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Introduction: This study aimed to characterize the severity of bleeding and its association with short-term neurologic outcomes in pediatric ECMO., Methods: Multicenter retrospective cohort study of pediatric ECMO patients at 10 centers utilizing the Pediatric ECMO Outcomes Registry (PEDECOR) database from December 2013-February 2019. Subjects excluded were post-cardiac surgery patients and those with neonatal pathologies. A novel ECMO bleeding scale was utilized to categorize daily bleeding events. Poor short-term neurologic outcome was defined as an unfavorable Pediatric Cerebral Performance Category (PCPC) or Pediatric Overall Performance Category (POPC) (score of >3) at hospital discharge., Results: This study included 283 pediatric ECMO patients with a median (interquartile range [IQR]) age of 1.3 years [0.1, 9.0], ECMO duration of 5 days [3.0, 9.5], and 44.1% mortality. Unfavorable PCPC and POPC were observed in 48.4% and 51.3% of patients at discharge, respectively. Multivariable logistic regression analysis included patient's age, cannulation type, duration of ECMO, need for cardiopulmonary resuscitation, acute kidney injury, new infection, and vasoactive-inotropic score. As the severity of bleeding increased, there was a corresponding increase in the likelihood of poor neurologic recovery, shown by increasing odds of unfavorable neurologic outcome (PCPC), with an adjusted odds ratio (aOR) of 0.77 (confidence interval [CI] 0.36-1.62), 1.87 (0.54-6.45), 2.97 (1.32-6.69), and 5.56 (0.59-52.25) for increasing bleeding severity (grade 1 to 4 events, respectively). Similarly, unfavorable POPC aOR (CI) was 1.02 (0.48-2.17), 2.05 (0.63-6.70), 5.29 (2.12-13.23), and 5.11 (0.66-39.64) for bleeding grade 1 to 4 events., Conclusion: Short-term neurologic outcomes in pediatric ECMO are proportional to the severity of bleeding events. Strategies to mitigate bleeding events could improve neurologic recovery in pediatric ECMO., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jun Teruya: Evaheart member of DSMB and STAGO honoraria for presentation: Ahmed Said: supported by the Children’s Discovery Institute Faculty Development Award at Washington University in St. Louis: Marie Steiner: Teaching contract (managing coagulation) with Medtronic and study advisory board for Octapharma (AT in Adult CPB heparin resistance). All other authors report no conflicts of interest.

Background: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care., Methods: Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted 12 March 2020-30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included., Results: Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P = .005) and hospitalization was longer (P = .01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P = .40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19., Conclusions: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities., Competing Interests: Potential conflicts of interest. B. M. C. reports grants from NHLBI, American Lung Association, Doris Duke Foundation/Walder Foundation, and American Thoracic Society; payment for expert testimony from Tripplett Woolf Garretson; and participation on a multidisciplinary team for Sobi. N. B. H. reports grants from Sanofi, Quidel, and Merck. C. V. H. reports royalties, consulting fees, for Reviewer for Up To Date and Dynamed clinical databases; payment for presentations from Biofire; and expert consultation for the AstraZeneca FluMist Board. A. G. R. reports licenses as a Section Editor for Pediatric Critical Care Medicine, UpToDate, Inc; consulting fees from ThermoFisher, Inotrem; honoraria from a Grand Rounds presentation at St. Jude; support for meetings and/or travel from International Sepsis Forum, Institut Merieux, ThermoFisher; participation on an advisory board for the NIH Grace Study, REMAP-CAP, NIH-PREVENT-VILI; a medical advisory board member for Families Fighting Flu; chair member for International Sepsis Forum; and received reagents from Illumina, Inc. M. K. reports support for meetings and/or travel from the National Institute of Health (NIH) and a role on an advisory board for KultureCity. H. D. reports honoraria from Delex Pharma International, Inc. N. Z. C. reports grants from Cincinnati Children's Hospital Medical Center. J. C. F. reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463 and P50DK114786), and Pennsylvania CURE Grant. M. W. H. reports licenses from Kiadis, sub-board service for the American Board of Pediatrics, participation on a Data and Safety Monitoring Board (DSMB) for Abbvie, and receipt of drugs from Partner Therapeutics and Sobi. J. C. reports receipt of equipment from Illumina. B. L. reports receipt of an Immune Deficiency Foundation Research Grant. G. E. M. reports payment for expert testimony from Orlando Health, Bush Ross, Hall, Schiefflin & Smith, PA, Poole Brooks and Plumlee, PA, Hilltop Specialty Insurance, Smith, Hulsey, and Busey, PA. J. E. S. reports grants from the Food and Drug Administration (FDA), consulting fees from the Association for Professionals in Infection Control and Epidemiology (APIC), payment for presentations from the American Academy of Pediatrics, and participation on an advisory board for the American Association of Medical Colleges. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.)

Objective: To identify risk factors for persistent impairments after pediatric hospitalization for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic., Methods: Across 25 U.S. Overcoming COVID-19 Network hospitals, we conducted a prospective cohort study of patients <21-years-old hospitalized for acute COVID-19 or MIS-C (May 2020 to March 2022) surveyed 2- to 4-months post-admission. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI)., Results: Of 232 children with acute COVID-19, 71 (30.6%) had persistent symptoms and 50 (21.6%) had activity impairments at follow-up; for MIS-C ( n  = 241), 56 (23.2%) had persistent symptoms and 58 (24.1%) had activity impairments. In adjusted analyses of patients with acute COVID-19, receipt of mechanical ventilation was associated with persistent symptoms [aRR 1.83 (95% CI: 1.07, 3.13)] whereas obesity [aRR 2.18 (95% CI: 1.05, 4.51)] and greater organ system involvement [aRR 1.35 (95% CI: 1.13, 1.61)] were associated with activity impairment. For patients with MIS-C, having a pre-existing respiratory condition was associated with persistent symptoms [aRR 3.04 (95% CI: 1.70, 5.41)] whereas obesity [aRR 1.86 (95% CI: 1.09, 3.15)] and greater organ system involvement [aRR 1.26 (1.00, 1.58)] were associated with activity impairments., Discussion: Among patients hospitalized, nearly one in three hospitalized with acute COVID-19 and one in four hospitalized with MIS-C had persistent impairments for ≥2 months post-hospitalization. Persistent impairments were associated with more severe illness and underlying health conditions, identifying populations to target for follow-up., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Maddux, Young, Kucukak, Zambrano, Newhams, Rollins, Halasa, Gertz, Mack, Schwartz, Kong, Loftis, Irby, Rowan, Tarquinio, Zinter, Crandall, Cvijanovich, Schuster, Fitzgerald, Staat, Hobbs, Nofziger, Shein, Flori, Cullimore, Chatani, Levy, Typpo, Hume, Campbell, Randolph and the Overcoming COVID-19 Investigators.)

