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Item Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19(AMA, 2021-02) Feldstein, Leora R.; Tenforde, Mark W.; Friedman, Kevin G.; Newhams, Margaret; Rose, Erica Billig; Dapul, Heda; Soma, Vijaya L.; Maddux, Aline B.; Mourani, Peter M.; Bowens, Cindy; Maamari, Mia; Hall, Mark W.; Riggs, Becky J.; Giuliano, John S.; Singh, Aalok R.; Li, Simon; Kong, Michele; Schuster, Jennifer E.; McLaughlin, Gwenn E.; Schwartz, Stephanie P.; Walker, Tracie C.; Loftis, Laura L.; Hobbs, Charlotte V.; Halasa, Natasha B.; Doymaz, Sule; Babbitt, Christopher J.; Hume, Janet R.; Gertz, Shira J.; Irby, Katherine; Clouser, Katharine N.; Cvijanovich, Natalie Z.; Bradford, Tamara T.; Smith, Lincoln S.; Heidemann, Sabrina M.; Zackai, Sheemon P.; Wellnitz, Kari; Nofziger, Ryan A.; Horwitz, Steven M.; Carroll, Ryan W.; Rowan, Courtney M.; Tarquinio, Keiko M.; Mack, Elizabeth H.; Fitzgerald, Julie C.; Coates, Bria M.; Jackson, Ashley M.; Young, Cameron C.; Son, Mary Beth F.; Patel, Manish M.; Newburger, Jane W.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineImportance 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.Item Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents(Elsevier, 2021-08-31) Geva, Alon; Patel, Manish M.; Geva, Alon; Patel, Manish M.; Newhams, Margaret M.; Young, Cameron C.; Son, Mary Beth F.; Kong, Michele; Maddux, Aline B.; Hall, Mark W.; Riggs, Becky J.; Singh, Aalok R.; Giuliano, John S.; Hobbs, Charlotte V.; Loftis, Laura L.; McLaughlin, Gwenn E.; Schwartz, Stephanie P.; Schuster, Jennifer E.; Babbitt, Christopher J.; Halasa, Natasha B.; Gertz, Shira J.; Doymaz, Sule; Hume, Janet R.; Bradford, Tamara T.; Irby, Katherine; Carroll, Christopher L.; McGuire, John K.; Tarquinio, Keiko M.; Rowan, Courtney M.; Mack, Elizabeth H.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Spinella, Philip C.; Staat, Mary A.; Clouser, Katharine N.; Soma, Vijaya L.; Dapul, Heda; Maamari, Mia; Bowens, Cindy; Havlin, Kevin M.; Mourani, Peter M.; Heidemann, Sabrina M.; Horwitz, Steven M.; Feldstein, Leora R.; Tenforde, Mark W.; Newburger, Jane W.; Mandl, Kenneth D.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineBackground 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.Item A Description of COVID-19-Directed Therapy in Children Admitted to US Intensive Care Units 2020(Oxford University Press, 2022) Schuster, Jennifer E.; Halasa, Natasha B.; Nakamura, Mari; Levy, Emily R.; Fitzgerald, Julie C.; Young, Cameron C.; Newhams, Margaret M.; Bourgeois, Florence; Staat, Mary A.; Hobbs, Charlotte V.; Dapul, Heda; Feldstein, Leora R.; Jackson, Ashley M.; Mack, Elizabeth H.; Walker, Tracie C.; Maddux, Aline B.; Spinella, Philip C.; Loftis, Laura L.; Kong, Michele; Rowan, Courtney M.; Bembea, Melania M.; McLaughlin, Gwenn E.; Hall, Mark W.; Babbitt, Christopher J.; Maamari, Mia; Zinter, Matt S.; Cvijanovich, Natalie Z.; Michelson, Kelly N.; Gertz, Shira J.; Carroll, Christopher L.; Thomas, Neal J.; Giuliano, John S., Jr.; Singh, Aalok R.; Hymes, Saul R.; Schwarz, Adam J.; McGuire, John K.; Nofziger, Ryan A.; Flori, Heidi R.; Clouser, Katharine N.; Wellnitz, Kari; Cullimore, Melissa L.; Hume, Janet R.; Patel, Manish; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineBackground: 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.Item Extracorporeal Membrane Oxygenation Characteristics and Outcomes in Children and Adolescents With COVID-19 or Multisystem Inflammatory Syndrome Admitted to U.S. ICUs(Wolters Kluwer, 2023) Bembea, Melania M.; Loftis, Laura L.; Thiagarajan, Ravi R.; Young, Cameron C.; McCadden, Timothy P.; Newhams, Margaret M.; Kucukak, Suden; Mack, Elizabeth H.; Fitzgerald, Julie C.; Rowan, Courtney M.; Maddux, Aline B.; Kolmar, Amanda R.; Irby, Katherine; Heidemann, Sabrina; Schwartz, Stephanie P.; Kong, Michele; Crandall, Hillary; Havlin, Kevin M.; Singh, Aalok R.; Schuster, Jennifer E.; Hall, Mark W.; Wellnitz, Kari A.; Maamari, Mia; Gaspers, Mary G.; Nofziger, Ryan A.; Lim, Peter Paul C.; Carroll, Ryan W.; Munoz, Alvaro Coronado; Bradford, Tamara T.; Cullimore, Melissa L.; Halasa, Natasha B.; McLaughlin, Gwenn E.; Pannaraj, Pia S.; Cvijanovich, Natalie Z.; Zinter, Matt S.; Coates, Bria M.; Horwitz, Steven M.; Hobbs, Charlotte V.; Dapul, Heda; Graciano, Ana Lia; Butler, Andrew D.; Patel, Manish M.; Zambrano, Laura D.; Campbell, Angela P.