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

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COVID-19: Multisystem inflammatory syndrome in children

(MIS-C) clinical features, evaluation, and diagnosis
Authors: Mary Beth F Son, MD, Kevin Friedman, MD
Section Editors: David R Fulton, MD, Sheldon L Kaplan, MD, Robert Sundel, MD, Adrienne G Randolph, MD, MSc
Deputy Editor: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2021. | This topic last updated: Apr 02, 2021.

What's New

Clinical features of MIS-C compared with severe acute COVID-19 in children and
adolescents (March 2021)

The clinical features of multisystem inflammatory syndrome in children (MIS-C) and sever…
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INTRODUCTION

A novel coronavirus was identified in late 2019 that rapidly reached pandemic proportions. The
World Health Organization has 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).

In children, COVID-19 is usually mild. However, in rare cases, children can be severely affected,
and clinical manifestations may differ from adults. In April of 2020, reports from the United Kingdom
documented a presentation in children similar to incomplete Kawasaki disease (KD) or toxic shock
syndrome [2,3]. Since then, there have been reports of similarly affected children in other parts of
the world [4-11]. The condition has been termed multisystem inflammatory syndrome in children
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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis

(MIS-C; also referred to as pediatric multisystem inflammatory syndrome [PMIS], pediatric

inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [PIMS-TS], pediatric
hyperinflammatory syndrome, or pediatric hyperinflammatory shock).

The epidemiology, pathophysiology, clinical presentation, evaluation, and diagnosis of MIS-C will be
discussed here. The management and outcome of MIS-C and other aspects of COVID-19 in
children and adults are discussed separately:

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

outcome".)
● (See "COVID-19: Clinical manifestations and diagnosis in children".)
● (See "COVID-19: Management in children".)
● (See "COVID-19: Epidemiology, virology, and prevention".)
● (See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)
● (See "COVID-19: Infection control for persons with SARS-CoV-2 infection".)
● (See "COVID-19: Management in hospitalized adults".)
● (See "COVID-19: Hypercoagulability".)
● (See "COVID-19: Outpatient evaluation and management of acute illness in adults".)

Understanding of COVID-19 and MIS-C is evolving. Interim guidance has been issued by the WHO
and by the United States Centers for Disease Control and Prevention (CDC) [4,12,13]. Links to
these and other related society guidelines are found elsewhere. (See 'Society guideline links'
below.)

EPIDEMIOLOGY

While the incidence of MIS-C is uncertain, it appears to be a relatively rare complication of COVID-
19 in children, occurring in <1 percent of children with confirmed SARS-CoV-2 infection. In one
report from New York State, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection
in individuals <21 years old was 322 per 100,000 and the incidence of MIS-C was 2 per 100,000
[14].

The initial reports of MIS-C emerged from the United Kingdom in April 2020 [2,3]. Since then, there
have been reports of similarly affected children in other parts of the world, including Europe,
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Canada, the United States, and South Africa [4-6,8-11,14-18]. Notably, there have been
disproportionately few reports of MIS-C from China and other Asian countries with high rates of
COVID-19 early in the pandemic [19].

While some children with MIS-C meet criteria for complete or incomplete Kawasaki disease (KD)
(see 'Clinical manifestations' below), the epidemiology differs from that of classic KD. Most MIS-C
cases have occurred in older children and adolescents who were previously healthy [2,8-
11,15,16,20,21]. Black and Hispanic children appear to be disproportionally affected. By contrast,
classic KD typically affects infants and young children and has a higher incidence in East Asia and
in children of Asian descent. (See "Kawasaki disease: Epidemiology and etiology", section on
'Epidemiology'.)

The epidemiology of MIS-C also differs from that of severe acute COVID-19 illness in children,
which more often occurs in children with underlying health problems. (See "COVID-19: Clinical
manifestations and diagnosis in children", section on 'Risk factors for severe disease'.)

The first report of MIS-C was a series of eight children seen at a tertiary center in South East
England [2]. In subsequent larger case series from the United Kingdom and the United States, >70
percent of affected children were previously healthy [11,22]. The most common comorbidities were
obesity and asthma. The median age was 8 to 11 years (range 1 to 20 years). There have been
rare reports of an illness resembling MIS-C occurring in adults [23]. (See "COVID-19: Care of adult
patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for rheumatologic
disease'.)

Rates of MIS-C appear to vary by race and ethnicity, with Black and Hispanic children accounting
for a disproportionally high number of cases and Asian children accounting for a small number of
cases. In three large case series, 25 to 45 percent of cases occurred in Black children, 30 to 40
percent in Hispanic children, 15 to 25 percent in White children, and 3 to 28 percent in Asian
children [11,14,22].

In most studies, there was a lag of several weeks between the peak of COVID-19 cases within
communities and the rise of MIS-C cases [8,9,11,14,24]. For example, in London, the peak of
COVID-19 cases occurred in the first to second weeks of April, while the spike of MIS-C cases
occurred in the first to second week of May [9,24]. This three- to four-week lag coincides with the

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timing of acquired immunity and suggests that MIS-C may represent a post-infectious complication
of the virus rather than acute infection, at least in some children.

PATHOPHYSIOLOGY

The pathophysiology of MIS-C is not well understood.

