{'fraction_non_alphanumeric': 0.03552846737029879, 'fraction_numerical': 0.021852237252861603, 'mean_word_length': 5.237830319888734, 'pattern_counts': {'":': 0, '<': 6, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City

Objective To assess clinical characteristics and outcomes of severe acute respiratory syndrome coronavirus 2-associated multisystem inflammatory syndrome in children (MIS-C). Study design Children with MIS-C admitted to pediatric intensive care units in New York City between April 23 and May 23, 2020, were included. Demographic and clinical data were collected. Results Of 33 children with MIS-C, the median age was 10 years; 61% were male; 45% were Hispanic/Latino; and 39% were black. Comorbidities were present in 45%. Fever (93%) and vomiting (69%) were the most common presenting symptoms. Depressed left ventricular ejection fraction was found in 63% of patients with median ejection fraction of 46.6% (IQR, 39.5-52.8). C-reactive protein, procalcitonin, d-dimer, and pro-B-type natriuretic peptide levels were elevated in all patients. For treatment, intravenous immunoglobulin was used in 18 (54%), corticosteroids in 17 (51%), tocilizumab in 12 (36%), remdesivir in 7 (21%), vasopressors in 17 (51%), mechanical ventilation in 5 (15%), extracorporeal membrane oxygenation in 1 (3%), and intra-aortic balloon pump in 1 (3%). The left ventricular ejection fraction normalized in 95% of those with a depressed ejection fraction. All patients were discharged home with median duration of pediatric intensive care unit stay of 4.7 days (IQR, 4-8 days) and a hospital stay of 7.8 days (IQR, 6.0-10.1 days). One patient (3%) died after withdrawal of care secondary to stroke while on extracorporeal membrane oxygenation. Conclusions Critically ill children with coronavirus disease-2019-associated MIS-C have a spectrum of severity broader than described previously but still require careful supportive intensive care. Rapid, complete clinical and myocardial recovery was almost universal.


COVID-19
Coronavirus ORIGINAL ARTICLES multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 and introduced a case definition. 8 The detailed clinical profile, therapies, interventions, and outcomes in children from the US with MIS-C are lacking. We report a multicenter cohort of children with COVID-19-associated MIS-C from the epicenter of COVID-19 in New York City, describing the spectrum of clinical presentation, hospital course, therapies, and outcomes.

Methods
This is a retrospective observational study of pediatric patients (aged 1 month to 21 years) with a confirmed infection with SARS-CoV-2 who meet criteria for MIS-C admitted from April 23 to May 23, 2020, to 3 New York City tertiary care children's hospitals (Children's Hospital at Montefiore, Mount Sinai Kravis Children's Hospital, and Jacobi Medical Center); the institutional review boards at the 3 institutions have approved this multicenter study. Waiver of informed consent was obtained with only deidentified data transmitted and analyzed. Four patients of the 16 reported from Mount Sinai Kravis Children's Hospital were previously described in a recently published case series. 9 Additionally, some of the patients' data are being reported to an ongoing Society of Critical Care Medicine's national registry-the Discovery Virus Infection and Respiratory Illness Universal Study COVID-19 Registry.

Definitions
A confirmed case of COVID-19 was defined as a positive result from real-time reverse transcription polymerase chain reaction (RT-PCR) testing of a specimen using a nasopharyngeal swab for SARS-CoV-2 or positive SARS-CoV-2 antibody assay. The Centers for Disease Control and Prevention case definition for MIS-C is used to define a confirmed case of MIS-C, which is as follows: an individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic); and no alternative plausible diagnoses; and positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks before the onset of symptoms. 8 There were additional suspected patients with similar symptomatology and management without confirmed SARS-CoV-2 infection/exposure who were not included in this analysis because we strictly intended to include only cases confirmed by positive SARS-CoV-2 RT-PCR or antibody assay.
Depressed left ventricular (LV) function was defined as an LV ejection fraction of <50%, and severely depressed LV function as an LV ejection fraction of <30%.
Demographic, clinical, and outcome data were recorded. Race/ethnicity was identified by documentation in the medical record or by surname for some Latino patients when not documented. Laboratory and radiologic results were recorded as well. All tests and treatments were performed at the discretion of the treating physicians.

Statistical Analyses
Statistics for the study were descriptive with data presented as numbers with percentages and continuous data as median with IQR.
Laboratory test results on admission are presented in Table II.   Table III. Cardiomegaly was present in 10 patients (30%). Focal or bilateral pulmonary opacities were noted in 11 patients (33%). To the best of our knowledge, none of the patients had typical lung disease as described in adults with COVID-19 pneumonia, although none of these patients had a computed tomography scan of the chest performed, limiting this evaluation. Echocardiograms were performed in 32 (97%) patients, of whom 21 (65.6%) had a depressed LV ejection fraction (<50%). Of the patients with depressed LV ejection fraction, 4 (12%) had an ejection fraction of <30%, and 17 (53%) had an ejection fraction between 30% and 50%. Twenty-four patients (72%) had a second echocardiogram performed; 20 of 21 with depressed function (95%) had recovery of ventricular function with normal ejection fraction. Details of patients with depressed systolic function are described in Table IV.
Five patients (15%) required invasive mechanical ventilation. Two patients (6%) required mechanical circulatory support, 1 each by extracorporeal membrane oxygenation (ECMO) and an intra-aortic balloon pump. A 5-year-old with severely depressed LV function and cardiogenic shock was cannulated for venoarterial ECMO within 24 hours of presentation, but developed an ischemic brain infarction  with subarachnoid hemorrhage on day 6 of ECMO. Lifesustaining therapies were withdrawn after neurologic examination consistent with brain death. Support using an intra-aortic balloon pump was used for a 20-year-old male who presented with 3 days of fever, nausea, vomiting, diarrhea, and abdominal pain and was found to have severely depressed LV function. He required inotropic support with epinephrine and dobutamine infusions as well as intubation and mechanical ventilation. Owing to rising serum lactate and troponin levels, he underwent diagnostic cardiac catheterization, which excluded coronary artery stenosis or anatomic abnormality. An intra-aortic balloon pump was inserted with which he was supported for 24 hours. He was treated with methylprednisolone and convalescent plasma. He was weaned off invasive mechanical ventilation by day 3 of hospitalization and was discharged home on day 12. Thirty-two patients were discharged home with a median duration of pediatric intensive care unit (PICU) stay of 4.7 days (IQR, 4-8 days) and hospital stay of 7.8 days (IQR, 6.0-10.1 days). One patient (3%) died after withdrawal of care secondary to hemorrhagic stroke while on ECMO support, as discussed.

