key: cord-0874345-t6t5aeqv
authors: Derespina, Kim R.; Kaushik, Shubhi; Plichta, Anna; Conway, Edward E.; Bercow, Asher; Choi, Jaeun; Eisenberg, Ruth; Gillen, Jennifer; Sen, Anita I.; Hennigan, Claire M.; Zerihun, Lillian M.; Doymaz, Sule; Keenaghan, Michael A.; Jarrin, Stephanie; Oulds, Franscene; Gupta, Manoj; Pierre, Louisdon; Grageda, Melissa; Ushay, H. Michael; Nadkarni, Vinay M.; Agus, Michael S.D.; Medar, Shivanand S.
title: Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with COVID-19 in New York City
date: 2020-07-16
journal: J Pediatr
DOI: 10.1016/j.jpeds.2020.07.039
sha: 45d1b5f14a29a1028d7a343128d71c3658c945f7
doc_id: 874345
cord_uid: t6t5aeqv

OBJECTIVES: To describe the clinical manifestations and outcomes of critically ill children with coronavirus disease-19 (COVID-19) in New York City. STUDY DESIGN: Retrospective observational study of children 1 month to 21 years admitted March 14 to May 2, 2020 to 9 New York City pediatric intensive care units (PICUs) with SARS-CoV-2 infection. RESULTS: Of 70 children admitted to PICUs: median age 15 [IQR 9, 19] years; 61.4% male; 38.6% Hispanic; 32.9% Black; 74.3% with comorbidities. Fever (72.9%) and cough (71.4%) were the common presenting symptoms. Twelve patients (17%) met severe sepsis criteria; 14 (20%) required vasopressor support; 21 (30%) developed acute respiratory distress syndrome (ARDS); 9 (12.9%) met acute kidney injury criteria; 1 (1.4%) required renal replacement therapy, and 2 (2.8%) had cardiac arrest. For treatment, 27 (38.6%) patients received hydroxychloroquine; 13 (18.6%) remdesivir; 23 (32.9%) corticosteroids; 3 (4.3%) tocilizumab; 1 (1.4%) anakinra; no patient was given immunoglobulin or convalescent plasma. Forty-nine (70%) patients required respiratory support: 14 (20.0%) non-invasive mechanical ventilation, 20 (28.6%) invasive mechanical ventilation (IMV), 7 (10%) prone position, 2 (2.8%) inhaled nitric oxide, and 1 (1.4%) extracorporeal membrane oxygenation. Nine (45%) of the 20 patients requiring IMV were extubated by day 14 with median IMV duration of 218 [IQR 79, 310.4] hours. Presence of ARDS was significantly associated with duration of PICU and hospital stay, and lower probability of PICU and hospital discharge at hospital day 14 (P < .05 for all). CONCLUSIONS: Critically ill children with COVID-19 predominantly are adolescents, have comorbidities, and require some form of respiratory support. The presence of ARDS is significantly associated with prolonged PICU and hospital stay.

As the novel coronavirus disease 2019 pandemic began in December 2019, children were reported to be at lower risk of developing severe symptoms or critical illness compared with adults with a large study from China demonstrating critical illness in <1% of children. (1, 2) Preliminary studies from Europe and the United States have provided early data on critically ill children. (3) (4) (5) (6) (7) The clinical manifestations, including pulmonary findings, and outcomes of critically ill children with confirmed SARS-CoV-2 infection have been described only in a small number of cases, and the factors associated with development of progressive critical illness and mortality are unclear.

The objectives of this study are to describe the clinical manifestations of critically ill children with COVID-19 admitted in PICUs across New York City during the first wave of the U.S. pandemic, and to identify factors associated with pediatric intensive care unit (PICU) and hospital length of stay.

The Albert Einstein College of Medicine Institutional Review Board reviewed and approved this multicenter retrospective observational study. The institutional review boards at each individual center approved this study, as applicable. Only deidentified data were transmitted and analyzed. Informed consent was waived.

We identified critically ill pediatric patients 1 month to 21 years of age with confirmed SARS-CoV-2 infection from March 14 to May 2, 2020 (7 weeks) admitted to nine New York City Laboratory; Roche). Patients with the more recently recognized entity of multisystem inflammatory syndrome in children (MIS-C) were not represented in this study because the description was defined, and cases began to occur after the study time period.

Data from each institution's electronic medical record were obtained through a research form in Research Electronic Data Capture software (REDCap, Vanderbilt University). Demographic and clinical data and laboratory and radiologic results were obtained. All tests and treatments were performed at the discretion of the treating physicians.

