-CoV-2-infected individuals were asymptomatic [12]. However, there is still some uncertainty around the proportion of asymptomatic infections, with a wide range reported across studies. Additionally, the definition of "asymptomatic" may vary across studies, depending on which specific symptoms were assessed. The range of findings in studies evaluating asymptomatic infections is reflected in the following examples:

●In a COVID-19 outbreak on a cruise ship where nearly all passengers and staff were screened for SARS-CoV-2, approximately 19 percent of the population on board tested positive; 58 percent of the 712 confirmed COVID-19 cases were asymptomatic at the time of diagnosis [13,14]. In studies of subsets of those asymptomatic individuals, who were hospitalized and monitored, approximately 77 to 89 percent remained asymptomatic over time [14,15].

●In a smaller COVID-19 outbreak within a skilled nursing facility, 27 of the 48 residents (56 percent) who had a positive screening test were asymptomatic at the time of diagnosis, but 24 of them developed symptoms over the next seven days [16].

●Other studies, particularly those conducted among younger populations, have reported higher proportions of infections that are asymptomatic [7,17-21]. As an example, in an outbreak on an aircraft carrier, a quarter of the crew, among whom the mean age was 27 years, tested positive for SARS-CoV-2 [20]. Among the 1271 cases, only 22 percent were symptomatic at the time of testing and 43 percent remained asymptomatic throughout the observation period. High rates of asymptomatic infection have also been reported among pregnant women presenting for delivery [7,18].

Patients with asymptomatic infection may have objective clinical abnormalities [6,22]. As an example, in a study of 24 patients with asymptomatic infection who all underwent chest computed tomography (CT), 50 percent had typical ground-glass opacities or patchy shadowing, and another 20 percent had atypical imaging abnormalities [22]. Five patients developed low-grade fever, with or without other typical symptoms, a few days after diagnosis. In another study of 55 patients with asymptomatic infection identified through contact tracing, 67 percent had CT evidence of pneumonia on admission; only two patients developed hypoxia, and all recovered [6].

As above, some individuals who are asymptomatic at the time of diagnosis go on to develop symptoms (ie, they were actually presymptomatic). In one study, symptom onset occurred a median of four days (range of three to seven) after the initial positive RT-PCR test [14].

The risk of transmission from patients with asymptomatic infection is discussed elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral shedding and period of infectiousness'.)

SEVERITY OF SYMPTOMATIC INFECTION

Spectrum of severity and fatality rates

●Spectrum of infection severity – The spectrum of symptomatic infection ranges from mild to critical; most infections are not severe [23-28]. Specifically, a report from the Chinese Center for Disease Control and Prevention during the first months of the pandemic included approximately 44,500 confirmed infections and found the following [27]:

•Mild disease (no or mild pneumonia) was reported in 81 percent.

•Severe disease (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours) was reported in 14 percent.

•Critical disease (eg, with respiratory failure, shock, or multiorgan dysfunction) was reported in 5 percent.

•The overall case fatality rate was 2.3 percent; no deaths were reported among noncritical cases.

Similarly, in a report of 1.3 million cases reported to the United States Centers for Disease Control and Prevention (CDC) through the end of May 2020, 14 percent were hospitalized, 2 percent were admitted to the intensive care unit (ICU), and 5 percent died [28]. The individual risk of severe illness varies by age, underlying comorbidities, and vaccination status. (See 'Risk factors for severe illness' below.)

Additionally, different SARS-CoV-2 variants have been associated with varying risks of severe disease. As an example, Omicron variant (B.1.1.529) appears to be associated with milder illness [29-32]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Omicron (B.1.1.529) and its sublineages'.)

●Infection fatality rates – The case fatality rate only indicates the mortality rate among documented cases. Since many SARS-CoV-2 infections are asymptomatic and many mild infections do not get diagnosed, the infection fatality rate (ie, the estimated mortality rate among all individuals with infection) is considerably lower and has been estimated in some analyses of unvaccinated individuals to be between 0.15 and 1 percent, with substantial heterogeneity by location and across risk groups [33-36]. In a systematic analysis that calculated the total number of community infections through seroprevalence surveys from 53 countries (including both resource-rich and resource-limited settings) prior to vaccine availability, the infection fatality rate [IFR] was 0.005 percent at 1 year, decreased to 0.002 percent by age 7, and increased exponentially after that: 0.006 percent at age 15, 0.06 percent at age 30, 0.4 percent at age 50, 2.9 percent at age 70, and 20 percent at age 90) [37]. The median IFR decreased from 0.47 percent in April 2020 to 0.31 percent in January 2021.

