COVID-19 - Clinical Features - UpToDate

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Author: Kenneth McIntosh, MD

Section Editor: Martin S Hirsch, MD
Deputy Editor: Milana Bogorodskaya, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2022. | This topic last updated: Jan 10, 2022.
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: Outpatient evaluation and management of acute illness in adults".)

● (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 [4-12]. One review performed prior to
the introduction of COVID-19 vaccination estimated that 33 percent of people with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection never develop symptoms
[13]. 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. However,
there is still 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 [14,15]. In studies of subsets of those asymptomatic individuals, who were
hospitalized and monitored, approximately 77 to 89 percent remained asymptomatic
over time [15,16].
● 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 [17].
● Other studies, particularly those conducted among younger populations, have reported
even higher proportions of infections that are asymptomatic [10,18-22]. 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 [21]. 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 [10,19].
Patients with asymptomatic infection may have objective clinical abnormalities [9,23]. 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 [23]. 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 [9].
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 [15].
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 [4,24-29]. 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
[30]:
• 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
[31]. The individual risk of severe illness varies by age, underlying comorbidities, and
vaccination status. (See 'Risk factors for severe illness' below.)
Additionally, different severe acute respiratory syndrome coronavirus 2 (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 [32,33]. (See
"COVID-19: Epidemiology, virology, and prevention", section on 'Omicron (B.1.1.529
lineage)'.)
● 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 [34-37]. In a systematic
review and meta-analysis of 27 studies from resource-rich settings that calculated the
total number of community infections through seroprevalence surveys or
comprehensive tracing programs up to September 2020, the infection fatality rate was
estimated to increase exponentially by age (0.002 percent at age 10, 0.01 percent at age
25, 0.4 percent at age 55, 1.4 percent at age 65, 4.6 percent at age 75, 15 percent at age
85, and >25 percent at age ≥90 years) [38]. These age-related differences appeared to
account for most of the geographic variability in reported infection fatality rates (ie,
locations with a higher median population age reported higher fatality rates).
Nevertheless, given the challenges in accurately assessing overall infection rates and
deaths, there is a high level of uncertainty with these estimates.
● Fatality rates among hospitalized patients – Among hospitalized patients, the risk of
critical or fatal disease is high among unvaccinated individuals [39-45], and the in-
hospital fatality rate associated with COVID-19 is higher than that for influenza [46-48].
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 [49]. Over the course of the pandemic,
declining in-hospital fatality rates had been reported, even prior to widespread
vaccination [50-53]. 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 [54]. 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 [55-58].
● 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. 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 [59,60].
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 [25-27]. 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 [30]. 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 [61].
Older age is also associated with increased mortality [30,39,62,63]. 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 [30]. 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 [63].
In the United States, 2449 patients diagnosed with COVID-19 between February 12 and March
16, 2020, had age, hospitalization, and ICU information available [64]; 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
[65].
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
'Frequency of severe disease in children'.)
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) [30,42,63,65-73]. 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 [62].
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 [74]. 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 [31].
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 [39,42,62,75-77].
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 [63,78-83]. 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 [84,85].
Higher COVID-19-associated mortality has also been reported among other socioeconomically
vulnerable groups, such as the prison population [86].
Laboratory abnormalities — Particular laboratory features have also been associated with

