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Coronavirus disease 2019 (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 Editors: Carrie Armsby, MD, MPH, Elizabeth TePas, MD, MS

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

Literature review current through: Sep 2020. | This topic last updated: Sep 25, 2020.

INTRODUCTION

At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases
in Wuhan, a city in the Hubei province of China. It rapidly spread, resulting in an epidemic throughout
China, followed by an increasing number of cases in other countries globally. In February 2020, the
World Health Organization (WHO) 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). The WHO declared COVID-19 a pandemic on March 11, 2020 [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 [3,4]. Since then, there have been reports of similarly affected children in other parts of the
world [5-12]. 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 "Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children

(MIS-C) management and outcome".)
● (See "Coronavirus disease 2019 (COVID-19): Clinical manifestations and diagnosis in children".)
● (See "Coronavirus disease 2019 (COVID-19): Management in children".)
● (See "Coronavirus disease 2019 (COVID-19): Epidemiology, virology, and prevention".)
● (See "Coronavirus disease 2019 (COVID-19): Clinical features" and "Coronavirus disease 2019
(COVID-19): Diagnosis".)
● (See "Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings".)
● (See "Coronavirus disease 2019 (COVID-19): Management in hospitalized adults".)
● (See "Coronavirus disease 2019 (COVID-19): Hypercoagulability".)
● (See "Coronavirus disease 2019 (COVID-19): Outpatient evaluation and management 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) [5,13,14]. 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 rare complication of COVID-19 in

children. In one report, 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 [15].

The initial reports of MIS-C emerged from the United Kingdom in April 2020 [3,4]. 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 [5-7,9-12,15-19]. Notably, there have been no reports of MIS-C
from China or other Asian countries with high rates of COVID-19 early in the pandemic.

While many 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 [3,9-12,16,17,20]. 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 acute COVID-19 illness in children, which tends to
be most severe in infants <1 year of age and in children with underlying health problems. (See
"Coronavirus disease 2019 (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
[3]. In subsequent larger case series from the United Kingdom and the United States, >70 percent of
affected children were previously healthy [12,21]. 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 [22]. (See "Coronavirus disease 2019 (COVID-19): Care of
adult patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for
rheumatologic disease'.)

The risk of developing MIS-C appears 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 patients were black, 30 to 40 percent
Hispanic, 15 to 25 percent white, and 3 to 28 percent Asian [12,15,21].

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 [9,10,12,15,23]. 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 [10,23]. 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
[24,25]. The 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.)

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 "Clinical features and diagnosis of hemophagocytic
lymphohistiocytosis", section on 'Pathophysiology' 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 available case series, there were 783
children in whom both PCR and serology were performed [9,10,12,18,20,26]. 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
[27]. 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 "Coronavirus disease 2019 (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 [28]. 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 [29]. 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
"Coronavirus disease 2019 (COVID-19): Myocardial injury".)

CLINICAL MANIFESTATIONS

Presenting symptoms — In the available case series, clinical presentations were similar, including
(table 1) [10,12,15,18,21,30-32]:

● Persistent fevers (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 – 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

Most patients present with three to five days of fever, though fewer days of fever have been reported.
In the largest series, which included 186 patients, 10 percent had three days of fever, 12 percent had
four days, and 78 percent had ≥5 days [12].

Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are particularly common and
prominent, with the presentation in some children mimicking appendicitis [19,20,33]. Some children
have been noted to have terminal ileitis on abdominal imaging and/or colitis on colonoscopy. (See
'Other imaging findings' below.)

Respiratory symptoms (tachypnea, labored breathing), when present, are most often due to severe
shock. 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 are common and may include headache, lethargy, confusion, or irritability.
A minority of patients present with more severe neurologic manifestations, including encephalopathy,
seizures, coma, meningoencephalitis, muscle weakness, and brainstem and/or cerebellar signs
[12,34].