●Fatality rates among hospitalized patients – Among hospitalized patients, the risk of critical or fatal disease is high among unvaccinated individuals [38-44], and the in-hospital fatality rate associated with COVID-19 is higher than that for influenza [45-47]. As an example, in a United States survey of over 16,000 patients hospitalized for COVID-19 between March and December 2020, the fatality rate was 11.4 percent overall and ranged monthly from 7.1 to 17.1 percent [48]. Over the course of the pandemic, declining in-hospital fatality rates had been reported, even prior to widespread vaccination [49-52]. The reasons for this observation are uncertain, but potential explanations include improvements in hospital care of COVID-19 and better allocation of resources when hospitals are not overburdened.

In resource-limited settings, in-hospital mortality rates may be higher than those reported elsewhere. As an example, in a study from 10 countries in Africa, where there was a median of two intensive care specialists in each hospital and a minority of facilities did not have pulse oximetry, the in-hospital 30-day mortality rate following critical care admission was 48 percent [53]. Mortality was associated with underlying comorbidities as well as resource shortages.

●Excess deaths during the pandemic – Neither the case fatality rate nor the infection fatality rate account for the full burden of the pandemic, which includes excess mortality from other conditions because of delayed care, overburdened health care systems, and social determinants of health [54-57]. A systematic analysis that compared all-cause mortality reports of 74 countries during 2020 and 2021 with those of the previous 11 years estimated a global all-age excess mortality rate of 120.3 deaths per 100,000 persons and 18.2 million deaths due to the COVID-19 pandemic worldwide [58].

●Impact of vaccination – Vaccination against COVID-19 substantially reduces the risk of severe illness and is associated with decreased mortality. Impact of COVID-19 vaccination is discussed in detail elsewhere. (See "COVID-19: Vaccines", section on 'Indications and vaccine selection' and "COVID-19: Vaccines", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

Risk factors for severe illness — Severe illness can occur in otherwise healthy individuals of any age, but it predominantly occurs in adults with advanced age or certain underlying medical comorbidities. Specific demographic features and laboratory abnormalities have also been associated with severe disease. These are discussed in detail in the sections that follow.

COVID-19 vaccination substantially reduces the risk of severe illness, although some patient populations, such as adults older than 80 years of age, immunocompromised hosts, and those with comorbidities (eg, chronic kidney disease), remain at increased (albeit lower) risk for severe disease [59]. This is discussed in detail separately. (See "COVID-19: Vaccines", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

Several prediction tools have been proposed to identify patients who are more likely to have severe illness based on epidemiologic, clinical, and laboratory features; however, most of the studies evaluating these tools are limited by risk of bias, and they have not been validated adequately for clinical management [60,61].

Increasing age — Individuals of any age can acquire SARS-CoV-2 infection, although adults of middle age and older are most commonly affected, and older adults are more likely to have severe disease.

In several cohorts of hospitalized patients with confirmed COVID-19, the median age ranged from 49 to 56 years [23-25]. In a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections, 87 percent of patients were between 30 and 79 years old [27]. Similarly, in a modeling study based on data from mainland China, the hospitalization rate for COVID-19 increased with age, with a 1 percent rate for those 20 to 29 years old, 4 percent rate for those 50 to 59 years old, and 18 percent for those older than 80 years [62].

Older age is also associated with increased mortality [27,37,38,63,64]. In a report from the Chinese Center for Disease Control and Prevention, case fatality rates were 8 and 15 percent among those aged 70 to 79 years and 80 years or older, respectively, in contrast to the 2.3 percent case fatality rate among the entire cohort [27]. In an analysis from the United Kingdom, the risk of death among individuals 80 years and older was 20-fold that among individuals 50 to 59 years old [64].

In the United States, 2449 patients diagnosed with COVID-19 between February 12 and March 16, 2020, had age, hospitalization, and ICU information available [65]; 67 percent of cases were diagnosed in those aged ≥45 years, and, similar to findings from China, mortality was highest among older individuals, with 80 percent of deaths occurring in those aged ≥65 years. In contrast, individuals aged 18 to 34 years accounted for only 5 percent of adults hospitalized for COVID-19 in a large health care database study and had a mortality rate of 2.7 percent; morbid obesity, hypertension, and male sex were associated with mortality in that age group [66].

