A broad, surveillance case definition was implemented when multisystem inflammatory syndrome in children (MIS-C) emerged in 2020. In 2023, a revised MIS-C case definition was constructed to improve specificity and reduce misclassification with other pediatric inflammatory conditions. This study aims to describe the impact of the updated definition on the classification of patients with MIS-C and Kawasaki Disease (KD).
Patients hospitalized from March 2020 to November 2022 with clinician-diagnosed KD and MIS-C at a single center were studied retrospectively. Specificity and positive predictive value were assessed; McNemar test was used to compare specificity.
Among 119 patients with MIS-C per the 2020 definition, 20 (17%) did not fulfill the 2023 definition. Six of these 20 (30%) had shock or cardiac involvement. Of 59 KD patients, 10 (17%) met the 2020 MIS-C definition. Five patients (8%) met the 2023 MIS-C definition. Specificity for the 2020 and 2023 MIS-C definitions among KD patients were 83.1% and 91.5% respectively (McNemar, P = .0736). Positive predictive value was higher for the 2023 MIS-C case definition compared with the 2020 MIS-C case definition (95.2% vs 92.2%).
Approximately 1 in 5 patients diagnosed with MIS-C using the 2020 case definition did not meet the 2023 definition, including patients with cardiovascular dysfunction. Overlap persisted between patients meeting KD and 2023 MIS-C case definitions, with a false positive rate of 8%. Implications for treatment should be considered, particularly in settings where presumed MIS-C may be treated with corticosteroid monotherapy.
A broad definition for multisystem inflammatory syndrome in children (MIS-C) allowed for national surveillance; however, overlap with other inflammatory conditions posed a challenge. A new case definition was constructed in 2023 to reduce misclassification and the impact is unknown.
The 2023 definition showed improvement in the ability to accurately identify MIS-C cases and discriminate between MIS-C and Kawasaki disease, however this was not statistically significant. Importantly, patients with MIS-C and cardiac involvement were not captured and overlap with Kawasaki disease persisted.
Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition characterized by fever and multiorgan involvement including cardiac dysfunction as well as shock occurring 2 to 8 weeks after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 When this novel syndrome emerged in early 2020, the Centers for Disease Control and Prevention (CDC) constructed a case definition to facilitate US national surveillance1 requiring the presence of fever, systemic inflammation using a number of biomarkers, and involvement of at least 2 of 7 organ systems. Similar definitions were devised for use in the United Kingdom and Europe.2 –4 The CDC’s intentionally broad definition allowed for inclusion of the full spectrum of a novel illness. However, the overlap with other infectious and inflammatory conditions posed a challenge for clinicians across care settings.5 –8 Conditions that have overlapping features with MIS-C include Kawasaki Disease (KD), culture negative sepsis, and macrophage activation syndrome. However, KD is the most analogous with hallmarks of fever, systemic inflammation, mucocutaneous changes, and cardiovascular findings.1,5 Under the 2020 MIS-C definition, patients who met criteria for both KD and MIS-C were considered to have MIS-C.1
In light of the growing wealth of knowledge related to MIS-C9 and the need to reduce complexity and misclassification, the Council of State and Territorial Epidemiologist (CSTE) implemented a revised MIS-C case definition.10 The 2023 definition differs from the original in that it includes a threshold for inflammation (C-reactive protein [CRP] ≥3 mg/dL), reduced the number of organ systems included (neurologic, respiratory, and renal systems were eliminated), and revised definitions of involvement for cardiac and hematologic systems. Importantly, KD is designated as an alternative diagnosis under the 2023 MIS-C definition.
