COVID-19: Clinical manifestations and diagnosis in children

INTRODUCTION — Starting in late 2019, a novel coronavirus rapidly spread throughout the world, resulting in a global pandemic. The virus was designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the illness it caused coronavirus disease 2019 (COVID-19). The clinical spectrum of COVID-19 ranges from asymptomatic infection to mild respiratory tract symptoms to severe pneumonia with acute respiratory distress syndrome and multiorgan dysfunction.

Understanding of COVID-19 is evolving. The World Health Organization, the United States Centers for Disease Control and Prevention, the American Academy of Pediatrics, and other expert groups provide ongoing guidance for evaluation, management, and prevention. Links to these and other related society guidelines are provided separately. (See 'Society guideline links' below.)

This topic will discuss aspects of COVID-19 epidemiology and clinical manifestations of acute COVID-19 infection that are specific to children. The management and prevention of COVID-19 in children, multisystem inflammatory syndrome in children, and COVID-19 in pregnancy are discussed separately:

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

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

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

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

●(See "COVID-19: Antepartum care of pregnant patients with symptomatic infection".)

●(See "COVID-19: Intrapartum and postpartum issues".)

In addition, please refer to our COVID-19 homepage to view the complete list of UpToDate COVID-19 topics.

EPIDEMIOLOGY — The epidemiology of COVID-19 is discussed in detail separately. This section focuses on the epidemiology of COVID-19 in children. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Epidemiology'.)

Transmission — Transmission of SARS-CoV-2 is discussed in detail separately. This section focuses on transmission to children and by children. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Transmission'.)

●Transmission to children – In case series early in the pandemic, most cases in children resulted from household exposure, usually with an adult as the index patient [1-7]. These findings must be interpreted with caution because the cases were identified after implementation of strict physical distancing measures (eg, school closure), limiting the exposure of children to close contacts outside their household [8].

In observational studies of household transmission before the emergence of more transmissible variants, the secondary attack rate among pediatric contacts (<18 years of age) ranged from 4 to 57 percent [9-14]. In a meta-analysis of 87 studies of household transmission including 1,249,163 household contacts from multiple countries, the secondary attack rate was 18 percent among pediatric contacts (age <18 years) and 30 percent among adult contacts [15]. Household transmission rates are increased with more transmissible variants [16].

Health care-associated outbreaks and cases of possible transmission from teachers or school staff to students and among students in the school setting have also been reported [17-21]. The risk is greater for individuals who are unvaccinated [22].

In utero and peripartum transmission and transmission through breast milk or during infant feeding are discussed separately. (See "COVID-19: Overview of pregnancy issues".)

●Transmission by children – Although SARS-CoV-2 virus shedding varies from person to person [23], infected children appear to shed SARS-CoV-2 virus with nasopharyngeal viral loads comparable to or higher than those in adults [24-27], and children of all ages can transmit SARS-CoV-2 to others in household, child care, educational, and community settings [28-33]. Transmission may occur whether or not the child has symptoms [34-36]. Asymptomatic transmission by adults is well documented. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral shedding and period of infectiousness'.)

The relative transmissibility of SARS-CoV-2 by children in various age groups is uncertain, given the differing contributions of biologic, host, and environmental factors (eg, community transmission, ventilation, class size) [28,37-39].

Household contact studies have identified variable rates of transmission from pediatric index cases [13,31,34,40-44]. The variable rates may be related to different community prevalence and mitigation measures, age, history of past infection, methods of diagnosing secondary cases, timing of sample collection, predominant variants, and levels of adherence to infection control measures in the home, which is particularly challenging when the index patient is a young child [45-48].

Although transmission can occur in child care and educational settings [29,33,49], studies performed before COVID-19 vaccines were authorized for children <16 years and before emergence of more transmissible variants suggested that transmission by children and adolescents in the school setting was uncommon when there was strict adherence to multiple public health measures (eg, vaccination of eligible teachers, staff, and students; isolation/quarantine; case-contact testing; improved ventilation; cohorting; physical distancing) [21,34,49-55].

In the United States and other countries, resumption of in-person primary and secondary education before the emergence of more transmissible variants was associated with relatively few reports of school outbreaks when public health measures were followed [51-53,56-67].

Number of cases and seroprevalence — Children of all ages can get COVID-19 [68]. More than 16 million laboratory-confirmed cases of SARS-CoV-2 in children <18 years of age have been reported to the Centers for Disease Control and Prevention [69]. However, this is likely an underestimation given the number of cases that are asymptomatic or not reported (eg, following a home test) [70,71]. The American Academy of Pediatrics provides information about the number of cases in children in individual states [72].

As of December 11, 2022, the seroprevalence estimate for children (6 months to 17 years) was 96.3 percent (95% CI 95.9-96.6%) [73]; many seroconversions occurred after December 2021 (concurrent with the predominance of the Omicron variant). Seroprevalence increased with increasing age: 0 to 4 years: 89.9 percent; 5 to 11 years: 97.1 percent; 12 to 17 years: 98.9 percent. Seroprevalence does not necessarily correlate with protection against reinfection, severe outcomes, or SARS-CoV-2-related complications.

Hospitalization and death

●Hospitalization – In population-based surveillance, the annual COVID-19-associated hospitalization rate among children <18 years of age in the United States is 48.2 per 100,000 overall but varies with age (66.8 per 100,000 children age 0 to 4 years, 25 per 100,000 children age 5 to 11 years, and 59.9 per 100,000 children age 12 to 17 years) [74]. For children age 12 to 17 years, the COVID-19-associated hospitalization rate is greater than that for influenza during the three years before the COVID-19 pandemic; for children <12 years, the COVID-19-associated hospitalization rate is similar to or lower than that for influenza.