Symptomatic infection in children and adolescents is usually mild, although a small proportion experience severe and even fatal disease. Details of COVID-19 in children are discussed elsewhere. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Spectrum of disease severity'.)

Comorbidities — Multiple comorbidities and underlying conditions have been associated with severe illness (ie, infection resulting in hospitalization, admission to the ICU, intubation or mechanical ventilation, or death) [27,41,64,66-74]. These risk factors are outlined in the table (table 1).

Although severe disease can occur in any individual, most with severe disease have at least one risk factor. In a report of 355 patients who died with COVID-19 in Italy, the mean number of pre-existing comorbidities was 2.7, and only 3 patients had no underlying condition [63].

Among patients with advanced age and medical comorbidities, COVID-19 is frequently severe. For example, in a SARS-CoV-2 outbreak across several long-term care facilities in Washington state, the median age of the 101 facility residents affected was 83 years, and 94 percent had a chronic underlying condition; the hospitalization and preliminary case fatality rates were 55 and 34 percent, respectively [75]. In an analysis of nearly 300,000 confirmed COVID-19 cases reported in the United States, the mortality rate was 12 times as high among patients with reported co-morbidities compared with those with none [28].

Physical inactivity — Physical inactivity has been associated with more severe disease and worse outcomes [76-80]. As an example, in a retrospective, nationwide study of over 65,000 people participating in a physical activity rewards program, high physical activity levels (>150 minutes/week) were associated with lower rates of hospitalization (risk ratio [RR] 0.66, 95% CI 0.63-0.70), ICU admission (RR 0.59, 95% CI 0.52-0.66), mechanical ventilation (RR 0.55, 95% CI 0.47-0.64), and death (RR 0.58, 95% CI 0.50-0.68) compared with low physical activity levels (<60 minutes/week) [78]. In another retrospective, nationwide cohort of 2295 adults infected with SARS-CoV-2, those who engaged in both aerobic and muscle strengthening activities had a lower risk of severe COVID-19 illness and COVID-19-related death compared with those who did not engage in exercise [79]. A metabolic equivalent task (MET) range of 500 to 1000 MET min/week was associated with the maximum benefit of reduced risk.

Socioeconomic background and sex — Certain demographic features have also been associated with more severe illness.

Males have comprised a disproportionately high number of critical cases and deaths in multiple cohorts worldwide [38,41,63,81-83].

Black, Hispanic, and Southern Asian individuals comprise a disproportionately high number of infections and deaths due to COVID-19 in the United States and United Kingdom, likely related to underlying disparities in the social determinants of health [64,84-90]. Some analyses that have controlled for comorbidities and socioeconomic status have not found an association between African-American origin or Hispanic ethnicity and adverse COVID-19 outcomes in hospitalized patients [91,92].

Higher COVID-19-associated mortality has also been reported among other socioeconomically vulnerable groups, such as the prison population [93].

Laboratory abnormalities — Particular laboratory features have also been associated with worse outcomes (table 2). These include [67,94-97]:

•Lymphopenia

•Thrombocytopenia

•Elevated liver enzymes

•Elevated lactate dehydrogenase

•Elevated inflammatory markers (eg, C-reactive protein, ferritin) and inflammatory cytokines (ie, interleukin 6 and tumor necrosis factor-alpha)

•Elevated D-dimer (>1 mcg/mL)

•Elevated prothrombin time

•Elevated troponin

•Elevated creatine phosphokinase

•Acute kidney injury

As an example, in one study, progressive decline in the lymphocyte count and rise in the D-dimer over time were observed in nonsurvivors compared with more stable levels in survivors [25].

Deficiencies in certain micronutrients, in particular vitamin D [98,99], have been associated with more severe disease in observational studies, but multiple confounders likely impact the observed associations. There is also no high-quality evidence that reversing micronutrient deficiencies with supplementation improves COVID-19 outcomes.

Viral factors — Patients with severe disease have also been reported to have higher viral ribonucleic acid (RNA) levels in respiratory specimens than those with milder disease [100,101], although some studies have found no association between respiratory viral RNA levels and disease severity [102,103]. Detection of viral RNA in the blood has been associated with severe disease, including organ damage (eg, lung, heart, kidney), coagulopathy, and mortality [104-106].

Genetic factors — Host genetic factors are also being evaluated for associations with severe disease [107-109].