Clinical findings — Common clinical findings reported in the available case series include (table 1)
[12,18,21,28,29,34,35]:

● Shock – 32 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 (see 'Spectrum of disease' below). The initial 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 likely 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)
[3,6,9,12,18,20,21,26,36,37]:

● 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, including:

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

• Erythrocyte sedimentation rate – 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. 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 [10]. In addition,
children with shock more commonly had elevated cardiac markers.

Echocardiography — Echocardiographic findings may include [20,38,39]:

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

The frequency of cardiac involvement in MIS-C is uncertain. In three large case series, approximately
30 to 40 percent of children had depressed LV function and 8 to 19 percent had CA abnormalities
[10,12,18]. 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) [10,21,28].

Reports providing more detailed information on cardiac imaging findings in MIS-C are limited by small
study size and possible selection bias towards including more severely affected children [38,39]. In
one 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 (only one child in the MIS-C group had CA involvement) [38]. Functional
parameters correlated with biomarkers of myocardial injury. During the subacute period, there was
good recovery of systolic function, but diastolic dysfunction persisted.
In another study describing the findings of more comprehensive cardiac imaging in 20 patients with
MIS-C, almost all patients displayed abnormal strain and tissue Doppler indices at the time of
admission [39]. LV ejection fraction was <55 percent in one-half of the patients. Serial
echocardiography demonstrated that LV ejection fraction deteriorated before improving at discharge,
with the worst cardiac function occurring a median of seven days after admission. CA dilation was
noted at the time of admission in 15 percent and developed after admission in another 40 percent.
More than one-half of these had multiple sites of CA dilation. All 20 patients underwent cardiac
magnetic resonance imaging at a median of 20 days after admission, at which time LV function
remained mildly depressed (ejection fraction <50 percent) in 20 percent. Cardiac magnetic resonance
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) [3,9,10,12,20,26]:

● Chest radiograph – Many patients had normal chest radiographs. Abnormal findings included
pleural effusions, patchy consolidations, focal consolidation, and atelectasis.

● Computed tomography (CT) of chest – Chest CT (when obtained) generally had findings similar
to those on chest radiograph. A few patients had nodular ground-glass opacification.

● 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 [33].

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 [40-42].

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 (optional: procalcitonin)
• 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)
• Cytokine panel (if available)

Inflammatory markers (CRP, erythrocyte sedimentation rate, procalcitonin, ferritin) are measured
at the time of admission and then serially to monitor progression. Similarly, if cardiac markers
(troponin and BNP) are elevated, they should be followed serially to monitor progression.

● 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.

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 [35].

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.)
Testing for SARS-CoV-2 is discussed in greater detail separately. (See "Coronavirus disease 2019
(COVID-19): Diagnosis", section on 'Specific diagnostic techniques'.)

Testing for other pathogens — Testing for other viral and bacterial pathogens includes [37]:

● 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
● 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 [28].
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.
In children with MIS-C, baseline ECGs may be nonspecific, though arrhythmia and heart block have
been described [3,43]. Findings on initial echocardiography may include CA dilation, left ventricular
(LV) systolic dysfunction, and pericardial effusion. The CA abnormalities can progress to aneurysm,
including giant coronary aneurysms [3].

● Echocardiographic evaluation – The echocardiographic evaluation includes the following:

• Quantitative assessment of LV size and systolic function (LV end-diastolic volume, ejection
fraction)
• 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 3),
as discussed separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features
and evaluation", section on 'Echocardiography'.)

● Timing of follow-up echocardiography – At our center, echocardiography is performed at the

time of diagnosis, with follow-up examinations at the following intervals:

• In patients who initially have normal function and normal CA dimensions, follow-up
echocardiogram is performed one to two weeks post-diagnosis to recheck CA size.

• In patients who have CA dilation/aneurysm on initial echocardiogram, echocardiography is

repeated every two to three days until CA size is stable and then every one to two weeks for
the next four to six weeks.

