Most children with severe inflammatory disease have mild COVID-19 infections with no symptoms


Most children with a serious inflammatory illness linked to the coronavirus had initial COVID-19 infections with no symptoms or only mild ones, new U.S. research shows.

The unusual post-infection condition tends to be milder in kids who were sicker with COVID-19, although more than half of affected youngsters received intensive hospital care, according to an analysis by the federal Centers for Disease Control and Prevention published Tuesday in JAMA Pediatrics.

The study represents the largest analysis to date on U.S. cases of multisystem inflammatory syndrome in children and bolsters evidence that it is a delayed immune response to COVID-19. The study included almost 1,800 cases reported to the CDC from March 2020 through mid-January. Most were in kids younger than 15 but the study included up to age 20.

Upticks in cases have occurred two to five weeks after COVID-19 peaks and have followed spread of initial infections from urban to rural areas, the researchers said. More recent CDC data indicate there’s another emerging peak in the pediatric condition consistent with that trend.

State-reported cases through March 29 totaled 3,185 and included 36 deaths, the CDC’s website shows. State reports aren’t always timely so it is uncertain how many U.S. children developed the illness since the study ended.

Most kids who had COVID-19 don’t develop the post-infection illness. Almost 3.5 million U.S. children and teens have tested positive for COVID-19, according to data compiled by the American Academy of Pediatrics and the Children’s Hospital Association.

The condition was first reported in Europe in late winter and spring of last year. Some cases, especially those that follow silent, undiagnosed COVID-19 infections, may be mistaken for Kawasaki disease, a rare condition that can cause red skin, swelling and heart problems.

Dr. Sean O’Leary, vice chairman of the pediatrics academy’s infectious diseases committee, said the inflammatory condition typically causes children to become very sick very quickly, but that most ”respond very well to treatment and the vast majority get completely better.”

Treatments may include steroids and other medicines that can reduce inflammation.

The best way to prevent it is to prevent COVID-19 infections, ”which vaccines are very good at doing,” he said. COVID-19 vaccine studies in children are underway.

In the CDC analysis, fever was among the most common symptoms. Abdominal pain, vomiting, diarrhea and red skin rash occurred in at least half of affected kids. Almost one-third had heart inflammation or other cardiac involvement. These symptoms were least common among children up to age 4, who were also less likely to require intensive care than older children.

Presentation of SARS-CoV-2 infection in children

The most common symptoms in children with acute SARS-CoV-2 infection (covid-19 disease) are fever and cough. Other symptoms may include sore throat, rhinorrhoea, or congestion, myalgias, headache, fatigue, and gastrointestinal symptoms including nausea, vomiting, or diarrhoea. The range of symptom prevalence is reported from three large meta-analyses, one with 131 studies and 7780 paediatric patients,1 the second with 28 studies and 1614 patients,2 and the third with 46 studies and 551 patients3 and summarised in table 1.

Though children have a similar distribution of initial symptoms as compared with adults, children are more likely to have mild, self-resolving symptoms without progression to the lower pulmonary disease that necessitates hospitalisation.4 Dermatological manifestations in children with mild disease are uncommon: acute infection has at times been associated with a maculopapular exanthem, but the pseudo chilblain lesions or “covid toes” seen in adults are rare.56

Although assessing the prevalence of loss of taste or smell among children may be challenging (especially when children are unable to report these symptoms),7 as with adults, some studies suggest the presence of loss of taste or smell may also be relatively specific for covid-19 among children.8

Table 1

Prevalence of symptoms in children with acute SARS-CoV-2 infection, summarised from three meta-analyses

Rhinorrhoea, nasal congestion7-20%
Sore throat14-18%
Tachypnoea, dyspnoea8-12%
Nausea, vomiting2-9%
Abdominal pain6-7%

(Early studies did not specify loss of taste or smell because younger children are not able to report this symptom)