Weekly COVID-19 hospitalization rates in children and adolescents have varied throughout the pandemic. They peaked initially in January 2021 (1.5 per 100,000 population), again in September 2021 with predominance of the Delta (B.1.617.2) variant (1.8 per 100,000 population), and then again in January 2022 with predominance of the Omicron variant (7.1 per 100,000 population) [75,76]. A smaller peak followed in August 2022, with the predominance of Omicron subvariants [76]. Despite increasing numbers of hospitalizations with Delta and Omicron variants, the proportions of hospitalized children requiring intensive care or invasive mechanical ventilation was similar with Delta and lower with Omicron than with earlier circulating strains [76,77].

During the Omicron predominant periods, weekly hospitalization rates were particularly high in infants younger than six months, who remain ineligible for vaccination, and in children age six months through four years, who were not eligible for vaccination until June 2022 [76,78]. Among children age 5 to 11 years (who became eligible for vaccination in early November 2021), hospitalization rates were approximately twice as high in unvaccinated than in vaccinated children (19 versus 9 per 100,000) during the period of early Omicron predominance (December 19, 2021 to February 28, 2022) [77]. Higher proportions of unvaccinated than fully vaccinated adolescents had COVID-19 as the primary reason for hospitalization (70 versus 41 percent) and required intensive care (30 versus 16 percent) [76].

Underlying conditions are associated with higher rates of hospitalization and intensive care unit (ICU) admission [79]. Whether underlying conditions are associated with increased severity or a lower threshold for admission (eg, because of concern for complications) is unclear [80]. Age <1 year has also been associated with increased rates of hospitalization [1,81], although hospitalization of infants may not reflect severity of illness.

With universal testing for SARS-CoV-2 upon admission at most hospitals, the rates of hospitalization for SARS-CoV-2 in children may be overestimated if hospitalizations for SARS-CoV-2-related illness are not differentiated from hospitalizations for other reasons (eg, elective surgery, trauma) with incidental detection of SARS-CoV-2 [82], particularly when highly transmissible variants are circulating.

Additional information regarding hospitalization of children in the United States is available through the CDC's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) [75].

●Death – SARS-CoV-2-related death in children and adolescents is rare [83]. In pooled analysis from seven countries (France, Germany, Italy, Spain, South Korea, the United Kingdom, and the United States), the COVID-19-related death rate among children (age 0 to 19 years) was 0.17 per 100,000 population as of February 2021 [84,85]. In the United States, as of June 1, 2022, there were >13 million cases of COVID-19 and 1533 COVID-19-associated deaths in children <18 years of age reported to the CDC [69]. Between August 1, 2021 and July 31, 2022 (during the emergence of the Delta and Omicron variants), the crude death rate for COVID-19 among children (0 to 19 years) in the United States was 1.0 per 100,000 overall; the crude death rate was greater among those younger than 1 year (4.3 per 100,000) and those age 15 to 19 years (1.8 per 100,000) than in other age groups (ranging from 0.4 to 0.6 per 100,000) [86].

●Racial and ethnic disparities – Children from underrepresented racial and ethnic groups appear to be disproportionately affected by acute COVID-19 and COVID-19-associated hospitalizations and deaths, perhaps related to social determinants of health (ie, conditions in the places where people live, learn, work, play, and worship) [87,88]. As of May 2022, COVID-19 hospitalization rates were 2.2 to 2.5 times greater among non-Hispanic American Indian/Alaska Native children, non-Hispanic Black children, and Hispanic/Latino children than among non-Hispanic White children <18 years of age (158.5 to 179.2 versus 72 per 100,000 population) [87]. SARS-CoV-2-related deaths are disproportionately represented among Hispanic/Latino children, non-Hispanic Black children, non-Hispanic Native Hawaiian/other Pacific Islander children, and non-Hispanic American Indian/Alaska Native children.

Risk factors for severe disease

●Host factors – Although children with underlying medical conditions are at greater risk for severe disease (eg, hospitalization, need for intensive care or mechanical ventilation, death) than children without underlying conditions [68,79,89-101], robust evidence associating specific underlying conditions with severe illness in children is limited [96,102].

The following conditions may be associated with increased risk of severe disease in children [81,91,96,97,103,104]:

•Medical complexity

•Genetic conditions

•Neurologic conditions [101,105,106]

•Metabolic conditions

•Congenital heart disease/cardiovascular disease [101,106-111]

•Obesity (body mass index >95^th percentile for age and sex (calculator 1 and calculator 2)) [89,98,101,105,106,112,113]

•Diabetes mellitus [106,112]

•Chronic pulmonary diseases; the evidence for asthma is inconsistent [89,98,105,106,111,114]

•Sickle cell disease [115]

•Immunosuppression

•Being unvaccinated or not being up-to-date on COVID-19 vaccination [116]

Having multiple underlying conditions is also associated with an increased risk of severe disease [106,117]. In multicenter studies of children admitted to ICUs with SARS-CoV-2-related illness and case series of SARS-CoV-2-related deaths in children, most (but not all) children had one or more underlying conditions [90,91,100,101]. The most common underlying conditions included chronic pulmonary disease, obesity, neurologic and developmental conditions, and cardiovascular conditions.

Although immune compromise has been reported as an underlying condition in children with severe COVID-19 disease in some case series, the relationship between immune compromise and severe COVID-19 disease has not been well established. In small surveys of children who developed COVID-19 while receiving immunosuppressive medications for kidney disease, inflammatory bowel disease, and rheumatic disease, COVID-19 was mild [118-121]. In another study that included eight children with rheumatic disease, active disease and use of glucocorticoids were associated with severe disease [122].

