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: Oct 2021. | This topic last updated: Apr 02, 2021.

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 (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, 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 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 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 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 '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 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 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 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].

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 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.)
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 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
•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.

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.)
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.)
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.
•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:
●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 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 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 5 th 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

●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 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.)