• For patients with systolic dysfunction/myocarditis and normal CAs on initial

echocardiogram, the echocardiogram is repeated as clinically indicated, including repeat
imaging of the CAs with each study.

• For patients who had evidence of CA involvement or systolic dysfunction/myocarditis in the

acute phase, cardiac magnetic resonance imaging can be considered at approximately two
to six months after the acute illness to assess ventricular function and evaluate for edema,
diffuse fibrosis, and scar by myocardial delayed enhancement.
CASE DEFINITION

CDC and WHO case definitions — The criteria used for case definition vary slightly between different
health agencies [5,7,37]. 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 4). 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)
[10,26]. 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. 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 acute COVID-19 or Kawasaki disease (KD) – 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 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.
 ● 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.

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) [9,10,12,15,44]. 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 "Coronavirus disease 2019 (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
[12]. 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 [10]. In addition, absolute lymphocyte and platelet counts
tend to be lower in MIS-C compared with KD [40]. (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 spreads,
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. Ultimately, better characterizing the distinct immunophenotypes
of these syndromes may help clinicians distinguish one from the other [24,25]. (See 'Pathophysiology'
above.)

CASE REPORTING

Health care providers who have cared or are caring for patients younger than 21 years of age meeting
MIS-C criteria (table 4) should report suspected cases to their local, state, or territorial health
department. Additional information can be found on the 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:

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

fever, shock, and elevated inflammatory markers. All children with suspected moderate to severe
MIS-C should have blood cultures sent, and empiric antibiotics should be administered pending
culture results. Certain clinical features can help distinguish MIS-C from bacterial sepsis. For
example, cardiac involvement, particularly coronary artery (CA) involvement, is uncommon in
bacterial sepsis. 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'.)

● 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.)

● Toxic shock syndrome – Staphylococcal and streptococcal toxic shock syndromes share many
similarities with MIS-C (table 5). 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".)

● 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
"Coronavirus disease 2019 (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: Coronavirus disease 2019 (COVID-19) – Guidelines for specialty care" and "Society
guideline links: Coronavirus disease 2019 (COVID-19) – International public health and government
guidelines" and "Society guideline links: Coronavirus disease 2019 (COVID-19) – Resources for
patients".)

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: Coronavirus disease 2019 (COVID-19) and children (The Basics)".)
• (See "Patient education: Coronavirus disease 2019 (COVID-19) overview (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 rare complication of

COVID-19 in children. Most MIS-C cases have occurred in older children and adolescents who
were previously healthy. Black and Hispanic children appear to be disproportionally affected.
(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, 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 4). There appears
to be a spectrum of disease (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, toxic shock syndrome, and appendicitis. Other
less common conditions that can present with similar manifestations are discussed above. (See
'Differential diagnosis' above.)

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Topic 128190 Version 19.0

Contributor Disclosures
Mary Beth F Son, MD Nothing to disclose Kevin Friedman, MD Nothing to disclose David R Fulton, MD Nothing
to disclose Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [Streptococcus pneumoniae];
Merck [Staphylococcus aureus]; MeMed Diagnostics [Bacterial and viral infections]; Allergan [Staphylococcus
aureus]. Other Financial Interest: Pfizer [PCV13; linezolid]; Elsevier [Pediatric infectious diseases]. Robert Sundel,
MD Grant/Research/Clinical Trial Support: SimulConsult [Pediatric rheumatology diagnostics]; AbbVie
Pharmaceuticals [Polyarticular JIA]. Speaker's Bureau: Medical Education Resources [Pediatric rheumatology
CME]. Adrienne G Randolph, MD, MSc Equity Ownership/Stock Options: Abbvie. Grant/Research/Clinical Trial
Support: Genentech [Influenza critical illness]. Consultant/Advisory Boards: La Jolla Pharmaceuticals [Pediatric
refractory shock]. Carrie Armsby, MD, MPH Nothing to disclose Elizabeth TePas, MD, MS Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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