● Immune dysregulation – It has been suggested that the syndrome results from an abnormal
immune response to the virus, with some clinical similarities to Kawasaki disease (KD),
macrophage activation syndrome (MAS), and cytokine release syndrome. However, based on
the available studies, MIS-C appears to have an immunophenotype that is distinct from KD and
MAS [25,26]. The exact mechanisms by which SARS-CoV-2 triggers the abnormal immune
response are unknown. A post-infectious process is suggested, based on the timing of the rise
of these cases relative to the peak of COVID-19 cases in communities, as discussed above.
(See 'Epidemiology' above.)

Preliminary studies suggest that patients with severe MIS-C have persistent immunoglobulin G
(IgG) antibodies with enhanced ability to activate monocytes [27], persistent cytopenias
(particularly T cell lymphopenia) [25,26,28], and greater activation of CD8+ T cells [28] that
differ from findings in acute COVID-19 infection. The certainty of these findings is limited due to
the small number of patients in these studies.

Understanding the mechanisms of the exaggerated immune response in MIS-C is an area of

active investigation. The pathophysiology of KD, MAS, and cytokine release syndrome are
discussed separately. (See "Kawasaki disease: Epidemiology and etiology", section on
'Immunologic response' and "Cytokine release syndrome (CRS)", section on
'Pathophysiology'.)

● SARS-CoV-2 virus – Many affected children have negative polymerase chain reaction (PCR)
testing for SARS-CoV-2 but have positive serology, a finding that further supports the
hypothesis that MIS-C is related to immune dysregulation occurring after acute infection has
passed. However, some children do have positive PCR testing. In the early case series, there
were 783 children in whom both PCR and serology were performed [8,9,11,17,20,29]. Of
these, 60 percent had positive serology with negative PCR, 34 percent were positive on both
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tests, and 5 percent were negative on both tests.

A study examining SARS-CoV-2 viral sequences from 11 children with MIS-C did not detect
any differences compared with the viral sequences from children with acute COVID-19 without
MIS-C [30]. These preliminary data suggest that viral factors are less likely to explain why
some children develop multisystem inflammation following SARS-CoV-2 infection, while others
do not. It is more likely that host factors are responsible for the abnormal inflammatory
response in MIS-C.

Additional details of the virology of SARS-CoV-2 and the immune response are provided
separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Virology'.)

● Mechanisms of myocardial injury – The mechanisms of myocardial injury in MIS-C are not
well characterized. Possible causes include injury from systemic inflammation, acute viral
myocarditis, hypoxia, stress cardiomyopathy, and, rarely, ischemia caused by coronary artery
(CA) involvement [31]. Cardiac dysfunction may result from a combination of these
mechanisms in some patients. Given the variability in clinical presentation, it is likely that
different mechanisms are responsible in different patients.

There are limited data characterizing cardiac histopathology in MIS-C. In a report of a fatal
case of MIS-C, autopsy findings were notable for evidence of myocarditis, pericarditis, and
endocarditis characterized by inflammatory cell infiltration [32]. In addition, SARS-CoV-2 virus
was detected in cardiac tissue by electron microscopy and PCR. However, some clinical
features in this patient were uncharacteristic of MIS-C (most notably, there was severe
pulmonary involvement), and it is possible that these autopsy findings are more reflective of
severe acute COVID-19 rather than MIS-C. As discussed below, there is considerable overlap
in the presentation of MIS-C and severe acute COVID-19. (See 'Spectrum of disease' below.)

Mechanisms of myocardial injury in adult patients with COVID-19 are discussed separately.
(See "COVID-19: Cardiac manifestations in adults", section on 'Etiology'.)

CLINICAL MANIFESTATIONS

Onset of symptoms — The timing of onset of symptoms relative to the acute SARS-CoV-2
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infection is variable. In children who have a known history of documented or suspected COVID-19,
the usual duration between acute infection and onset of MIS-C symptoms is two to six weeks.
However, rare cases of MIS-C occurring >6 weeks after the acute SARS-CoV-2 infection have been
reported [33]. In many cases, the duration of time between acute infection and onset of MIS-C
symptoms is unknown because the child was asymptomatic at the time of acute infection. However,
due to increased surveillance testing, patients in the later surges of MIS-C more often knew about
their exposure and/or date of positive testing. (See 'Epidemiology' above.)

Presenting symptoms — The relative frequencies of various presenting symptoms in the available
case series were as follows (table 1) [9,11,14,17,21,22,34-37]:

● Fever, usually persistent (median duration four to six days) – 100 percent
● Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) – 60 to 100 percent
● Rash – 45 to 76 percent
● Conjunctivitis – 30 to 81 percent
● Mucous membrane involvement (red or swollen lips, strawberry tongue) – 27 to 76 percent
● Neurocognitive symptoms (headache, lethargy, confusion) – 29 to 58 percent
● Respiratory symptoms – 21 to 65 percent
● Sore throat – 10 to 16 percent
● Myalgia – 8 to 17 percent
● Swollen hands/feet – 9 to 16 percent
● Lymphadenopathy – 6 to 16 percent

Common presenting symptoms include:

● Fever – Most patients present with three to five days of fever, though fewer days of fever have
been reported. In one series of 186 patients, 10 percent had three days of fever, 12 percent
had four days, and 78 percent had ≥5 days [11].

● Gastrointestinal symptoms – Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea)

are particularly common and prominent, with the presentation in some children mimicking
appendicitis [18,20,38]. Some children have been noted to have terminal ileitis on abdominal
imaging and/or colitis on colonoscopy. (See 'Other imaging findings' below.)

