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.

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 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

● 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.)

REFERENCES

1. World Health Organization. Director-General's remarks at the media briefi

ng on 2019-nCoV on 11 February 2020. http://www.who.int/dg/speeches/
detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-nco
v-on-11-february-2020 (Accessed on February 12, 2020).
2. Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory
shock in children during COVID-19 pandemic. Lancet 2020; 395:1607.
3. Paediatric Intensive Care Society (PICS) Statement: Increased number of r
eported cases of novel presentation of multi
system inflammatory diseas
e. Available at https://picsociety.uk/wp-content/uploads/2020/04/PICS-stat
ement-re-novel-KD-C19-presentation-v2-27042020.pdf (Accessed on May
15, 2020).
4. Health Alert Network (HAN): Multisystem Inflammatory Syndrome in Child
ren (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). https://
emergency.cdc.gov/han/2020/han00432.asp (Accessed on May 15, 2020).
5. European Centre for Disease Prevention and Control Rapid Risk Assessme
nt: Paediatric inflammatory multisystem syndrome and SARS CoV 2 infecti
on in children. Available at: https://www.ecdc.europa.eu/sites/default/file
s/documents/covid-19-risk-assessment-paediatric-inflammatory-multisyst
em-syndrome-15-May-2020.pdf (Accessed on May 17, 2020).
 6. World Health Organization Scientif Brief: Multisystem inflammatory syndr
ome in children and adolescents with COVID-19. Available at: World Healt
h Organization Scientif Brief: Multisystem inflammatory syndrome in child
ren and adolescents with COVID-19 (Accessed on May 17, 2020).
7. Licciardi F, Pruccoli G, Denina M, et al. SARS-CoV-2-Induced Kawasaki-Like
Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children.
Pediatrics 2020; 146.
8. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-
like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an
observational cohort study. Lancet 2020; 395:1771.
9. Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58
Children With a Pediatric Inflammatory Multisystem Syndrome Temporally
Associated With SARS-CoV-2. JAMA 2020; 324:259.
10. Cheung EW, Zachariah P, Gorelik M, et al. Multisystem Inflammatory
Syndrome Related to COVID-19 in Previously Healthy Children and
Adolescents in New York City. JAMA 2020; 324:294.
11. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory
Syndrome in U.S. Children and Adolescents. N Engl J Med 2020; 383:334.
12. Centers for Disease Control and Prevention. 2019 Novel coronavirus, Wuh
an, China. Information for Healthcare Professionals. https://www.cdc.gov/
coronavirus/2019-nCoV/hcp/index.html (Accessed on February 14, 2020).
13. World Health Organization. Novel Coronavirus (2019-nCoV) technical guid
ance. https://www.who.int/emergencies/diseases/novel-coronavirus-201
9/technical-guidance (Accessed on February 14, 2020).
14. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem Inflammatory
Syndrome in Children in New York State. N Engl J Med 2020; 383:347.
15. Dallan C, Romano F, Siebert J, et al. Septic shock presentation in
adolescents with COVID-19. Lancet Child Adolesc Health 2020; 4:e21.
16. Latimer G, Corriveau C, DeBiasi RL, et al. Cardiac dysfunction and
thrombocytopenia-associated multiple organ failure inflammation
phenotype in a severe paediatric case of COVID-19. Lancet Child Adolesc
Health 2020; 4:552.
17. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-Associated Multisystem
Inflammatory Syndrome in Children - United States, March-July 2020.
MMWR Morb Mortal Wkly Rep 2020; 69:1074.
18. Webb K, Abraham DR, Faleye A, et al. Multisystem inflammatory
syndrome in children in South Africa. Lancet Child Adolesc Health 2020;
4:e38.
19. Li W, Tang Y, Shi Y, et al. Why multisystem inflammatory syndrome in
children has been less commonly described in Asia? Transl Pediatr 2020;
9:873.
20. Belhadjer Z, Méot M, Bajolle F, et al. Acute Heart Failure in Multisystem
Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2
Pandemic. Circulation 2020; 142:429.
21. Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and