As an example, one genome-wide association study identified a relationship between polymorphisms in the genes encoding the ABO blood group and respiratory failure from COVID-19 (type A associated with a higher risk) [110]. Type O has been associated with a lower risk of both infection and severe disease [111]. (See "Red blood cell antigens and antibodies", section on 'Disease predisposition (including COVID-19)'.)

CLINICAL MANIFESTATIONS

Incubation period — The incubation period for COVID-19 is generally within 14 days following exposure with most cases occurring approximately four to five days after exposure [112-114]. The median incubation period for the SARS-CoV-2 Omicron variant (B.1.1.159) appears to be slightly shorter, with symptoms first appearing at around three days [114-116].

In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation period was four days (interquartile range two to seven days) [113]. Using data from 181 confirmed cases in China with identifiable exposure, one modeling study estimated that symptoms would develop in 2.5 percent of infected individuals within 2.2 days and in 97.5 percent of infected individuals within 11.5 days [117]. The median incubation period in this study was 5.1 days. In a study of 81 individuals infected with the Omicron variant at a party in Norway, the median time for symptom onset was three days (range of zero to eight days) [115].

However, determinations of the incubation period can be imprecise and may differ by the method of assessing exposure and the specific calculations used for the estimate. Another study performed early in the epidemic estimated the incubation period using data from 1084 patients who had traveled or resided in Wuhan and were subsequently diagnosed with COVID-19 after leaving Wuhan [118]. This study suggested a longer median incubation period of 7.8 days, with 5 to 10 percent of individuals developing symptoms 14 days or more after exposure.

Initial presentation — Among patients with symptomatic COVID-19, cough, myalgias, and headache are the most commonly reported symptoms. Other features, including diarrhea, sore throat, and smell or taste abnormalities, are also well described (table 3). Mild upper respiratory symptoms (eg, nasal congestion, sneezing) appear to be more common with the Delta and Omicron variant [31]. Pneumonia is the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging [23-25,113]. Although some clinical features (in particular smell or taste disorders) are more common with COVID-19 than with other viral respiratory infections [119], there are no specific symptoms or signs that can reliably distinguish COVID-19 [120]. However, development of dyspnea approximately one week after the onset of initial symptoms may be suggestive of COVID-19. (See 'Acute course and complications' below.)

In a report of over 370,000 confirmed COVID-19 cases from January to May 2020 with known symptom status reported to the CDC in the United States, cough (50 percent), fever (43 percent), myalgias (36 percent), and headache (34 percent) were the most common presenting symptoms [28]. Other cohort studies of patients with confirmed COVID-19 have reported a similar range of clinical findings [23,25,121-124]. In an observational study that evaluated the reported clinical symptoms of 63,000 confirmed COVID-19 cases from two time periods (June to November 2021 when Delta variant was predominant and December 2021 to January 2022 when Omicron was predominant), nasal congestion (77 to 82 percent), headache (75 to 78 percent), sneezing (63 to 71 percent), and sore throat (61 to 71 percent) were the most common presenting symptoms [31]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)

●Fever − Fever is not a universal finding on presentation, even among hospitalized cohorts. In one study, fever was reported in almost all patients, but approximately 20 percent had a very low-grade fever <100.4°F (38°C) [23]. In another study of 1099 patients from Wuhan and other areas in China, fever (defined as an axillary temperature over 99.5°F [37.5°C]) was present in only 44 percent on admission but was ultimately noted in 89 percent during the hospitalization [113]. In a study of over 5000 patients who were hospitalized with COVID-19 in New York, only 31 percent had a temperature >100.4°F (38°C) at presentation [38].

●Smell and taste abnormalities − In some studies, smell and taste disorders (eg, anosmia and dysgeusia) have been frequently reported [125-130], although these abnormalities appear to be less common with the Omicron variant [31,131,132]. In a meta-analysis of observational studies, the pooled prevalence estimates for smell or taste abnormalities were 52 and 44 percent, respectively (although rates ranged from 5 to 98 percent across studies) [128]. In one survey of 202 outpatients with mild COVID-19 in Italy, 64 percent reported alterations in smell or taste, and 24 percent reported very severe alterations; smell or taste changes were reported as the only symptom in 3 percent overall and preceded symptoms in another 12 percent [133]. However, the rate of objective smell or taste anomalies may be lower than the self-reported rates. In another study, 38 percent of the 86 patients who reported total lack of smell at the time of evaluation had a normal smell function on objective testing [134]. Most subjective smell and taste disorders associated with COVID-19 do not appear to be permanent; in a meta-analysis of 18 observational studies, 74 and 96 percent recovered their sense of smell and 78 and 98 percent recovered their sense of taste at 30 days and 180 days, respectively [135].