Childhood cancer appears to be associated with increased severity of COVID-19 disease. In a global registry study of COVID-19 in children with cancer including 1500 patients, 20 percent had severe or critical infection, and mortality (4 percent) was higher than that in the general pediatric population [123]. Among children with cancer, severe disease has been associated with intensive chemotherapy, neutropenia, lymphopenia, comorbidity, and coinfection [123,124]. Children with hematologic malignancy do not appear to be at greater risk of severe COVID-19 than children with nonhematologic malignancy [125].

Other conditions that may be associated with severe disease in children, but for which the evidence is inconsistent, include age <1 year [93,100,106,126,127], Down syndrome [128,129], and prematurity (gestational age <37 weeks) [112,130].

Whether vitamin D deficiency increases the risk of SARS-CoV-2 infection in children is uncertain [131]. The association may be confounded by other risk factors for both vitamin D deficiency and SARS-CoV-2 infection (eg, obesity) [132,133]. Vitamin D deficiency in children, including indications for screening (which are unchanged by the COVID-19 pandemic), is discussed separately. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Underlying conditions that increase or may increase the risk of severe disease in adults are discussed separately (table 1). (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)

●Virus factors – COVID-19 disease severity may be related to the strain of SARS-CoV-2 [134-138]. In observational studies in children and adolescents, the rates of admission to the ICU and mechanical ventilation were lower with the Omicron than the Delta variant [134,135,139].

The association between SARS-CoV-2 variants and severity of disease is discussed in greater detail separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)

CLINICAL MANIFESTATIONS — The clinical features of COVID-19 are discussed in detail separately. This section focuses on the clinical features of acute COVID-19 in children. (See "COVID-19: Clinical features".)

Spectrum of disease severity — The clinical spectrum of SARS-CoV-2 infections in children ranges from asymptomatic to life-threatening. Although severe and fatal cases have been reported, most children appear to have asymptomatic or nonsevere symptomatic infections [5,79,140-142]. (See 'Severe disease in children' below and 'Hospitalization and death' above.)

Asymptomatic infection is common in children. In a 2020 systematic review of 18 reviews of symptoms and signs in children <20 years of age with documented SARS-CoV-2 infection, the proportion of asymptomatic infections ranged from 15 to 42 percent [143]. In a subsequent review of electronic health records of 82,798 United States children <18 years of age with laboratory-confirmed SARS-CoV-2 infection between March 2020 and December 2021, 66 percent were asymptomatic, 27 percent were mild (COVID-19-related symptoms), 5 percent were moderate (moderately severe COVID-19-related condition such as pneumonia, gastroenteritis, dehydration), and 2 percent were severe (unstable COVID-19-related condition, requiring intensive care unit [ICU] admission or mechanical ventilation) [140].

Among children with COVID-19 admitted to the ICU, the severity appears to be similar to that of influenza. In a multicenter study comparing children admitted to the ICU with influenza and children admitted to the ICU with COVID-19, approximately 30 percent in each group required mechanical ventilation, 20 percent required vasopressor support, and 2 to 3 percent required extracorporeal membrane oxygenation [144].

Why severe COVID-19 appears to be less frequent in children than in adults is unclear. One possibility is that children have a less-intense immune response to the virus than adults; cytokine release syndrome is thought to be important in the pathogenesis of severe COVID-19 infections [145-147]. Other possibilities include: viral interference in the respiratory tract of young children, which may lead to a lower SARS-CoV-2 viral load; different expression of the angiotensin converting enzyme 2 receptor (the receptor for SARS-CoV-2) in the respiratory tracts of children and adults; pre-existing cross-reactive antibody; a vigorous early mucosal immune response; protective off-target effects of live vaccines; relatively healthier blood vessels in children than in adults; developmental differences in adaptive immune responses during the first years of life; and age-related differences in the nasopharyngeal microbiome [148-158].

Clinical findings

In children of all ages — Children of all ages can be infected with SARS-CoV-2. Males and females are equally affected [79].

The clinical presentation of symptomatic SARS-CoV-2 infection in children is variable and overlaps with other clinical syndromes (eg, pneumonia, bronchiolitis, croup, e-cigarette or vaping product use-associated lung injury [159], gastroenteritis). The clinical presentation is similar in immunocompetent and immunocompromised children [160].

In case surveillance in the United States, commonly reported symptoms among children and adolescents included [68,79]:

●Fever

●Cough

●Shortness of breath

●Myalgia

●Rhinorrhea

●Sore throat

●Headache

●Nausea/vomiting

●Abdominal pain

●Diarrhea

●Loss of smell or taste (in nonverbal children, this may manifest as solid food aversion or refusal) [161]

The frequency of specific symptoms varies with age [79]. During the first months of the pandemic, fever, cough, or shortness of breath were reported in ≥60 percent of children and adolescents. Myalgia, sore throat, and headache were more frequently reported in children ≥10 years of age than in younger children (approximately 30 to 40 percent versus 10 to 15 percent). Loss of smell or taste was also more frequently reported among older children (approximately 10 versus 1 percent) [79].

●Respiratory tract symptoms – Although symptoms of respiratory tract infection are common, the frequency of specific symptoms may vary with the SARS-CoV-2 variant. Early in the pandemic, fever or chills and cough were the most frequently reported symptoms in children and adolescents [68,79,143]. During the predominance of the Delta and Omicron variants, nasal congestion, headache, sneezing, sore throat, and croup-like symptoms were more common; sore throat and altered sense of smell were more common with Delta than Omicron [162-169].