Background: Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection., Methods: We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05)., Results: Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation ( RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways ( RPL3, MRPL3, HLA-DMB, EEF1G , CD8A ) were associated with MODS recovery within a week., Conclusion: Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome., Competing Interests: AGR, TN, and MMN: NIH/NIAID as declared in the funding statement - grant support paid to Boston Children’s Hospital. Also current CDC grant for COVID-19 work unrelated to current manuscript also paid to Boston Children’s Hospital under PI AGR. AGR also receives Royalties from UpToDate, Inc. as Section editor of Pediatric Critical Care Medicine. Honoraria: Grand Rounds presentations on MIS-C not related to current manuscript. Participation on a Data Safety Monitoring/Advisory Board: NIH Grace Study. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Medical Advisory Board for Families Fight Flu and Chair of International Sepsis Forum. JCC: additionally declares support from ALSAC for the current work. Other entities not related to the current work: U01AI150747, R01AI136514, U01AI144616; American Association of Immunologists Abstract award 2021, Patent: Methods for Treating or Reducing the Severity of a Viral Infection Publication no. WO 2021/226174 A1. MWH declared Kiadis, Licensing income, unrelated to the content of this manuscript, American Board of Pediatrics Payment, Abbive payment. Partner Therapeutics Provision of study drug, unrelated to the current manuscript, Sobi Provision of study drug, unrelated to the current manuscript. JC: NIH, paid to institution not related to this work; GLG Group payment to her, Elsevier payment made to her for work done as Associate Editor; Patent pending for Methods and compositions for treating and preventing T cell-driven diseases. BMC: Not related to current work: receives grants paid to institution from American Lung Association. Sobi Participation on a Data Safety Monitoring Board/Advisory Board. SLW: Receives royalties from UpToDate, Inc. Has grants/contracts with Pennsylvania Dept of Health not related to current manuscript. PGT: declares support from ALSAC and NIAID R01 AI154470 for the current work. Has several grants not associated with current work: NIAID 5R01AI128805-05; 1R01AI154470; NIAID 75N93019C00052; 5R01AI136514; 5R01AI35025; NIAID 5U01AI144616; NIAID U01AI150747. Royalties/licenses paid to both PGT and his institution: TCR cloning technology—Miltenyi Biotec & TCR amplification technology—Shennon Bio. Consulting fees paid to him: Johnson and Johnson, Cytoagents, Immunoscape, Shennon Bio. Payment or honoraria for lectures, presentations, or other events: Illumina—Future Genomic Advances, Yale University, CZ Biohub, PACT Pharma, UCSD, Tufts, University of Arizona, Mt. Sinai, Umass, OSU, Korean Association of Immunology, SISMID, University of Washington, MSKCC, Washington University, University of Missouri, Fred Hutch, UNM Illumina Single Cell, Cincinnati Childrens, University of Toronto, Purdue University, Iowa State University, University of Georgia. Patent: Methods for Treating or Reducing the Severity of a Viral Infection Publication no. WO 2021/226174 A1. (continued disclosures for PGT:) Support for attending meetings and/or travel: NIH Study Section, Keystone Viral Immunity, NIAID CEIRR, CEIRS and CIVIC meetings, GRC, 10X Users Symposium, Illumina Symposia, ImmunOktoberfest, Options for the Control of Influenza XI, Carghese Workshop, FOCIS, Max Planck for Complex Systems, Santa Fe Institute, AAI, Weizmann Institute, APS Society, Banff Institute, ISIRV meeting, University of Melbourne, British Society of Immunology. Stock or stock options: Shennon Bio Scientific advisory board payments. (Additional patents:) US20170304293A1 Coordinated metabolic reprogramming in response to productive viral infections; Cloning and expression system for t-cell receptors; License payments made to me and institution; Method for detecting SARS-CoV-2 infection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Novak, Crawford, Hahn, Hall, Thair, Newhams, Chou, Mourani, Tarquinio, Markovitz, Loftis, Weiss, Higgerson, Schwarz, Pinto, Thomas, Gedeit, Sanders, Mahapatra, Coates, Cvijanovich, Ackerman, Tellez, McQuillen, Kurachek, Shein, Lange, Thomas and Randolph.)

Objectives: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed., Design: Case series of patients from the Overcoming COVID-19 public health surveillance registry., Setting: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021., Patients: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19., Interventions: None., Measurements and Main Results: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period., Conclusions: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge., Competing Interests: Dr. Bembea’s institution received funding from the National Institute of Neurological Disorders and Stroke (R01NS106292) and Grifols Investigator Sponsored Research Grant. Drs. Bembea, Heidemann, Zinter, and Randolph received support for article research from the National Institutes of Health (NIH). Dr. Thiagarjan’s institution received funding from the U.S. Department of Defense (Peer Reviewed Medical Research Project Clinical Trial Award No. W81XWH2210301 Trial of Indication-based Transfusion of Red blood cells in Extracorporeal Membrane Oxygenation); he received funding from Society of Critical Care Medicine and the Extracorporeal Life Support Organization. Drs. Young’s, McCadden’s, Newhams’s, Kucuak’s, Mack’s, Fitzgerald’s, Rowan’s, Maddux’s, Kolmar’s, Heidemann’s, Schwartz’s, Kong’s, Crandall’s, Singh’s, Schuster’s, Hall’s, Wellnitz’s, Maamari’s, Gaspers’s, Nofziger’s, Cullimore’s, Halasa’s, McLaughlin’s, Pannaraj’s, Cvijanovich’s, Coates’s, Horwitz’s, Hobbs’s, Dapul’s, and Randolph’s institutions received funding from the U.S. Centers for Disease Control and Prevention (CDC). Dr. McCadden disclosed work for hire. Dr. Newhams’ institution received funding from the National Institute of Allergy and Infectious Diseases. Drs. Fitzgerald’s, Kong’s, Cullimore’s, Cvijanovich’s, and Randolph’s institutions received funding from the NIH. Dr. Rowan’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) (K23HL150244). Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018). Drs. Irby, Crandall, Singh, Wellnitz, Nofziger, Bradford, McLaughlin, Coates, Hobbs, and Zambrano received support for article research from the CDC. Dr. Schuster’s institution received funding from Merck. Dr. Hall received funding from Abbvie, Kiadis, and the American Board of Pediatrics. Dr. Wellnitz’s institution received funding from the University of Pennsylvania (prime sponsor NIH) and the University of Nebraska (prime sponsor Administration for Strategic Preparedness and Response). Dr. Gaspers received funding from Abbott Laboratories. Dr. Munoz’s institution received funding from Boston’s Children’s Hospital; he received funding from the University of Texas Health Science Center at Houston. Dr. Halasa’s institution received funding from Sanofi. Dr. McLaughlin received funding from expert witness fees from two entities. Dr. Pannaraj’s institution received funding from AstraZeneca and Pfizer. Dr. Coates’ institution received funding from the NHLBI and the American Lung Association; she received funding from Sobi. Drs. Hobbs and Randolph received funding from UpToDate. Dr. Hobbs received funding from Dynamed.com; she disclosed that she was a speaker for Biomerieux 2021–2022. Drs. Zambrano and Campbell disclosed government work. Dr. Randolph had full access to all the data in the investigation and takes responsibility for the integrity of the data and the accuracy of the data analysis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by 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.)

