key: cord-0921939-43a8xhup
authors: Miller, Allison D; Zambrano, Laura D; Yousaf, Anna R; Abrams, Joseph Y; Meng, Lu; Wu, Michael J; Melgar, Michael; Oster, Matthew E; Godfred Cato, Shana E; Belay, Ermias D; Campbell, Angela P
title: Multisystem Inflammatory Syndrome in Children—United States, February 2020–July 2021
date: 2021-12-05
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab1007
sha: 3f11fa5a57f32acade01e55dbddd738895f87c7a
doc_id: 921939
cord_uid: 43a8xhup

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition in persons aged <21 years associated with antecedent SARS-CoV-2 infection. Our objective was to describe MIS-C cases reported to CDC’s national surveillance since the COVID-19 pandemic began. METHODS: We included patients meeting the MIS-C case definition with onset date from February 19, 2020 through July 31, 2021, using CDC’s MIS-C case report form, which collects information on demographics, clinical presentation, and laboratory results. Trends over time across 3 MIS-C pandemic waves were assessed using Cochran-Armitage test for categorical and Jonckheere-Terpstra test for continuous variables. RESULTS: Of 4,901 reported cases, 4,470 met inclusion criteria. Median patient age increased over time (P<0.001), with a median of 9 years (interquartile range, 5–13 years) during the most recent (third) wave. Male predominance also increased (62% in third wave, P<0.001). A significant (P<0.001) increase in severe hematologic and gastrointestinal involvement was observed across the study period. Frequency of several cardiovascular complications (i.e., cardiac dysfunction, myocarditis, and shock/ vasopressor receipt) and renal failure declined (P<0.001). Provision of critical care including mechanical ventilation (P<0.001) and extracorporeal membrane oxygenation (ECMO; P=0.046) decreased, as did duration of hospitalization and mortality (each P<0.001). CONCLUSIONS: Over the first 3 pandemic waves of MIS-C in the United States, cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time. These data serve as a baseline for monitoring future trends associated with SARS-CoV-2 B.1.617.2 (Delta) or other variants and increased COVID-19 vaccination among children.

A c c e p t e d M a n u s c r i p t 4 transmissible SARS-CoV-2 variants including the B.1.617.2 (Delta) variant, which comprised <15% of circulating variants as of June 5, 2021 , and rose to >95% by July 31, 2021 [19, 20] .

In this analysis we summarize over 4,000 MIS-C cases reported to CDC's national surveillance since the start of the COVID-19 pandemic; cases reported through January 2021 have been summarized previously [13] . This period represents surveillance prior to and including the first months of authorization and recommendation for vaccination for persons aged ≥12 years. We present patient characteristics, detailed clinical and radiologic features, illness management, and clinical outcomes by each of the three waves of MIS-C over the study period.

Local, state, and territorial health departments reported cases using a standardized case report form based on medical chart abstractions performed by clinicians, hospital staff, or health department staff (Supplement 1). Patients' illnesses were evaluated to confirm they met the CDC MIS-C case definition: 1) clinically severe illness requiring hospitalization in persons aged <21 years, 2) fever ≥38°C for ≥24 hours or report of subjective fever for ≥24 hours, 3) laboratory evidence of inflammation, 4) multisystem (≥2) organ involvement, 5) laboratory evidence of acute or previous SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serology, or antigen test, or known COVID-19 exposure within 4 weeks of symptom onset, and 6) no alternative plausible diagnosis [21] .

Information collected included patient demographics, clinical manifestations, complications, illness management, imaging studies, laboratory test results, outcomes, and vaccination status (added to case report form May 21, 2021).

To account for delays in reporting and maximize data completeness, we included patients with an MIS-C onset date on or before July 31, 2021 who were reported on or before August 18, 2021. Patients with known SARS-CoV-2 exposure without subsequent laboratory confirmation of infection were excluded from this analysis because of concerns about potential misclassification. We performed A c c e p t e d M a n u s c r i p t 5 clinical review of free-text responses and supplemented patient comorbidities by classifying into available categorical variables or, for obesity, calculated body mass index using national reference standards for those with available height, weight, sex, and age information [22] . Race and ethnicity data were obtained from medical records as documented at time of hospitalization and categorized in accordance with previously established methods as missing race and ethnicity data accounted for 5.8% of patients in our cohort [23] .

To assess case characteristics and outcomes over time, we reviewed the epidemic curve of MIS-C illness onset dates. If onset date was unavailable, fever onset or hospitalization admission date was used as a proxy. We identified three peaks of reported MIS-C cases and two nadirs (Figure 1) . We defined the three time periods or "waves" of MIS-C activity in the pandemic with respect to timing of MIS-C symptom onset dates among cases to (1) February 19 through June 28, 2020, (2) June 29 through October 17, 2020, and (3) October 18, 2020 through July 31, 2021. Geographic regions were categorized in accordance with the four US census regions [24] . Intensive care unit (ICU) admission was defined as having a documented date of ICU admission or known length of ICU stay or having received ICU-level care, including mechanical ventilation, vasopressor support, or extracorporeal membranous oxygenation (ECMO). We defined values for lymphopenia and thrombocytopenia using age standards [25] . We adapted previously established frameworks to describe severe organ-system involvement (Supplement 2) [1, 26] . We performed clinical review and supplemented radiographic findings using free-text responses when available. Analyses of laboratory markers of inflammation were performed only on those with available data collected in section 6 of the case report form (Supplement 1).

Using SAS version 9.4 (SAS Institute, Cary, NC) we calculated the frequency of clinical features, relevant laboratory findings, and treatments among patients stratified by wave of MIS-C onset.