It is not clear if use of the updated case definition will better distinguish MIS-C from other febrile conditions compared with the original definition. It is particularly important to examine the possibility of misclassification in regard to KD given the lack of viable differentiating factors and implications for treatment. There is precedent in the literature11 –14 for treatment of MIS-C with corticosteroid monotherapy, which would be contraindicated in KD, as the standard of care for KD is treatment with intravenous immunoglobulin (IVIG).15
We applied the 2023 MIS-C case definition to a single-center cohort of MIS-C patients diagnosed using the 2020 case definition and aimed to describe the impact of the updated case definition on this cohort. We also aimed to examine the risk of misclassification of patients with clinician-diagnosed KD by applying the 2020 and 2023 MIS-C definitions (Table 1).1,10,15
Multisystem Inflammatory Syndrome in Children 2020 and 2023 and Kawasaki Disease Case Definitions
| MIS-C 20201 | MIS-C 202310 | Kawasaki Disease 201713 |
|---|---|---|
| An individual aged <21 y presenting with: | An individual aged <21 y that meets: | Complete: Illness in a patient with fever ≥5 or more days and at least 4 of 5 of the following: |
| ▪ Fever: ≥38.0°C for ≥24 h, or report of subjective fever lasting ≥24 h | ▪ Clinical criteria and laboratory criteria or | ▪ Rash |
| ▪ Laboratory evidence of inflammation: Including, but not limited to, 1 or more of the 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 | ▪ Clinical criteria and epidemiologic link or | ▪ Cervical lymphadenopathy |
| ▪ Evidence of clinically severe illness requiring hospitalization | ▪ Vital records criteria | ▪ Bilateral conjunctival injection |
| ▪ Multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurologic) and | Clinical criteria: An illness characterized by all of the following, in the absence of a more likely alternative diagnosisb: | ▪ Oral mucosal changes |
| ▪ Subjective or documented fever (temperature ≥38.0°C) and | ▪ Peripheral extremity changes | |
| ▪ Clinical severity requiring hospitalization or resulting in death and | Patients whose illness does not meet the above case definition but who have fever and coronary artery abnormalities are classified as having atypical or incomplete Kawasaki disease. | |
| No alternative plausible diagnosesa and | ▪ Evidence of systemic inflammation indicated by C-reactive protein ≥3.0 mg/dL and | Suspected incomplete: Prolonged unexplained fever (≥5 d) plus 2–3/5 clinical criteria or infants <6 mo with explained fevers ≥7 d and compatible laboratory or echocardiographic findings: |
| Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 wk before the onset of symptoms | ▪ New onset manifestations in at least 2 of the following categories | ▪ C-reactive protein ≥3 mg/dL or erythrocyte sedimentation rate ≥40 mm per hour and 3 or more of the following: |
| 1. Cardiac involvement indicated by: left ventricular ejection fraction <55 or coronary artery dilatation or elevated troponin | ▪ Anemia for age | |
| 2. Mucocutaneous involvement indicated by: rash, or inflammation of the oral mucosa, or conjunctivitis, or extremity findings | ▪ Platelets ≥450 000 cells/µL after day 7 of fever | |
| 3. Shockc | ▪ Albumin ≤3 g/dL | |
| 4. Gastrointestinal involvement indicated by: abdominal pain or vomiting or diarrhea | ▪ Elevated alanine aminotransferase | |
| 5. Hematologic involvement indicated by: platelet count <150 000 cells/µL or absolute lymphocyte count <1000 cells/µL | ▪ Elevated white blood cells ≥15 000/mm3 | |
| Laboratory criteria | ▪ Urine white blood cells ≥10/hpf | |
| ▪ Detection of SARS-CoV-2 RNA in a clinical specimen up to 60 d before or during hospitalization or | ▪ If any of the 3 conditions are met: | |
| ▪ Detection of SARS-CoV-2 specific antigen in a clinical specimen up to 60 d before or during hospitalization or | ▪ Z = score of left anterior descending or right coronary artery ≥2.5 | |
| ▪ Detection of SARS-CoV-2 specific antibodies in serum, plasma, or whole blood associated with current illness resulting in or during hospitalization | ▪ Coronary artery aneurysm is observed | |
| Epidemiologic linkage criteria | ▪ Or ≥3 suggestive features exist, including left ventricular dysfunction, mitral regurgitation, pericardial effusion or z-scores of 2.25 | |
| ▪ Close contact with a confirmed or probable case of COVID-19 disease in the 60 d before hospitalization. | ||
| Vital records criteria | ||
| ▪ A person whose death certificate lists MIS-C or multisystem inflammatory syndrome as an underlying cause of death or a significant condition contributing to death |
| MIS-C 20201 | MIS-C 202310 | Kawasaki Disease 201713 |