Background: Community-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce., Methods: We evaluated children and adolescents aged <19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes., Results: Of the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01-1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05-1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36-2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15-4.62]) was associated with bacterial coinfection., Conclusions: Community-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely., Competing Interests: Potential conflicts of interest. K. L. M. reports receiving funds from ContraFect as site investigator of a drug study and as patent beneficiary of technology licensed to Affinivax, Inc, outside the submitted work. C. V. H. reports receiving funds from UpToDate, Dynamed.com, and bioMérieux, outside the submitted work. M. W. H. reports receiving licensing fees from Kiadis, consulting fees from AbbVie for service on a data and safety monitoring board, consulting fees from the American Board of Pediatrics for service on a subboard, fees from Sobi for participating in a drug study, and fees from Partner Therapeutics for participating in a drug study, outside the submitted work. E. R. L. reports receiving grants to the institution from the National Institute of Allergy and Infectious Diseases (NIAID; AI 144301-01) and the CDC (CDC 75D30120C07725-01). A. G. R. reports receiving grants from NIAID and funds from UpToDate for editorial work. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients., Methods: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity., Results: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78-2.15; P = .32)., Conclusions: Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19., Competing Interests: Potential conflicts of interest. N. B. H. reports grants or contracts from Sanofi and Quidell outside of the submitted work and an educational grant for honorarium from Genentech. M. M. B. reports grants or contracts from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke, Grifols Investigator Sponsored Research Grant, and NIH/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) outside of the submitted work and paid to institution. B. M. C. reports grants or contracts from the NIH, American Thoracic Society, and American Lung Association outside the submitted work and paid to institution and payment to author for expert testimony from Triplett Woolf Garretson, LLC. N. Z. C. reports grants or contracts from the NIH outside of the submitted work. H. R. F. reports grants or contracts from the NIH, National Heart, Lung, and Blood Institute (NHLBI), and NICHD outside of the submitted work; support for attending meetings and/or travel from the Society of Critical Care Medicine; participation on a data and safety monitoring board (DSMB) for a cardiothoracic surgery trial (single center) and a DSMB for an intrathecal chemotherapy trial; an unpaid position on the Michigan Thoracic Society Executive Committed and Pediatric Acute Lung Injury and Sepsis Investigators network Executive Committee; and the following other financial or nonfinancial interests: Lucira Health advisory committee and Aerogen Pharma advisory unfunded. M. W. H. reports grants or contracts from the NIH and royalties from Kiadis outside of the submitted work; participation on a DSMB or advisory board for AbbVie and La Jolla Pharmaceuticals (payment to author); and leadership or fiduciary role on the American Board of Pediatrics (payment to author). J. R. H. reports grants or contracts from the NIH–NICHD outside of the submitted work and participation on a DSMB for an institutional study at the University of Minnesota (no financial reimbursements). M. K. reports grants or contracts from the NIH outside of the submitted work to institution. E. R. L. reports grants or contracts from the NIH outside of the submitted work and paid to institution. M. M. Nakamura reports grants or contracts from Gilead for participation in their remdesivir trial. R. A. N. reports grants or contracts from the NIH outside of the submitted work. C. M. R. reports grants or contracts from the NIH outside of the submitted work and payment for honoraria to author for the Contemporary Critical Care Complications of SCT/Cellular Therapies Conference by MD Anderson. J. E. S. reports grants or contracts from Merck outside of the submitted work and paid to institution. M. S. Z. reports grants or contracts from the NIH outside of the submitted work and paid to institution. A. G. R. reports grants or contracts from the National Institute of Allergy and Infectious Diseases to institution outside of the submitted work; royalties or licenses from UpToDate as a Pediatric Critical Care Section Editor paid to author; and is an unpaid treasurer for International Sepsis Forum. M. L. C. reports grants or contracts to institution for projects unrelated to this work from the CDC. J.C.F. reports an NIH award unrelated to this study and paid to institution. C. V. H. reports payment or honoraria as a consultant for Biofire (bioMérieux). G. E. M. reports payment for expert testimony in a malpractice case involving influenza related death. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complications., Objective: To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021., Design, Setting, and Participants: Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits)., Results: Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated., Conclusions and Relevance: SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.

Background: Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children., Methods: We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score., Results: Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity., Conclusions: We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease., Competing Interests: Potential conflicts of interest. A. G. R. reports receiving reagents to her institution from Illumina Inc for work outside of this project. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Patient selection for pediatric extracorporeal membrane oxygenation (ECMO) support has broadened over the years to include children with pre-existing neurologic morbidities. We aimed to determine the prevalence and nature of pre-ECMO neurologic disorders or disability and investigate the association between pre-ECMO neurologic disorders or disability and mortality and unfavorable neurologic outcome., Design: Multicenter retrospective observational cohort study., Setting: Eight hospitals reporting to the Pediatric ECMO Outcomes Registry between October 2011 and June 2019., Patients: Children younger than 18 years supported with venoarterial or venovenous ECMO., Interventions: The primary exposure was presence of pre-ECMO neurologic disorders or moderate-to-severe disability, defined as Pediatric Cerebral Performance Category (PCPC) or Pediatric Overall Performance Category (POPC) 3-5. The primary outcome was unfavorable outcome at hospital discharge, defined as in-hospital mortality or survival with moderate-to-severe disability (discharge PCPC 3-5 with deterioration from baseline)., Measurements and Main Results: Of 598 children included in the final cohort, 68 of 598 (11%) had a pre-ECMO neurologic disorder, 70 of 595 (12%) had a baseline PCPC 3-5, and 189 of 592 (32%) had a baseline POPC 3-5. The primary outcome of in-hospital mortality ( n = 267) or survival with PCPC 3-5 with deterioration from baseline ( n = 39) was observed in 306 of 598 (51%). Overall, one or more pre-ECMO neurologic disorders or disability were present in 226 of 598 children (38%) but, after adjustment for age, sex, diagnostic category, pre-ECMO cardiac arrest, and ECMO mode, were not independently associated with increased odds of unfavorable outcome (unadjusted odds ratio [OR], 1.34; 95% CI, 1.07-1.69; multivariable adjusted OR, 1.30; 95% CI, 0.92-1.82)., Conclusions: In this exploratory study using a multicenter pediatric ECMO registry, more than one third of children requiring ECMO support had pre-ECMO neurologic disorders or disability. However, pre-existing morbidities were not independently associated with mortality or unfavorable neurologic outcomes at hospital discharge after adjustment for diagnostic category and other covariates., Competing Interests: Dr. Dante’s institution received funding from the National Heart, Lung, and Blood Institute (T32 HL 125239). Drs. Dante, Ng, Patel, Steiner, and Bembea received support for article research from the National Institutes of Health (NIH). Drs. Ng’s and Patel’s institutions received funding from the NIH. Dr. Ng received funding from Ashvattha Therapeutics. Dr. Steiner received funding from Infant Jarvik Heart Data Safety Monitoring Board honorarium from HealthCore and Octapharma. Dr. Bembea’s institution received funding from the National Institute of Neurological Disorders and Stroke (R01NS106292) and a Grifols Investigator Sponsored Research Grant. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background Cardiac complications related to COVID-19 in children and adolescents include ventricular dysfunction, myocarditis, coronary artery aneurysm, and bradyarrhythmias, but tachyarrhythmias are less understood. The goal of this study was to evaluate the frequency, characteristics, and outcomes of children and adolescents experiencing tachyarrhythmias while hospitalized for acute severe COVID-19 or multisystem inflammatory syndrome in children. Methods and Results This study involved a case series of 63 patients with tachyarrhythmias reported in a public health surveillance registry of patients aged <21 years hospitalized from March 15, 2020, to December 31, 2021, at 63 US hospitals. Patients with tachyarrhythmias were compared with patients with severe COVID-19-related complications without tachyarrhythmias. Tachyarrhythmias were reported in 22 of 1257 patients (1.8%) with acute COVID-19 and 41 of 2343 (1.7%) patients with multisystem inflammatory syndrome in children. They included supraventricular tachycardia in 28 (44%), accelerated junctional rhythm in 9 (14%), and ventricular tachycardia in 38 (60%); >1 type was reported in 12 (19%). Registry patients with versus without tachyarrhythmia were older (median age, 15.4 [range, 10.4-17.4] versus 10.0 [range, 5.4-14.8] years) and had higher illness severity on hospital admission. Intervention for treatment of tachyarrhythmia was required in 37 (59%) patients and included antiarrhythmic medication (n=31, 49%), electrical cardioversion (n=11, 17%), cardiopulmonary resuscitation (n=8, 13%), and extracorporeal membrane oxygenation (n=9, 14%). Patients with tachyarrhythmias had longer hospital length of stay than those who did not, and 9 (14%) versus 77 (2%) died. Conclusions Tachyarrhythmias were a rare complication of acute severe COVID-19 and multisystem inflammatory syndrome in children and adolescents and were associated with worse clinical outcomes, highlighting the importance of close monitoring, aggressive treatment, and postdischarge care.

