key: cord-0972616-w04drzo2
authors: Riollano‐Cruz, Mariawy; Akkoyun, Esra; Briceno‐Brito, Eudys; Kowalsky, Shanna; Posada, Roberto; Sordillo, Emilia Mia; Tosi, Michael; Trachtman, Rebecca; Paniz‐Mondolfi, Alberto
title: Multisystem Inflammatory Syndrome in Children (MIS‐C) Related to COVID‐19: A New York City Experience
date: 2020-06-25
journal: J Med Virol
DOI: 10.1002/jmv.26224
sha: 8b4eadfbc5624baef5ffc318127ac6732976a247
doc_id: 972616
cord_uid: w04drzo2

In December 2019, the 2019 novel coronavirus disease (COVID‐19) caused by Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) first emerged in Wuhan, China. This has now spread worldwide and was declared a pandemic by March 2020. Initially, the pediatric population was described as low risk for severe COVID‐19. However, reports have emerged recently of cases of COVID‐19 in children with a systemic inflammatory disease, with features that overlap with Kawasaki Disease (KD). We describe the first 15 cases with multi‐system inflammatory syndrome in children (MIS‐C), temporally related to COVID‐19, who presented for care to a tertiary pediatric referral center in New York City. We discuss the disproportionate burden of disease among Hispanic/Latino and black/African‐American ancestry, the distinct cytokine signature across the disease spectrum (IL‐1/IL‐6), and the potential role and pathogenesis of SARS‐CoV‐2 in this new clinical entity. This article is protected by copyright. All rights reserved.

who met criteria, we collected demographic data; past medical history; clinical symptoms; physical examination findings; and results of imaging, cardiac, and laboratory testing performed at presentation and throughout the hospital admission. We also gathered information about complications, outcome, and length of hospital stay.

Initial evaluation at admission included a chest radiograph (CXR) and electrocardiogram (EKG). A trans-thoracic echocardiogram (TTE) was performed if indicated based on EKG results. All patients were evaluated by molecular testing of nasopharyngeal specimens in universal transport media for infections with SARS-CoV-2 (SARS-CoV-2 Test, cobas® 6800 system, RocheDiagnostics) and other respiratory pathogens (FilmArray Respiratory Panel 2, BioMerieux), SARS-CoV-2 antibody assay (COVID-19 Antibody), and cultures of blood and urine. A cytokine panel was performed upon admission to determine interleukin (IL-1β, IL-6, IL-8) and tumor necrosis factor (TNF) levels. Other laboratory evaluation included daily monitoring of the serum inflammatory markers C-reactive protein (CRP) and ferritin; the coagulation parameters prothrombin time, international standardized ratio, and D-dimer; brain natriuretic peptide (BNP), creatinine kinase-MB, troponin I; comprehensive metabolic panels, and a complete blood count with differential leukocyte count.

Patients who met criteria for KD, or who had any evidence of myocardial injury, were treated with high dose intravenous immunoglobulin (IVIG) plus acetylsalicylic acid (ASA). Patients with hemodynamic instability or rapid clinical decompensation also received immunomodulatory therapy with Tocilizumab (monoclonal antibody against IL6) or Anakinra (IL-1 receptor antagonist). Remdesivir was given to patients who met criteria for compassionate use established by the sponsor (Gilead Sciences, Inc).

Between April 24 and May 14, 2020, 15 patients age 3 years to 20 years old (mean 12 years) who presented with suspected MIS-C secondary to SARS-CoV-2 infection were admitted to the Mount Sinai Hospital. The clinical features of these cases at presentation are detailed in Table 2 . Eleven patients (73%) were male and four (27%) female. More than half (10 patients, 66%) identified as Hispanic or Latino, in comparison to 25% of overall pediatric cases admitted to our hospital during the period April 1, 2020 through June 1,

Eleven patients had no known underlying medical conditions; 4 patients had asthma, and one had hypothyroidism and non-alcoholic fatty liver disease. Four patients (27%) reported having an acute febrile or respiratory illness during the 4 weeks preceding hospitalization, and 2 had been previously diagnosed with SARS-CoV-2 infection confirmed by a positive molecular test from a nasopharyngeal swab specimen. Three patients (20%) reported prior contacts with sick household members, one of whom had confirmed SARS-CoV-2 infection.

Symptoms at presentation included fever in all patients. Of note, 13 patients (87%) had gastrointestinal complaints including vomiting, abdominal pain and diarrhea. Respiratory symptoms were less common; only 3 patients complained of cough or dyspnea, and 2 additional patients complained of chest pain. Just under half of the patients presented with some features consistent with KD, including rash in 7 (47%), conjunctivitis in 4 (27%), and swollen hands and feet in 4 (27%) cases. Tachycardia and hypotension were noted in 13 (87%) patients, and 9 (60%) patients required inotropic or vasopressor support.

