A New Definition for Multisystem Inflammatory

Syndrome in Children
Mary Beth F. Son, MD,a,b Jane C. Burns, MD,c Jane W. Newburger, MD, MPHb,d

In Spring 2020, public health agencies worldwide rapidly issued alerts

about a rare, hyperinflammatory illness in children, presumed to be a
postinfectious immune response to coronavirus disease 2019 (COVID-19),
using somewhat different diagnostic criteria and nomenclature. In the
United States, the Centers for Disease Control and Disease Prevention
(CDC) termed it the multisystem inflammatory syndrome in children
(MIS-C) associated with COVID-19.

Much has been learned since the CDC published its first MIS-C a
Division of Immunology, and dDepartment of Cardiology, Boston
definition in May 2020. The initial definition was intentionally broad Children’s Hospital, Boston, Massachusetts; bDepartment of Pediatrics,
Harvard Medical School, Boston, Massachusetts; and cDepartment of
and somewhat nonspecific. Because of the public health emergency, the Pediatrics, University of California at San Diego School of Medicine,
2020 definition had not been approved by the Council of State and La Jolla, California
Territorial Epidemiologists (CSTE), as would be expected for a
condition reportable to CDC. Therefore, in 2021, the CDC and CSTE Dr Son conceptualized and drafted the initial manuscript
and critically reviewed and revised the manuscript;
convened a working group to construct the CSTE/CDC MIS-C Drs Burns and Newburger critically reviewed and revised
surveillance case definition1 with the objectives of reducing (1) the risk the manuscript; and all authors approved the final
of misclassification with other pediatric inflammatory conditions, and manuscript as submitted and agree to be accountable for
(2) complexity for nonclinically trained public health practitioners who all aspects of the work.
perform case ascertainment. The CSTE approved this new surveillance DOI: https://doi.org/10.1542/peds.2022-060302
case definition in June 2022, and it became effective for non-mandatory
Accepted for publication December 5, 2022
CDC reporting on January 1, 2023. In December 16, 2022’s Morbidity
and Mortality Weekly Report, Melgar et al describe the process and Address correspondence to Mary Beth Son, Division of
Immunology, Boston Children’s Hospital 300 Longwood Ave,
rationale by which the working group developed the CSTE/CDC MIS-C Boston MA 02115. E-mail: [email protected].
surveillance case definition.2 The definition was based on 3 sources of edu
data: a panel of experts who commented on features of MIS-C that PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
distinguish it from other pediatric illnesses, a literature review and
Copyright © 2023 by the American Academy of Pediatrics
assessment of data from the Overcoming COVID-19 Network MIS-C
Registry and the Best Available Treatment Study,3 and the application FUNDING: No external funding.
of the new case definition to a dataset of 8800 MIS-C cases previously CONFLICT OF INTEREST DISCLOSURES: The authors have
reported to the CDC with the 2020 definition. Specifically, they indicated they have no potential conflicts of interest
determined the proportion of cases meeting the new definition, and the relevant to this article to disclose.
proportion of cases meeting the new definition with adjustments for
clinical and laboratory features. To cite: Son MBF, Burns JC, Newburger JW. A New Definition
for Multisystem Inflammatory Syndrome in Children.
Pediatrics. 2023;151(3):e2022060302