Background: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery)., Methods: Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n = 36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n = 53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n = 67) or within 24 hours of negative RT-PCR (n = 43)., Results: Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28-3844 pg/mL (N) and 1.65-1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw., Conclusions: Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis., Competing Interests: Potential conflicts of Interest . G. B. S., A. M., N. M., P. B, J. J., N. P., and D. R. are employees of Meso Scale Diagnostics. N. B. H. receives unrelated research support from Sanofi and Quidel. J. E. S. has received unrelated research support from Merck. H. R. F. is an Advisor for LuciraHealth. A. G. R. reports grants or contracts from National Institute of Allergy and Infectious Diseases to the institution outside of the submitted work; royalties or licenses from UpToDate for Pediatric Critical Care Section Editor; and is an unpaid Treasurer for International Sepsis Forum. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C)., Methods: Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients <21-years-old, hospitalized May 2020 to May 2021 for acute COVID-19 or MIS-C with follow-up 2 to 4 months after admission. We assessed readmissions, persistent symptoms or activity impairment, and new morbidities. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI)., Results: Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04-1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06-1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55-6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35-4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C)., Conclusions: Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

Objectives: To compare outcomes associated with timing-early versus late-of any neurologic dysfunction during pediatric sepsis., Design: Secondary analysis of a cross-sectional point prevalence study., Setting: A total of 128 PICUs in 26 countries., Patients: Less than 18 years with severe sepsis on 5 separate days (2013-2014)., Interventions: None., Measurements and Main Results: Patients were categorized as having either no neurologic dysfunction or neurologic dysfunction (i.e., present at or after sepsis recognition), which was defined as Glasgow Coma Scale score less than 5 and/or fixed dilated pupils. Our primary outcome was death or new moderate disability (i.e., Pediatric Overall [or Cerebral] Performance Category score ≥3 and change ≥1 from baseline) at hospital discharge, and 87 of 567 severe sepsis patients (15%) had neurologic dysfunction within 7 days of sepsis recognition (61 at sepsis recognition and 26 after sepsis recognition). Primary site of infection varied based on presence of neurologic dysfunction. Death or new moderate disability occurred in 161 of 480 (34%) without neurologic dysfunction, 45 of 61 (74%) with neurologic dysfunction at sepsis recognition, and 21 of 26 (81%) with neurologic dysfunction after sepsis recognition (p < 0.001 across all groups). On multivariable analysis, in comparison with those without neurologic dysfunction, neurologic dysfunction whether at sepsis recognition or after was associated with increased odds of death or new moderate disability (adjusted odds ratio, 4.9 [95% CI, 2.3-10.1] and 10.7 [95% CI, 3.8-30.5], respectively). We failed to identify a difference between these adjusted odds ratios of death or new moderate disability that would indicate a differential risk of outcome based on timing of neurologic dysfunction (p = 0.20)., Conclusions: In this severe sepsis international cohort, the presence of neurologic dysfunction during sepsis is associated with worse outcomes at hospital discharge. The impact of early versus late onset of neurologic dysfunction in sepsis on outcome remains unknown, and further work is needed to better understand timing of neurologic dysfunction onset in pediatric sepsis., Competing Interests: Drs. Weiss’ and Fitzgerald’s institutions received funding from Children’s Hospital of Philadelphia Center for Pediatric Clinical Effectiveness. Dr. Fitzgerald’s institution received funding from the National Institutes of Health (NIH). Dr. Loftis received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered., Methods: Between March 15, 2020 and December 27, 2020, children <18 years of age in the ICU/SDU with acute COVID-19 at 48 pediatric hospitals in the United States were identified. Demographics, laboratory values, and clinical course were compared in children who did and did not receive COVID-19-directed therapies. Trends in COVID-19-directed therapies over time were evaluated., Results: Of 424 children in the ICU/SDU, 235 (55%) received COVID-19-directed therapies. Children who received COVID-19-directed therapies were older than those who did not receive COVID-19-directed therapies (13.3 [5.6-16.2] vs 9.8 [0.65-15.9] years), more had underlying medical conditions (188 [80%] vs 104 [55%]; difference = 25% [95% CI: 16% to 34%]), more received respiratory support (206 [88%] vs 71 [38%]; difference = 50% [95% CI: 34% to 56%]), and more died (8 [3.4%] vs 0). Of the 235 children receiving COVID-19-directed therapies, 172 (73%) received systemic steroids and 150 (64%) received remdesivir, with rising remdesivir use over the study period (14% in March/April to 57% November/December)., Conclusion: Despite the lack of pediatric data evaluating treatments for COVID-19 in critically ill children, more than half of children requiring intensive or high acuity care received COVID-19-directed therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5-11, 12-21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19., Methods: Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients >7 days to <1 year old hospitalized with symptomatic acute COVID-19., Results: We report 232 infants >7 days to <1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients >7 days to <18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and <1% died., Conclusions: Infants accounted for over a fifth of children <18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were <6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants.