● Cardiorespiratory symptoms – As discussed below, cardiac involvement is common (see

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'Echocardiography' below). Respiratory symptoms (tachypnea, labored breathing), when

present, may be due to shock or cardiogenic pulmonary edema. Cough is uncommon. Though
some children require supplemental oxygen or positive pressure ventilation for cardiovascular
stabilization, severe pulmonary involvement (eg, acute respiratory distress syndrome) is not a
prominent feature.

● Neurocognitive symptoms – Neurocognitive symptoms are common and may include

headache, lethargy, confusion, or irritability. A minority of patients present with more severe
neurologic manifestations, including encephalopathy, seizures, coma, stroke,
meningoencephalitis, muscle weakness, and brainstem and/or cerebellar signs [11,39,40]. In a
report of 616 patients with MIS-C, 20 percent had documented neurologic involvement [40].
Life-threatening neurologic conditions occurred in 20 patients (3 percent), including severe
encephalopathy (n = 8), central nervous system demyelination (n = 6), stroke (n = 3), acute
fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1).

Clinical findings — Common clinical findings reported in the available case series include (table 1)
[11,17,21,22,31,32,39,41,42]:

● Shock – 32 to 76 percent
● Mucocutaneous findings (red or swollen lips, strawberry tongue) – 27 to 76 percent
● Criteria met for complete Kawasaki disease (KD) (table 2) – 22 to 64 percent
● Myocardial dysfunction (by echocardiogram and/or elevated troponin or brain natriuretic
peptide [BNP]) – 51 to 90 percent
● Arrhythmia – 12 percent
● Acute respiratory failure requiring noninvasive or invasive ventilation – 28 to 52 percent
● Acute kidney injury (most cases were mild) – 8 to 52 percent
● Serositis (small pleural, pericardial, and ascitic effusions) – 24 to 57 percent
● Hepatitis or hepatomegaly – 5 to 21 percent
● Encephalopathy, seizures, coma, or meningoencephalitis – 6 to 7 percent

Different case definitions were used in different studies, which may explain some of the variability in
the reported frequency of these findings. As more is learned about MIS-C, it is becoming apparent
that there is a wide spectrum of disease severity (figure 1) (see 'Spectrum of disease' below). Initial
smaller case series largely reported the most severe end of the spectrum, resulting in a high
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reported incidence of shock, myocardial involvement, and respiratory failure. It is possible that as
recognition of milder forms of MIS-C increases, the incidence of shock, left ventricular (LV)
dysfunction, respiratory failure, and acute kidney injury will be lower.

Laboratory findings — Laboratory abnormalities noted in the available case series include (
table 1) [2,5,8,11,17,20,22,29,43,44]:

● Abnormal blood cell counts, including:

• Lymphocytopenia – 80 to 95 percent
• Neutrophilia – 68 to 90 percent
• Mild anemia – 70 percent
• Thrombocytopenia – 31 to 80 percent

● Elevated inflammatory markers (often, these are markedly elevated), including:

• C-reactive protein (CRP) – 90 to 100 percent

• Erythrocyte sedimentation rate (ESR) – 75 to 80 percent
• D-dimer – 67 to 100 percent
• Fibrinogen – 80 to 100 percent
• Ferritin – 55 to 76 percent
• Procalcitonin – 80 to 95 percent
• Interleukin-6 (IL-6) – 80 to 100 percent

● Elevated cardiac markers:

• Troponin – 50 to 90 percent
• BNP or N-terminal pro-BNP (NT-pro-BNP) – 73 to 90 percent

● Hypoalbuminemia – 48 to 95 percent
● Mildly elevated liver enzymes – 62 to 70 percent
● Elevated lactate dehydrogenase – 10 to 60 percent
● Hypertriglyceridemia – 70 percent

Laboratory markers of inflammation appear to correlate with severity of illness [9,45]. For example,
in one series, children who developed shock had higher CRP values (mean 32.1 versus 17.6
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mg/dL), higher neutrophil counts (16 versus 10.8 x 109/L), lower lymphocyte counts (0.7 versus 1.3
x 109/L), and lower serum albumin (2.2 versus 2.7 g/dL) compared with children without shock [9].
In addition, children with shock more commonly had elevated cardiac markers.

Echocardiography — Echocardiographic findings may include [20,46-48]:

● Depressed LV function
● Coronary artery (CA) abnormalities, including dilation or aneurysm
● Mitral regurgitation
● Pericardial effusion

Cardiac involvement is common in MIS-C. In several large case series, approximately 30 to 40

percent of children had depressed LV function and 8 to 24 percent had CA abnormalities
[9,11,17,21,48]. These reports included patients with severe MIS-C as well as milder cases. Case
series including only severely affected patients reported considerably higher rates of depressed LV
function (approximately 50 to 60 percent) and CA abnormalities (approximately 20 to 50 percent)
[9,22,31]. As discussed below, cardiac involvement is a key feature that helps to distinguish MIS-C
from severe acute COVID-19. (See 'Differentiating MIS-C and acute COVID-19' below.)

In a study that included 503 patients with MIS-C who underwent echocardiography, 34 percent had
depressed LV ejection fraction (EF) and 13 percent had CA aneurysms [21]. Among patients with
depressed LV function, LV was mildly depressed in 55 percent, moderately depressed in 23
percent, and severely depressed in 22 percent. Most CA aneurysms (93 percent) were mild, 7
percent were moderate, and there were no large or giant CA aneurysms. In 91 percent of patients,
LV function normalized within 30 days and nearly all patients with available 90-day follow-up data
had normal LV EF. Outcomes for CA aneurysms were similarly favorable, regressing to normal (Z-
score <2.5) in more than three-quarters of affected patients within 30 days and in all patients with
available 90-day follow-up data.