PEDIATRICS Volume 151, number 3, March 2023:e2022060302 PEDIATRICS PERSPECTIVES

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 TABLE 1 Side-by-Side Comparison of Criteria Included in the 2020 CDC MIS-C Case Definition and in the CSTE/CDC MIS-C Surveillance Case Definition
Criterion 2020 CDC MIS-C Case Definition CSTE/CDC MIS-C Surveillance Case Definition
Patient age <21 y <21 y
Hospitalization Clinically severe illness requiring Clinical severity requiring hospitalization or
hospitalization resulting in death
No alternative diagnosis No alternative plausible diagnoses Absence of a more likely alternative
diagnosis
Fever Fever $38.0 C for $24 h, or report of Subjective or documented fever
subjective fever lasting $24 h (temperature $38.0 C)
Laboratory evidence of systemic Including, but not limited to, 1 or more of the C-reactive protein $3.0 mg/dL (30 mg/L)
inflammation following: an elevated C-reactive protein,
erythrocyte sedimentation rate, fibrinogen,
procalcitonin, d-dimer, ferritin, lactic acid
dehydrogenase, or interleukin 6, elevated
neutrophils, reduced lymphocytes and low
albumin
Evidence of SARS-CoV-2 infection or exposure Positive for current or recent SARS-CoV-2 Detection of SARS-CoV-2 RNA in a clinical
infection by RT-PCR, serology, or antigen specimen up to 60 d before or during
test, or exposure to a suspected or hospitalization, or in a postmortem
confirmed COVID-19 case within the 4 wks specimen using a diagnostic molecular
before the onset of symptoms amplification test (eg, PCR), OR
Detection of SARS-CoV-2-specific antigen in a
clinical specimen up to 60 before or
during hospitalization, or in a
postmortem specimen, OR
Detection of SARS-CoV-2-specific antibodies
in serum, plasma, or whole blood
associated with current illness resulting
in or during hospitalization, OR
Close contact with a confirmed or probable
case of COVID-19 in the 60 d before
hospitalization
Multisystem involvement Multisystem ($2) organ involvement: New onset manifestations in at least 2 of
the following categories:
Cardiovascular (eg, shock, elevated troponin Cardiac involvement indicated by left
and/or BNP, ventricular ejection fraction <55%, OR
abnormal echocardiogram, arrhythmia) coronary artery dilatation, aneurysm, or
ectasia, OR troponin elevated to greater
than laboratory normal range, or
indicated as elevated in a clinical note
Renal (eg, acute kidney injury, renal failure) Mucocutaneous involvement indicated by
rash, OR inflammation of the oral mucosa
(eg, mucosal erythema or swelling,
drying, or fissuring of the lips,
strawberry tongue), OR conjunctivitis or
conjunctival injection (redness of the
eyes), OR extremity findings (eg, erythema
[redness] or edema [swelling] of the
hands or feet)
Respiratory (eg, pneumonia, ARDS, pulmonary Shock
embolism)
Hematologic (eg, elevated D-dimer, Gastrointestinal involvement indicated by
thrombophilia, thrombocytopenia) abdominal pain, OR vomiting, OR diarrhea
Gastrointestinal (eg, abdominal pain, vomiting, Hematologic involvement indicated by
diarrhea, elevated bilirubin, platelet count <150 000 cells/lL, OR
elevated liver enzymes) absolute lymphocyte count (ALC) <1000
cells/lL
Dermatologic (eg, rash, mucocutaneous
lesions)
Neurologic (eg, CVA, aseptic meningitis,
encephalopathy, seizure)

