key: cord-0883467-2ljsxyf2
authors: Capone, Christine A.; Subramony, Anupama; Sweberg, Todd; Schneider, James; Shah, Sareen; Rubin, Lorry; Schleien, Charles; Epstein, Shilpi; Johnson, Jennifer C.; Kessel, Aaron; Misra, Nila; Mitchell, Elizabeth; Palumbo, Nancy; Rajan, Sujatha; Rocker, Josh; Williamson, Kristy; Davidson, Karina W.
title: Characteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection
date: 2020-06-14
journal: J Pediatr
DOI: 10.1016/j.jpeds.2020.06.044
sha: 21123bd1eb0e964517f761295169bf4b1631c580
doc_id: 883467
cord_uid: 2ljsxyf2

nan

We report on the presentation and course of 33 children with multisystem inflammatory syndrome in children (MIS-C) and confirmed SARS-CoV-2 infection.

Hemodynamic instability and cardiac dysfunction were prominent findings, with most patients exhibiting rapid resolution following anti-inflammatory therapy. issued a different case definition. (5, 6) The objective of this report is to describe a large cohort of this COVID-19-related inflammatory syndrome, focusing on clinical manifestations, disease severity, therapeutic interventions, and early outcomes.

This case series was approved by the Northwell Health Institutional Review Board. No case included in this report has been published previously in the medical literature, or as part of a multicenter registry. This is a single-center retrospective study of pediatric patients admitted to Cohen Children's Medical Center, located in New Hyde Park in Queens, NY. New York state has been the epicenter of COVID-19 in the United States and the borough of Queens (Queens County) has had the highest number of cases of COVID-19 of any county in New York state (6a) All sequentially hospitalized febrile patients from April 17, 2020 through May 13, 2020 with fever and an inflammatory illness that met the CDC case definition for MIS-C were included.(5) Importantly, all cases were required to have a positive test for SARS-CoV-2 by detection of serum antibodies or nucleic acid from a nasopharyngeal specimen.

Patients with COVID-like lower respiratory tract involvement were excluded.

Data were collected from the enterprise electronic health record (Sunrise Clinical Manager, Allscripts, Chicago, IL), and all analyses were performed using Excel (Office Professional +13, Microsoft, Seattle, WA). Data included patient demographic information, presenting symptoms, respiratory support requirements, use of vasoactive medications, and initial laboratory and other test results, including markers of inflammation and cardiac function. Acute kidney injury (AKI) was defined by KDIGO criteria(7) and liver dysfunction was defined as an ALT of >80.

Left ventricular (LV) dysfunction was defined as a LV ejection fraction (LVEF) of < 55% based on Boston Z-scores; mild dysfunction was defined as LVEF, 45-54% (Zscore -2.0 to -4.0), moderate, 35-44% (Z-score -4.0 to -6.0), and severe, <35% (Z-score < -6.0). Aneurysm and dilation of a coronary artery (right coronary artery [RCA] and/or left anterior descending [LAD]) artery were defined by a Z-score ≥ 2.5 and 2.0 to 2.49, respectively. (8) Continuous variables were summarized using median and interquartile range and categorical variables using frequency.

We identified 33 patients who met CDC (5) (Table) . Most patients were previously healthy with the exception of a high proportion of patients who were overweight (2,6%) or obese (12, 39%) . This compares to our general in-hospital population (2019 data) of 71% non-Hispanic, and by race, 37% white, non-Hispanic, 21% Black non-Hispanic,15% Asian, and 24% Other. Our region has a childhood obesity rate of 18%. Patients presented with a median of 4 days (4, IQR 3-5) of fever and almost all (32, 97%) had gastrointestinal symptoms as well as involvement of other organ systems. In the total cohort, 21 (64%) had symptoms and signs fulfilling complete criteria for KD. The majority of patients with complete KD criteria had shock (16, 76%).