A total of 31 of the 70 patients described in this study were included in other published reports, including three patients who met criteria the Centers for Disease Control use definition for multisystem inflammatory syndrome (MIS-C). (5, 6, 8, 9, 10) Definitions ARDS was defined using Pediatric Acute Respiratory Distress (PARDS) criteria (11): oxygenation index (OI) 4-8 or oxygen saturation index (OSI) 5-7.5 as mild severity ARDS, OI 8-16 or OSI 7.5-12.3 as moderate severity ARDS, and OI >16 or OSI >12.5 as severe ARDS. Management of ARDS was at the discretion of the treating physician and generally was based on PARDS recommendations of low tidal volume and limiting plateau pressure to ≤ 30 cm of water. (11, 12) Acute kidney injury (AKI) was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) classification based upon a change in serum creatinine level and creatinine clearance. (13) Sepsis, severe sepsis, and septic shock were defined using the Pediatric Surviving Sepsis Guidelines. (14) Virus-associated sepsis was defined as the presence of ≥2 systemic inflammatory syndrome (SIRS) criteria; severe sepsis as sepsis with organ dysfunction or tissue hypoperfusion, and septic shock as severe sepsis with volume-refractory hypotension. (14) Obesity was considered a comorbidity and was defined as body mass index (BMI) >30 kg/m 2 . Asthma was considered a respiratory comorbidity. Severity of illness was described using Pediatric Index of Mortality-2 (PIM-2) scores, and standardized mortality ratio (SMR) was calculated as standardized mortality ratio = observed mortality of our cohort/expected mortality using PIM-2 score. (15) Outcomes Outcomes reported included need for invasive mechanical ventilation, PICU length of stay (PICU LOS), hospital length of stay (HLOS), and mortality within the first 14 days and 28 days of PICU admission.

Demographic and clinical characteristics were summarized as frequencies and percentages for categorical variables, as medians and interquartile ranges for continuous variables, and compared between patients with and without ARDS by using Chi-squared test or Fisher exact test, and Wilcoxon rank sum test for categorical and continuous variables, respectively. Patients were followed up at 14 days and 28 days from PICU admission, and Kaplan-Meier curves of PICU and hospital LOS were compared in patients with and without ARDS using log-rank tests.

Cox proportional hazards regression was employed to investigate the association of presence of ARDS with PICU and hospital discharges, adjusting for need for mechanical ventilation during PICU stay and platelet count measured on admission day 1 in multivariable analyses. A p-value <0.05 was considered statistically significant. Data were analyzed by using SAS software (version 9.4; SAS Institute Inc, Cary, NC). Demographics and baseline characteristics of the whole cohort as well as for those with and without ARDS are shown in Table I k/µL, p=0.04). Serum levels of C-reactive protein, procalcitonin, lactate, pro-B type natriuretic peptide (pro-BNP), and interleukin-6 (IL-6) were elevated among ARDS patients, but levels were statistically significantly different than non-ARDS patients only for IL-6 (78. 7 On chest radiography, 71% of patients with ARDS had bilateral infiltrates compared with 41% of those without ARDS (p=0.02). Fifteen patients had documented formal echocardiograms performed, of which six had left ventricular dysfunction, and three had right ventricular (RV) dysfunction.

As presented in Table 3 , 57 patients met criteria for sepsis, of which 12 patients met criteria for severe sepsis. Ten of these 12 patients meeting severe sepsis criteria also had ARDS compared (Table 3) . Inhaled nitric oxide was used in 2 patients (2.8%).

One patient (1.4%) was cannulated to venoarterial extracorporeal membrane oxygenation support (VA ECMO) for acute decompensated heart failure in the setting of the previously diagnosed condition of dilated cardiomyopathy. Two patients (2.9%) required cardiopulmonary resuscitation, one of whom survived. Extracorporeal cardiopulmonary resuscitation was not utilized in any center for this cohort of patients.

By hospital day 14, 49 patients (70%) were discharged home; 14 (20%) remain hospitalized in PICU, and 5 (7.1%) remain hospitalized out of the PICU. Two patients (2.9%) died, one after withdrawal of life sustaining therapies associated with end-stage osteosarcoma with extensive pulmonary metastases. The second death occurred in a patient with hemoglobinopathy who suffered from a hypoxic bradycardic arrest without return of spontaneous circulation after cardiopulmonary resuscitation.

By hospital day 28, 55 patients (78.6%) were discharged home; 9 (12.9%) remained hospitalized in PICU, and 4 (5.7%) remained hospitalized out of the PICU. Mortality remained at 2 deaths (2.9%) on hospital day 28. The patient on ECMO remained cannulated on day 28 awaiting cardiac transplant/ ventricular assist device placement. The standardized mortality rate at hospital day 14 and 28 day for our cohort is 3.4, which represents 3.4 times excess mortality than that predicted by the PIM-2 score.

The presence of ARDS was associated with significantly longer PICU and hospital duration of stay (both p<0.0001, Figure 3 , A and B [available at www.jpeds.com]). In a multivariable analysis of time to discharge, ARDS (but not race or comorbidity) was independently associated with lower probability of PICU and hospital discharge (p=0.001 for both) and Black/Latino race was associated with higher probability of hospital discharge by day 28 (p=0.04) ( Table 4 and Table   5 ).

In this study, we describe clinical manifestations of critically ill children with COVID-19 disease admitted to PICUs in New York City, the epicenter of the COVID-19 pandemic in the United

States. This study adds to the growing literature on critical illness and outcomes in children with COVID-19, especially that associated with ARDS.