●Gastrointestinal symptoms – Gastrointestinal symptoms may occur without respiratory symptoms [4,148,170-172]. Diarrhea, vomiting, and abdominal pain are the most common gastrointestinal symptoms reported in children [1,170,173-175]. Acute cholestasis, pancreatitis, and hepatitis have also been reported [176-182]. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Acute hepatitis' and "Acute liver failure in children: Etiology and evaluation", section on 'Outbreak 2022'.)

In a retrospective study, the prevalence of SARS-CoV-2 positivity in children with acute gastroenteritis (>3 episodes of vomiting or diarrhea in 24 hours) was similar to that in children with isolated respiratory symptoms (approximately 7 to 8 percent) [183].

●Neurologic manifestations – Neurologic manifestations have been described in children hospitalized with acute COVID-19 and may be life threatening [184-186]. In a cross-sectional multicenter study of 15,137 children hospitalized with COVID-19 or a COVID-19-associated complication, 7 percent had one or more neurologic complications, including febrile seizures in 3.8 percent, nonfebrile seizures in 2.3 percent, and encephalopathy in 2.2 percent; less common neurologic complications included brain abscess, bacterial meningitis, and cerebral infarction [184]. Neurologic manifestations reported in other studies include stroke, central nervous system infection/demyelination, Guillain-Barré syndrome/variants, acute fulminant cerebral edema, headache, weakness, anosmia, ageusia, and delirium [185-188]. Seizures in febrile children with COVID-19 appear to be more common with the Omicron variant than with earlier variants [189].

●Cutaneous findings – Cutaneous findings have been reported infrequently and are not well characterized; they include maculopapular, urticarial, and vesicular eruptions; transient livedo reticularis; and acral peeling [190-194]. Reddish-purple nodules on the distal digits (picture 1A-B) (sometimes called "COVID toes") are described predominantly in children and young adults, although an association with COVID-19 has not been clearly established. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19'.)

●Cardiovascular abnormalities – Cardiovascular abnormalities (eg, heart failure, arrhythmias, myocarditis, pericarditis, cardiogenic shock, pulmonary embolism, ST elevation myocardial infarction) have been reported in small case series [5,195-202]. COVID-19 is associated with an increased risk of myocarditis, but the absolute risk is low (<0.15 percent) [203].

The risk of COVID-19 vaccine-associated myocarditis is discussed separately. (See "COVID-19: Vaccines", section on 'Myocarditis'.)

●Kidney dysfunction – Kidney dysfunction may occur in severely ill children and those with multisystem inflammatory syndrome in children (MIS-C) [204,205]. The incidence of acute kidney injury (AKI) in children with COVID-19 ranges from <1 to 70 percent, varying with the study population, AKI definition, and geographic location [204]. In a retrospective analysis of 2546 children (<21 years) admitted to ICUs in the United States with documented SARS-CoV-2 infection, 10.8 percent had AKI (determined by Kidney Disease Improving Global Outcomes staging (table 2)): 62.8 percent had stage 1, 14.6 percent had stage 2, and 22.6 percent had stage 3 [204].

In infants <12 months of age — Additional presentations associated with SARS-CoV-2 infection in infants <12 months of age include:

●Feeding difficulty [68,206-209]

●Fever without an obvious source [210-212]

●Intussusception [213]

●Bronchiolitis [214,215]

●Apnea [216]

Respiratory symptoms may be minimal in infants; when present, they are similar to those caused by other coronaviruses and influenza, although cough may be less prominent [217].

In a multicenter registry study of 232 infants <12 months of age hospitalized with documented acute COVID-19 infection during 2020, approximately 55 percent had severe disease (as defined by severe involvement of one or more organ systems) [127,218]. Among infants with severe disease, two-thirds were previously healthy; most had respiratory complications and 13 percent required mechanical ventilation.

●Special infant populations

•Neonates – In a registry study of 176 neonates (<28 days of age) who acquired SARS-CoV-2 infection after discharge from the birth hospital, symptoms included [207]:

-Fever – 64 percent

-Feeding intolerance – 26 percent

-Cough – 22 percent

-Tachypnea – 19 percent

-Diarrhea – 8 percent

-Rhinorrhea – 8 percent

-Somnolence/irritability – 7 percent

-Rash – 2 percent

In a separate retrospective cross-sectional study using electronic health record data, COVID-19 was diagnosed in 918 neonates (91 per 100,000 neonatal encounters) [219]. The median age at diagnosis was 14.5 days. Most neonates (64 percent) were asymptomatic at initial presentation. Among symptomatic infants, tachypnea and fever were the most common presenting signs and 28 percent had pneumonia. Approximately 8 percent of neonates had severe infection.

•Preterm infants – Hyperglycemia and bone marrow dysfunction (leukopenia or leukocytosis) have been reported in preterm infants with SARS-CoV-2 infection [220].

Severe disease in children — A consensus definition for severe disease in children is lacking and different definitions have been used in studies categorizing severity. Using a definition of severe disease that encompasses care in an ICU/step-down unit, requiring invasive mechanical ventilation, or in-hospital death, approximately one-third of children in the United States with COVID-19-related hospitalization have severe disease [89,117,221]. This proportion remained relatively stable or declined with the predominance of the Delta and Omicron variants [76].