Results of tests of inflammation were markedly elevated (Table) . All patients had evidence of SARS-Co-2 infection including a positive serology in 30 patients; the remaining 3 came to attention prior to availability of serology testing, but had detection of viral nucleic acid. Blood cultures were negative in all patients; multiplex nucleic acid amplification test for multiple respiratory pathogens was negative in all patients with the exception of 1 patient who had influenza virus detected. During hospitalization, 26 (79%) patients required intensive level of care and 6 (18%) required mechanical ventilation.

Hemodynamic dysfunction was common with 58% having myocardial dysfunction and 76% requiring vasoactive medications. Coronary artery aneurysm and dilation were detected in 5 (15%) and 3 (9%) patients, respectively. All patients received IVIG, 88% received aspirin, and 70% received a corticosteroid. After incomplete response to these initial therapies, 24% received therapy with a biologic modifying medication. Most patients exhibited rapid clinical improvement. There were no deaths and median length of hospital stay was 4 days (IQR 4, 8). At the time of hospital discharge, mild cardiac dysfunction was still present in 9 of 19 patients who had impaired function during hospitalization.

In this report we describe 33 cases of a newly recognized inflammatory syndrome in a single U.S. children's medical center that exhibit some clinical and laboratory features of KD and appear to be related to antecedent COVID-19.(9) The association with COVID-19 is supported by two lines of evidence ) -all cases had COVID-19 as evidenced by the detection of SARS-CoV-2 serum antibodies or SARS-CoV-2 nasal RNA, and the onset and peak occurrence of cases followed the peak in the number of children with COVID-19 admitted to the same hospital by approximately 3 and 5.5 weeks, respectively (Figure) . The latent period between the peak of pediatric cases of COVID-19 and MIS-C suggests that MIS-C has a post-infectious, possibly immunologically mediated pathogenesis. (9, 10) Our case series shares many similarities with the smaller international case series reported as Kawasaki-like disease from Italy (3) None of the patients in our cohort developed a recognized thrombotic event such as a pulmonary embolus or stroke. Hypercoagulability has been widely reported in adults with COVID-19(15) and patients with Kawasaki disease are at risk for coronary artery thrombosis. Our patients were treated with aspirin as is routine for children with Kawasaki disease; additionally, enoxaparin was administered to patients with significantly elevated d-dimer and fibrinogen, if they had left ventricular dysfunction, coronary artery involvement, or electrocardiographic changes.

A potential limitation of this study is that some patients included in this case series may in fact have had acute COVID-19 with "cytokine storm" rather than MIS-C because of the difficulty in differentiating these clinical entities. However, we attempted to avoid inclusion of patients with acute COVID-19 by limiting included cases to a time period after the peak of acute COVID-19 at our center and excluding patients with lower respiratory tract involvement, a hallmark of acute COVID-19. (16) It is also possible that some pediatric patients diagnosed with acute COVID-19 and cytokine storm may in fact have had MIS-C. Additionally, for clarity in reporting, only cases with confirmed CoV infection were included; 3 additional patients who were hospitalized during the study period and met criteria for MIS-C but did not have a positive SARS-CoV-2 test were not included.

It is likely this newly described inflammatory syndrome is related to recent COVID-19 infection. A large proportion of patients developed shock requiring vasoactive medications, but with supportive intensive care and anti-inflammatory therapy most patients demonstrated a rapid clinical improvement. Further study to elucidate the pathophysiologic basis of MIS-C, to optimize treatment regimens, and to determine sequelae of this syndrome are of paramount importance. 

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(a) Patients with other diagnoses included 1 patient with hemodynamically insignificant VSD and 1 patient with renal tubular acidosis (b) NAA = Nucleic acid amplification (c) Creatinine > 50% increased from baseline or absolute increase of 0.3 mg/dL [7] (d) Vasoactive infusion Score = dopamine (mcg/kg/min) + dobutamine (mcg/kg/min) + 100*epinephrine (mcg/kg/min) + 100*norepinephrine (mcg/kg/min) + 10*milrinone (mcg/kg/min) + 10,000*vasopressin (U/kg/min)