●Gastrointestinal findings − Although not noted in the majority of patients, gastrointestinal symptoms (eg, nausea and diarrhea) may be the presenting complaint in some patients [23,25,123,136]. In a systematic review of studies reporting on gastrointestinal symptoms in patients with confirmed COVID-19, the pooled prevalence was 18 percent overall, with diarrhea, nausea/vomiting, or abdominal pain reported in 13, 10, and 9 percent, respectively [137].

●Dermatologic findings − A range of dermatologic findings in patients with COVID-19 may occur. There have been reports of maculopapular/morbilliform, urticarial, and vesicular eruptions and transient livedo reticularis [138-140]. Reddish-purple nodules on the distal digits similar in appearance to pernio (chilblains), or “COVID toes,” have also been described, mainly in adolescents and young adults with otherwise asymptomatic or mild infection; in some cases, these developed up to several weeks after initial COVID-19 symptoms [140-143]. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19'.)

●Other findings − Conjunctivitis may occur [144,145]. Other clinical manifestations, such as falls, general health decline, and delirium, have been reported in older adults, particularly those over 80 years old and those with underlying neurocognitive impairment [146]. Menstrual irregularities (including changes in duration of cycle and heavier bleeding) have also been described in female patients with COVID-19 [147].

Acute course and complications — As above, symptomatic infection can range from mild to critical. (See 'Spectrum of severity and fatality rates' above.)

Some patients with initially nonsevere symptoms may progress over the course of a week [148]. In one study of 138 patients hospitalized in Wuhan for pneumonia due to SARS-CoV-2, dyspnea developed after a median of five days since the onset of symptoms, and hospital admission occurred after a median of seven days of symptoms [25]. In another study, the median time to dyspnea was eight days [23].

Several complications of COVID-19 have been described:

●Respiratory failure – Acute respiratory distress syndrome (ARDS) is the major complication in patients with severe disease and can manifest shortly after the onset of dyspnea. In the study of 138 patients described above, ARDS developed in 20 percent a median of eight days after the onset of symptoms; mechanical ventilation was implemented in 12.3 percent [25]. In large studies from the United States, 12 to 24 percent of hospitalized patients have required mechanical ventilation [38,41]. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Clinical features in critically ill patients'.)

●Cardiac and cardiovascular complications – Other complications have included arrhythmias, myocardial injury, heart failure, and shock, as discussed in detail elsewhere [25,81,149,150]. (See "COVID-19: Cardiac manifestations in adults", section on 'Acute clinical manifestations'.)

●Thromboembolic complications – Venous thromboembolism, including extensive deep vein thrombosis and pulmonary embolism, is common in severely ill patients with COVID-19, particularly among patients in the intensive care unit (ICU), among whom reported rates have ranged from 10 to 40 percent [151-155]. Arterial thrombotic events, including acute stroke (even in patients younger than 50 years of age without risk factors) and limb ischemia, have also been reported [156-159]. These are discussed in detail elsewhere. (See "COVID-19: Hypercoagulability", section on 'Clinical features' and "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease' and "COVID-19: Acute limb ischemia".)

●Neurologic complications – Encephalopathy is a common complication of COVID-19, particularly among critically ill patients; as an example, in one series of hospitalized patients, encephalopathy was reported in one-third [160]. Stroke, movement disorders, motor and sensory deficits, ataxia, and seizures occur less frequently. (See "COVID-19: Neurologic complications and management of neurologic conditions".)

●Inflammatory complications – Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatory response, with persistent fevers, elevated inflammatory markers (eg, D-dimer, ferritin), and elevated proinflammatory cytokines; these laboratory abnormalities have been associated with critical and fatal illnesses [23,161,162]. Although these features had been likened to cytokine release syndrome (eg, in response to T cell immunotherapy), the levels of proinflammatory cytokines in COVID-19 are substantially lower than those seen with cytokine release syndrome as well as with sepsis [163]. (See 'Risk factors for severe illness' above.)

Other inflammatory complications and auto-antibody-mediated manifestations have been described [164,165]. Guillain-Barré syndrome may occur, with onset 5 to 10 days after initial symptoms [166]. A multisystem inflammatory syndrome with clinical features similar to those of Kawasaki disease and toxic shock syndrome has also been described in children with COVID-19 (table 4). In the rare adults in whom it has been reported, this syndrome has been characterized by markedly elevated inflammatory markers and multiorgan dysfunction (in particular cardiac dysfunction) [167,168]. These are discussed in detail elsewhere. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Guillain-Barré syndrome' and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for rheumatologic disease'.)