An observational study that compared characteristics of severe acute COVID-19 with MIS-C defined severe acute COVID-19 by [218]:

●A positive polymerase chain reaction test for SARS-CoV-2, and

●Severe organ system involvement in at least one of the following systems:

•Respiratory (eg, receipt of supplemental oxygen or increased respiratory support [for those receiving respiratory support at baseline], severe bronchospasm, lower respiratory infection, pleural effusion)

•Cardiovascular (eg, dysrhythmia/ arrhythmia, pulmonary edema due to left heart failure, coronary artery aneurysm, receipt of vasopressor/vasoactive support)

•Kidney (eg, AKI or receipt of dialysis)

•Neurologic (eg, stroke, acute intracranial hemorrhage, seizures, encephalitis)

•Gastrointestinal (eg, appendicitis, pancreatitis, hepatitis)

•Hematologic (eg, lymphopenia, neutropenia, severe anemia, deep vein thrombosis, pulmonary embolism)

Although the clinical features of severe acute COVID-19 and MIS-C overlap, they have differing patterns of clinical presentation and organ involvement, which may help in their differentiation (eg, severe pulmonary involvement is more prominent in severe acute COVID-19,whereas severe cardiac involvement is more prominent in MIS-C). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Differentiating MIS-C and acute COVID-19'.)

Clinical and laboratory findings that are associated with severe disease include [4,94,218,222-225]:

●Dyspnea, tachypnea, tachycardia, hypotension, and/or hypoxia at admission

●Gastrointestinal symptoms at admission

●Elevated inflammatory markers (eg, C-reactive protein, procalcitonin, interleukin 6, ferritin, D-dimer) at admission or during hospitalization

Clinical course — Although most children with nonsevere symptomatic acute SARS-CoV-2 infection recover within one to two weeks of disease onset [5,79,140,226], clinical deterioration may occur suddenly after approximately one week of symptoms and should prompt urgent re-evaluation, ideally at a medical center with expertise in caring for children with COVID-19 [227].

In a prospective cohort study with voluntary mobile application-based reporting of symptoms by an adult proxy, the median duration of illness was six days (interquartile range [IQR] 3 to 11 days) in 1734 children who tested positive for SARS-CoV-2 compared with three days (IQR 2 to 7 days) in a matched cohort of children who tested negative [226]; approximately 2 percent of each group presented to an emergency department or were hospitalized. Median duration of SARS-CoV-2 illness was shorter in children age 5 to 11 than 12 to 17 years (5 versus 7 days).

Complications

MIS-C — Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition associated with COVID-19. The clinical features of MIS-C may be similar to those of Kawasaki disease, Kawasaki disease shock syndrome, and toxic shock syndrome. They include persistent fever, hypotension, gastrointestinal symptoms, rash, myocarditis, and laboratory findings associated with increased inflammation; respiratory symptoms may be lacking (table 3A-B).

MIS-C is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Post-COVID-19 condition ("long COVID")

●Terminology – The Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics, and World Health Organization (WHO) use the umbrella term "post-COVID-19 condition" for the broad range of persistent, recurrent, or novel physical and mental health symptoms and conditions that are present ≥4 weeks after SARS-CoV-2 infection (of any severity); this condition is also called "long COVID" or "post-acute sequelae of SARS-CoV-2 infection" (PASC) [228-230].

The WHO provides a consensus clinical case definition that can be applied to children of all ages and includes [230]:

•Confirmed or probable SARS-CoV-2 infection

•Symptoms lasting ≥2 months and that initially occurred within three months of acute COVID-19

-In a systematic review, fatigue, altered smell/anosmia, and anxiety were more frequent among children with post-COVID-19 condition than controls (without post-COVID-19 condition); a wide range of other potential symptoms may occur (eg, cough, cognitive difficulty, diarrhea)

-Symptoms may be persistent or of new onset and may fluctuate or recur over time

•Symptoms affect everyday function (eg, eating habits, physical activity, interaction with friends and family, school performance)

•Co-occurrence of other diagnoses does not exclude the diagnosis of post-COVID-19

The WHO definition may change over time as more information becomes available [230].

●Epidemiology

•Prevalence – The prevalence of post-COVID-19 symptoms and conditions is unclear [231,232]. Ongoing follow-up of children with COVID-19 is necessary to better define the long-term outcome. Examples of relevant studies include the following:

-Children hospitalized with COVID-19 – In prospective observational studies of children hospitalized with acute COVID-19, approximately 10 to 27 percent report persistent symptoms or activity impairment two to five months after discharge [233-235]. In a review of administrative claims of 372 commercially insured children who were hospitalized with acute COVID-19, 20 percent had at least one SARS-CoV-2 sequelae-related readmission and 91 percent had at least one sequelae-related health care visit (median of six visits) in the five months after discharge; at least 25 percent had a sequelae-related visit in the fifth month [236]. Sequelae-related visits included cardiovascular (eg, dysrhythmia, pericarditis myocarditis), respiratory (eg, lower respiratory tract disease), gastrointestinal (eg, abdominal pain), and mental health (eg, anxiety, mood disorder) diagnoses.

A retrospective cohort study was conducted in a European country where the health registries achieve almost complete data acquisition of all citizens [237]. Of the more than 160,000 children aged 6 to 17 years diagnosed with COVID-19 between January 31, 2020 and February 9, 2022, 0.2 percent were subsequently diagnosed with post-COVID-19. The incidence per 100 person-years was higher among children hospitalized for COVID-19 treatment (1.25 percent, 95% CI 0.62-2.23) than those who were not (0.15 percent, 95% CI 0.13-0.17).

-Children treated as outpatients for COVID-19 – In a retrospective cohort study of electronic health records of 659,286 children <21 years of age (59,893 with a positive COVID-19 test), the incidence of ≥1 clinical feature of a post-COVID-19 condition (eg, symptom, syndrome/condition, or use of medication) was slightly greater in children with than without COVID-19 (41.9 versus 38.2 percent; proportion difference 3.7 percent, 95% CI 3.2-4.2) [238]. These findings support those of an earlier systematic review in which the proportion difference was 3 percent, underscoring the challenge of distinguishing symptoms related to SARS-CoV-2 infection from those related to the pandemic [239,240].