worse outcomes ( table 2). These include [66,87-90]:
• Lymphopenia
• Thrombocytopenia
• Elevated liver enzymes
• Elevated lactate dehydrogenase (LDH)
• Elevated inflammatory markers (eg, C-reactive protein [CRP], ferritin) and
inflammatory cytokines (ie, interleukin 6 [IL-6] and tumor necrosis factor [TNF]-alpha)
• Elevated D-dimer (>1 mcg/mL)
• Elevated prothrombin time (PT)
• Elevated troponin
• Elevated creatine phosphokinase (CPK)
• 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 [27].
Deficiencies in certain micronutrients, in particular vitamin D [91,92], 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
RNA levels in respiratory specimens than those with milder disease [93,94], although some
studies have found no association between respiratory viral RNA levels and disease severity
[95,96]. Detection of viral RNA in the blood has been associated with severe disease, including
organ damage (eg, lung, heart, kidney), coagulopathy, and mortality [97-99].
Genetic factors — Host genetic factors are also being evaluated for associations with severe
disease [100,101].
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) [100]. Type O has been associated with a lower
risk of both infection and severe disease [102]. (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
[4,103,104]. The median incubation period for the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.159) appears to be slightly shorter, with
symptoms first appearing at around three days [105,106].
In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation
period was four days (interquartile range two to seven days) [104]. 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 [107]. 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)
[105].
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 [108]. 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
Omicron variant [105]. Pneumonia is the most frequent serious manifestation of infection,
characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging
[25-27,104]. Although some clinical features (in particular smell or taste disorders) are more
common with COVID-19 than with other viral respiratory infections [109], there are no specific
symptoms or signs that can reliably distinguish COVID-19 [110]. 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.)
The range of associated symptoms was illustrated in a report of over 370,000 confirmed
COVID-19 cases with known symptom status reported to the CDC in the United States [31]:
● Cough in 50 percent
● Fever (subjective or >100.4°F/38°C) in 43 percent
● Myalgia in 36 percent
● Headache in 34 percent
● Dyspnea in 29 percent
● Sore throat in 20 percent
● Diarrhea in 19 percent
● Nausea/vomiting in 12 percent
● Loss of smell or taste, abdominal pain, and rhinorrhea in fewer than 10 percent each
Other cohort studies of patients with confirmed COVID-19 have reported a similar range of
clinical findings [25,27,111-114]. Notably, 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 [25]. 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 [104]. 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 [39].
In some studies, smell and taste disorders (eg, anosmia and dysgeusia) have been more
frequently reported [115-119]. 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) [118]. 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 [120]. 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 [121]. Most subjective smell and
taste disorders associated with COVID-19 do not appear to be permanent; in a follow-up
survey of the 202 patients in Italy with COVID-19, 89 percent of those who noted smell or taste
alterations reported resolution or improvement by four weeks [122].
Although not noted in the majority of patients, gastrointestinal symptoms (eg, nausea and
diarrhea) may be the presenting complaint in some patients [25,27,113,123]. 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 [124].
Conjunctivitis has also been described [125,126]. Nonspecific signs and symptoms, such as
falls, general health decline, and delirium, have been described in older adults, particularly
those over 80 years old and those with underlying neurocognitive impairments [127].
A range of dermatologic findings in patients with COVID-19 have been described. There have
been reports of maculopapular/morbilliform, urticarial, and vesicular eruptions and transient
livedo reticularis [128-130]. 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 [130-133]. (See "COVID-19: Cutaneous
manifestations and issues related to dermatologic care", section on 'Cutaneous
manifestations of COVID-19'.)
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
[134]. 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 [27]. In another study, the
median time to dyspnea was eight days [25].
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 [27]. In large studies from the United States, 12 to 24
percent of hospitalized patients have required mechanical ventilation [39,42]. (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
[27,75,135,136]. (See "COVID-19: Cardiac manifestations in adults", section on 'Spectrum
of clinical presentations'.)
● 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 [137-140]. 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 [141-144]. 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 [145]. 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
[25,146,147]. 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 [148]. (See 'Risk factors for severe illness' above.)
Other inflammatory complications and auto-antibody-mediated manifestations have

been described [149,150]. Guillain-Barré syndrome may occur, with onset 5 to 10 days
after initial symptoms [151]. 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) [152,153]. 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 [154-157]. 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 [157].
Klebsiella pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus were the
most common coinfecting pathogens, and Acinetobacter spp were the most common
superinfecting pathogens.
Fungal superinfections are also 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 [158-161] (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 [162-165].
(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 [166-169].
Recovery and long-term sequelae — The time to recovery from COVID-19 is highly variable
and depends on age and pre-existing comorbidities in addition to illness severity. 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, dyspnea, chest pain, cough,
and cognitive deficits ( table 5). Data also suggest the potential for ongoing respiratory
impairment [170-173] and cardiac sequelae [174,175]. These issues are discussed in detail
elsewhere. (See "COVID-19: Evaluation and management of adults following acute viral
illness", section on 'COVID-19 recovery'.)
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 [27,104,113].
Lymphopenia is especially common, even though the total white blood cell count can vary [25-
27,176]. 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 [113].
On admission, many patients with pneumonia have normal serum procalcitonin levels;
however, in those requiring ICU care, they are more likely to be elevated [25-27].
Several laboratory features, including high D-dimer levels and more severe lymphopenia, have
been associated with critical illness or mortality [26]. 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 [177]. 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