|---|---|---|
| An individual aged <21 y presenting with: | An individual aged <21 y that meets: | Complete: Illness in a patient with fever ≥5 or more days and at least 4 of 5 of the following: |
| ▪ Fever: ≥38.0°C for ≥24 h, or report of subjective fever lasting ≥24 h | ▪ Clinical criteria and laboratory criteria or | ▪ Rash |
| ▪ Laboratory evidence of inflammation: Including, but not limited to, 1 or more of the 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 | ▪ Clinical criteria and epidemiologic link or | ▪ Cervical lymphadenopathy |
| ▪ Evidence of clinically severe illness requiring hospitalization | ▪ Vital records criteria | ▪ Bilateral conjunctival injection |
| ▪ Multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurologic) and | Clinical criteria: An illness characterized by all of the following, in the absence of a more likely alternative diagnosisb: | ▪ Oral mucosal changes |
| ▪ Subjective or documented fever (temperature ≥38.0°C) and | ▪ Peripheral extremity changes | |
| ▪ Clinical severity requiring hospitalization or resulting in death and | Patients whose illness does not meet the above case definition but who have fever and coronary artery abnormalities are classified as having atypical or incomplete Kawasaki disease. | |
| No alternative plausible diagnosesa and | ▪ Evidence of systemic inflammation indicated by C-reactive protein ≥3.0 mg/dL and | Suspected incomplete: Prolonged unexplained fever (≥5 d) plus 2–3/5 clinical criteria or infants <6 mo with explained fevers ≥7 d and compatible laboratory or echocardiographic findings: |
| Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 wk before the onset of symptoms | ▪ New onset manifestations in at least 2 of the following categories | ▪ C-reactive protein ≥3 mg/dL or erythrocyte sedimentation rate ≥40 mm per hour and 3 or more of the following: |
| 1. Cardiac involvement indicated by: left ventricular ejection fraction <55 or coronary artery dilatation or elevated troponin | ▪ Anemia for age | |
| 2. Mucocutaneous involvement indicated by: rash, or inflammation of the oral mucosa, or conjunctivitis, or extremity findings | ▪ Platelets ≥450 000 cells/µL after day 7 of fever | |
| 3. Shockc | ▪ Albumin ≤3 g/dL | |
| 4. Gastrointestinal involvement indicated by: abdominal pain or vomiting or diarrhea | ▪ Elevated alanine aminotransferase | |
| 5. Hematologic involvement indicated by: platelet count <150 000 cells/µL or absolute lymphocyte count <1000 cells/µL | ▪ Elevated white blood cells ≥15 000/mm3 | |
| Laboratory criteria | ▪ Urine white blood cells ≥10/hpf | |
| ▪ Detection of SARS-CoV-2 RNA in a clinical specimen up to 60 d before or during hospitalization or | ▪ If any of the 3 conditions are met: | |
| ▪ Detection of SARS-CoV-2 specific antigen in a clinical specimen up to 60 d before or during hospitalization or | ▪ Z = score of left anterior descending or right coronary artery ≥2.5 | |
| ▪ Detection of SARS-CoV-2 specific antibodies in serum, plasma, or whole blood associated with current illness resulting in or during hospitalization | ▪ Coronary artery aneurysm is observed | |
| Epidemiologic linkage criteria | ▪ Or ≥3 suggestive features exist, including left ventricular dysfunction, mitral regurgitation, pericardial effusion or z-scores of 2.25 | |
| ▪ Close contact with a confirmed or probable case of COVID-19 disease in the 60 d before hospitalization. | ||
| Vital records criteria | ||
| ▪ A person whose death certificate lists MIS-C or multisystem inflammatory syndrome as an underlying cause of death or a significant condition contributing to death |
RT-PCR, reverse transcription PCR.
Some individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C.
A diagnosis of Kawasaki Disease should be considered an alternative diagnosis.
Clinician documentation of shock.
Methods
Our retrospective study included hospitalized patients diagnosed with MIS-C or KD from March 2020 to November 2022. This study was approved by the Boston Children’s Hospital Institutional Review Board and waiver of consent was granted.
Demographic, clinical, laboratory, and echocardiographic data were extracted from the medical record. In regard to serology testing for SARS CoV-2 infection, SARS-CoV-2 antinucleocapsid antibody testing is used at our institution.
KD Cohort
KD patients were identified from our institutional clinical database of patients treated for KD. Cases of KD were reviewed by 3 members of the study team (M.D.L., L.B., M.B.S.) and determined to meet complete or incomplete KD criteria (Table 1).15 Patients who were treated for KD but did not meet either incomplete or complete criteria, or who were not admitted during the acute phase of illness, were excluded.