●Secondary infections – Secondary infections occur in the minority of patients with COVID-19 [169-173]. In a systematic review of 118 studies, the rate of bacterial coinfections (identified at the time of COVID-19 diagnosis) was 8 percent and the rate of bacterial superinfections (identified during care for COVID-19) was 20 percent [172]. Klebsiella pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus were the most common coinfecting pathogens, and Acinetobacter spp were the most common superinfecting pathogens. A meta-analysis of 22 studies examined bacterial, fungal, and viral superinfections and found a superinfection rate of 16 percent [173]. Epstein-Barr virus was the most frequent organism, followed by Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Hemophilus influenza, and invasive pulmonary aspergillosis.

Fungal superinfections are a risk in certain populations. Several reports have described invasive aspergillosis among critically ill immunocompetent patients with ARDS from COVID-19, although the frequency varies widely across reports, in part because of differences in diagnostic criteria [174-177] (see "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'COVID-19-associated infection'). Cases of mucormycosis in patients with acute and recent COVID-19 have also been reported, particularly from India; the rhino-orbital region is the most common site of infection, and risk factors include diabetes mellitus and glucocorticoid receipt [178-181]. (See "Mucormycosis (zygomycosis)", section on 'Coronavirus disease 2019-associated'.)

Autopsy studies have noted detectable SARS-CoV-2 RNA (and, in some cases, antigen) in the kidneys, liver, heart, brain, and blood in addition to respiratory tract specimens, suggesting that the virus disseminates systemically in some cases; whether direct viral cytopathic effects at these sites contribute to the complications observed is uncertain [182-185].

Recovery and long-term sequelae — The time to recovery from COVID-19 is highly variable and depends on age, vaccination status, and pre-existing comorbidities in addition to illness severity. A minority of patients also experience transient rebound symptoms within two weeks of initial symptom onset, even in the absence of COVID-19-specific antiviral therapy [186,187]. Individuals with mild infection are expected to recover relatively quickly (eg, within two weeks) whereas many individuals with severe disease have a longer time to recovery (eg, two to three months). The most common persistent symptoms include fatigue, memory problems, dyspnea, chest pain, cough, and cognitive deficits (table 5) [188]. Data also suggest the potential for ongoing respiratory impairment [189-192] and cardiac sequelae [193,194]. These issues are discussed in detail elsewhere. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)

Some patients who have recovered from COVID-19 have persistently or recurrently positive nucleic acid amplification tests for SARS-CoV-2. Although recurrent infection or reinfection cannot be definitively ruled out in these settings, evidence suggests that these are unlikely. This is discussed elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Immune responses following infection'.)

Reinfection — Reinfection is discussed in greater detail separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Risk of reinfection'.)

LABORATORY FINDINGS — Common laboratory findings among hospitalized patients with COVID-19 include lymphopenia, elevated aminotransaminase levels, elevated lactate dehydrogenase levels, elevated inflammatory markers (eg, ferritin, C-reactive protein, and erythrocyte sedimentation rate), and abnormalities in coagulation tests [25,113,123].

Lymphopenia is especially common, even though the total white blood cell count can vary [23-25,195]. As an example, in a series of 393 adult patients hospitalized with COVID-19 in New York City, 90 percent had a lymphocyte count <1500/microL; leukocytosis (>10,000/microL) and leukopenia (<4000/microL) were each reported in approximately 15 percent [123].

On admission, many patients with pneumonia have normal serum procalcitonin levels; however, in those requiring ICU care, they are more likely to be elevated [23-25].

Several laboratory features, including high D-dimer levels and more severe lymphopenia, have been associated with critical illness or mortality [24]. These are discussed elsewhere. (See 'Risk factors for severe illness' above and "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Rate and risk of progression to critical illness'.)

Abnormalities in coagulation testing are also discussed in detail elsewhere. (See "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)

IMAGING FINDINGS

Chest radiographs — Chest radiographs may be normal in early or mild disease. In a retrospective study of 64 patients in Hong Kong with documented COVID-19, 20 percent did not have any abnormalities on chest radiograph at any point during the illness [196]. Common abnormal radiograph findings were consolidation and ground-glass opacities, with bilateral, peripheral, and lower lung zone distributions; lung involvement increased over the course of illness, with a peak in severity at 10 to 12 days after symptom onset.