  • * Hoang et al included 131 studies with 7780 patients; Assaker et al included 28 studies with 1614 patients; Zhang et al included 46 studies with 551 patients

Data that further disaggregate paediatric symptoms by age are relatively limited, but among infants the most common symptoms of acute covid-19 similarly include fever, cough, and nasal congestion. Infants may also present with isolated fever, poor feeding, or fussiness.9101112

Asymptomatic and mild disease

Multiple reports have described a mild illness trajectory and high rates of asymptomatic infection in children with acute covid-19. A retrospective case series of 2135 Chinese children with suspected or confirmed acute SARS-CoV-2 infection found that more than 90% of patients were asymptomatic or had mild to moderate illness.13 The true incidence of asymptomatic SARS-CoV-2 infection is difficult to confirm, as asymptomatic children may not be tested, however, meta-analyses estimate that between 16% and 19% of paediatric cases are asymptomatic.123

A recent prospective multicentre study of four French hospitals screened all admitted patients for SARS-CoV-2 infection by polymerase chain reaction testing and found that 45% of the 438 positive paediatric cases hospitalised were asymptomatic.14 In another study, investigators fit age structured mathematical models to epidemiological data from multiple countries and estimated that clinical symptoms only manifest in 21% of infected children.15 As of February 2021, the US Centers for Disease Control and Prevention (CDC) estimated that children age 0-4 years account for only 1.9% of covid-19 diagnoses, and those age 5-17 years account for 9.4% of covid-19 diagnoses in the US.16

Severe covid-19 disease

A small proportion of children go on to develop severe acute covid-19 disease and require hospitalisation because of respiratory compromise or complications of SARS-CoV-2 infection such as multisystem inflammatory syndrome in children (MIS-C). A CDC study in August 2020 of 576 children hospitalised with SARS-CoV-2 infection reported a lower hospitalisation rate compared with adults (8 versus 165 per 100 000); however, one in three hospitalised children required admission to intensive care units, a rate similar to adults.4 This report also describes a bimodal distribution in hospitalisation rate by age.

Infants <2 months accounted for 19% of admissions—which may reflect a general practice standard to admit and evaluate neonates with fever or other symptoms that could indicate a serious bacterial infection rather than disease severity—because most neonates have mild self-resolving infections with brief admissions.17

Children age 12-17 years accounted for 42% of admissions, which may reflect more severe illness in adolescents.4 It appears that children who become severely ill with acute covid-19 often have one or more underlying conditions, including medical complexity, obesity, asthma, sickle cell disease, and immunosuppression.418 Reassuringly, the mortality rate in paediatric patients remains low, accounting for <1% of all deaths associated with SARS-CoV-2 in the US.11819 The risk factors for severe illness in children will likely be further clarified by ongoing research.

Community transmission of SARS-CoV-2 is happening in my region. How should I approach a sick child?

In places where there is active community transmission of SARS-CoV-2, children with fever, respiratory tract symptoms, loss of taste or smell, or multiple infectious symptoms should undergo testing for covid-19 or be considered to have the disease until proved otherwise. Acute covid-19 does not appear to be easily distinguished from other viral infections based on symptomatology.

A retrospective cohort study compared children infected with influenza (n=1402) or SARS-CoV-2 (n=315) and found that those admitted with SARS-CoV-2 reported more frequent non-specific viral symptoms than those with influenza, but no difference was seen in the rate of hospitalisation, intensive care unit admission, or mechanical ventilation.20 In addition, a systematic review suggested that 6% of children with covid-19 also had a concurrent bacterial or viral co-infection.1

Though children with fever and respiratory tract symptoms will likely undergo testing for SARS-CoV-2 where covid-19 is endemic, clinicians should consider a range of other diagnoses, including other pulmonary infections and systemic illnesses with respiratory manifestations, including non-infectious diagnoses such as diabetic ketoacidosis (table 2). Encourage parents or caregivers to return to care if their child develops symptoms that suggest more serious disease, including rapid or laboured breathing, dehydration, persistent fever, severe abdominal pain, or altered mental status.