Purpose: Health-related quality of life (HRQL) has been identified as one of the core outcomes most important to assess following pediatric critical care, yet there are no data on the use of HRQL in pediatric critical care research. We aimed to determine the HRQL instruments most commonly used to assess children surviving critical care and describe study methodology, patient populations, and instrument characteristics to identify areas of deficiency and guide investigators conducting HRQL research., Methods: We queried PubMed, EMBASE, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Registry for studies evaluating pediatric critical care survivors published 1970-2017. We used dual review for article selection and data extraction., Results: Of 60,349 citations, 66 articles met inclusion criteria. The majority of studies were observational (89.4%) and assessed HRQL at one post-discharge time-point (86.4%), and only 10.6% of studies included a baseline assessment. Time to the first follow-up assessment ranged from 1 month to 10 years post-hospitalization (median 3 years, IQR 0.5-6). For 26 prospective studies, the median follow-up time was 0.5 years [IQR 0.25-1]. Parent/guardian proxy-reporting was used in 83.3% of studies. Fifteen HRQL instruments were employed, with four used in >5% of articles: the Health Utility Index (n = 22 articles), the Pediatric Quality of Life Inventory (n = 17), the Child Health Questionnaire (n = 16), and the 36-Item Short Form Survey (n = 9)., Conclusion: HRQL assessment in pediatric critical care research has been centered around four instruments, though existing literature is limited by minimal longitudinal follow-up and infrequent assessment of baseline HRQL., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia., Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients., Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients ( N  = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients ( N  = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients ( N  = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients., Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C., Competing Interests: All authors report receiving funding from the Centers for Disease Control and Prevention for the current study. AG reports receiving grants from the NIH outside of the submitted work. ABM reports receiving grants from the Francis Family Foundation and from the NIH/NICHD (K23HD096018) outside of the submitted work. CVH reports receiving consulting fees from DYNAMED and BIOFIRE outside of the submitted work. JES reports receiving grants from Merck outside of the submitted work. NBH reports receiving grants from Sanofi, Quidel, the NIH, and the CDC; consulting fees from Moderna; and an educational grant from Genetech outside of the submitted work. CMR reports receiving grants from the NIH/NHLBI (K23HL150244) outside of the submitted work. NZC reports receiving grants or contracts from Boston Children's Hospital and Cincinnati Children's Hospital and Medical Center outside of the submitted work. JCF reports receiving grants from the NIH outside of the submitted work. HD reports payments from Delex Pharma International Inc. outside of the submitted work. PMM reports receiving grants from the NIH and serving as a member of data safety monitoring board for the NIH supported KIDS-DOT trial outside of the submitted work. AGR reports receiving royalties from UpToDate outside of the submitted work. All other authors have nothing to declare., (© 2021 The Authors.)

Background: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy., Methods: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2., Results: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis., Conclusions: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.)., (Copyright © 2021 Massachusetts Medical Society.)

Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear., Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19., Setting, Design, and Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features., Exposures: Severe acute respiratory syndrome coronavirus 2., Main Outcomes and Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge., Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died., Conclusions and Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

Patients with respiratory failure requiring inotropes or vasopressors are often placed on venoarterial (VA) extracorporeal membrane oxygenation (ECMO), as venovenous (VV) ECMO does not provide direct circulatory support. This retrospective multicenter study compared outcomes for 103 pediatric patients, with hemodynamic compromise, placed on VV ECMO for respiratory failure to those placed on VA ECMO. The primary outcome was survival to hospital discharge. Fifty-seven (55%) study participants were supported on VV ECMO. The two groups had similar PRISM III scores at pediatric intensive care unit (PICU) admission, and vasoactive-inotropic scores at ECMO cannulation. More VV ECMO patients received inhaled nitric oxide (iNO) (54.4 vs. 34.8%; p = 0.04) and had a higher oxygenation index (median 41.5 vs. 19.5; p = 0.04) pre-ECMO. More VA ECMO patients had cardiac dysfunction and cardiac arrest pre-ECMO (50 vs. 14%; p < 0.0001). In univariable analysis, survival to hospital discharge was higher in the VV vs. VA ECMO group (72 vs. 44%; p = 0.005), however, in multivariable models, cannulation type was confounded by cardiopulmonary resuscitation and was not independently associated with survival. VV survivors had longer ECMO duration compared with VA survivors (median, 7 vs. 4.5 days; p = 0.036) but similar PICU and hospital days. No significant difference was noted in functional outcomes or comorbidities at discharge. Cannulation type is not independently associated with survival to hospital discharge in pediatric patients on vasoactive infusions at the time of ECMO cannulation for respiratory indications., Competing Interests: Disclosure: No funding was secured for this article. The authors have no financial relationships or conflicts of interest relevant to this article to disclose., (Copyright © ASAIO 2020.)

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes., Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19)., Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement., Exposure: SARS-CoV-2., Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19., Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days., Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

Background: Outcomes for patients with oncologic disease and/or after hematopoietic stem cell transplant (HSCT) requiring intensive care unit admission have improved, but indications for and outcomes after extracorporeal membrane oxygenation (ECMO) support in this population are poorly characterized., Procedure: We analyzed data from consecutive patients < 18 years with oncologic disease and/or after HSCT reported to a pediatric ECMO registry by nine pediatric centers in the United States between 2011 and 2018., Results: We identified 18 ECMO patients with oncologic disease and/or HSCT, and 415 ECMO controls matched with a propensity score algorithm based on age, gender, race, severity of illness at admission, and reason for ECMO. The primary indication for ECMO was respiratory failure in 66.7% in the oncologic disease and/or HSCT group, and in 70.7% in the matched ECMO control group. Eleven of 18 patients survived to hospital discharge (61.1%), similar to the matched control group (60.8%), P = 0.979. Children with oncologic disease and/or HSCT had lower mean platelet counts during ECMO and received higher volumes of platelets compared with the control group, mean 14.6 mL/kg/day (standard deviations [SD], 9.8) versus mean 9.3 mL/kg/day (SD, 10.4), P = 0.001. Of the 11 surviving children with oncologic disease and/or HSCT, five sustained new neurologic disorders (45.5%) versus 45 of 222 (20.3%) in the control group, P = 0.061. Bleeding complications were similar in the two groups., Conclusions: Outcomes of patients with oncologic disease and/or HSCT supported on ECMO in the current era are not significantly different compared with matched ECMO controls and are improved from previously published reports., (© 2020 Wiley Periodicals, Inc.)

Objectives: Acute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up., Design: Prospective cohort study with follow-up questionnaires at 6 and 12 months., Setting: Ten U.S. PICUs., Patients: Two-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively., Interventions: None., Measurements and Main Results: Pulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66-11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68-52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points., Conclusions: Persistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.