COVID-19 infection was diagnosed by a positive SARS-CoV-2 PCR test from a nasopharyngeal or lower respiratory specimen during the hospital admission in 7 (47%) patients, or during the month prior to admission in an additional 2 (13%) patients. COVID-recombinant SARS-CoV-2 spike proteins under a Food and Drug Administration Emergency Use Authorization. This assay is able to detect strong signal response specifically from IgG3, IgM, and IgA serum levels. 4

Thirteen patients (87%) showed features of severe cardiac involvement, including an abnormal TTE in 12 (80%) and elevated serum troponin or BNP in 13 (87%). The most common findings are summarized in Table 3 Table 4 ).

Initially, all patients were treated with broad-spectrum antibiotics for possible septic shock and toxic shock syndrome; antibiotics were discontinued if blood cultures were without growth after 48 hours of incubation. Additionally, all patients received prophylactic anticoagulation with Enoxaparin which continued until 2 weeks post-discharge. Only one patient was admitted to the general pediatric ward; 14 patients were admitted to an intensive care unit within 24 hours of presentation.

Three patients (20%) required intubation and mechanical ventilation, and an additional 5 (33%) patients required noninvasive mechanical ventilation. The child who died required extracorporeal membrane oxygenation (ECMO) during the 9 days of admission. Eight (53%) patients needed vasopressor and vasoactive therapy, and one patient required an intra-aortic balloon pump to treat cardiogenic shock.

Twelve (80%) patients received one to three intravenous doses of the anti-interleukin -6 (anti-IL-6) antibody tocilizumab; one of those patients also received SARS-CoV-2 convalescent plasma transfusion. Decision to repeat Tocilizumab was based on persistent elevation of inflammatory markers and hemodynamic instability. Cytokine levels were not trended. Two patients (13%) initially received Anakinra, and 12 (80%) received high dose IVIG. Three (20%) patients were treated with steroids. Two patients (13%) were treated with Remdesivir; one completed 5 days and the other one 9 days of treatment.

Of the initial 15 patients we describe, 9 had gradual normalization of D-dimer, BNP, and troponin levels during admission ( Figure 1 ). Thirteen remained admitted for a range of 6-13 days (mean 8 days) and have had continued improvement in inflammatory parameters upon outpatient follow up. One patient expired on day 9 after admission and one remains admitted.

Until late April 2020, SARS-CoV-2 infection in children was assumed to be asymptomatic or to cause mild febrile illness. Herein, we report 15 pediatric patients with COVID-19 who presented with symptoms suggestive of a multi-system, hyperinflammatory syndrome that shares many characteristics with known systemic inflammatory processes seen in childhood. This new syndrome has been termed multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. Importantly, not all our patients were positive for SARS-CoV-2 by molecular testing of nasopharyngeal specimens. However, all patients were SARS-CoV-2 antibody-positive, suggesting that although this entity is triggered by COVID-19, the hyperinflammatory syndrome seen in these children is likely due to postinfectious cytokine storm, rather than a result of direct cell injury caused by viral replication.

This novel entity appears to share some features with KD, and as in development of KD, infection appears to trigger a dysregulated immune response in genetically predisposed individuals. However, although KD and MIS-C share many similarities, they differ in several important ways. First, the complete clinical picture is distinct, as evidenced by our patients. Less than half of our patients had any symptoms of KD, and none had all of them. Furthermore, our patients had abdominal and cardiac symptoms that were atypical for KD.

Finally, while many patients had evidence of mild coronary artery dilation, despite their severe inflammatory picture none had major coronary artery findings, which would be very unusual in KD. A second important difference is that the profile of cytokines leading to the inflammatory process appears to be distinct in MIS-C and K. In patients with KD, IL-1 appears to be the main mediator of coronary artery inflammation, and IL-1 blockade has been used successfully to treat previously refractory KD cases. 5 In contrast, MIS-C appears to be driven predominantly by IL-6 and IL-8. As in other reports of critically ill COVID-19 cases, for our patients, IL-6 levels were elevated at presentation in all cases, in contrast to levels of IL-1, which were within the reference range.

The discordance between IL-1 and IL-6 levels is noteworthy, since for many infectious and inflammatory processes, production of IL-1 and IL-6 are linked. Several viruses have been shown to be able to increase IL-6 levels directly, either by enhanced IL-6 mRNA transcription, or by stabilization of IL-6 mRNA 6 . Also of note, the spike protein from a related virus identified in 2003, SARS-CoV, has been shown to induce increased IL-6 levels in murine macrophage and lung epithelial cell cultures 7, 8 . The efficacy of early determination of cytokine levels, particularly IL-6, and administration of specific antibody when indicated, in management of critically ill COVID-19 patients, has been reported for adults, and more recently for children, is consistent with our experience. 

The authors declare no conflicts of interest

Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units

Health alert #16: updated reporting for multisystem inflammatory syndrome in children associated with COVID-19

A serological assay to detect SARS-CoV-2 seroconversion in humans

IL-1 inhibition may have an important role in treating refractory Kawasaki disease

IL-6 in inflammation, immunity, and disease

Up-regulation of IL-6 and TNF-alpha induced by SARScoronavirus spike protein in murine macrophages via NF-kappaB pathway

Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells

A child with severe multi-system inflammatory syndrome following an asymptomatic COVID-19 infection: a novel management for a new disease

Endothelial cell infection and endotheliitis in COVID-19