In another study describing echocardiographic findings in 286 children with MIS-C, 34 percent had
depressed LV EF, 42 percent had mild to moderate mitral regurgitation, 6 percent had mild to
moderate tricuspid regurgitation, and 28 percent had pericardial effusions [48]. Cardiac magnetic
resonance imaging (MRI) was performed in 42 patients and showed evidence of myocardial edema
(ie, T2 hyperintensity) in one-third of patients who were evaluated; late gadolinium enhancement

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was seen in 14 percent.

In a study examining echocardiographic findings in 28 children with MIS-C compared with 20

children with classic KD, LV systolic and diastolic function were worse than in classic KD but CA
involvement was less common [46]. Functional parameters correlated with biomarkers of
myocardial injury. During the subacute period, LV systolic function usually normalized over short-
term follow-up, but diastolic dysfunction persisted in a subset of patients.

Several studies have reported abnormal strain patterns in patients with LV dysfunction [47,49]. In
one small study involving 20 patients with MIS-C who underwent both echocardiography and
cardiac MRI, almost all patients displayed abnormal strain and tissue Doppler indices at the time of
admission and one-half had depressed LV EF [47]. On serial imaging, LV EF deteriorated before
improving at discharge, with the worst cardiac function occurring a median of seven days after
admission. Cardiac MRI was performed at a median of 20 days after admission, at which time LV
function remained mildly depressed (EF <50 percent) in 20 percent. Cardiac MRI detected
abnormal strain in all patients, myocardial edema in 50 percent, and a subendocardial infarct in 1
patient.

Other imaging findings — Findings on diagnostic imaging may include (table 1)

[2,8,9,11,20,29,50]:

● Chest radiograph – Many patients had normal chest radiographs. Abnormal findings included
pleural effusions, patchy consolidations, focal consolidation, and atelectasis. In a report
describing findings in children with MIS-C (n = 539) compared with children with severe acute
COVID-19 (n = 577), approximately one-third of patients in each group had infiltrates on the
initial chest radiograph; however, patients with MIS-C more commonly had pleural effusions
(27 versus 8 percent) [21]. Similar findings were noted in a smaller case series, in which
ground-glass opacities were the most common finding in both groups [51].

● Computed tomography (CT) of chest – Chest CT (when obtained) generally had findings
similar to those on chest radiograph. Ground-glass opacification was a common finding.

● Abdominal imaging – Findings on abdominal ultrasound or CT included free fluid, ascites,

and bowel and mesenteric inflammation including terminal ileitis, mesenteric
adenopathy/adenitis, and pericholecystic edema [38,52].
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EVALUATION

Patients with suspected MIS-C should have laboratory studies performed to look for evidence of
inflammation and to assess cardiac, renal, and hepatic function (algorithm 1). Testing should also
include polymerase chain reaction (PCR) and serology for SARS-CoV-2. In addition, patients
should be assessed for other infectious or noninfectious conditions that may have a similar
presentation.

Our approach outlined below is generally consistent with published guidance from the American
College of Rheumatology, the American Academy of Pediatrics, and the pediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) National Consensus
Management Study Group in the United Kingdom [53-55].

Laboratory testing — The initial laboratory evaluation of a child with suspected MIS-C depends on
the presentation (algorithm 1).

● Moderate to severe – For children with moderate to severe symptoms, we suggest the
following:

• Complete blood count (CBC) with differential

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR; procalcitonin is
optional)
• Ferritin
• Liver function tests and lactate dehydrogenase
• Serum electrolytes and renal function tests
• Urinalysis
• Coagulation studies (prothrombin time/international normalized ratio, activated partial
thromboplastin time, D-dimer, fibrinogen)
• Troponin
• Brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-pro-BNP)

Inflammatory markers (CRP, ESR, procalcitonin, ferritin) are measured at the time of admission
and then serially to monitor progression. The ESR is not useful for serial monitoring, because
most patients with MIS-C are treated with intravenous immunoglobulin, which can elevate the
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ESR. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management

and outcome", section on 'Intravenous immune globulin'.)

Cardiac markers (troponin and BNP) should also be monitored serially if they are elevated on
initial evaluation or if the patient's cardiac status worsens.

● Mild symptoms – For patients presenting with fever for ≥3 days and who are well-appearing
(ie, normal vital signs and reassuring physical examination) with only mild symptoms
suggestive of MIS-C, we suggest a more limited evaluation initially. We typically start with the
following:

• CBC with differential

• CRP
• Serum electrolytes and renal function tests

If these results are abnormal, additional testing is performed (listed above).

The clinician should also assess for other common causes of fever (eg, streptococcal pharyngitis,
mononucleosis). While it does not definitively exclude MIS-C, identifying another source of fever
makes the diagnosis of MIS-C less likely, particularly in an otherwise well-appearing child.