Outcomes of US Children and Adolescents With Multisystem
Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute
COVID-19. JAMA 2021; 325:1074.
22. Davies P, Evans C, Kanthimathinathan HK, et al. Intensive care admissions
of children with paediatric inflammatory multisystem syndrome
temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre
observational study. Lancet Child Adolesc Health 2020; 4:669.
23. Case Series of Multisystem Inflammatory Syndrome in Adults Associated
with SARS-CoV-2 Infection — United Kingdom and United States, March–
August 2020. MMWR Morb Mortal Wkly Rep 2020.
24. Mahase E. Covid-19: Cases of inflammatory syndrome in children surge
after urgent alert. BMJ 2020; 369:1990.
25. Carter MJ, Fish M, Jennings A, et al. Peripheral immunophenotypes in
children with multisystem inflammatory syndrome associated with SARS-
CoV-2 infection. Nat Med 2020; 26:1701.
26. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and
immunological features of SARS-CoV-2-induced multisystem inflammatory
syndrome in children. J Clin Invest 2020; 130:5942.
27. Bartsch YC, Wang C, Zohar T, et al. Humoral signatures of protective and
pathological SARS-CoV-2 infection in children. Nat Med 2021; 27:454.
28. Vella LA, Giles JR, Baxter AE, et al. Deep immune profiling of MIS-C
demonstrates marked but transient immune activation compared to adult
and pediatric COVID-19. Sci Immunol 2021; 6.
29. Center for Disease Control and Prevention, Center for Preparedness and R
esponse: Multisystem Inflammatory Syndrome in Children (MIS-C) Associa
ted with Coronavirus Disease 2019 (COVID-19), Clinician Outreach and Co
mmunication (COCA) Webinar. Available at: https://emergency.cdc.gov/coc
a/calls/2020/callinfo_051920.asp?deliveryName=USCDC_1052-DM28623 (A
ccessed on May 19, 2020).
30. Pang J, Boshier FAT, Alders N, et al. SARS-CoV-2 Polymorphisms and
Multisystem Inflammatory Syndrome in Children. Pediatrics 2020; 146.
31. Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS-
CoV-2-associated multisystem inflammatory syndrome in children: a
comprehensive review and proposed clinical approach. Eur J Pediatr 2021;
180:307.
32. Dolhnikoff M, Ferreira Ferranti J, de Almeida Monteiro RA, et al. SARS-CoV-
2 in cardiac tissue of a child with COVID-19-related multisystem
inflammatory syndrome. Lancet Child Adolesc Health 2020; 4:790.
33. Cirks BT, Rowe SJ, Jiang SY, et al. Sixteen Weeks Later: Expanding the Risk
Period for Multisystem Inflammatory Syndrome in Children. J Pediatric
 Infect Dis Soc 2021; 10:686.
34. Kaushik A, Gupta S, Sood M, et al. A Systematic Review of Multisystem
Inflammatory Syndrome in Children Associated With SARS-CoV-2
Infection. Pediatr Infect Dis J 2020; 39:e340.
35. Radia T, Williams N, Agrawal P, et al. Multi-system inflammatory syndrome
in children & adolescents (MIS-C): A systematic review of clinical features
and presentation. Paediatr Respir Rev 2021; 38:51.
36. Ahmed M, Advani S, Moreira A, et al. Multisystem inflammatory syndrome
in children: A systematic review. EClinicalMedicine 2020; 26:100527.
37. Halepas S, Lee KC, Myers A, et al. Oral manifestations of COVID-2019-
related multisystem inflammatory syndrome in children: a review of 47
pediatric patients. J Am Dent Assoc 2021; 152:202.
38. Tullie L, Ford K, Bisharat M, et al. Gastrointestinal features in children with
COVID-19: an observation of varied presentation in eight children. Lancet
Child Adolesc Health 2020; 4:e19.
39. Abdel-Mannan O, Eyre M, Löbel U, et al. Neurologic and Radiographic
Findings Associated With COVID-19 Infection in Children. JAMA Neurol
2020; 77:1440.
40. LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic Involvement in
Children and Adolescents Hospitalized in the United States for COVID-19
or Multisystem Inflammatory Syndrome. JAMA Neurol 2021; 78:536.
41. Hanson KE, Caliendo AM, Arias CA, et al. Infectious Diseases Society of
America Guidelines on the Diagnosis of COVID-19:Serologic Testing. Clin
Infect Dis 2020.
42. Choi NH, Fremed M, Starc T, et al. MIS-C and Cardiac Conduction
Abnormalities. Pediatrics 2020; 146.
43. Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem
inflammatory syndrome in children during the covid-19 pandemic in Paris,
 France: prospective observational study. BMJ 2020; 369:m2094.