Spontaneous pneumothorax has also been described, although it is relatively uncommon [197,198]. In a retrospective review of over 70,000 patients with COVID-19 evaluated in emergency departments throughout Spain, spontaneous pneumothorax was identified in 40 patients (0.56 percent) [198].

Chest CT — Although chest computed tomography (CT) may be more sensitive than chest radiograph and some chest CT findings may be characteristic of COVID-19, no finding can completely rule in or rule out the possibility of COVID-19. In the United States, the American College of Radiology (ACR) recommends not using chest CT for screening or diagnosis of COVID-19 and recommends reserving it for hospitalized patients when needed for management [199]. If CT is performed, the Radiological Society of North America has categorized features as typical, indeterminate, or atypical for COVID-19, and has suggested corresponding language for the interpretation report (table 6) [200].

Chest CT in patients with COVID-19 most commonly demonstrates ground-glass opacification with or without consolidative abnormalities, consistent with viral pneumonia (image 1) [122,201,202]. As an example, in a systematic review of studies evaluating the chest CT findings in over 2700 patients with COVID-19, the following abnormalities were noted [203]:

●Ground-glass opacifications – 83 percent

●Ground-glass opacifications with mixed consolidation – 58 percent

●Adjacent pleural thickening – 52 percent

●Interlobular septal thickening – 48 percent

●Air bronchograms – 46 percent

Other less common findings were a crazy paving pattern (ground-glass opacifications with superimposed septal thickening), bronchiectasis, pleural effusion, pericardial effusion, and lymphadenopathy.

Chest CT abnormalities in COVID-19 are often bilateral, have a peripheral distribution, and involve the lower lobes.

Although these findings are common in COVID-19, they are not unique to it and are frequently seen with other viral pneumonias (image 2) [204,205]. In a study of 1014 patients in Wuhan who underwent both RT-PCR testing and chest CT for evaluation of COVID-19, a "positive" chest CT for COVID-19 (as determined by a consensus of two radiologists) had a sensitivity of 97 percent, using the PCR tests as a reference; however, specificity was only 25 percent [206]. The low specificity may be related to other etiologies causing similar CT findings. In another study comparing chest CTs from 219 patients with COVID-19 in China and 205 patients with other causes of viral pneumonia in the United States, COVID-19 cases were more likely to have a peripheral distribution (80 versus 57 percent), ground-glass opacities (91 versus 68 percent), fine reticular opacities (56 versus 22 percent), vascular thickening (59 versus 22 percent), and reverse halo sign (11 versus 1 percent), but less likely to have a central and peripheral distribution (14 versus 35 percent), air bronchogram (14 versus 23 percent), pleural thickening (15 versus 33 percent), pleural effusion (4 versus 39 percent), and lymphadenopathy (2.7 versus 10 percent) [207].

As with chest radiographs, chest CT may be normal soon after the onset of symptoms, with abnormalities more likely to develop over the course of illness [121,208]. However, chest CT abnormalities have also been identified in patients prior to the development of symptoms and even prior to the detection of viral RNA from upper respiratory specimens [122,209].

Among patients who clinically improve, resolution of radiographic abnormalities may lag behind improvements in fever and hypoxia [210].

Lung ultrasound — Point-of-care lung ultrasonography has been described for evaluation of lung involvement in patients with suspected COVID-19 when other imaging resources are not readily available. Findings on lung ultrasound in patients with documented COVID-19 have included thickening, discontinuation, and interruption of the pleural line; B lines visible under the pleura that appear discrete, multifocal, or confluent; patchy, strip, and nodular consolidations; and air bronchogram signs in the consolidations [211-213]. Although ultrasound appears to be relatively sensitive for the diagnosis of COVID-19, some studies have reported low specificity. In a systematic review of five studies, the pooled sensitivity and specificity were 86 and 55 percent, respectively [214].

SPECIAL POPULATIONS

Pregnant and breastfeeding women — The general approach to prevention, evaluation, diagnosis, and treatment of pregnant women with suspected COVID-19 is largely similar to that in nonpregnant individuals. Issues specific to pregnant and breastfeeding women are discussed elsewhere. (See "COVID-19: Overview of pregnancy issues".)