MIS-C Cohort
Data for the MIS-C patients were identified from an internal institutional database used for tracking and reporting cases to the Massachusetts Department of Public Health. Cases were adjudicated by a total of 3 clinicians in rheumatology and cardiology using the CDC 2020 case definition for MIS-C; cases were reported if ≥2 adjudicators agreed that MIS-C criteria was met. For this report, we excluded cases initially reported as MIS-C that were later found to have alternative diagnoses.
We then applied the updated 2023 case definition to the MIS-C and KD cohorts, and cases were adjudicated by 3 members of the study team (M.D.L., L.B., M.B.S.). The CSTE defines a confirmed case of MIS-C as one where clinical and laboratory criteria are met, and a probable case as one where clinical and epidemiologic criteria are met.10 For this study, patients were determined to fulfill the 2023 MIS-C case definition if they were a confirmed case. We did not include probable cases as the presence or absence of an epidemiologic link was not documented consistently. Cardiac involvement was defined as left ventricular ejection fraction <55% or left anterior descending or right coronary artery z-score ≥2.5. Clinician documentation was used to determine the presence of shock in accordance with the 2023 case definition.10 Severe features were defined as clinician-documented shock or cardiac involvement.
Statistical Analysis
Descriptive statistics were summarized as frequency (percent) for categorical variables and median (interquartile range) for continuous variables. McNemar test was used to compare specificity between the 2020 and 2023 MIS-C definitions among patients with KD with 95% confidence intervals. Positive predictive values and 95% confidence intervals are reported for the 2020 and 2023 MIS-C definitions.
Results
We identified 119 patients with MIS-C adjudicated using the 2020 MIS-C case definition. All patients had positive SARS-CoV-2 polymerase chain reaction (PCR) or antinucleocapsid antibody testing, or exposure to a known coronavirus disease 2019 (COVID-19) infection. Of the 112 patients with antibody testing, 109 (97%) were positive. Of the 109 patients in whom SARS-CoV-2 PCR or point-of-care testing was performed, 27 (25%) were positive. Four patients had negative testing, or it was not performed but had documented exposure to an individual with known COVID-19 within the appropriate timeframe.
The KD database search yielded 59 patients with clinician-diagnosed KD who met inclusion criteria. Forty-three patients (73%) met complete criteria, and 16 (27%) patients met incomplete criteria for KD. Demographics, clinical features and outcomes of KD and MIS-C patients can be found in Supplemental Table 2.
MIS-C Case Definitions
Twenty (17%) of the MIS-C patients adjudicated using the 2020 MIS-C case definition did not fulfill the 2023 MIS-C case definition (Fig 1). Eleven no longer had involvement of 2 organ systems, and 7 had a CRP <3 mg/dL. Two patients had both CRP <3 mg/dL and less than 2 organ systems involved. Six (30%) patients who did not meet the 2023 definition had shock (n = 4) and/or cardiac involvement (n = 3); 2 had elevated troponin and 3 had left ventricular (L.V.) dysfunction (ejection fraction 37% to 49%). None had coronary artery abnormalities. Despite these severe features, the 2023 case definition was not met because of CRP <3 mg/dL (n = 5) and having less than 2 organ systems involved (n = 1).
Patient classification and characteristics. MIS-C, multisystem inflammatory syndrome in children; KD, Kawasaki disease. a Severe features were defined as clinician-documented shock or cardiac involvement (left ventricular ejection fraction <55% or left anterior descending or right coronary artery z-score ≥2.5).
Patient classification and characteristics. MIS-C, multisystem inflammatory syndrome in children; KD, Kawasaki disease. a Severe features were defined as clinician-documented shock or cardiac involvement (left ventricular ejection fraction <55% or left anterior descending or right coronary artery z-score ≥2.5).
KD and MIS-C
Ten (17%) patients were diagnosed with KD despite meeting the 2020 MIS-C case definition, all of whom had positive SARS CoV-2 antibodies but inconsistent (n = 5) or unknown (n = 5) SARS-CoV-2 exposure timeline. One had left ventricle dysfunction (ejection fraction 49%), and 3 had coronary artery dilatation (z-scores 2.5–3.2) (Fig 1). None had clinician-documented shock or were diagnosed with Kawasaki disease shock syndrome.16 Five patients with KD (8%) met the 2023 MIS-C definition, including the 3 patients previously described with coronary changes.