Discussion
The clinical profile of COVID-19 MIS-C in our cohort of 33 children was heterogeneous in severity of illness, ranging from clinically stable patients with normal or mildly depressed myocardial function to decompensated circulatory shock requiring invasive mechanical ventilation and mechanical circulatory support.
Possible mechanisms of myocardial involvement are speculative and include direct viral invasion of myocytes and systemic inflammatory response triggering myocyte injury, which can be compounded by myocardial ischemia secondary to hypotension. 10 In the absence of myocardial biopsy, it is difficult to discern the exact mechanism of myocardial involvement, but given elevation of inflammatory markers, absence of strong data on coronaviruses being cardiotropic, occurrence after appearance of CoV antibodies in most patients, and the fact that not all critically ill children with shock developed myocardial dysfunction, it is plausible that the myocardial injury and circulatory shock in COVID-19 is secondary to inflammatory mediators. 11 Based on the positive antibody status and the elevated cytokines, especially IL-6, seen in our cohort, we hypothesize that this novel COVID-19 MIS-C is predominantly an antibody-mediated of other immune cell-mediated cytokine storm, with some contribution from direct myocardial injury. These findings suggest a potential role for both antiviral and immunomodulatory therapies in the treatment of MIS-C. In our cohort, remdesivir, a nucleoside analog that blocks virus replication, was used for patients with active SARS-CoV-2 infection, as evidenced by positive RT-PCR results. 12 However, for the vast majority of patients who have positive antibodies and cytokine storm, as evidenced by elevated inflammatory markers and IL-6 levels, immunomodulatory therapy has been the mainstay of treatment. IVIG or corticosteroids or both were given to most patients for anti-inflammatory and antibody-mediating effects, and tocilizumab, an IL-6 receptor inhibitor, which seems to mediate a significant portion of this cytokine storm and resulting myocardial injury, was used for children with high IL-6 levels. 13,14 The reasons for an exaggerated inflammatory response leading to MIS-C after SARS-CoV-2 infection are unclear, although cytokine-mediated storm has been described with other viral infections, though to a lesser degree. Although initially thought to be SARS-CoV-2-associated Kawasaki disease, emerging data have shown MIS-C to be a separate entity with age as a distinguishing feature. 5 In contrast with the infantile age distribution of Kawasaki disease, MIS-C is predominantly a disease of older children and adolescents, supported by the median age in our cohort of 10 years, which is consistent with other reports of MIS-C. 4,6 Critical illness with COVID-19 in children is infrequent but reported with younger age and comorbidities being risk factors for severe disease. 1,2 In contrast with the European studies, our cohort had lower morbidity with 51% requiring vasopressor support, 15% requiring invasive mechanical ventilation, and only 6% requiring mechanical circulatory support. 4,6 The median LV ejection fraction in our cohort was 44%, which is higher than that reported by Belhadjer et al in a cohort of 35 children in which almost one-third had severely depressed LV systolic function (LV ejection fraction of <30%). 6 The use of inotropic support (80%), mechanical ventilatory (62%), cir-culatory support (28%), therapy with IVIG (71%), and corticosteroids (34%) were all higher in their cohort compared with ours. Expectedly, recovery of LV function was higher in our cohort with 20 of 21 patients (95%) with depressed LV function having recovered LV function at hospital discharge compared with 71% in the report of Belhadjer et al. 6 Recovery of ventricular function on echocardiogram demonstrated a good correlation to normalization of BNP or pro-BNP level in all patients before discharge. It is unclear why children in other reports were of higher acuity, but 1 hypothesis may be related to a better, evolving understanding of this syndrome and its underpinnings.
Although isolated reports have described COVID-19 associated myocarditis in adults, MIS-C seems to be a separate entity; shock and hemodynamic compromise in MIS-C can occur in the absence of laboratory evidence of myocardial inflammation, and with preserved cardiac function and rapid reversibility. 15 The most common agent used for inotropic support was norepinephrine, consistent with management of inflammatory mediator-induced vasoplegic shock. A median vasopressor duration of 72 hours and median PICU stay of 4.6 days provide insight into the clinical courses of these patients, with improvement in the majority of patients by day 4-5 and discharge from the hospital by day 7. The duration of vasopressor support and PICU stay were similar between patients, suggesting that a majority of patients required close hemodynamic monitoring in PICU and that therapies such as respiratory support are required secondary to hemodynamic derangement. Based on PICU and hospital lengths of stay, it appears that inflammatory markers and myocardial function improved by days hospital 4-7.
Further larger multicenter studies are needed to further elucidate the spectrum of disease, risk factors for more severe illness, and response to supportive and medical therapies including IVIG, corticosteroids, biologic modifying agents, and anticoagulation strategies. Long-term follow-up will be required to determine any sequelae of MIS-C on myocardial function. n Submitted for publication Jun 4, 2020; last revision received Jun 9, 2020; accepted Jun 10, 2020.