2 SON et al
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 We summarize the differences the current illness. In the absence false positive rates as a tool in the
between the definitions in Table 1. of a positive laboratory test result real world of clinical practice cannot
In the CSTE/CDC MIS-C surveillance for SARS-CoV-2, the definition of a be estimated.
case definition, fever of any duration probable MIS-C case is met with an
is sufficient to meet that criterion, epidemiologic link, defined as close In addition, the CSTE/CDC MIS-C
whereas fever lasting $24 hours contact with a probable or surveillance case definition was
was previously required. The confirmed COVID-19 case within explicitly developed for MIS-C
criterion of systemic inflammation is 60 days of illness, plus the passive surveillance, not for
now met solely with a C-reactive required clinical criteria. When the diagnosis, and the CDC authors
protein $3mg/dL, instead of via a CSTE/CDC MIS-C surveillance case distinguish between the use of the
myriad of acute phase reactants. definition for confirmed and definition for reporting purposes
Multisystem involvement is now met probable cases was applied to MIS- versus clinical purposes. Specifically,
with $2 of 5 organ systems, instead C cases with an available they emphasize that clinicians
of $2 out of 7, because renal, quantitative C-reactive protein who should use all available data to
respiratory, and neurologic were reported to the CDC using the consider alternative diagnoses and
categories were eliminated, and the 2020 definition, 87% (6158/7081) determine treatment on the basis of
cardiac category is now split into 2 met the new case definition. clinical judgment. We agree that the
criteria: (1) shock and (2) cardiac use of the new case definition as a
involvement, as evidenced by low Many of the new features of the clinical instrument in isolation poses
ventricular ejection fraction CSTE/CDC MIS-C surveillance case important challenges. First, the new
(#55%), coronary artery definition, such as simpler definition was developed by using a
abnormalities, or elevated troponin. requirements for fever, systemic dataset that included MIS-C cases
The dermatologic category is now inflammation, organ involvement, and
from earlier in the pandemic when
mucocutaneous involvement, the identification of any positive
SARS- CoV-2 variants were more
including rash, inflammation of the serology result (not antigen specific),
likely to cause MIS-C and more
oral mucosa, conjunctival injection, were instituted to improve the
severe illness, many children were
or extremity findings. These criteria feasibility of data collection by
less exposed to usual childhood
are strongly reminiscent of classic jurisdictional health department staff,
viruses, and fewer children had
Kawasaki disease (KD) stigmata 1 of the 2 goals of the CDC/CSTE
been vaccinated and, hence,
but without unilateral working group. In regard to the
protected against MIS-C. Moreover,
lymphadenopathy. Gastrointestinal other goal (ie, decreasing the
seropositivity in the pediatric
involvement now specifies misclassification of MIS-C cases), the
population has become widespread
abdominal pain, vomiting, or working group primarily focused on
since MIS-C’s first description; by
diarrhea. Lastly, hematologic distinguishing MIS-C from severe
COVID-19, KD, and toxic shock August 2022, almost 62 million
involvement was simplified to require
syndrome. It is well documented that children, or 86% of the pediatric
the presence of thrombocytopenia
severe acute COVID-19 has significant population, had had at least 1 SARS-
(<150 000 cells/mL) or a low
absolute lymphocyte count overlap with MIS-C, and removing the CoV-2 infection. It is, thus, difficult
(<1000 cells/mL). Age <21 years, respiratory category from the MIS-C to interpret if positive serology
severe illness requiring case definition is expected to decrease results are associated with the MIS-
hospitalization, and absence of a more the misclassification of severe C illness in question, if there is not a
likely alternative diagnosis remain COVID-19 as MIS-C.4 The CDC has history of positive SARS-CoV-2 RNA
criteria for MIS-C in the new case also published diagnostic scores to PCR or antigen test results in the
definition. Notably, KD is now distinguish MIS-C, COVID-19, KD, and preceding 2 to 8 weeks. However,
considered an alternative diagnosis. toxic shock syndrome.5 It is unknown negative antigen, PCR, and serology
Laboratory criteria for confirmed how many children hospitalized test results against SARS-CoV-2
MIS-C cases require a positive severe with other febrile illnesses would likely exclude a diagnosis of MIS-C.
acute respiratory syndrome meet the new MIS-C definition Lastly, if new SARS-Co-V2 variants
coronavirus 2 (SARS-CoV-2) RNA given widespread seropositivity, continue to be associated with
polymerase chain reaction (PCR) or COVID-19 exposure, and nonspecific milder MIS-C,6 overlap with other
specific antigen test result within 60 features overlapping with acute viral illnesses will increase. Taken
days of illness or positive SARS-CoV-2 infectious illnesses and other together, these considerations
serology result (antigen-specificity hyperinflammatory conditions. As emphasize the importance of clinical
not required), if associated with such, the definition’s specificity and judgment in considering the broad

PEDIATRICS Volume 151, number 3, March 2023 3

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 array of alternative diagnoses that MIS-C that present without ABBREVIATIONS
may masquerade as MIS-C. life-threatening involvement.
However, in the absence of such CDC: Centers for Disease Control
Given increasing challenges to the tools, clinicians will need to use and Prevention
diagnosis of MIS-C, readily accessible clinical judgment, in collaboration COVID-19: coronavirus disease
diagnostic tools, such as machine with subspecialty experts, to 2019
learning physician support tools,7 accurately diagnose and treat CSTE: Council of State and
T cell receptor repertoire skewing MIS-C. Fortunately, the CSTE/CDC Territorial Epidemiologists
(ie, the expansion of TRbV11-2), or a MIS-C surveillance case definition KD: Kawasaki disease
more specific cytokine fingerprint8 will facilitate research by MIS-C: multisystem inflammatory
are needed to provide rapid, accurate aligning with a common set of syndrome in children
results to differentiate MIS-C from manifestations in the World Health SARS-CoV-2: severe acute
other febrile conditions of childhood Organization’s MIS-C definition, respiratory syndrome
and to determine a temporal link to thereby enhancing critical coronavirus 2
SARS-CoV-2 infection. Accurate international collaborations for
diagnostic tests may also facilitate our understanding of MIS-C
the diagnosis of milder forms of biology, diagnosis, and treatment.

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