We compared the specificity and positive predictive value (PPV) of the 2020 and 2023 MIS-C definitions to understand the impact of the updated case definition and the frequency of false positives among KD patients. The specificity of the 2020 MIS-C case definition was 83.1% (71.5%–90.5%), compared with 91.5% (81.6%–96.3%) for the 2023 definition (McNemar P = .0736). The 2020 MIS-C case definition had a PPV of 92.2% (86.3%–95.7%), and the 2023 MIS-C case definition has a PPV of 95.2% (89.2%–97.9%).
Discussion
In our center’s MIS-C cohort, 17% of MIS-C patients adjudicated using the 2020 case definition did not meet the 2023 definition, including 6 patients with shock and/or cardiac dysfunction. Among patients with KD, the specificity of the 2023 MIS-C definition was numerically higher compared with the 2020 definition, but this difference was not statistically significant.
The updated 2023 case definition for MIS-C was designed to reduce complexity and misclassification.10 However, we note that a number of patients who were excluded had shock or cardiac dysfunction that warranted treatment. These findings emphasize, as the CSTE and CDC did,10 that the 2023 case definition should be used as a means of surveillance rather than to aid in diagnosis, as it may not capture all patients who might benefit from treatment of MIS-C.
Differentiating between MIS-C and KD has presented a significant challenge for clinicians given overlapping features and a lack of diagnostic testing for either condition. We demonstrated that the updated 2023 criteria trended toward better discrimination between KD and MIS-C, although overlap persisted. In our cohort, all patients with KD who had positive antibody testing met criteria for MIS-C. As such, the ability to identify a clear timeline of infection is imperative to confer a diagnosis of MIS-C. However, this is increasingly challenging in the setting of widespread seroprevalence to SARS-CoV-2 and evolving behaviors around testing within communities. The risk of misclassification is important to consider from a surveillance point of view as clinicians transition from the 2020 MIS-C case definition, which included patients who met criteria for KD, to the 2023 case definition, which designates KD as an alternative diagnosis.
In addition to repercussions for accurate surveillance, possible misclassification between KD and MIS-C has implications for management. Treatment of both KD and MIS-C includes IVIG15,17 ; however, use of corticosteroids differs. In KD, corticosteroids are typically reserved for cases with refractory fever or high-risk features such as coronary artery changes on baseline echocardiogram.15,18 In MIS-C, initial therapy with IVIG plus steroids has been shown to result in improved short-term cardiovascular outcomes compared with IVIG alone.19,20 Notably, other publications have suggested that steroid monotherapy may be appropriate for some MIS-C patients, particularly in resource-limited settings where IVIG is less accessible.11 –13 However, steroid monotherapy would be contraindicated in KD.15 In our cohort, 3 of the 5 patients with KD who met the 2023 MIS-C case definition had coronary changes, for which treatment with IVIG is essential.
Our study is limited by its retrospective, single-center design. The sample size and degree of acuity in our cohort was consistent with studies published from other tertiary care referral centers.5,6 However, it may not reflect the experience at smaller or community hospitals. Poor access to testing early in the pandemic likely limited clinicians’ ability to diagnose or rule-out MIS-C. In the absence of a gold standard diagnostic tool for MIS-C and KD, we relied on clinician conferred diagnoses. Lastly, this study examined the impact of the new MIS-C case definition on KD, which is only 1 of a number of other infectious and inflammatory conditions that share significant clinical overlap with MIS-C.7,8
In comparing the 2020 and 2023 MIS-C case definitions and the risk of misclassification of KD in our cohort, we identified likely improvements in accuracy of MIS-C cases identified for surveillance and in the ability to differentiate between KD and MIS-C. Nonetheless, MIS-C cases with severe features such as shock or cardiac involvement were excluded in our cohort by the updated MIS-C 2023 case definition. As such, clinicians are encouraged to consider MIS-C in patients with a MIS-C phenotype and such features. Additionally, although the 2023 case definition seems better able to discern MIS-C from KD, there continues to be overlap. Implications for treatment should be carefully considered, particularly in settings where presumed MIS-C may be treated with corticosteroid monotherapy.
Ms Day-Lewis and Dr Son conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript; Ms Berbert analyzed the data, verified the analytical methods, and drafted the initial manuscript; Drs Newburger, Dionne, and Ms Baker conceptualized and designed the study, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: Funding was provided by the Samara Jan Turkel Center for Autoimmune Disease, Boston Children’s Hospital.
CONFLICT OF INTEREST DISCLOSURES: The authors have no conflicts of interest to disclose.
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