Table 2

Differential diagnosis of acute covid-19 and multisystem inflammatory disease (MIS-C)

Acute covid-19
(chief concern: respiratory tract symptoms)
(chief concern: fever with abdominal pain and/or rash)
Infectious causes
Other respiratory viral infections (eg, influenza, adenovirus, respiratory syncytial virus, rhinovirus) causing upper and/or lower respiratory tract infection
Atypical pneumonia
Acute bacterial pneumonia
Bacterial sinusitis
Acute covid-19 or other viral infections (eg, adenovirus, enterovirus/coxsackie viruses)
Toxic shock syndrome
Bacterial sepsis
Abdominal abscess
Non-infectious causes
Reactive airway disease/asthma
Cardiac dysfunction
Diabetic ketoacidosis
Foreign body
Kawasaki disease
Haematological malignancy
Macrophage activation syndrome
Haemophagocytic lymphohistiocytosis
Systemic juvenile idiopathic arthritis
Systemic lupus erythematosus

Children with fever and gastrointestinal symptoms (abdominal pain, vomiting, or diarrhoea) or any child with other features consistent with Kawasaki disease (eg, persistent fever plus lymphadenopathy, mucocutaneous changes, conjunctivitis, or swelling of extremities) could have MIS-C. These patients require urgent evaluation in an emergency department, preferably staffed by paediatric specialists.

Multisystem inflammatory disease in children

MIS-C (box 1) is thought to be a hyperinflammatory syndrome that develops approximately 2-6 weeks after SARS-CoV-2 infection.Box 1

Case definition of MIS-C

  • Presence of fever for ≥24 hours
  • Elevated inflammatory markers
  • Multi-organ dysfunction (≥2 systems: cardiac, dermatological, gastrointestinal, renal, respiratory, haematological, and/or neurological)
  • No plausible alternative diagnosis
  • Positive viral or serological testing for SARS-CoV-2 or close contact with a person with covid-19 within four weeks of symptom onset21

Typically, school aged children are affected (median age 8 years), though MIS-C has been reported in children from infancy through young adulthood.222324 Children with MIS-C present with persistent fever, and most often have gastrointestinal symptoms (eg, abdominal pain, vomiting, diarrhoea), mucocutaneous changes (eg, rash, conjunctivitis), and may experience neurological symptoms (eg, headache, meningismus) (table 3).

Patients with MIS-C may present with some features consistent with Kawasaki disease (particularly fever and mucocutaneous changes); however, MIS-C is likely a distinct clinical entity. Patients with MIS-C often have predominant cardiac dysfunction and gastrointestinal symptoms, in addition to biomarker and cytokine differences that appear distinct from Kawasaki disease.23262728

One study observed that younger patients (aged 0-5 years) with MIS-C were more likely to meet Kawasaki disease or atypical Kawasaki disease criteria compared with adolescents (48% v 12%), had a higher prevalence of mucocutaneous symptoms (87% v 62%), and had a lower prevalence of myocarditis (39% v 73%) or neurological symptoms (13% v 39% of adolescents).26 Though there are hypotheses around risk factors for MIS-C, such as lower pre-existing immunity to coronaviruses, specific risk factors for developing MIS-C in children are not well established.28

Table 3

Clinical features of patients with MIS-C, summarised from two surveillance studies and one meta-analysis

Previously healthy66-73%
Median age8 years
(range 0- 20 years)
Organ system involvement
Admission to intensive care64-80%
Mechanical ventilation13-30%
Vasoactive support42-48%
  • * Feldstein et al included 186 patients; Godfred-Cato et al included 570 patients; and Jiang et al included 660 patients in their meta-analysis

MIS-C is typically a progressive illness, and patients who initially had mild symptoms can develop severe illness with multi-organ dysfunction within a few days of symptom onset. Critical signs may include haemodynamic instability, tachycardia, left ventricular dysfunction, and respiratory distress, which could be primary or caused by cardiac dysfunction.