Continuous variables were expressed as medians and interquartile ranges (IQRs); trends in median A c c e p t e d M a n u s c r i p t 6 values over time were assessed through the Jonckheere-Terpstra test. Categorical variables were expressed as counts and percentages; trends over time were assessed through the Cochran-Armitage test. Two-sided P values were considered significant at α<0.05. This activity was reviewed by CDC, was determined to meet the requirements of public health surveillance and was conducted in consistence with applicable federal law and CDC policy (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq) [27, 28] .

Out of 4,901 total patients reported with suspected MIS-C, we excluded 249 patients who did not meet the case definition, 87 with missing illness onset date or onset after the study period, and 95 who otherwise met clinical criteria of the CDC case definition but who lacked laboratory evidence of SARS-CoV-2 infection (Supplements 3 and 4) . The 4,470 included cases were reported from 49 state health departments, the District of Columbia, New York City, and Puerto Rico. Median patient age for the overall cohort of MIS-C patients was 9 years ([IQR], 5-13 years); 59.9% were male ( Table 1) . Of patients with complete race and ethnicity information, 31.1% were non-Hispanic Black, 30.6% Hispanic/Latino, and 28.9% non-Hispanic White. Underlying medical conditions were reported for 37.6%

of MIS-C patients; obesity (25.1%) and chronic lung disease including asthma (9.6%) were most frequent among all MIS-C patients.

All patients with MIS-C had reported fever as indicated by the case definition. The median reported duration of fever was 5 days (IQR: 4-7 days). The most common additional signs and symptoms included abdominal pain (68.5%), vomiting (66.6%), rash (55.2%), conjunctival injection (55.4%), diarrhea (53.8%), and hypotension (51.7%) ( Table 2) . Seventy-four percent of MIS-C patients reported mucocutaneous involvement (e.g., skin rash, mucocutaneous lesions, and/or conjunctivitis). including acute kidney injury (19.0%), renal failure (3.3%) and receipt of dialysis (0.9%), and severe neurologic complications (8.5%), including meningitis (5.3%), encephalopathy (4.0%), and stroke (0.6%), were rare ( Table 2) .

Most MIS-C patients underwent radiography including echocardiography (94%) and chest X-ray or computed tomography (71%), and 42% underwent abdominal imaging. Over half of those for whom these radiographic studies were performed had abnormal findings, including 59% of those who underwent echocardiography, 55% of those who underwent chest imaging, and 61% of those who Table 2) .

Vaccination status was reported for 4% of MIS-C patients, only 0.4% of whom were vaccinated.

There were three defined waves of MIS-C illness, with most cases (68.3%) occurring during the third wave, compared with the first (17.2%) and second (14.5%) (Table 1; Figure 1 ). By region, the Northeast had the highest proportion of cases in the first wave (52.2%) followed by a significant decrease over the remaining waves (P<0.001) ( Table 1) . By the third wave, cases were spread similarly across the Midwest (26%), South (32%), and West (27%), whereas the Northeast reported only 14% of cases.

The proportion of patients aged 12-15 years significantly increased over time (P<0.001) ( Table   1 ). The proportion of males and of patients who were non-Hispanic White increased significantly with successive waves (P <0.001 for each), and were 62% and 35%, respectively, by the third wave. The proportion of MIS-C patients with each reported underlying medical condition did not differ significantly over time. A c c e p t e d M a n u s c r i p t 9 The proportion of those with severe respiratory complications peaked during the second wave, with pneumonia, pleural effusion, and acute respiratory distress syndrome the highest in the second wave (31%, 26%, and 8%, respectively). However, the proportion of patients receiving invasive mechanical ventilation trended downward over the study period (P<0.001) ( Table 2) . 

This study describes the largest cohort of MIS-C patients to date, including patients from nearly all reporting jurisdictions within the United States since MIS-C national surveillance began. MIS-C is an important complication of COVID-19 in children, with half of reported cases occurring among children aged 5-13 years. Over half of MIS-C patients were of Hispanic ethnicity or Black race, particularly in the first two MIS-C waves, similar to findings from previous studies [11, [29] [30] [31] . The proportion of non-M a n u s c r i p t 10 Hispanic White patients significantly increased over the course of the pandemic; similar racial and ethnic trends have been described in studies of hospitalized COVID-19 patients, which suggest that increased COVID-19 incidence among White persons and regional and temporal patterns may be contributors [32, 33] . Further investigation into the impact of spatiotemporal trends on the racial and ethnic distribution of MIS-C patients over time is warranted given these findings. The proportion of cases with cardiac dysfunction and myocarditis, conditions associated with severe outcomes of MIS-C [3] , declined after the first wave. The duration of hospitalization and death also significantly decreased over time; these decreases in case fatality were previously described [26] . M a n u s c r i p t 20 Abbreviations: ICU = intensive care unit; IVIG = intravenous immune globulin *Represents significance using Cochran-Armitage test for trend across the three waves (P<0.001).

Note: p-Values for immune modulators (P=0.513) and ICU admission (P=0.056) were not significant using Cochran-Armitage test for trend across the three waves. A c c e p t e d M a n u s c r i p t 29 Figure 3 

Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19

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A c c e p t e d M a n u s c r i p t 17 5 (4-8) <.001 ICU admission, days, median (IQR) u 4 (2-6) 5 (3-7) 4 (2-6) 3 (2-5) <.001Abbreviations: BNP = brain natriuretic peptide; ICU = intensive care unit; IL-6 = Interleukin 6; IQR = interquartile range; NT-proBNP = N-terminal pro b-type natriuretic peptide; RT-PCR = reverse transcription polymerase chain reaction