The exact PICU admission rate in children with COVID-19 remains unknown, with prior reports ranging from 1.3% to 28.2%. (1, 5, 7, 13 7) Although some of these studies show a higher rate of critical illness than previously reported, detailed clinical characteristics and multicenter longitudinal outcomes were not reported.

Our study focused on multiple PICUs in the catchment area that includes all of NYC, the epicenter of the COVID-19 pandemic in the US. A prior report was only from one of 25 PICUs in NYC (6) . Although our cohort represents approximately 46% of PICU beds, the proportion of critically ill children represented by our cohort is substantially higher because multiple hospitals' PICU beds were re-purposed to accommodate critically ill adults during the pandemic surge. Similarly, a report from China which did not include the epicenter of Wuhan (2) underestimated the presence of critical illness in children compared with studies from Wuhan, the Chinese epicenter. (1) Studies that do not emanate from an epicenter may not represent the experience of a city consumed by pandemic infection. In addition, we report comprehensive details of ventilatory support and oxygenation markers, with concurrent standard scoring of patient criteria for severe sepsis (14) , ARDS (11, 12) , and AKI (13).

Compared with previous reports, we provide comprehensive details of patients' multiorgan 13 involvement, longer enrollment duration (7 weeks vs. 2 weeks), and longer outcome follow up (14 and 28 days vs. 8 days).

The median age in our cohort was 15 years, different from early reports that suggested infants and preschool-aged children may be at higher risk of critical illness with COVID-19 infection (1), but similar to a more recent cross-sectional point-prevalence report from North America. (6) Similar to previous findings (5) , approximately 50% of our critically ill patients reported no known sick contact, indicating a high rate of community spread, which may be explained partially by the high population density of New York City. (17) There was no difference in the median PIM-2 scores in patients with and without ARDS with a median risk of expected mortality of 0.8%. The overall cohort mortality of 2.8% (all in patients with ARDS) is higher than that expected by the PIM-2 scores. In addition, patients with ARDS had significantly higher prevalence of severe sepsis and required higher levels of respiratory and hemodynamic support.

One of the known risk factors for the development of critical illness in adults is the presence of comorbidities. (18-21) A high percentage (74%) of our cohort of critically ill children had at least one comorbidity, consistent with data from both pediatric and adult studies. (5, 6, (17) (18) (19) (20) Despite the presence of significant comorbidities, however, these comorbidities were not associated with ARDS in our cohort.

ARDS is reported to occur in 2-3% of critically ill children (22) and in 17% of critically ill children with viral infections. (23) We found a 30% ARDS prevalence in our COVID-19 cohort, which is substantially higher. When COVID-19 patients develop ARDS, their intubation rates (86% in our study) are higher than that for other viral infection. One possible reason for a higher intubation rate is the early recommendation to limit use of non-invasive ventilation and to consider early intubation of COVID-19 patients in an attempt to limit aerosolization of the virus. (24, 25) In patients who required mechanical ventilation, a lung-protective strategy of using a low tidal volume and limiting the plateau pressure as recommended by Pediatric Acute Lung Injury Consensus Conference (PALICC) (11) seem to be effective in COVID-19 ARDS. The moderate median PEEP of 9.5 cm of water in our cohort is similar to that reported by Grasselli et al (18) Reassuringly, our observed discharge rate (70% by 14 days and 78.6% by 28 days) is higher than that reported in adults. (18) (19) (20) (21) Those with ARDS, however, had longer PICU and hospital lengths of stay compared with those without ARDS.

Our cohort had mortality rates similar to other pediatric studies (5,6) but lower than that reported in adults. (18-21) However, our 3.5-fold excess standardized mortality of COVID-19 patients is noteworthy. Whether excess mortality ratio is truly related to COVID-19 or is rather an artifact due to low patient numbers or a reflection of sociodemographic factors of New York City is not clear and may be clarified by future large multicenter studies. This early mortality rate of 2.9% in our cohort, however, must be considered in the context of 18.6% of our patients still remaining hospitalized at day 28 and 38.9% of children with ARDS still receiving invasive ventilatory support at day 28.

This study has the limitations of being a retrospective study of a relatively small sample size.

Our results may not be applicable to other parts of the country and world, considering the unique demographics of New York City. Additionally, this study had not been designed to *Chi-squared test, Fisher exact test, or Wilcoxon rank-sum test **7 patients did not reach 28 days from PICU admission as they were discharged prior to this benchmark. 

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Positive End-Expiratory Pressure Lower Than the ARDS Network Protocol Is Associated with Higher ARDS: acute respiratory distress syndrome; IQR: interquartile range; no.: number; BMI: body mass index; PIM-2: Pediatric Index of Mortality 2 score; Temp: temperature; ( o C): degree Celsius; HR: heart rate; bpm: beats per minute; SBP: systolic blood pressure; mm Hg: millimeters of mercury; DBP: diastolic blood pressure; RR: respiratory rate; bpm: breaths per minute

We thank the multidisciplinary teams for their expert care of these patients, particularly the divisions of Pediatric Infectious Disease, Pediatric Rheumatology, Pediatric Hematology, Pediatric Hospital Medicine, and Pediatric Cardiology at the participating institutions.