Approximately two-thirds of patients in the US with MIS-C required admission to intensive care.23 and 30 deaths among 2060 patients with MIS-C have been reported in the US as of 8 February 2021.21 Laboratory abnormalities often include lymphopenia, anaemia, and thrombocytopenia, in addition to elevations in liver enzymes, creatinine, pro-brain natriuretic protein, troponin, and coagulation studies.

If MIS-C is suspected, it is important to obtain laboratory tests to evaluate for evidence of inflammation, cardiac, and other organ dysfunction, and to obtain additional diagnostic imaging based on physical examination findings or laboratory results. All patients in whom there is a strong suspicion for MIS-C should have an echocardiogram to evaluate cardiac function and to look for evidence of coronary artery dilatation.

The presenting signs and symptoms of MIS-C in children can overlap with other time-sensitive diagnoses, such as sepsis, toxic shock, myocarditis, appendicitis, or meningitis. Therefore, it is important to consider these diseases processes, pursue evaluation, and initiate antibiotic therapy if necessary (table 2). Overall, MIS-C is a rare complication of SARS-CoV-2. A May 2020 systematic review from 26 countries reported a MIS-C incidence of 0.14% among all children with SARS-CoV-2 infection,1 but this estimated incidence may be imprecise because of potential underestimation of overall SARS-CoV-2 infections in children. Although it is rare, MIS-C is a critical diagnosis to consider in any child with fever, evidence of inflammation, and organ dysfunction where covid-19 is endemic.29 Prompt treatment with intravenous immunoglobulin and steroids can reduce the inflammatory response and may improve outcomes.

Transmission dynamics of SARS-CoV-2 in children

While questions remain regarding the susceptibility of children to covid-19 when exposed to the SARS-CoV-2 virus and their ability to transmit it to others, transmission of the virus from children to contacts in their households, camps, and schools303132 has been clearly documented, particularly when face masks are not worn universally.33 For example, a 13 year old boy whose only symptom was nasal congestion transmitted the infection to a household of people in the US.32

In contrast, when universal masking and distancing guidelines were used, a prospective observational study followed 90 000 students and staff in a North Carolina school system for nine weeks and found 773 community acquired SARS-CoV-2 infections, with a very low rate of within school infections (32 cases total).34

In addition, a recent CDC case-control study in Mississippi found that close contacts with anyone outside the household and inconsistent mask use in school was associated with SARS-CoV-2 infection, but school or day care attendance itself was not associated SARS-CoV-2 infection when masks were used.35

Though further research is needed to clarify viral transmission dynamics specific to the unique immunobiology of children, they are able to transmit the virus to others and appropriate prevention measures are important in all settings. If a household or other close contact contracts SARS-CoV-2, the exposed child should therefore quarantine and stay away from school or other activities. Family members may consider physical separation and wearing masks around other exposed household members when in common areas to try to reduce potential for household transmission, though this may not always be feasible.

Considerations for testing

If a child has symptoms of a viral infection and SARS-CoV-2 is circulating in the community, testing for SARS-CoV-2 infection is warranted. Even if symptoms are mild, confirming SARS-CoV-2 infection informs isolation and contact tracing of positive cases. For the purposes of school attendance, attempts have been made to risk stratify children with symptoms regarding likelihood of SARS-CoV-2.363738 However, manifestations in an individual can vary greatly, the virus can transmit among asymptomatic people, and co-infections are possible.

