{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:58:28Z","timestamp":1792205908990,"version":"4.4.0"},"reference-count":37,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Multisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness that occurs 2 to 6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severity differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes.<\/jats:p><\/jats:sec>Objective<\/jats:title>To characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>In this cohort study, MIS-C phenotypic clusters were inferred using latent class analysis applied to the largest cohort to date of cases from US national surveillance data from 55 US public health jurisdictions. Cases reported to the Centers for Disease Control and Prevention MIS-C national surveillance program as of April 4, 2023, with symptom onset on or before December 31, 2022, were retrospectively analyzed. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with 20% or more missingness and 10% or less or 90% or more prevalence. A total of 389 cases missing 10 or more variables were excluded, and multiple imputation was conducted on the remaining cases.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Differences by cluster in prevalence of each clinical sign and symptom, percentage of patients admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time.<\/jats:p><\/jats:sec>Results<\/jats:title>Among 8944 included MIS-C cases (median [IQR] patient age, 8.7 [5.0-12.5] years; 5407 [60.5%] male), latent class analysis identified 3 clusters characterized by (1) frequent respiratory findings primarily affecting older children (respiratory cluster; 713 cases [8.0%]; median [IQR] age, 12.7 [6.3-16.5] years), (2) frequent shock and\/or cardiac complications (shock and cardiac cluster; 3359 cases [37.6%]; median [IQR] age, 10.8 [7.7-14.0] years), and (3) remaining cases (undifferentiated cluster; 4872 cases [54.5%]; median [IQR] age, 6.8 [3.6-10.3] years). The percentage of patients with MIS-C admitted to the ICU was highest for the shock and cardiac cluster (82.3% [2765\/3359]) followed by the respiratory (49.5% [353\/713]) and undifferentiated clusters (33.0% [1609\/4872]). Among patients with data on length of stay available, 129 of 632 hospitalizations (20.4%) and 54 of 281 ICU stays (19.2%) in the respiratory cluster lasted 10 or more days compared with 708 of 3085 (22.9%) and 157 of 2052 (7.7%), respectively, in the shock and cardiac cluster and 293 of 4467 (6.6%) and 19 of 1220 (1.6%), respectively, in the undifferentiated cluster. The proportion of cases in both the respiratory cluster and the shock and cardiac cluster decreased after emergence of the Omicron variant in the US.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this cohort study, MIS-C cases clustered into 3 subgroups with distinct clinical phenotypes, severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and identify groups at highest risk for severe outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.56272","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T16:00:49Z","timestamp":1738080049000},"page":"e2456272","source":"Crossref","is-referenced-by-count":12,"title":["Phenotypic Classification of Multisystem Inflammatory Syndrome in Children Using Latent Class Analysis"],"prefix":"10.1001","volume":"8","author":[{"given":"Kevin C.","family":"Ma","sequence":"first","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"},{"name":"Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna R.","family":"Yousaf","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Miller","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine N.","family":"Lindsey","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"},{"name":"4ES Corporation, San Antonio, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Wu","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Melgar","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami B.","family":"Popovic","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"},{"name":"General Dynamics Information Technology, Falls Church, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela P.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura D.","family":"Zambrano","sequence":"additional","affiliation":[{"name":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"issue":"5","key":"zoi241581r1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11882-022-01031-4","article-title":"Multisystem inflammatory syndrome in children (MIS-C).","volume":"22","author":"Patel","year":"2022","journal-title":"Curr Allergy Asthma Rep"},{"issue":"6","key":"zoi241581r2","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1038\/s41390-022-02263-w","article-title":"Multisystem inflammatory syndrome in children (MIS-C) and neonates (MIS-N) associated with COVID-19: optimizing definition and management.","volume":"93","author":"Molloy","year":"2023","journal-title":"Pediatr Res"},{"issue":"11","key":"zoi241581r3","doi-asserted-by":"publisher","first-page":"e400","DOI":"10.1097\/INF.0000000000003294","article-title":"Racial and ethnic disparities in multisystem inflammatory syndrome in children in the United States, March 2020 to February 2021.","volume":"40","author":"Stierman","year":"2021","journal-title":"Pediatr Infect Dis