Background: Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear., Objectives: We sought to evaluate suppression of the TLR4 and the antiviral retinoic acid-inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection., Methods: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand polyinosinic-polycytidylic acid-low-molecular-weight/LyoVec and LPS to evaluate IFN-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively)., Results: Suppression of either IFN-α or TNF-α production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n = 33 of 103 [32%]) were more likely to have prolonged (≥7 days) multiple-organ dysfunction syndrome (30.3% vs 8.6%; P = .004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4%; P = .001) compared with those with single- or no pathway suppression., Conclusions: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective antiviral and antibacterial responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial coinfection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric acute kidney injury (AKI) is associated with long-term morbidity and mortality; however, outcomes improve when AKI is detected earlier. Current definitions of AKI use baseline creatinine; community-acquired AKI (CA-AKI) is difficult to define and detect in the pediatric emergency department (ED) when no baseline creatinine is available. Our objective was to compare age- and gender-based creatinine norms to the traditional baseline (lowest creatinine in previous 3 months) to diagnose CA-AKI., Methods: This was a retrospective cross-sectional study conducted in children 1 month-18 years of age seen in the pediatric ED in whom a creatinine was obtained., Results: Per the Kidney Disease Improving Global Outcomes AKI definition in encounters with baseline creatinine available, 343/2338 (14.7%) had CA-AKI. When the upper limit of the age- and gender-based creatinine norm was applied as a surrogate baseline creatinine, CA-AKI was diagnosed in 1.5% of encounters (239/15,486). Additionally, CA-AKI was diagnosed in 178 cases using the upper limit of age- and gender-based creatinine norms only, as these cases did not have a baseline creatinine., Conclusions: Age- and gender-based creatinine norms can be applied as a surrogate baseline to detect CA-AKI in all children regardless of whether baseline creatinine is available, potentially detecting it earlier.

Objective: Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children., Design: Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity., Setting: PICU., Patients: Children at risk of bleeding in PICUs., Interventions: None., Measurements and Main Results: Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57-0.91) representing substantial inter-rater reliability., Conclusions: The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2 &#95;Gly54Asp("B") mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 "low-producer" variants rs11003125("H/L"), rs7096206("Y/X"), rs1800450 Gly54Asp ("B"), rs1800451 Gly57Glu ("C"), rs5030737 Arg52Cys ("D") in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes ("B/B," "C/C") to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection ( n = 33, 8% overall) was associated with death ( p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.

Objectives: High Vasoactive-Inotropic Scores have demonstrated association with poor outcomes in pediatric cardiac ICUs and are being calculated more frequently in studies of critically ill noncardiac patients. Available studies differ in their approach to assigning Vasoactive-Inotropic Scores, making direct comparisons difficult. The goal of this investigation is to compare multiple approaches to Vasoactive-Inotropic Score assignment to determine their strength of association with mortality in a general pediatric intensive care population. In doing so, we aim to help validate the use of the Vasoactive-Inotropic Score in noncardiac patients and to help inform future studies of the relative strength of available approaches in assigning this score., Design: Retrospective chart review., Setting: PICU at an academic freestanding children's hospital., Patients: Two-thousand seven-hundred fifty-two consecutive patients admitted over a 17-month time period were screened for receiving inotrope or vasopressor therapies regardless of disease process. Four-hundred seventy-four patients met inclusion criteria., Interventions: None., Measurements and Main Results: For each patient treated with continuous infusions of vasoactive medications, a Vasoactive-Inotropic Score was calculated (and then recalculated) every time they had a documented dose change. Multiple strategies were evaluated to generate receiver operating characteristic curves in relation to mortality. Area under the curve was greatest when evaluating the maximum Vasoactive-Inotropic Score (Max Any) during the initial treatment course (0.788) with an increasing relative risk as the score increased. The Vasoactive-Inotropic Score at 48 hours after treatment initiation had next highest area under the curve (0.736). Primary diagnosis categories were also analyzed, and area under the curve was greatest for the cardiovascular group (0.879)., Conclusions: Increasing Vasoactive-Inotropic Scores for patients in the PICU are associated with mortality risk. The scoring strategy used can influence the strength of the association, as can the primary diagnosis category.

Objectives: Acute kidney injury (AKI) is a significant risk factor for morbidity and mortality in children. Little is known about community-acquired AKI (CA-AKI) in the pediatric emergency department (PED). Early recognition of AKI allows for nephroprotective measures. The goal of this investigation was to determine the incidence of CA-AKI and the frequency of clinician identified CA-AKI to better inform future nephroprotective interventions., Methods: This was a retrospective cross-sectional study in the PED of a children's hospital. Children 1 month to 18 years of age seen in the PED from January 1 to December 31, 2015, and in whom at least one creatinine level was obtained were included. Patients with chronic kidney disease or end-stage renal disease or who died in the PED were excluded. Patients had CA-AKI based on modified Kidney Disease-Improving Global Outcomes criteria using the creatinine obtained in the PED compared to age-specific norms. Patients were considered identified if the PED clinician diagnosed AKI. The primary outcome was the incidence of CA-AKI. Secondary outcomes included frequency of AKI identification, nephrotoxic medication use, hospital length of stay, renal replacement therapy, and death. Fisher exact test or Pearson's chi-square test was used to calculate odds ratio (OR) with 95% confidence intervals (CIs); multivariable analyses were performed using logistic regression., Results: In 2015 there were 119,151 PED visits; 15,486 met inclusion criteria. CA-AKI was present in 239 of 15,486 (1.5%) encounters. AKI was identified by PED clinicians in 46 of 239 (19%) of encounters and by the inpatient team in 123 of 199 (62%) of the encounters admitted. AKI was never recognized by a PED or inpatient clinician in 74 of 199 (37%) encounters. Encounters with AKI correctly diagnosed were older (13 years old vs. 10 years old, p = 0.0114), had more severe (stage 2 or 3) AKI (OR = 5.5, 95% CI = 2.6-11.8), and were more likely to be admitted (OR = 10.3, 95% CI = 1.38-77.4) than encounters with missed AKI., Conclusions: CA-AKI remains an underrecognized entity in the PED. Better tools for early recognition of AKI in the busy PED environment are needed., (© 2018 by the Society for Academic Emergency Medicine.)

Objective: Interruptive acute kidney injury alerts are reported to decrease acute kidney injury-related mortality in adults. Critically ill children have multiple acute kidney injury risk factors; although recognition has improved due to standardized definitions, subtle changes in serum creatinine make acute kidney injury recognition challenging. Age and body habitus variability prevent a uniform maximum threshold of creatinine. Exposure of nephrotoxic medications is common but not accounted for in kidney injury scores. Current severity of illness measures do not include fluid overload, a well-described mortality risk factor. We hypothesized that a multidimensional measure of renal status would better characterize renal severity of illness while maintaining or improving on correlation measures with adverse outcomes, when compared with traditional acute kidney injury staging., Design: A novel, real-time, multidimensional, renal status measure, combining acute kidney injury, fluid overload greater than or equal to 15%, and nephrotoxin exposure, was developed (Fluid Overload Kidney Injury Score) and prospectively applied to all patient encounters. Peak Fluid Overload Kidney Injury Score values prior to discharge or death were used to measure correlation with outcomes., Setting: Quarternary PICU of a freestanding children's hospital., Patients: All patients admitted over 18 months., Intervention: None., Results: Peak Fluid Overload Kidney Injury Score ranged between 0 and 14 in 2,830 PICU patients (median age, 5.5 yr; interquartile range, 1.3-12.9; 55% male), 66% of patients had Fluid Overload Kidney Injury Score greater than or equal to 1. Fluid Overload Kidney Injury Score was independently associated with PICU mortality and PICU and hospital length of stay when controlled for age, Pediatric Risk of Mortality-3, ventilator, pressor, and renal replacement therapy use (p = 0.047). Mortality increased from 1.5% in Fluid Overload Kidney Injury Score 0 to 40% in Fluid Overload Kidney Injury Score 8+. When urine output points were excluded, Fluid Overload Kidney Injury Score was more strongly correlated with mortality than fluid overload or acute kidney injury definitions alone., Conclusion: A multidimensional score of renal disease burden was significantly associated with adverse PICU outcomes. Further studies will evaluate Fluid Overload Kidney Injury Score as a warning and decision support tool to impact patient-centered outcomes.