In a report of 67 children who underwent outpatient laboratory evaluation for febrile illness, findings
that were more common in patients with MIS-C (n = 44) compared with those with other febrile
illnesses (n = 23) included lymphopenia, thrombocytopenia, and markedly elevated CRP [56]. In
another report of 39 patients who underwent evaluation for MIS-C at a single center, alternate
diagnoses made among children found not to have MIS-C included staphylococcal toxic shock
syndrome, lymphadenitis, urinary tract infection, Epstein-Barr virus, Lyme disease, herpangina,
human metapneumovirus upper respiratory infection, and intussusception with small bowel
perforation [57]. (See 'Differential diagnosis' below.)

Testing for SARS-CoV-2 — All patients with suspected MIS-C should be tested for SARS-CoV-2,
including both serology and reverse transcription PCR (RT-PCR) on a nasopharyngeal swab [41].

As previously discussed, approximately 60 percent of patients have positive serology with negative
PCR, and approximately 30 to 35 percent are positive on both tests. (See 'Pathophysiology' above.)

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A minority of patients (approximately 5 to 10 percent) have negative results on both tests. In these
cases, the diagnosis of MIS-C requires an epidemiologic link to SARS-CoV-2 (eg, exposure to an
individual with known COVID-19 within the four weeks prior to the onset of symptoms). (See 'Case
definition' below.)

Quantitative SARS-CoV-2 serology may help distinguish MIS-C from acute COVID-19 since higher
titers are seen in MIS-C [58]. (See 'Differentiating MIS-C and acute COVID-19' below.)

It should be noted that several different serologic tests are available, and their sensitivity and
specificity are variable. (See "COVID-19: Diagnosis", section on 'Serology to identify prior/late
infection'.)

It should also be noted that as the pandemic continues to progress, the baseline rate of
seropositivity for SARS-CoV-2 will increase (in some regions, it may be as high as 20 percent).
Thus, there will be an increasing number of febrile children who may incidentally have positive
serologies.

Testing for SARS-CoV-2 is summarized in the table (table 3) and discussed in greater detail
separately. (See "COVID-19: Diagnosis", section on 'Specific diagnostic techniques'.)

Testing for other pathogens — Testing for other viral and bacterial pathogens includes [44]:

● Blood culture
● Urine culture
● Throat culture
● Stool culture
● Nasopharyngeal aspirate or throat swab for respiratory viral panel
● Epstein-Barr virus serology and PCR
● Cytomegalovirus serology and PCR
● Enterovirus PCR
● Adenovirus PCR

This testing is appropriate for children with moderate to severe MIS-C (ie, children who require
hospitalization). However, an extensive infectious work-up is generally not necessary in well-
appearing children presenting with mild symptoms. In such patients, microbiologic testing should be
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done as clinically indicated according to the age of the child and his/her specific symptoms (eg,
throat culture if the child has sore throat, respiratory viral panel if there are respiratory symptoms).
Testing should follow the same general approach as is used for fever evaluation more broadly. (See
"Fever without a source in children 3 to 36 months of age: Evaluation and management".)

Detection of other respiratory pathogens (eg, rhinovirus, influenza, respiratory syncytial virus) in
nasopharyngeal specimens does not exclude COVID-19.

Additional testing for other pathogens may be warranted, depending on the geographic location and
exposure history. This may include:

● Murine typhus [59]

● Leptospirosis serology

Cardiac testing — In addition to troponin and BNP/NT-pro-BNP levels, the cardiac evaluation of a
patient with suspected MIS-C includes a 12-lead electrocardiogram (ECG) and echocardiography
[31]. Echocardiography is also recommended for children with documented SARS-CoV-2 who do
not meet all criteria for MIS-C but who have either shock or features consistent with incomplete or
complete Kawasaki disease (KD).

Children and adolescents with mild COVID-19 without signs of systemic inflammation are unlikely
to have coronary artery (CA) changes or myocarditis. In such children, echocardiography is
generally not necessary but may be considered if there are specific clinical concerns.

● ECG findings – In children with MIS-C, baseline ECGs may be nonspecific (eg, repolarization
changes with abnormal ST- or T-wave segments), though arrhythmia and heart block have
been described [2,42,48,60]. First-degree atrioventricular block occurs in approximately 20
percent of hospitalized patients [61]. Telemetry monitoring is appropriate in such cases since
this can progress to high-degree atrioventricular block.

● Echocardiographic evaluation – The echocardiographic evaluation includes the following:

• Quantitative assessment of LV size and systolic function (LV end-diastolic volume, ejection
fraction [EF])
• Qualitative assessment of right ventricular systolic function

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• CA abnormalities (dilation or aneurysm)

• Assessment of valvar function
• Evaluation for the presence and size of pericardial effusion
• Evaluation for intracardiac thrombosis and/or pulmonary artery thrombosis, particularly
apical thrombus in severe LV dysfunction
• Strain imaging and LV diastolic function (optional)

CA assessment is based on Z-scores, with the same classification schema used in KD (table 4
), as discussed separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical
features and evaluation", section on 'Echocardiography'.)

The timing of follow-up echocardiography is discussed separately. (See "COVID-19:

Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section
on 'Follow-up'.)

Echocardiographic findings are described above. (See 'Echocardiography' above.)

CASE DEFINITION

CDC and WHO case definitions — The criteria used for case definition vary slightly between
different health agencies [4,6,44]. The case definitions put forth by the United States Centers for
Disease Control and Prevention (CDC) and the World Health Organization (WHO) are summarized
in the table (table 5). Both definitions require fever (though they differ with respect to duration),
elevated inflammatory markers, at least two signs of multisystem involvement, evidence of SARS-
CoV-2 infection or exposure, and exclusion of other potential causes. The CDC case definition
requires that the child have severe symptoms requiring hospitalization, whereas the WHO case
definition does not. These definitions are likely to change as more information becomes available.