J"},{"issue":"6","key":"zoi241581r4","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.16420","article-title":"Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2.","volume":"4","author":"Payne","year":"2021","journal-title":"JAMA Netw Open"},{"issue":"11","key":"zoi241581r6","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1001\/jama.2021.2091","article-title":"Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19.","volume":"325","author":"Feldstein","year":"2021","journal-title":"JAMA"},{"issue":"32","key":"zoi241581r7","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.15585\/mmwr.mm6932e2","article-title":"COVID-19-associated multisystem inflammatory syndrome in children\u2014United States, March-July 2020.","volume":"69","author":"Godfred-Cato","year":"2020","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"4","key":"zoi241581r9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr7104a1","article-title":"Council of State and Territorial Epidemiologists\/CDC surveillance case definition for multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection\u2014United States.","volume":"71","author":"Melgar","year":"2022","journal-title":"MMWR Recomm Rep"},{"key":"zoi241581r10","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101112","article-title":"Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents.","volume":"40","author":"Geva","year":"2021","journal-title":"EClinicalMedicine"},{"issue":"4","key":"zoi241581r11","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1097\/INF.0000000000003449","article-title":"Distinguishing multisystem inflammatory syndrome in children from COVID-19, Kawasaki disease and toxic shock syndrome.","volume":"41","author":"Godfred-Cato","year":"2022","journal-title":"Pediatr Infect Dis J"},{"issue":"5","key":"zoi241581r12","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/S2352-4642(21)00050-X","article-title":"Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study.","volume":"5","author":"Abrams","year":"2021","journal-title":"Lancet Child Adolesc Health"},{"issue":"8","key":"zoi241581r13","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofab388","article-title":"Demographic and clinical factors associated with death among persons <21 years old with multisystem inflammatory syndrome in children\u2014United States, February 2020-March 2021.","volume":"8","author":"Bowen","year":"2021","journal-title":"Open Forum Infect Dis"},{"issue":"8","key":"zoi241581r14","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/S2213-2600(14)70097-9","article-title":"Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials.","volume":"2","author":"Calfee","year":"2014","journal-title":"Lancet Respir Med"},{"issue":"1","key":"zoi241581r15","doi-asserted-by":"publisher","first-page":"21005","DOI":"10.1038\/s41598-023-47655-y","article-title":"Spectrum of severity of multisystem inflammatory syndrome in children: an EHR-based cohort study from the RECOVER program.","volume":"13","author":"Rao","year":"2023","journal-title":"Sci Rep"},{"issue":"2","key":"zoi241581r16","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2023-063259","article-title":"Updated case definition of MIS-C and implications for clinical care.","volume":"153","author":"Day-Lewis","year":"2024","journal-title":"Pediatrics"},{"issue":"1","key":"zoi241581r17","doi-asserted-by":"publisher","first-page":"e1165","DOI":"10.1093\/cid\/ciab1007","article-title":"Multisystem inflammatory syndrome in children\u2014United States, February 2020-July 2021.","volume":"75","author":"Miller","year":"2022","journal-title":"Clin Infect Dis"},{"key":"zoi241581r18","doi-asserted-by":"publisher","first-page":"S303","DOI":"10.1093\/cid\/ciac471","article-title":"Multisystem inflammatory syndrome in children during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variant circulation\u2014United States, July 2021-January 2022.","volume":"75","author":"Miller","year":"2022","journal-title":"Clin Infect Dis"},{"issue":"3","key":"zoi241581r19","doi-asserted-by":"publisher","first-page":"e518","DOI":"10.1093\/cid\/ciac553","article-title":"Lower risk of multisystem inflammatory syndrome in children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2.","volume":"76","author":"Cohen","year":"2023","journal-title":"Clin Infect Dis"},{"key":"zoi241581r20","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102212","article-title":"Clinical phenotypes and outcomes in children with multisystem inflammatory syndrome across SARS-CoV-2 variant eras: a multinational study from the 4CE consortium.","volume":"64","author":"Sperotto","year":"2023","journal-title":"EClinicalMedicine"},{"key":"zoi241581r21","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanwpc.2022.100604","article-title":"Lower risk of multi-system inflammatory syndrome in children (MIS-C) with the Omicron variant.","volume":"27","author":"Lopez","year":"2022","journal-title":"Lancet Reg Health West Pac"},{"issue":"6","key":"zoi241581r22","doi-asserted-by":"publisher","first-page":"2865","DOI":"10.1007\/s00431-023-04968-4","article-title":"MIS-C across three SARS-CoV-2 variants: changes in COVID-19 testing and clinical characteristics in a cohort of U.S. children.","volume":"182","author":"Laird-Gion","year":"2023","journal-title":"Eur J Pediatr"},{"issue":"6","key":"zoi241581r23","doi-asserted-by":"publisher","first-page":"e218","DOI":"10.1097\/INF.0000000000004272","article-title":"Not