Objectives: Multiplex rapid viral tests and nasopharyngeal flocked swabs are increasingly used for viral testing in PICUs. This study aimed at evaluating how the sampling site and the type of diagnostic test influence test results in children with suspected severe viral infection., Design: Prospective cohort study., Setting: PICUs at 21 tertiary pediatric referral centers in the United States., Patients: During the 2010-2011 and 2011-2012 influenza seasons, we enrolled children (6 mo to 17 yr old) who were suspected to have severe viral infection., Interventions: We collected samples by using a standardized protocol for nasopharyngeal aspirate and nasopharyngeal flocked swabs in nonintubated patients and for endotracheal tube aspirate and nasopharyngeal flocked swabs in intubated patients., Measurements and Main Results: Viral testing included a single reverse transcription-polymerase chain reaction influenza test and the GenMark Respiratory Viral Panel (20 viruses). We enrolled 90 endotracheally intubated and 133 nonintubated children. We identified influenza in 45 patients with reverse transcription-polymerase chain reaction testing; the multiplex panel was falsely negative for influenza in two patients (4.4%). Six patients (13.3%) had not been diagnosed with influenza in the PICU. Non-influenza viruses were identified in 172 of 223 children (77.1%). In nonintubated children, the same virus was identified by nasopharyngeal flocked swabs and nasopharyngeal aspirate in 133 of 183 paired samples (72.7%), with +nasopharyngeal aspirate/-nasopharyngeal flocked swabs in 32 of 183 paired samples (17.4%). In intubated children, the same virus was identified by nasopharyngeal flocked swabs and endotracheal tube aspirate in 67 of 94 paired samples (71.3%), with +nasopharyngeal flocked swabs/- endotracheal tube aspirate in 22 of 94 paired samples (23.4%). Most discrepancies were either adenovirus or rhinovirus in both groups., Conclusions: Standardized specimen collection and sensitive diagnostic testing with a reverse transcription-polymerase chain reaction increased the identification of influenza in critically ill children. For most pathogenic viruses identified, results from nasopharyngeal flocked swabs agreed with those from nasopharyngeal or endotracheal aspirates.

Rationale: Fluid overload is common in the critically ill and is thought to contribute to oxygenation failure and mortality. Since increasing disease severity often requires more fluid for resuscitation, it is unclear whether fluid overload is a causative factor in morbidity or is simply an indicator of disease severity., Objective: Investigate the association between fluid overload and oxygenation while controlling for severity of illness by daily Pediatric Logistic Organ Dysfunction scores., Design and Setting: Retrospective chart review, tertiary children's hospital., Patients and Methods: The oxygenation index, fluid overload percent, and daily Pediatric Logistic Organ Dysfunction scores were obtained in a retrospective chart review of 80 patients (mean age 58.7 ± 73.0 months) with respiratory failure. Univariate and multivariate approaches were used to assess the independent relation between fluid overload percent and duration of stay and ventilation., Interventions: None., Main Results: Higher peak fluid overload percent predicted higher peak oxygenation index, independent of age, gender, and Pediatric Logistic Organ Dysfunction (p = .009). Fluid overload percent ≥15% on any given day was also independently associated with that day's oxygenation index, controlled for age, gender, and Pediatric Logistic Organ Dysfunction (p < .05). Peak fluid overload percent and severe fluid overload percent (≥15%) were both independently associated with longer duration of ventilation (p = .004, p = .01), and pediatric intensive care unit (p = .008, p = .01) and hospital length of stay (p = .02, p = .04), controlled for age, gender, Pediatric Logistic Organ Dysfunction, and in the case of ventilation, respiratory admission., Conclusion: This is the first study to report that positive fluid balance adversely affected the pediatric intensive care unit course in children who did not receive renal replacement therapy. While timely administration of fluids is lifesaving, positive fluid balance after hemodynamic stabilization may impact organ function and negatively influence important outcomes in critically ill patients.

Background: The 2009 pandemic influenza A (H1N1) (pH1N1) virus continues to circulate worldwide. Determining the roles of chronic conditions and bacterial coinfection in mortality is difficult because of the limited data for children with pH1N1-related critical illness., Methods: We identified children (<21 years old) with confirmed or probable pH1N1 admitted to 35 US PICUs from April 15, 2009, through April 15, 2010. We collected data on demographics, baseline health, laboratory results, treatments, and outcomes., Results: Of 838 children with pH1N1 admitted to a PICU, the median age was 6 years, 58% were male, 70% had ≥1 chronic health condition, and 88.2% received oseltamivir (5.8% started before PICU admission). Most patients had respiratory failure with 564 (67.3%) receiving mechanical ventilation; 162 (19.3%) received vasopressors, and 75 (8.9%) died. Overall, 71 (8.5%) of the patients had a presumed diagnosis of early (within 72 hours after PICU admission) Staphylococcus aureus coinfection of the lung with 48% methicillin-resistant S aureus (MRSA). In multivariable analyses, preexisting neurologic conditions or immunosuppression, encephalitis (1.7% of cases), myocarditis (1.4% of cases), early presumed MRSA lung coinfection, and female gender were mortality risk factors. Among 251 previously healthy children, only early presumed MRSA coinfection of the lung (relative risk: 8 [95% confidence interval: 3.1-20.6]; P < .0001) remained a mortality risk factor., Conclusions: Children with preexisting neurologic conditions and immune compromise were at increased risk of pH1N1-associated death after PICU admission. Secondary complications of pH1N1, including myocarditis, encephalitis, and clinical diagnosis of early presumed MRSA coinfection of the lung, were mortality risk factors.

Objective: To estimate nursing workload from the patient acuity level (PAL) assigned to patients in a pediatric intensive care unit (PICU) and to determine its influence on unplanned extubations., Design: Prospective cohort study., Setting: The 19-bed PICU of an urban, university-affiliated, tertiary children's hospital., Patients: All patients admitted to the PICU., Interventions: None., Measurements and Main Results: The study encompassed 2,193 nursing shifts and 1,919 admissions to the PICU over 24 months. The shift census averaged 12.0 patients (range 5-18) and was staffed by 9.4 nurses (range 4-16) for an average patient/nurse ratio of 1.3 +/- 0.2. Patients were assigned a PAL of 1-7 based on a classification system derived from time studies of 12 general nursing tasks. The total PALs per shift divided by the number of nursing staff yielded an average assignment of 5.8 +/- 0.7 PALs. Forty unplanned extubations (0.76 unplanned extubations/100 ventilator days) were observed during the study period. Logistic regression revealed positive associations between unplanned extubations and patient/nurse ratio (p = .03) and the shift PAL/nurse ratio (p = .01). The likelihood of an unplanned extubation when nurses covered >6.3 PALs was 3.8 times higher than during those shifts when they covered <5.3 PALs., Conclusions: The likelihood of an unplanned extubation increased with higher patient/nurse and patient acuity/nurse ratios. Successful interventions to reduce the frequency of this medical error may need to address both nurse demand methodology and workload.