44. Royal College of Paediatrics and Child Health Guidance: Paediatric multisy
stem inflammatory syndrome temporally associated with COVID-19. Avail
able at: https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Pae
diatric-multisystem-%20inflammatory%20syndrome-20200501.pdf (Access
ed on May 17, 2020).
45. Abrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe
outcomes in multisystem inflammatory syndrome in children (MIS-C) in
the USA: a retrospective surveillance study. Lancet Child Adolesc Health
2021; 5:323.
46. Matsubara D, Kauffman HL, Wang Y, et al. Echocardiographic Findings in
Pediatric Multisystem Inflammatory Syndrome Associated With COVID-19
in the United States. J Am Coll Cardiol 2020; 76:1947.
47. Theocharis P, Wong J, Pushparajah K, et al. Multimodality cardiac
evaluation in children and young adults with multisystem inflammation
associated with COVID-19. Eur Heart J Cardiovasc Imaging 2021; 22:896.
48. Valverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute Cardiovascular
Manifestations in 286 Children With Multisystem Inflammatory Syndrome
Associated With COVID-19 Infection in Europe. Circulation 2021; 143:21.
49. Kobayashi R, Dionne A, Ferraro A, et al. Detailed Assessment of Left
Ventricular Function in Multisystem Inflammatory Syndrome in Children,
Using Strain Analysis. CJC Open 2021; 3:880.
50. Blumfield E, Levin TL, Kurian J, et al. Imaging Findings in Multisystem
Inflammatory Syndrome in Children (MIS-C) Associated With Coronavirus
Disease (COVID-19). AJR Am J Roentgenol 2021; 216:507.
51. Rostad BS, Shah JH, Rostad CA, et al. Chest radiograph features of
multisystem inflammatory syndrome in children (MIS-C) compared to
pediatric COVID-19. Pediatr Radiol 2021; 51:231.
52. Morparia K, Park MJ, Kalyanaraman M, et al. Abdominal Imaging Findings
in Critically Ill Children With Multisystem Inflammatory Syndrome
Associated With COVID-19. Pediatr Infect Dis J 2021; 40:e82.
53. Henderson LA, Canna SW, Friedman KG, et al. American College of
Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome
in Children Associated With SARS-CoV-2 and Hyperinflammation in
Pediatric COVID-19: Version 1. Arthritis Rheumatol 2020; 72:1791.
54. American Academy of Pediatrics clinical guidance: Multisystem Inflammat
ory Syndrome in Children (MIS-C), available at: https://services.aap.org/e
n/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/mul
tisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/ (Acc
essed on November 23, 2020).
55. Harwood R, Allin B, Jones CE, et al. A national consensus management
pathway for paediatric inflammatory multisystem syndrome temporally
associated with COVID-19 (PIMS-TS): results of a national Delphi process.
Lancet Child Adolesc Health 2021; 5:133.
56. Carlin RF, Fischer AM, Pitkowsky Z, et al. Discriminating Multisystem
Inflammatory Syndrome in Children Requiring Treatment from Common
Febrile Conditions in Outpatient Settings. J Pediatr 2021; 229:26.
57. Campbell JI, Roberts JE, Dubois M, et al. Non-SARS-CoV-2 Infections
Among Patients Evaluated for MIS-C Associated With COVID-19. Pediatr
Infect Dis J 2021; 40:e90.
58. Rostad CA, Chahroudi A, Mantus G, et al. Quantitative SARS-CoV-2
Serology in Children With Multisystem Inflammatory Syndrome (MIS-C).
Pediatrics 2020; 146.
59. Dean A, Asaithambi R, Neubauer HC. Murine Typhus in 5 Children
Hospitalized for Multisystem Inflammatory Syndrome in Children. Hosp
Pediatr 2021; 11:e61.
60. Liu PP, Blet A, Smyth D, Li H. The Science Underlying COVID-19:
Implications for the Cardiovascular System. Circulation 2020; 142:68.
61. Dionne A, Mah DY, Son MBF, et al. Atrioventricular Block in Children With
Multisystem Inflammatory Syndrome. Pediatrics 2020; 146.
62. Ouldali N, Pouletty M, Mariani P, et al. Emergence of Kawasaki disease
related to SARS-CoV-2 infection in an epicentre of the French COVID-19
epidemic: a time-series analysis. Lancet Child Adolesc Health 2020; 4:662.
63. Swann OV, Holden KA, Turtle L, et al. Clinical characteristics of children
and young people admitted to hospital with covid-19 in United Kingdom:
prospective multicentre observational cohort study. BMJ 2020;
370:m3249.

Topic 128190 Version 26.0

© 2021 UpToDate, Inc. All rights reserved.