Spectrum of disease — Initial reports of MIS-C described mostly severely affected children.
However, as more is learned about COVID-19 and MIS-C in children, it is becoming apparent that
the spectrum of COVID-19-associated disease ranges from mild to severe, as illustrated in the
figure (figure 1) [9,29]. It remains unclear how common each presentation is, how frequently
children progress from mild to more severe manifestations, and what the risk factors are for such
progression.
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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis

Our understanding of the full spectrum of MIS-C, including subphenotypes, is evolving.

In a study of 570 children with MIS-C reported to the CDC through July 2020, investigators used a
statistical modeling technique called latent class analysis to identify different subtypes of the
syndrome [17]. The study had important limitations, chiefly that it relied on state public health
reports with limited and incomplete clinical data. Nevertheless, the analysis identified three
subgroups based on underlying similarities:

● MIS-C without overlap with Kawasaki disease (KD) or acute COVID-19 – This group
comprised 35 percent of the cohort. Nearly all patients in this group had cardiovascular and
gastrointestinal involvement, and one-half had ≥4 additional organ systems involved. Patients
in this group were more likely to have shock, cardiac dysfunction, and markedly elevated C-
reactive protein (CRP) and ferritin. Nearly all patients in this group had positive SARS-CoV-2
serology (with or without positive polymerase chain reaction [PCR]).

● MIS-C overlapping with KD – This group comprised 35 percent of the cohort. Children in this
group were younger than the other two groups (median age 6 versus 9 and 10 years,
respectively). They more commonly had rash and mucocutaneous involvement and less
commonly had shock or myocardial dysfunction. Approximately two-thirds of patients in this
group had positive SARS-CoV-2 serology with negative PCR, and one-third were positive on
both tests. (See 'Differentiating MIS-C and Kawasaki disease' below.)

● MIS-C overlapping with severe acute COVID-19 – This group comprised 30 percent of the
cohort. Many children in this group presented with respiratory involvement, including cough,
shortness of breath, pneumonia, and acute respiratory distress syndrome. Most of these
children had positive SARS-CoV-2 PCR without seropositivity. The mortality rate was higher in
this subgroup compared with the other two subgroups (5.3 versus 0.5 and 0 percent,
respectively). In our experience, patients in this category tend to be older than those with KD-
like features and they more commonly have comorbidities. (See 'Differentiating MIS-C and
acute COVID-19' below.)

Importantly, the incidence of coronary artery (CA) abnormalities was similar in all three subgroups
(21, 16, and 18 percent, respectively), highlighting the importance of routine echocardiography in all
children with MIS-C, regardless of apparent subphenotype. (See 'Cardiac testing' above.)
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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis

Differentiating MIS-C and Kawasaki disease — There is considerable phenotypic overlap with
MIS-C and KD. In the available case series, approximately 40 to 50 percent of children with MIS-C
met criteria for complete or incomplete KD (table 2) [8,9,11,14,62]. In particular, there are
similarities between MIS-C and the well-recognized KD shock syndrome (KDSS), which occurs in
approximately 5 percent of KD cases and is characterized by prominent cardiovascular
involvement. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease:
Complications", section on 'Shock' and "COVID-19: Multisystem inflammatory syndrome in children
(MIS-C) management and outcome", section on 'Features of Kawasaki disease'.)

Key distinctions between MIS-C and KD include:

● MIS-C commonly affects older children and adolescents, whereas classic KD typically affects
infants and young children. (See 'Epidemiology' above.)

● In MIS-C, Black and Hispanic children appear to be disproportionally affected and Asian
children account for only a small number of cases. By contrast, classic KD has a higher
incidence in East Asia and in children of Asian descent. (See 'Epidemiology' above and
"Kawasaki disease: Epidemiology and etiology", section on 'Epidemiology'.)

● Gastrointestinal symptoms (particularly abdominal pain) are very common in MIS-C, whereas
these symptoms are less prominent in classic KD. (See 'Presenting symptoms' above.)

● Myocardial dysfunction and shock occur more commonly in MIS-C compared with classic KD
[11]. Though, as mentioned above, these are characteristic findings in KDSS. (See 'Clinical
findings' above.)

● Inflammatory markers (especially CRP, ferritin, and D-dimer) tend to be more elevated in MIS-
C compared with classic KD and KDSS [9]. In addition, absolute lymphocyte and platelet
counts tend to be lower in MIS-C compared with KD [53]. (See 'Laboratory findings' above.)

● It is unclear if the risk of CA involvement in MIS-C is comparable with the risk in classic KD.
Among patients with KD, those with KDSS more frequently have CA abnormalities and
intravenous immune globulin (IVIG) resistance compared with those without shock. It is unclear
if MIS-C is similar to KDSS in this regard. (See 'Other imaging findings' above.)