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineObjectives: 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.Item Frequency, Characteristics and Complications of COVID-19 in Hospitalized Infants(Wolters Kluwer, 2022) Hobbs, Charlotte V.; Woodworth, Kate; Young, Cameron C.; Jackson, Ashley M.; Newhams, Margaret M.; Dapul, Heda; Maamari, Mia; Hall, Mark W.; Maddux, Aline B.; Sing, Aalok R.; Schuster, Jennifer E.; Rowan, Courtney M.; Fitzgerald, Julie C.; Irby, Katherine; Kong, Michele; Mack, Elizabeth H.; Staat, Mary A.; Cvijanovich, Natalie Z.; Bembea, Melania M.; Coates, Bria M.; Halasa, Natasha B.; Walker, Tracie C.; McLaughlin, Gwenn E.; Babbitt, Christopher J.; Nofziger, Ryan A.; Loftis, Laura L.; Bradford, Tamara T.; Campbell, Angela P.; Patel, Manish M.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of MedicineBackground: 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.Item Infants Admitted to US Intensive Care Units for RSV Infection During the 2022 Seasonal Peak(American Medical Association, 2023-08-01) Halasa, Natasha; Zambrano, Laura D.; Amarin, Justin Z.; Stewart, Laura S.; Newhams, Margaret M.; Levy, Emily R.; Shein, Steven L.; Carroll, Christopher L.; Fitzgerald, Julie C.; Michaels, Marian G.; Bline, Katherine; Cullimore, Melissa L.; Loftis, Laura; Montgomery, Vicki L.; Jeyapalan, Asumthia S.; Pannaraj, Pia S.; Schwarz, Adam J.; Cvijanovich, Natalie Z.; Zinter, Matt S.; Maddux, Aline B.; Bembea, Melania M.; Irby, Katherine; Zerr, Danielle M.; Kuebler, Joseph D.; Babbitt, Christopher J.; Glas Gaspers, Mary; Nofziger, Ryan A.; Kong, Michele; Coates, Bria M.; Schuster, Jennifer E.; Gertz, Shira J.; Mack, Elizabeth H.; White, Benjamin R.; Harvey, Helen; Hobbs, Charlotte V.; Dapul, Heda; Butler, Andrew D.; Bradford, Tamara T.; Rowan, Courtney M.; Wellnitz, Kari; Allen Staat, Mary; Aguiar, Cassyanne L.; Hymes, Saul R.; Randolph, Adrienne G.; Campbell, Angela P.; RSV-PIC Investigators; Pediatrics, School of MedicineImportance: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide. Objective: To evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission. Design, setting, and participants: This cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection. Exposure: Respiratory syncytial virus. Main outcomes and measures: Data were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity. Results: The first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days. Conclusions and relevance: In this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.Item Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome(AMA, 2021-03) LaRovere, Kerri L.; Riggs, Becky J.; Poussaint, Tina Y.; Young, Cameron C.; Newhams, Margaret M.; Maamari, Mia; Walker, Tracie C.; Singh, Aalok R.; Dapul, Heda; Hobbs, Charlotte V.; McLaughlin, Gwenn E.; Son, Mary Beth F.; Maddux, Aline B.; Clouser, Katharine N.; Rowan, Courtney M.; McGuire, John K.; Fitzgerald, Julie C.; Gertz, Shira J.; Shein, Steven L.; Munoz, Alvaro Coronado; Thomas, Neal J.; Irby, Katherine; Levy, Emily R.; Staat, Mary A.; Tenforde, Mark W.; Feldstein, Leora R.; Halasa, Natasha B.; Giuliano, John S.; Hall, Mark W.; Kong, Michele; Carroll, Christopher L.; Schuster, Jennifer E.; Doymaz, Sule; Loftis, Laura L.; Tarquinio, Keiko M.; Babbitt, Christopher J.; Nofziger, Ryan A.; Kleinman, Lawrence C.; Keenaghan, Michael A.; Cvijanovich, Natalie Z.; Spinella, Philip C.; Hume, Janet R.; Wellnitz, Kari; Mack, Elizabeth H.; Michelson, Kelly N.; Flori, Heidi R.; Patel, Manish M.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Gaspers, Mary G; Typpo, Katri V; Sanders, Ronald C; Schwarz, Adam J; Harvey, Helen; Zinter, Matt S; Mourani, Peter M; Coates, Bria M; Bhoojhawon, Guru; Havlin, Kevin M; Montgomery, Vicki L; Sullivan, Janice E; Bradford, Tamara T; Bembea, Melania M; Lipton, Susan V; Graciano, Ana Lia; Chen, Sabrina R; Kucukak, Suden; Newburger, Jane W; Carroll, Ryan W; Fernandes, Neil D; Yager, Phoebe H; Marohn, Kimberly L; Heidemann, Sabrina M; Cullimore, Melissa L; McCulloh, Russell J; Horwitz, Steven M; Li, Simon; Walsh, Rowan F; Ratner, Adam J; Soma, Vijaya L; Gillen, Jennifer K; Zackai, Sheemon P; Ackerman, Kate G; Cholette, Jill M; Harwayne-Gidansky, Ilana; Hymes, Saul R; Overby, Philip J; Schwartz, Stephanie P; Lansell, Amanda N; Koncicki, Monica L; Carcillo, Joseph; Fink, Ericka; Kimura, Dai; Bowens, Cindy; Crandall, Hillary; Smith, Lincoln S; Cengiz, Pelin; Pediatrics, School of MedicineImportance 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.