Search

Objectives: To develop, evaluate, and explore the use of a pediatric ordinal score as a potential clinical trial outcome metric in children hospitalized with acute hypoxic respiratory failure caused by viral respiratory infections., Design: We modified the World Health Organization Clinical Progression Scale for pediatric patients (CPS-Ped) and assigned CPS-Ped at admission, days 2-4, 7, and 14. We identified predictors of clinical improvement (day 14 CPS-Ped ≤ 2 or a three-point decrease) using competing risks regression and compared clinical improvement to hospital length of stay (LOS) and ventilator-free days. We estimated sample sizes (80% power) to detect a 15% clinical improvement., Setting: North American pediatric hospitals., Patients: Three cohorts of pediatric patients with acute hypoxic respiratory failure receiving intensive care: two influenza (pediatric intensive care influenza [PICFLU], n = 263, 31 sites; PICFLU vaccine effectiveness [PICFLU-VE], n = 143, 17 sites) and one COVID-19 ( n = 237, 47 sites)., Interventions: None., Measurements and Main Results: Invasive mechanical ventilation rates were 71.4%, 32.9%, and 37.1% for PICFLU, PICFLU-VE, and COVID-19 with less than 5% mortality for all three cohorts. Maximum CPS-Ped (0 = home at respiratory baseline to 8 = death) was positively associated with hospital LOS ( p < 0.001, all cohorts). Across the three cohorts, many patients' CPS-Ped worsened after admission (39%, 18%, and 49%), with some patients progressing to invasive mechanical ventilation or death (19%, 11%, and 17%). Despite this, greater than 76% of patients across cohorts clinically improved by day 14. Estimated sample sizes per group using CPS-Ped to detect a percentage increase in clinical improvement were feasible (influenza 15%, n = 142; 10%, n = 225; COVID-19, 15% n = 208) compared with mortality ( n > 21,000, all), and ventilator-free days (influenza 15%, n = 167)., Conclusions: The CPS-Ped can be used to describe the time course of illness and threshold for clinical improvement in hospitalized children and adolescents with acute respiratory failure from viral infections. This outcome measure could feasibly be used in clinical trials to evaluate in-hospital recovery., Competing Interests: Drs. Newhams, Young, Maddux, Hall, Coates, Kong, Nofziger, Cullinmore, Halasa, Schuster, Gertz, Hume, and Randolph’s (contracts 75D30119C05584 and 75D30120C07725) institutions received funding from the U.S. Centers for Disease Control and Prevention (CDC). Drs. Newhams and Randolph’s institutions received funding from the National Institute of Allergy and Infectious Diseases. Drs. Newhams, Nofziger, Cvijanovich, Flori, and Randolph (AI084011 and AI154470) received support for article research from the National Institutes of Health (NIH). Dr. Khemani received funding from Orange Med/Nihon Kohden and Bayer Pharmaceutical. Dr. Marshall’s institution received funding from the Canadian Institutes of Health Research; he received funding from AM-Pharma and Adrenomed. Drs. Maddux, Kong, Nofziger, Cullimore, Cvijanovich, Schuster, Flori, and Hume’s institutions received funding from the NIH. Dr. Hall received funding from Abbvie, Kiadis, and the American Board of Pediatrics. Dr. Coates’ institution received funding from the National Heart, Lung, and Blood Institute (NHLBI), the American Lung Association, the American Thoracic Society, and the Doris Duke Foundation/Walder Foundation; she received funding from Sobi and Triplett Woolf Garretson LLC. Drs. Kong, Nofziger, Cullimore, Gertz, and Hume received support for article research from the CDC. Drs. Thomas and Cvijanovich’s institution received funding from Boston Children’s Hospital. Dr. Thomas received funding from Bayer AG. Dr. Halasa’s institution received funding from Sanofi and Quidel. Dr. Cvijanovich’s institution received funding from the Cincinnati Children’s Hospital Medical Center. Dr. Shuster’s institution received funding from the AAMC; she received funding from the AAP Department of Health and Human Services. Dr. Flori received funding from Nota Laboratories and Lucira Health; she disclosed that they are a commissioner for a Lancet Child Health report and that they worked as an expert for the NIH-funded pediatric acute respiratory distress syndrome Master Protocol development. Drs. Olson and Patel disclosed government work. Dr. Randolph received funding from UpToDate, Inc. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown., Objective: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections., Methods: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control., Results: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity., Conclusions: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry., Design: Retrospective study., Setting: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry., Patients: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021., Interventions: None., Measurements and Main Results: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased., Conclusions: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults., Competing Interests: Dr. Bhalala is currently funded by the National Institutes of Health (NIH) (Site Principal Investigator [PI] for Stress Hydrocortisone in Pediatric Septic Shock—R01HD096901), The Children’s Hospital of Philadelphia (Site-PI for Pediatric Resuscitation Quality Collaborative – PediResQ), Voelcker Pilot Grant (PI for project on prearrest electrocardiographic changes), The Children’s Hospital of San Antonio Endowed Chair Funds for ancillary projects related to Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) (coronavirus disease 2019 [COVID-19]) Registry and SCCM VIRUS electronic medical records, automation pilot. Ms. Boman’s institution received funding from The Gordon and Betty Moore Foundation. Ms. Boman and Drs. Kumar and Kashyap's institutions received funding from Janssen Research and Development, LLC. Dr. Kumar is currently funded by Gordon and Betty Moore Foundation, Centers for Disease Control and Prevention (CDC) Foundation through University of Washington and Janssen Research & Development, LLC. Dr. Chiotos funded by Agency for Healthcare Research and Quality(K12-HS026393). Dr. Bjornstad’s institution received funding from the International Society of Nephrology, The NIH-National Institute of Diabetes and Digestive and Kidney Diseases/T32, and Bioporto. Dr. Dapul disclosed that the deidentified data of some patients submitted to the VIRUS registry were also used in the Overcoming COVID-19 Virus Registry. Dr. Blatz funded by NIH grant T32GM-075766. Dr. Levy’s institution received funding from the CDC (No. 75D30120C07725) and the National Institute of Allergy and Infectious Diseases (AI 144301); she received funding from SinoUnited Health Shanghai Children’s Hospital. Drs. Kaufman’s, Abdelaty’s, and Briton’s institutions received funding from SCCM. Dr. Kaufman received funding from EngleWood Health for consulting work as medical director. Dr. Khanna’s institution received funding for COVID-19 trials Blood Volume Analyzer-Daxor and Chair Steering Committee for the Siltuximab in Selected Hospitalized Patients With Viral Acute Respiratory Distress Syndrome trial. Dr. Khanna is currently funded by a Clinical Translational Science Institute NIH/National Center for Advanced Translational Science KL2 TR001421 award for a trial on continuous postoperative hemodynamic and saturation monitoring and is a site PI (institutional funding) for a randomized trial of cytokine filtration in severe COVID-19 and a prospective observational trial of blood volume assessment in COVID-19. His institution also received funding for the SCCM VIRUS EMR automation pilot. Dr. Stulce received funding from the American Physician Institute. Dr. Anderson III disclosed that he is on the Advisory Board for the Gift of Life Michigan. Dr. Bello disclosed government work. Dr. Walkey currently funded the NIH/National Heart, Lung and Blood Institute (NHLBI) grants R01HL151607, R01HL139751, R01HL136660, Agency of Healthcare Research and Quality, R01HS026485, Boston Biomedical Innovation Center/NIH/NHLBI 5U54HL119145-07, and royalties from UptoDate. Dr. Bihorac received support for article research from the NIH. His institution received funding from the NIH (R01 GM110240 R21 EB 027344), Atox Bio, Astute Medical Research, Mallinckrodt Pharmaceuticals, and La Jolla Pharmaceuticals; she disclosed three institutional patents (20200161000, WO2020172607A12020, and 20190326013). Dr. Zimmerman’s institution received funding from the NIH-National Institute of Child Health and Human Development and Immunexpress; he received funding from Elsevier Publishing. Dr. Kashyap receives funding from the NIH/NHLBI: R01HL 130881, UG3/UH3HL 141722; Gordon and Betty Moore Foundation, and Janssen Research & Development, LLC; and royalties from Ambient Clinical Analytics. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)