•Risk factors – Among children with acute COVID-19, post-COVID-conditions appear to be associated with severe symptoms during initial infection, hospitalization, the number of organ systems involved, the number of symptoms at presentation, lack of vaccination against COVID-19, and body mass index ≥85^th percentile for age and sex [233,235,237,238,241].

●Clinical features – Commonly reported symptoms include fatigue, weakness, headache, sleep disturbance, muscle and joint pain, respiratory problems, palpitations, and altered sense of smell or taste [226,233-235,242-250]. Other symptoms include dizziness and dysautonomia [250,251].

Whether post-COVID-19 symptoms and conditions (eg, fatigue, sleep disturbance) are caused by SARS-CoV-2 infection or related to the pandemic is unclear [231,252,253]. The CDC analyzed medical claims of >781,400 children <18 years of age with documented COVID-19 and >2.3 million children without COVID-19 (or with unrecognized COVID-19) who were followed between 60 and 365 days to identify which symptoms and conditions were more likely among children with COVID-19 [246]. In general, symptoms/conditions that were more likely in children with COVID-19 were serious and rare or uncommon (incidence ranging from 13 to 817 per 100,000), and symptoms/conditions that were only slightly more likely or less likely in children with COVID-19 were less serious and more common (incidence >4600 per 100,000) [246].

•Symptoms/conditions that were more likely among children with than without COVID-19 included [246]:

-Pulmonary embolism (adjusted hazard ratio [aHR] 2.01)

-Myocarditis and cardiomyopathy (aHR 1.99)

-Venous thromboembolic events (aHR 1.87)

-Acute and unspecified renal failure (aHR 1.32)

-Type 1 diabetes mellitus (aHR 1.23)

-Coagulation and hemorrhagic disorders (aHR 1.18)

-Smell and taste disturbances (aHR 1.17)

-Type 2 diabetes (aHR 1.17)

-Cardiac dysrhythmias (1.16)

These findings are supported by a similar multicenter cohort study in which myocarditis and loss of smell or taste were more likely in children with COVID-19 [238] and a retrospective cohort study in which COVID-19 infection in children <18 years of age was associated with increased health care utilization for pulmonary embolism or deep vein thrombosis, arrhythmias, dyspnea, and ear nose and throat disorders [254].

In a separate multicenter cohort study that evaluated neurologic and psychiatric trajectories following COVID-19 infection in 185,748 children with COVID-19, children with COVID-19 had an increased risk of cognitive deficit; insomnia; intracranial hemorrhage; ischemic stroke; nerve, nerve root, and plexus disorders; psychotic disorders; and seizures in the six months after infection compared with matched controls with any other respiratory infection [247].

•In the CDC study, symptoms/conditions that were only slightly more likely in children with COVID-19 included [246]:

-Circulatory signs and symptoms (aHR 1.07)

-Malaise and fatigue (aHR 1.05)

-Musculoskeletal pain (aHR 1.02)

•In the CDC study, symptoms/conditions that were less or equally likely in children with COVID-19 included [246]:

-Respiratory symptoms

-Anxiety and fear-related disorders

-Gastroesophageal and esophageal disorders

-Asthma

Follow-up of children with SARS-CoV-2 infection and persistent symptoms, and persistent symptoms in adults with COVID-19, are discussed separately. (See "COVID-19: Management in children", section on 'Follow-up' and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)

Reinfection — The risk of reinfection increased with the emergence of the Omicron variant and Omicron sublineages (table 4). Reinfection is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Risk of reinfection'.)

LABORATORY FINDINGS — Laboratory findings in children with symptomatic SARS-CoV-2 infection are variable. In a meta-analysis of 66 studies in children that included 9335 children (0 to 19 years) with documented SARS-CoV-2 (including 1208 with multisystem inflammatory syndrome in children [MIS-C]), mean proportions of children with the following laboratory abnormalities were as follows [68]:

●Elevated C-reactive protein – 54 percent

●Elevated serum ferritin – 47 percent

●Elevated lactate dehydrogenase – 37 percent

●Elevated D-dimers – 35 percent

●Elevated procalcitonin – 21 percent

●Elevated erythrocyte sedimentation rate – 19 percent

●Elevated leukocytes – 20 percent

●Lymphocytopenia – 19 percent

●Lymphocytosis – 8 percent

●Elevated serum aminotransferases – 30 percent

●Elevated creatine kinase myocardial band – 25 percent

Elevated inflammatory markers and lymphocytopenia may indicate MIS-C (table 3B). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

IMAGING FINDINGS — Imaging findings are variable and may be present before symptoms [255-257]. In a systematic review that included imaging for 3670 children with laboratory-confirmed COVID-19, 44 percent had abnormalities on chest radiograph or computed tomography (CT) [68]. In a separate meta-analysis of 1026 children with laboratory-confirmed COVID-19 who underwent CT imaging of the chest, 36 percent had normal findings and 28 percent had bilateral lesions [258]. Ground glass opacities (37 percent) and consolidation or pneumonic infiltrates (22 percent) were most common. Findings typical of other viral respiratory infections (eg, hyperinflation, peribronchial markings) were not reported. In a small retrospective study from a single institution, 9 of 11 children with multisystem inflammatory syndrome in children (MIS-C) had pleural effusions compared with none of 16 children with COVID-19 without MIS-C [259].

