Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program

Abstract

Background: Multi-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. Methods: We conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. Findings: We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44.4%) were aged between 5-11 years, with a male predominance (61.0%), and non-Hispanic white ethnicity (40.2%). Most (67.8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72.5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51.1% of children early in the pandemic, which decreased to 33.9% from the pre-delta period to the omicron period. Interpretation: MIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time.

Changes in Treatment and Severity of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program

“…This study suggests a decrease in the severity of MIS-C during the months of January through mid-July 2022 compared to prior years of the pandemic. For three of the four laboratory results identified a priori as important indicators of MIS-C severity (i.e., troponin, platelets, and lymphocytes), 15,16 the percentage of children with abnormal results declined across the three time periods examined in the study. These results suggest that the observed changes in treatment patterns were not solely attributable to evolving clinical guidelines or preferences for the management of MIS-C.…”

“…Finally, MIS-C diagnosis in this study was based on diagnoses in EHR rather than institutional registries of confirmed cases. This aspect of the study precludes the ability to confirm that all children with MIS-C met the CDC criteria for MIS-C, 4 but it allows the capture of cases that may represent milder subphenotypes of MIS-C that do not meet all CDC criteria 16,31 and/or cases that may not have been reported in institutional registries.…”

“…Of the eight laboratory measurements included in the study, troponin, platelets, lymphocytes, and creatinine were considered the most relevant because they have been identified as important indicators of MIS-C severity. 15,16…”

“…Of the eight laboratory measurements included in the study, troponin, platelets, lymphocytes, and creatinine were considered the most relevant because they have been identified as important indicators of MIS-C severity. 15,16 Descriptive statistics for the variables of interest were computed using R 4.1.2 17 for the cohort overall and separately according to three time periods of cohort entry based on the emergence of coronavirus variants in the United States: 18 March 1, 2020 -May 31, 2021 (pre-Delta); June 1 -December 31, 2021 (primarily Delta); January 1 -July 20, 2022 (primarily Omicron). We calculated the percentage of children that received each treatment at any time from 7 days prior to 30 days after the MIS-C diagnosis.…”

Multisystem Inflammatory Syndrome in Children (MIS-C)

“…MIS-C is new, so the factors that cause a child to evolve from mild-to-severe disease with cardiovascular involvement are still unknown. It is likely that laboratory tests that show a greater range of general inflammation are more frequently present in cases that are going to evolve to severe (3.2 laboratory tests); however, the severity of the disease is determined by cardiovascular involvement and presence of shock rather than by the results of laboratory tests [49]. What has been seen is that there are phenotypes resulting from associations combining the severity of the clinical presentation, the KD criteria, and the presence of shock.…”