The local prevalence of SARS-CoV-2 and the child’s personal exposures should be taken into consideration. If testing is not available, regardless of the actual cause of symptoms, it is safest to keep children at home until fevers resolve and symptoms improve, following regional public health guidance on when they may return to school. Generally, SARS-CoV-2 testing among children is considered as reliable as testing in adults, because at least one study has shown that children with mild to moderate SARS-CoV-2 infection have similar or even higher nasopharyngeal SARS-CoV-2 viral loads compared with adults.39 Antibody testing is generally not recommended unless a patient is being evaluated for MIS-C, as the presence or absence of antibodies would not otherwise inform clinical management or modify the need for preventive behaviours.40

Health disparities in clinical outcomes and social determinants of health

The covid-19 pandemic has dramatically highlighted health disparities among racial and ethnic groups. In the US, children of Latinx, Black, and minority ethnicities experienced higher rates of hospitalisation owing to SARS-CoV-2 compared with non-Hispanic white children (16.4 v 10.5 per 100 000),4 and Indigenous Americans/Alaska Natives were 5.3 times more likely to be hospitalised.41 In the UK, a prospective study found that Black children were over-represented in their cohort with increased odds of admission to intensive care. Children with MIS-C were also more likely to be of non-white ethnicity (64% v 42%), which may reflect increased rate of covid-19 infection in their communities.42

These racial and ethnic differences may reflect vulnerabilities to viral transmission related to occupational exposures, housing arrangements, or need to use public transportation. These factors, in addition to limitations in healthcare access and systemic inequities, contribute to the disparities highlighted by the covid-19 pandemic. Moreover, school closures disproportionately affect children from low income communities by affecting in-person learning services, while also jeopardising nutrition, medical, and mental health services provided through schools.

Given that ethnic minorities and low income families are also disproportionately more likely to experience unemployment, home foreclosures, evictions, and other financial insecurities as a result of the pandemic, the mental health impacts of the pandemic on these families and their children are likely to be vast and enduring. Consider asking families about financial and psychosocial stressors and connect families with local support services, where available.

Therapeutic and prevention efforts

Children with mild acute covid-19 benefit from usual supportive care measures, including rest, hydration, and antipyretics as needed. Dexamethasone was shown to decrease mortality in adults with moderate to severe respiratory distress, and may be considered in children with significant respiratory illness, though paediatric data are still forthcoming.43

Similarly, though efficacy is still being evaluated in children, remdesivir may be prescribed for children with respiratory deterioration. Other treatments, such as convalescent plasma or monoclonal antibodies, might be considered in high risk patients, but these therapeutics require further study in adults and children. Children with MIS-C most commonly are treated with intravenous immunoglobulin and often steroids.

Data on outcomes and treatment efficacy is limited overall. However, a recent retrospective cohort study in France found that children with MIS-C who were treated with both intravenous immunoglobulin (IVIg) and methylprednisolone (n=72) had a lower risk of treatment failure compared with those treated with IVIg alone (n=34).29 Further study is still needed to understand the pathophysiology of MIS-C to inform the most effective therapeutic interventions.

Primary measures to prevent infection and transmission of SARS-CoV-2 remain important for children and their families and include basic steps such as face masks for children aged 2 years and older, social distancing, and hand hygiene for both children and the adults around them. Young children or those with developmental delays may not tolerate or wear masks properly; however, there is value in practising. Several vaccines have been authorised for emergency use in persons ≥16 or 18 years. Given that the risks associated with SARS-CoV-2 are much lower in children than in adults, initial studies and vaccine distribution did not prioritise children. Fortunately, several studies are now enrolling younger children as it will be important to understand vaccine safety and efficacy before vaccines are widely administered to younger age groups. Patients should maintain routine preventive care and vaccination schedules, including seasonal influenza vaccine, as a critical strategy to stay healthy during and beyond the pandemic. Families should continue to follow infection prevention measures, even after individual vaccination, until community rates are low to avoid the potential for asymptomatic transmission to others.

More information: Ermias D. Belay et al. Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic, JAMA Pediatrics (2021). DOI: 10.1001/jamapediatrics.2021.0630


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