In a study of eight Italian children hospitalized with documented COVID-19, findings on lung ultrasonography included subpleural consolidations and individual or confluent B lines [260]. These findings were concordant with radiographic findings in seven of the eight patients. They are similar to findings in adult patients with COVID-19. (See "Bedside pleural ultrasonography: Equipment, technique, and the identification of pleural effusion and pneumothorax", section on 'B lines and lung consolidation' and "COVID-19: Clinical features", section on 'Lung ultrasound'.)

APPROACH TO DIAGNOSIS

Criteria for COVID-19 testing — Laboratory testing is necessary to confirm the diagnosis of COVID-19 because no single symptom or combination of symptoms reliably differentiates SARS-CoV-2 from other community-acquired viruses and because coinfection is common [81,261-267].

Considerations for testing for COVID-19 and information regarding testing may be updated periodically. In the United States, guidance regarding testing is provided by the Centers for Disease Control and Prevention [268], Infectious Diseases Society of America [269], and the American Academy of Pediatrics [270].

Testing criteria suggested by the World Health Organization can be found in its interim guidance on diagnostic testing for SARS-CoV-2 online. These are the same criteria used by the European Centre for Disease Prevention and Control. Guidance for testing in other countries is discussed separately. (See 'Society guideline links' below.)

Outpatient testing criteria — In the emergency department, urgent care, or outpatient setting, we perform COVID-19 testing (independent of vaccination status) in children who [268,270]:

●Have symptoms consistent with COVID-19 (eg, fever, cough, rhinorrhea, shortness of breath, vomiting, diarrhea, sore throat, body aches, fatigue, altered sense of smell or taste), independent of vaccination status, severity of symptoms, and risk for severe disease. (See 'Clinical findings' above and 'Risk factors for severe disease' above.)

●Have clinical manifestations of multisystem inflammatory syndrome in children (table 3B). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Clinical manifestations'.)

●Have known in-person exposure to a close contact with laboratory-confirmed case of COVID-19 within the previous 14 days.

Symptomatic contacts are tested at the time of presentation; asymptomatic contacts ideally are tested at least five days after the most recent exposure.

●Develop recurrent symptoms two to eight days after completing treatment with nirmatrelvir-ritonavir.

●Require clearance to return to in-person school attendance after recovery from a symptomatic illness or asymptomatic, nonhousehold COVID-19 exposure.

Inpatient testing criteria — Testing children at the time of admission to the hospital may be beneficial when community transmission is high or in settings where other control measures are limited (eg, shared patient rooms, congregate care, behavioral health issues) [271]. Decisions regarding testing of asymptomatic children at the time of admission usually are made at the institutional level. Several of our institutions test only children who have symptoms of COVID-19 at the time of admission or who develop symptoms during admission. Vaccination status is not considered in the decision. For patients with suspected hospital-acquired acquisition of a respiratory virus, we test for common respiratory pathogens (eg, influenza, respiratory syncytial virus [RSV]) as well as COVID-19 via multiplex reverse transcriptase polymerase chain reaction (PCR).

Asymptomatic individuals — In certain circumstances, testing asymptomatic individuals is important for public health or infection control purposes (eg, high-risk congregate settings, hospital admission in communities with high prevalence, preoperative screening). Potential indications for testing asymptomatic individuals are discussed separately. (See "COVID-19: Diagnosis", section on 'Selected asymptomatic individuals'.)

Children with a history of SARS-CoV-2 infection — In the United States, the Centers for Disease Control and Prevention (CDC) recommendations for testing (whether to test and preferred type of test) for SARS-CoV-2 in people with a history of SARS-CoV-2 infection vary with the timing of the previous infection. These recommendations are discussed separately. (See "COVID-19: Diagnosis", section on 'Selected asymptomatic individuals' and "COVID-19: Diagnosis", section on 'Choosing an initial diagnostic test'.)

Laboratory tests for SARS-CoV-2 — The preferred laboratory test for SARS-CoV-2 in children depends upon the clinical scenario (eg, symptoms compatible with COVID-19, duration of symptoms, timing of exposure, surveillance, clearance for a specific setting or event), local guidance, and availability of testing (table 5) [270].

An approved or authorized PCR test is considered the reference standard for diagnosis of acute SARS-CoV-2 infection in symptomatic children or asymptomatic children with SARS-CoV-2 exposure [270].

Antigen tests are less sensitive and may require follow-up testing, particularly negative antigen test results in children with symptoms compatible with COVID-19 or high-risk exposures (algorithm 1). In a meta-analysis of cross-sectional or cohort studies of eight point-of-care rapid antigen tests in children, the sensitivity was 64 percent overall (95% CI 57-71 percent; 17 studies, 6287 participants), 72 percent in symptomatic children (95% CI 64-79 percent; 13 studies, 3407 participants), and 56 percent in asymptomatic children (95% CI 48-64 percent; 10 studies, 2431 participants) [272]. The specificity was 99 percent in all groups. In all but one of the included studies, trained staff conducted the tests; results may not be generalizable to other testing conditions.

Laboratory tests for COVID-19 (table 5) and interpretation of laboratory tests for COVID-19 are discussed in detail separately. (See "COVID-19: Diagnosis", section on 'Antigen testing' and "COVID-19: Diagnosis", section on 'NAAT (including RT-PCR)'.)