gone, and should not be forgotten: multisystem inflammatory syndrome in children.","volume":"43","author":"Hensley","year":"2024","journal-title":"Pediatr Infect Dis J"},{"issue":"10","key":"zoi241581r24","doi-asserted-by":"publisher","first-page":"225","DOI":"10.15585\/mmwr.mm7310a2","article-title":"Notes from the field: surveillance for multisystem inflammatory syndrome in children\u2014United States, 2023.","volume":"73","author":"Yousaf","year":"2024","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"7624","key":"zoi241581r26","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1136\/bmj.39335.541782.AD","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.","volume":"335","author":"von Elm","year":"2007","journal-title":"BMJ"},{"issue":"3","key":"zoi241581r27","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1093\/cid\/ciac637","article-title":"BNT162b2 mRNA vaccination against coronavirus disease 2019 is associated with a decreased likelihood of multisystem inflammatory syndrome in children aged 5-18 years-United States, July 2021-April 2022.","volume":"76","author":"Zambrano","year":"2023","journal-title":"Clin Infect Dis"},{"issue":"6","key":"zoi241581r28","doi-asserted-by":"publisher","first-page":"206","DOI":"10.15585\/mmwr.mm7106a4","article-title":"Genomic surveillance for SARS-CoV-2 variants: predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) variants\u2014United States, June 2021-January 2022.","volume":"71","author":"Lambrou","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"24","key":"zoi241581r29","doi-asserted-by":"publisher","first-page":"651","DOI":"10.15585\/mmwr.mm7224a2","article-title":"Genomic surveillance for SARS-CoV-2 variants: circulation of Omicron lineages\u2014United States, January 2022-May 2023.","volume":"72","author":"Ma","year":"2023","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"4","key":"zoi241581r31","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1214\/17-AOAS1061","article-title":"Variable selection for latent class analysis with application to low back pain diagnosis.","volume":"11","author":"Fop","year":"2017","journal-title":"Ann Appl Stat"},{"key":"zoi241581r32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v042.i10","article-title":"poLCA: an R package for polytomous variable latent class analysis.","volume":"42","author":"Linzer","year":"2011","journal-title":"J Stat Softw"},{"issue":"1","key":"zoi241581r33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s43586-022-00184-w","article-title":"Principal component analysis.","volume":"2","author":"Greenacre","year":"2022","journal-title":"Nat Rev Methods Primers"},{"issue":"12","key":"zoi241581r34","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.46829","article-title":"Obesity and outcomes of Kawasaki disease and COVID-19\u2013related multisystem inflammatory syndrome in children.","volume":"6","author":"Khoury","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"5","key":"zoi241581r35","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2023-062101","article-title":"Epidemiology and severity of illness of MIS-C and Kawasaki disease during the COVID-19 pandemic.","volume":"152","author":"Molloy","year":"2023","journal-title":"Pediatrics"},{"issue":"24","key":"zoi241581r36","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1001\/jama.2022.8025","article-title":"Severity and incidence of multisystem inflammatory syndrome in children during 3 SARS-CoV-2 pandemic waves in Israel.","volume":"327","author":"Levy","year":"2022","journal-title":"JAMA"},{"key":"zoi241581r30","author":"Parker","year":"2017"},{"key":"zoi241581r5","unstructured":"COVID data tracker MIS-C national surveillance. Centers for Disease Control and Prevention. Accessed March 13, 2024. https:\/\/covid.cdc.gov\/covid-data-tracker\/#mis-national-surveillance"},{"key":"zoi241581r8","unstructured":"Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Centers for Disease Control and Prevention. September 21, 2021. Accessed March 13, 2024. https:\/\/web.archive.org\/web\/20230305233605\/https:\/\/emergency.cdc.gov\/han\/2020\/han00432.asp"},{"key":"zoi241581r25","unstructured":"Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). Centers for Disease Control and Prevention. October 4, 2023. Accessed January 25, 2024. https:\/\/www.cdc.gov\/mis\/hcp\/case-definition-reporting\/index.html"},{"key":"zoi241581r37","unstructured":"Urgent need to increase immunization coverage for influenza, COVID-19, and RSV and use of authorized\/approved therapeutics in the setting of increased respiratory disease activity during the 2023\u20132024 winter season. Centers for Disease Control and Prevention. December 14, 2023. Accessed January 25, 2024. https:\/\/emergency.cdc.gov\/han\/2023\/han00503.asp"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2829663\/ma_2025_oi_241581_1737490243.88691.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T16:00:53Z","timestamp":1738080053000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2829663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,28]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,2]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.56272","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,28]]}}}