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

The above clinical features can help distinguish MIS-C with KD-like features from KD not related to
SARS-CoV-2, but ultimately, the designation of MIS-C versus KD is based on SARS-CoV-2 testing
and exposure history. Patients with positive SARS-CoV-2 testing (or with an exposure to an
individual with COVID-19) who also fulfill criteria for complete or incomplete KD are considered to
have MIS-C and are treated with standard treatment for KD. However, as the COVID-19 pandemic
evolves, distinguishing patients with KD-like MIS-C from those with true KD will be difficult. The
baseline incident rate of true KD will continue as more children are exposed to SARS-CoV-2, with
subsequent seroconversion. Accordingly, classifying patients who have KD features and positive
antibodies as MIS-C versus KD will be challenging. Quantitative antibody titers may help make the
distinction [58]. Ultimately, better characterizing the distinct immunophenotypes of these syndromes
may help clinicians distinguish one from the other [25,26]. (See 'Pathophysiology' above.)

Differentiating MIS-C and acute COVID-19 — The clinical features of MIS-C and severe acute
COVID-19 overlap. However, differing patterns of clinical presentation and organ system
involvement may help differentiate MIS-C from severe acute COVID-19 [17,21,63]:

● Most MIS-C cases have occurred in children who were previously healthy, whereas most cases
of severe acute COVID-19 occur in children with underlying health problems. (See
'Epidemiology' above.)

● Children with MIS-C may have a history of known or suspected SARS-CoV-2 infection in the
weeks preceding the onset of febrile/inflammatory symptoms.

● The pattern of organ system involvement differs [17,21]:

• Severe pulmonary involvement (ie, pneumonia, acute respiratory distress syndrome) is a

prominent feature in severe acute COVID-19. While respiratory symptoms are common in
patients with MIS-C, they are more often secondary to shock and/or impaired cardiac
function.

• Myocardial dysfunction and shock are more common in MIS-C than in severe acute
COVID-19.

• Gastrointestinal symptoms (particularly abdominal pain) are more common in MIS-C.

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

• Mucocutaneous findings are common in MIS-C and are rarely seen in severe acute
COVID-19.

● Inflammatory markers (CRP, ferritin, and D-dimer) tend to be more elevated in MIS-C
compared with severe acute COVID-19 [21]. In addition, lymphopenia and thrombocytopenia
are more common in MIS-C. (See 'Laboratory findings' above.)

● SARS-CoV-2 antibody titers are higher in patients with MIS-C compared with acute COVID-19
[58].

In a multicenter case series of 1116 pediatric patients hospitalized with MIS-C (n = 539) or severe
acute COVID-19 (n = 577), children with MIS-C were younger (median age 8.9 versus 11.7 years),
less likely to have underlying medical conditions (31 versus 62 percent), and more likely to have
multiple organ systems involved (median 4 versus 2) [21]. More than one-half of patients with MIS-
C had combined cardiovascular and respiratory involvement, and 24 percent had respiratory
involvement without cardiovascular involvement. Among children with severe acute COVID-19, 71
percent had respiratory involvement without cardiovascular involvement and only 9 percent had
combined cardiorespiratory involvement.

The clinical presentation of acute COVID-19 in children is discussed in detail separately. (See
"COVID-19: Clinical manifestations and diagnosis in children", section on 'Clinical manifestations'.)

CASE REPORTING

Health care providers who have cared or are caring for patients younger than 21 years of age
meeting MIS-C criteria (table 5) should report suspected cases to their local, state, or territorial
health department. Additional information can be found on the Centers for Disease Control and
Prevention (CDC) website and the World Health Organization (WHO) website.

DIFFERENTIAL DIAGNOSIS

In children presenting with signs and symptoms consistent with MIS-C, the differential diagnosis is
broad and includes other infectious and inflammatory conditions:

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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis
● Kawasaki disease (KD) – Some children along the MIS-C spectrum meet criteria for complete
or incomplete KD (table 2). Key distinctions between MIS-C and KD are discussed above. (See
'Differentiating MIS-C and Kawasaki disease' above.)

● Severe acute COVID-19 – The clinical features of MIS-C and severe acute COVID-19 overlap
(figure 1). Key distinctions between MIS-C and severe acute COVID-19 are discussed above.
(See 'Differentiating MIS-C and acute COVID-19' above.)

● Bacterial sepsis – Bacterial sepsis is an important consideration in children presenting with

fever, shock, and elevated inflammatory markers. For most patients with these manifestations,
it is appropriate to obtain blood cultures and start empiric antibiotics pending culture results.
Certain clinical features (eg, cardiac involvement, coronary artery [CA] abnormalities) may
suggest the diagnosis of MIS-C rather than bacterial sepsis, but, ultimately, microbiologic tests
(ie, SARS-CoV-2 testing, bacterial cultures) are necessary to make the distinction. (See
"Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions,
epidemiology, clinical manifestations, and diagnosis" and "Septic shock in children: Rapid
recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy'.)

● Toxic shock syndrome – Staphylococcal and streptococcal toxic shock syndromes share
many similarities with MIS-C (table 6). Microbiologic tests (ie, SARS-CoV-2 testing, bacterial
cultures) are necessary to make the distinction. (See "Staphylococcal toxic shock syndrome"
and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical
manifestations, and diagnosis".)

● Appendicitis – As discussed above, many children with MIS-C present with fever associated
with abdominal pain and vomiting (see 'Presenting symptoms' above). This can mimic the
presentation of acute appendicitis. Abdominal imaging may be necessary to make the
distinction. (See 'Other imaging findings' above and "Acute appendicitis in children: Clinical
manifestations and diagnosis".)