A classification system has been proposed to standardize the definition of acute kidney injury in adults. These criteria of risk, injury, failure, loss, and end-stage renal disease were given the acronym of RIFLE. We have modified the criteria based on 150 critically ill pediatric RIFLE (pRIFLE) patients to assess acute kidney injury incidence and course along with renal and/or non-renal comorbidities. Of these children, 11 required dialysis and 24 died. Patients without acute kidney injury in the first week of intensive care admission were less likely to subsequently develop renal Injury or Failure; however, 82% of acute kidney injury occurred in this initial week. Within this group of 123 children, 60 reached pRIFLEmax for Risk, 32 reached Injury, and 31 reached Failure. Acute kidney injury during admission was an independent predictor of intensive care; hospital length of stay and an increased risk of death independent of the Pediatric Risk of Mortality (PRISM II) score (odds ratio 3.0). Our results show that a majority of critically ill children develop acute kidney injury by pRIFLE criteria and do so early in the course of intensive care. Acute kidney injury is associated with mortality and may lead to increased hospital costs. We suggest that the pRIFLE criteria serves to characterize the pattern of acute kidney injury in critically ill children.

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.

Objective: To find a body measurement that would serve as an index for determining the length of femoral venous catheter to be inserted to achieve a position near the right atrium., Methods: A candidate index measurement was chosen, and radiographic measurements of routine femoral venous catheter placements were compared with the placement that may have resulted from use of the index in a group of patients. In a subsequent group, the candidate index was used to choose catheter insertion length, the accuracy of which was again evaluated from routine placement radiographs., Results: The first series of radiographic measurements predicted that use of the sternal-umbilical-puncture (SUP) index would result in acceptable and accurate catheter tip placement. This was confirmed in the second group of patients in which 11 of 12 catheter tips were within 1 cm of the target position., Conclusions: The use of the SUP index ensures acceptable accuracy in estimating the required insertion length of femoral catheter when tip placement near the right atrium is the clinical goal.

Study Objective: To determine whether adding IV theophylline to an aggressive regimen of inhaled and IV beta-agonists, inhaled ipratropium, and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric ICU (PICU)., Design: A prospective, randomized, controlled trial. Asthma scoring was performed by investigators not involved in treatment decisions and blinded to group assignment., Setting: The PICU of an urban, university-affiliated, tertiary-care children's hospital., Patients: Children with a diagnosis of status asthmaticus who were admitted to the PICU for < or = 2 h and who were in severe distress, as indicated by a modified Wood-Downes clinical asthma score (CAS) of > or = 5., Interventions: All subjects initially received continuous albuterol nebulizations; intermittent, inhaled ipratropium; and IV methylprednisolone. The theophylline group was also administered infusions of IV theophylline to achieve serum concentrations of 12 to 17 microg/mL. A CAS was tabulated twice daily., Measurements and Results: Forty-seven children (median age, 8.3 years; range, 13 months to 17 years) completed the study. Twenty-three children received theophylline. The baseline CASs of both groups were similar and included three subjects receiving mechanical ventilation in each group. All subjects receiving mechanical ventilation and theophylline were intubated before drug infusion. Among the 41 subjects who were not receiving mechanical ventilation, those receiving theophylline achieved a CAS of < or = 3 sooner than control subjects (18.6 +/- 2.7 h vs 31.1 +/- 4.5 h; p < 0.05). Theophylline had no effect on the length of PICU stay or the total incidence of side effects. Subjects receiving theophylline had more emesis (p < 0.05), and control patients had more tremor (p < 0.05)., Conclusions: Theophylline safely hastened the recovery of children in severe status asthmaticus who were also receiving albuterol, ipratropium, and methylprednisolone. The role of theophylline in the management of asthmatic children in impending respiratory failure should be reexamined.

Reductions in hepatic O(2) delivery are common early after gram-negative bacteremic sepsis owing to cardiopulmonary dysfunction and derangements in sinusoidal perfusion. Although gram-negative endotoxin and cellular hypoxia independently enhance activation of nuclear factor-kappaB (NF-kappaB) via generation of reactive O(2) species (ROS), the combination of these stimuli downregulates hepatic TNF-alpha gene expression. Here we tested the hypothesis that hypoxic suppression of postbacteremic TNF-alpha gene expression is transcriptionally mediated by reduced activation of NF-kappaB. Buffer-perfused rat livers (n = 52) were studied over 180 min after intraportal infection at t = 0 with 10(9) live Escherichia coli (EC), serotype O55:B5, or 0.9% NaCl controls under normoxic conditions, compared with 0.5 h of constant-flow hypoxia (PO(2) approximately 41 +/- 7 Torr) beginning at t = 30 min, followed by 120 min of reoxygenation. In parallel studies, tissue was obtained at peak hypoxia (t = 60 min). To determine the role of xanthine oxidase (XO)-induced ROS in modulating NF-kappaB activity after hypoxia/reoxygenation (H/R), livers were pretreated with the XO inhibitor allopurinol, with results confirmed in organs of tungstate-fed animals. Electrophoretic mobility shift assays were performed on nuclear extracts of whole liver lysates using (32)P-labeled oligonucleotides specific for NF-kappaB. Compared with normoxic EC controls, hypoxia reduced postbacteremic NF-kappaB nuclear translocation and TNF-alpha bioactivity, independent of reoxygenation, tissue levels of reduced glutathione, or posthypoxic O(2) consumption. XO inhibition reversed the hypoxic suppression of NF-kappaB nuclear translocation and ameliorated decreases in cell-associated TNF-alpha. Thus decreases in hepatic O(2) delivery reduce postbacteremic nuclear translocation of NF-kappaB and hepatic TNF-alpha biosynthesis by signaling mechanisms involving low-level generation of XO-mediated ROS.

The abilities of pentoxifylline and recombinant interleukin-10 (rIL-10) to inhibit tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS) production in RAW 264.7 murine macrophages were compared. Pentoxifylline consistently inhibited the accumulation of both TNF and iNOS in a dose-dependent manner whether the stimulus was bacterial lipopolysaccharide (LPS), recombinant interferon-gamma (rIFN-gamma), or LPS plus rIFN-gamma. Similarly, rIL-10 consistently reduced TNF production by cells stimulated with LPS, rIFN-gamma, or LPS plus rIFN-gamma. However, rIL-10 weakly inhibited LPS-induced iNOS production but failed to block (and often augmented) rIFN-gamma-induced iNOS production. Combinations of pentoxifylline and rIL-10 led to additive or synergistic inhibition of TNF but not iNOS production; in fact, rIL-10 appeared to interfere with the ability of pentoxifylline to block iNOS accumulation. These data suggest that combinations of antiinflammatory agents may have unanticipated effects on inflammatory mediator production.