Children — Symptomatic infection in children is usually mild, although severe cases have been reported [215-218]. In addition, a post-COVID syndrome entitled Multisystem Inflammatory Syndrome of Children (MIS-C) has emerged with features resembling Kawasaki Disease and occasionally exhibiting long-term sequelae [219]. Details of COVID-19 in children are discussed elsewhere. (See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

People with HIV — Clinical features of COVID-19 appear the same in people with human immunodeficiency virus (HIV) as in the general population. Among patients with well controlled HIV, a large proportion remain asymptomatic [220,221]. However, those with HIV remain at increased risk for severe COVID-19 and complications. In several large observational studies, HIV infection has been associated with more severe COVID-19, higher rates of hospitalization, higher rates of breakthrough infections after vaccination, and in some cases, higher mortality from COVID-19 [222-230]. As an example, in a multicenter cohort study from Spain, the age- and sex-adjusted mortality rate of patients with HIV and COVID-19 was 3.7 compared with 2.1 per 10,000 people in the general Spanish population [222]. In another database study of more than 1 million COVID-19 cases in the United States, COVID-19-associated hospitalization and mortality were higher in patients with HIV compared to those without HIV after adjusting for demographics, smoking, and presence of comorbidities [226].

Among people with HIV, those who are older [222,226,231], have multiple comorbidities [227,231-233], have lower CD4 cell counts [224,226,227,231], and who identify as Black or Hispanic are at highest risk for adverse outcomes [223,224,226,227,232].

Issues specific to the management of patients with HIV and COVID-19 are discussed elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'People with HIV'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Asymptomatic infection – The clinical spectrum of SARS-COV-2 infection ranges from asymptomatic infection to critical and fatal illness. The proportion of infections that are asymptomatic is uncertain, as the definition of "asymptomatic" varies across studies and longitudinal follow-up to identify those who ultimately develop symptoms is often not performed. Nevertheless, some estimates suggest that up to 40 percent of infections are asymptomatic. (See 'Asymptomatic infections' above.)

●Risk of severe disease – Most symptomatic infections are mild. Severe disease (eg, with hypoxia and pneumonia) has been reported in 15 to 20 percent of symptomatic infections in unvaccinated individuals; it can occur in otherwise healthy individuals of any age, but predominantly occurs in adults with advanced age or certain underlying medical comorbidities (table 1). In North America and Europe, Black, Hispanic, and South Asian individuals are also more likely to have severe disease, likely related to underlying disparities in the social determinants of health. (See 'Severity of symptomatic infection' above.)

The impact of COVID-19 vaccination on the risk of severe disease is discussed elsewhere. (See "COVID-19: Vaccines", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

●Incubation period – The incubation period from the time of exposure until the onset of symptoms is three to five days on average, partly depending on the variant, but it may be as long as 14 days. (See 'Incubation period' above.)

●Initial presentation – Cough, myalgias, and headache are the most commonly reported symptoms. Other features, including diarrhea, sore throat, and smell or taste abnormalities, are also well described (table 3). Mild upper respiratory symptoms (eg, nasal congestion, sneezing) appear to be more common with the Delta and Omicron variants. Pneumonia, with fever, cough, dyspnea, and infiltrates on chest imaging, is the most frequent serious manifestation of infection. There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections although loss of smell and/or taste is unusual in common-cold syndromes other than COVID-19. (See 'Initial presentation' above and 'Imaging findings' above.)

Certain laboratory features, such as lymphopenia, elevated D-dimer, and elevated inflammatory markers have been associated with severe COVID-19 (table 2). (See 'Laboratory abnormalities' above.)

●Complications – Acute respiratory distress syndrome (ARDS) is the major complication in patients with severe disease and can manifest shortly after the onset of dyspnea. Other complications of severe illness include thromboembolic events, acute cardiac injury, kidney injury, and inflammatory complications. (See 'Acute course and complications' above and "COVID-19: Hypercoagulability" and "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Clinical features in critically ill patients'.)

Persistent symptoms following acute COVID-19 are discussed in detail elsewhere. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)

●Clinical suspicion – The possibility of COVID-19 should be considered primarily in patients with compatible symptoms (table 3), in particular fever and/or respiratory tract symptoms, who reside in or have traveled to areas with community transmission or who have had recent close contact with a confirmed or suspected individual with COVID-19. All symptomatic patients with suspected SARS-CoV-2 infection should undergo testing. Testing for and diagnosis of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

When COVID-19 is suspected, infection control measures should be implemented. Infection control in the home and in health care settings is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the health care setting'.)