● Other viral infections – Other viral pathogens that may manifest with multisystem
involvement and/or myocarditis include Epstein-Barr virus, cytomegalovirus, adenovirus, and
enteroviruses. These viruses rarely cause severe multisystem disease in immunocompetent
children. Serology and polymerase chain reaction (PCR) testing can distinguish these from

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

COVID-19-related MIS-C. (See "Clinical manifestations and treatment of Epstein-Barr virus

infection" and "Overview of cytomegalovirus infections in children" and "Pathogenesis,
epidemiology, and clinical manifestations of adenovirus infection".)

● Other infections – Other infections that may present with persistent fevers and multisystem
findings include Lyme disease and rickettsial infections (eg, murine typus, Rocky Mountain
spotted fever) [59]. Appropriate serologies and PCR testing can distinguish these from COVID-
19-related MIS-C. (See "Lyme disease: Clinical manifestations in children" and "Murine typhus"
and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Other
spotted fever group rickettsial infections".)

● Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) –

HLH and MAS are aggressive and life-threatening conditions that have some features in
common with MIS-C. HLH/MAS are syndromes of excessive immune activation that can occur
in previously healthy children (often triggered by an infection) and in children with underlying
rheumatologic conditions. Most children with HLH/MAS are acutely ill with multiorgan
involvement, cytopenias, liver function abnormalities, and neurologic symptoms. Cardiac and
gastrointestinal involvement are less common, and neurologic symptoms are more prominent.
The diagnosis of HLH/MAS requires specialized immunologic testing, as discussed separately.
(See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on
'Specialized testing' and "Systemic juvenile idiopathic arthritis: Course, prognosis, and
complications", section on 'Macrophage activation syndrome'.)

● Systemic lupus erythematosus (SLE) – SLE can present with fulminant multisystem illness.
Such patients generally have considerable kidney and central nervous system involvement,
which are not common features of MIS-C. In addition, though patients with SLE may present
acutely with fulminant illness, most report feeling fatigued and unwell for a period of time prior
to the onset of severe symptoms. This is not the case with MIS-C, in which most children are
completely well prior to acute onset of febrile illness. (See "Childhood-onset systemic lupus
erythematosus (SLE): Clinical manifestations and diagnosis".)

● Vasculitis – Vasculitides other than KD can present with fevers, rash, and elevated
inflammatory markers. Rashes seen in COVID-19-associated illness can have an appearance
that can mimic vasculitis (eg, pernio [chilblain]-like lesions of acral surfaces, sometimes
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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis

referred to as "COVID toes"), but they are not vasculitic. (See "Vasculitis in children: Evaluation
overview" and "COVID-19: Cutaneous manifestations and issues related to dermatologic care",
section on 'Cutaneous manifestations of COVID-19'.)

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: Kawasaki disease" and "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
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)".)

• (See "Patient education: COVID-19 overview (The Basics)" and "Patient education:
COVID-19 vaccines (The Basics)".)
• (See "Patient education: Kawasaki disease (The Basics)".)

SUMMARY AND RECOMMENDATIONS

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COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis
● Coronavirus disease 2019 (COVID-19) in children is usually mild. However, in rare cases,
children can be severely affected, and clinical manifestations may differ from adults.
Multisystem inflammatory syndrome in children (MIS-C) is an uncommon complication of
COVID-19 that has a presentation similar to Kawasaki disease (KD) or toxic shock syndrome.
(See 'Introduction' above.)

● Epidemiology – While the incidence of MIS-C is uncertain, it appears to be a relatively rare

complication of COVID-19 in children. MIS-C can occur at any age from infancy through late
adolescence. Most cases have occurred in previously healthy children between the ages of 6
to 12 years. Black and Hispanic children appear to be disproportionally affected. Cases of MIS-
C typically peak several weeks after surges of COVID-19 in the community. (See
'Epidemiology' above.)

● Pathophysiology – The pathophysiology of MIS-C is not well understood. It is thought to

result from an abnormal immune response to the virus, with some clinical similarities to KD,
macrophage activation syndrome (MAS), and cytokine release syndrome. However, MIS-C
appears to have an immunophenotype that is distinct from KD and MAS. Most affected children
have positive serology for SARS-CoV-2 with negative polymerase chain reaction (PCR), a
finding that further supports the hypothesis that MIS-C is related to immune dysregulation
occurring after acute infection has passed. However, some children do have positive PCR
testing. (See 'Pathophysiology' above.)

● Clinical presentation – The clinical presentation of MIS-C may include persistent fevers,
gastrointestinal symptoms (abdominal pain, vomiting, diarrhea), rash, and conjunctivitis.
Patients typically present with three to five days of fever, followed by development of shock
and/or multisystem involvement. Laboratory findings include lymphocytopenia, elevated
inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-
dimer), and elevated cardiac markers (troponin, brain natriuretic peptide [BNP]). Other clinical
findings are summarized in the table (table 1). (See 'Clinical manifestations' above.)

● Evaluation – The approach to evaluating a child with suspected MIS-C is summarized in the
algorithm (algorithm 1) and described in greater detail above. (See 'Evaluation' above.)

● Case definition – Case definitions for MIS-C are summarized in the table (table 5). There is a

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

spectrum of disease severity (figure 1). (See 'Case definition' above and 'Spectrum of disease'
above.)

● Differential diagnosis – Important considerations in the differential diagnosis of MIS-C include

KD not related to SARS-CoV-2, bacterial sepsis, severe acute COVID-19, toxic shock
syndrome, and appendicitis. Other less common conditions that can present with similar
manifestations are discussed above. (See 'Differential diagnosis' above.)

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