Laboratory testing for other viruses

●Influenza and RSV - During influenza and RSV season, children who are tested for SARS-CoV-2 generally should also be tested for influenza [104,270], and children younger than two years generally should be tested for RSV. Multiplex PCR assays for the three viruses are available, including one that has US Food and Drug Administration emergency use authorization for use without a prescription (the sample is collected at home and sent to a laboratory for testing) [273-277]. The clinical features of SARS-CoV-2 and these viruses overlap [278], and coinfection may occur [279]. The clinical features and diagnosis of influenza and RSV in children are discussed separately. (See "Seasonal influenza in children: Clinical features and diagnosis" and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Infants and young children'.)

Confirmation of infection with SARS-CoV-2, influenza, RSV, or coinfection is necessary because the management of these infections differ. (See "COVID-19: Management in children" and "Seasonal influenza in children: Management", section on 'Antiviral therapy' and "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

●Rhinoviruses and enteroviruses – During late summer and early fall, testing for enterovirus (EV)-D68 may be warranted for children with severe respiratory illness requiring hospitalization and for children with weakness or acute flaccid myelitis. In August 2022, the CDC received reports of increased numbers of children hospitalized with severe respiratory illness who tested positive for rhinoviruses or enteroviruses and noted more detections of EV-D68 than in the three previous years [280]. Additional information is available from the CDC.

Enteroviruses, including EV-D68, and acute flaccid myelitis are discussed separately. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis'.)

Detection of other respiratory pathogens — Detection of other respiratory pathogens (eg, influenza, RSV, Mycoplasma pneumoniae) in nasopharyngeal specimens does not exclude COVID-19 [3,81,100,146,281-286]. In a systematic review of COVID-19 in 1183 children from 26 countries, coinfection was detected in 5.6 percent. M. pneumoniae was most common (58 percent of coinfections), followed by influenza (11 percent) and RSV (9.7 percent) [6].

Imaging studies — Chest imaging is not routinely necessary for the diagnosis of COVID-19 in children [287,288]. It should be obtained as indicated to evaluate clinical findings suggestive of lower respiratory involvement, risk factors for disease progression, potential complications, or worsening respiratory status. Decisions about nonthoracic imaging should be individualized according to clinical findings.

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 email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Epidemiology and transmission – COVID-19 is a pandemic infectious disease caused by SARS-CoV-2. Most cases in children result from household exposure. Children of all ages can transmit SARS-CoV-2 to others in household, child care, educational, and community settings. The relative transmissibility of SARS-CoV-2 by children in various age groups is uncertain. (See 'Transmission' above.)

●Risk factors – Although children with underlying medical conditions have an increased risk for severe disease (eg, hospitalization, need for intensive care, death), robust evidence associating specific underlying conditions with severe illness is limited. Conditions that may be associated with severe disease in children include (see 'Risk factors for severe disease' above):

•Medical complexity

•Genetic, neurologic, and metabolic conditions

•Congenital heart disease/cardiovascular disease

•Obesity (body mass index >95th percentile for age and sex (calculator 1 and calculator 2))

•Diabetes mellitus

•Chronic pulmonary diseases

•Sickle cell disease

•Immunosuppression

•Being unvaccinated or not being up-to-date on COVID-19 vaccination

●Clinical manifestations

•The clinical spectrum of SARS-CoV-2 infections in children ranges from asymptomatic to life-threatening. (See 'Spectrum of disease severity' above and 'Severe disease in children' above.)

•The most common clinical findings in children are fever and cough. Other findings include shortness of breath, myalgia, rhinorrhea, headache, nausea/vomiting, abdominal pain, diarrhea, sore throat, fatigue, and loss of smell or taste. Although clinical deterioration may occur suddenly after approximately one week and should prompt urgent re-evaluation, most children recover within one to two weeks. (See 'Clinical findings' above and 'Clinical course' above.)

•Complications of SARS-CoV-2 infection in children include multisystem inflammatory syndrome in children (MIS-C; (table 3A-B)) and post-COVID-19 condition (persistent, recurrent, or novel physical or mental health symptoms that are present ≥4 weeks after SARS-CoV-2 infection). (See 'Complications' above.)

●Laboratory findings – Laboratory findings are often normal but may include leukopenia, lymphocytopenia, and elevated procalcitonin or C-reactive protein. (See 'Laboratory findings' above.)

●Criteria for testing

•Outpatient settings – In the emergency department, urgent care, or outpatient setting, we perform COVID-19 testing in children who (see 'Outpatient testing criteria' above):

-Have symptoms consistent with COVID-19 (eg, fever, cough, rhinorrhea, shortness of breath, vomiting, diarrhea, sore throat, body aches, fatigue, altered sense of smell or taste), independent of vaccination status, severity of symptoms, and risk for severe disease (see 'Clinical findings' above and 'Risk factors for severe disease' above)

-Have clinical manifestations of MIS-C in children (table 3B) (see "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Clinical manifestations')

-Have known in-person exposure to a close contact with laboratory-confirmed case of COVID-19 within the previous 14 days

-Develop recurrent symptoms two to eight days after completing treatment with nirmatrelvir-ritonavir

-Require clearance to return to in-person school attendance after recovery from a symptomatic illness or asymptomatic, nonhousehold COVID-19 exposure

•Hospitalized children – Testing children at the time of admission to the hospital may be beneficial when community transmission is high or in settings where other control measures are limited (eg, shared patient rooms, congregate care, behavioral health issues). Decisions regarding testing of asymptomatic children at the time of admission usually are made at the institutional level. (See 'Inpatient testing criteria' above.)

●Laboratory tests and interpretation – Laboratory tests for COVID-19 (table 5) and interpretation of laboratory tests for COVID-19, including antigen tests (algorithm 1), are discussed separately. (See "COVID-19: Diagnosis", section on 'Antigen testing' and "COVID-19: Diagnosis", section on 'NAAT (including RT-PCR)'.)