[178,179]. 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) [179].
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 [180]. 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) [181].
Chest CT in patients with COVID-19 most commonly demonstrates ground-glass opacification

with or without consolidative abnormalities, consistent with viral pneumonia ( image 1)
[112,182,183]. 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 [184]:
● 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) [185,186]. 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 [187].
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) [188].
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 [111,189]. 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 [112,190].
Among patients who clinically improve, resolution of radiographic abnormalities may lag
behind improvements in fever and hypoxia [191].
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 [192-194]. 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 [195].
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 [196-199]. Details of COVID-19 in children are discussed elsewhere. (See
"COVID-19: Clinical manifestations and diagnosis in children".)
People with HIV — Although clinical features of COVID-19 appear the same in people with
HIV as in the general population, those with HIV are 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, and in some cases, higher mortality
from COVID-19 [200-206]. 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 [200]. 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 [204].
Among people with HIV, those who are older [200,204,207], have multiple comorbidities
[205,207-209], have lower CD4 cell counts [202,204,205,207], and who identify as Black or
Hispanic are at highest risk for adverse outcomes [201,202,204,205,208].
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 5th to 6th
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 10th to 12th
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 severe acute respiratory syndrome

coronavirus 2 (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). 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. (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 following acute viral illness", section
on 'COVID-19 recovery'.)
● 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'.)
Use of UpToDate is subject to the Terms of Use.
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Topic 128323 Version 40.0

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Author: Kenneth McIntosh, MD

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

● (See "COVID-19: Outpatient evaluation and management of acute illness in adults".)

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

SEVERITY OF SYMPTOMATIC INFECTION

Spectrum of severity and fatality rates

● Spectrum of infection severity – The spectrum of symptomatic infection ranges from

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

Additionally, different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

In resource-limited settings, in-hospital mortality rates may be higher than those

● Impact of vaccination – Vaccination against COVID-19 substantially reduces the risk of

Comorbidities — Multiple comorbidities and underlying conditions have been associated

Socioeconomic background and sex — Certain demographic features have also been

Laboratory abnormalities — Particular laboratory features have also been associated with

As an example, one genome-wide association study identified a relationship between

Incubation period — The incubation period for COVID-19 is generally within 14 days

Initial presentation — Among patients with symptomatic COVID-19, cough, myalgias, and

Several complications of COVID-19 have been described:

● Respiratory failure – Acute respiratory distress syndrome (ARDS) is the major

● Cardiac and cardiovascular complications – Other complications have included

● Thromboembolic complications – Venous thromboembolism, including extensive deep

● Neurologic complications – Encephalopathy is a common complication of COVID-19,

● Inflammatory complications – Some patients with severe COVID-19 have laboratory

Other inflammatory complications and auto-antibody-mediated manifestations have

● Secondary infections – Secondary infections occur in the minority of patients with

Reinfection — Reinfection is discussed in greater detail separately. (See "COVID-19:

Common laboratory findings among hospitalized patients with COVID-19 include

Chest radiographs — Chest radiographs may be normal in early or mild disease. In a

Spontaneous pneumothorax has also been described, although it is relatively uncommon

Chest CT in patients with COVID-19 most commonly demonstrates ground-glass opacification

● Ground-glass opacifications – 83 percent

Lung ultrasound — Point-of-care lung ultrasonography has been described for evaluation of

Pregnant and breastfeeding women — The general approach to prevention, evaluation,

Children — Symptomatic infection in children is usually mild, although severe cases have

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Asymptomatic infection – The clinical spectrum of severe acute respiratory syndrome

Certain laboratory features, such as lymphopenia, elevated D-dimer, and elevated

● Complications – Acute respiratory distress syndrome (ARDS) is the major complication in

● Clinical suspicion – The possibility of COVID-19 should be considered primarily in

When COVID-19 is suspected, infection control measures should be implemented.

Use of UpToDate is subject to the Terms of Use.

3. World Health Organization. Novel Coronavirus (2019-nCoV) technical guidance. https://w

7. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion

23. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with

36. Meyerowitz-Katz G, Merone L. A systematic review and meta-analysis of published

39. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities,

47. Xie Y, Bowe B, Maddukuri G, Al-Aly Z. Comparative evaluation of clinical manifestations

103. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel

106. Jansen L, Tegomoh B, Lange K, et al. Investigation of a SARS-CoV-2 B.1.1.529 (Omicron)

126. Ma N, Li P, Wang X, et al. Ocular Manifestations and Clinical Characteristics of Children

128. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad

132. Kolivras A, Dehavay F, Delplace D, et al. Coronavirus (COVID-19) infection-induced

139. Bilaloglu S, Aphinyanaphongs Y, Jones S, et al. Thrombosis in Hospitalized Patients With

141. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Antiphospholipid Antibodies in

153. Patel P, DeCuir J, Abrams J, et al. Clinical Characteristics of Multisystem Inflammatory

163. Patel A, Agarwal R, Rudramurthy SM, et al.. Multicenter Epidemiologic Study of

164. Joshi S, Telang R, Tambe M, et al. Outbreak of Mucormycosis in Coronavirus Disease

168. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological Features of Covid-

172. Mo X, Jian W, Su Z, et al. Abnormal pulmonary function in COVID-19 patients at time of

206. https://www.who.int/publications/i/item/WHO-2019-nCoV-Clinical-HIV-2021.1 (Accessed