IMPORTANCE: An estimated 1% to 3% of children with SARS-CoV-2 infection will develop post-COVID-19 condition (PCC). OBJECTIVE: To evaluate the odds of PCC among children with COVID-19 vaccination prior to SARS-CoV-2 infection compared with odds among unvaccinated children. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, children were enrolled in a multisite longitudinal pediatric cohort from July 27, 2021, to September 1, 2022, and followed up through May 2023. Analysis used a case (PCC reported)-control (no PCC reported) design and included children aged 5 to 17 years whose first real time-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection occurred during the study period, who were COVID-19 vaccine age-eligible at the time of infection, and who completed a PCC survey at least 60 days after infection. From December 1, 2022, to May 31, 2023, children had weekly SARS-CoV-2 testing and were surveyed regarding PCC (≥1 new or ongoing symptom lasting ≥1 month after infection). EXPOSURES: COVID-19 mRNA vaccination status at time of infection was the exposure of interest; participants were categorized as vaccinated (≥2-dose series completed ≥14 days before infection) or unvaccinated. Vaccination status was verified through vaccination cards or vaccine registry and/or medical records when available. MAIN OUTCOME AND MEASURES: Main outcomes were estimates of the odds of PCC symptoms. Multivariate logistic regression was performed to estimate the odds of PCC among vaccinated children compared with odds of PCC among unvaccinated children. RESULTS: A total of 622 participants were included, with 28 (5%) case participants and 594 (95%) control participants. Median (IQR) age was 10.0 (7.0-11.9) years for case participants and 10.3 (7.8-12.7) years for control participants (P = .37). Approximately half of both groups reported female sex (13 case participants [46%] and 287 control participants [48%]). Overall, 57% of case participants (16 children) and 77% of control participants (458 children) were vaccinated (P = .05). After adjusting for demographic characteristics, number of acute COVID-19 symptoms, and baseline health, COVID-19 vaccination was associated with decreased odds of 1 or more PCC symptom (adjusted odds ratio [aOR], 0.43; 95% CI, 0.19-0.98) and 2 or more PCC symptoms (aOR, 0.27; 95% CI, 0.10-0.69). CONCLUSIONS AND RELEVANCE: In this study, mRNA COVID-19 vaccination was associated with reduced odds of PCC in children. The aORs correspond to an estimated 57% and 73% reduced likelihood of 1 or more and 2 or more PCC symptoms, respectively, among vaccinated vs unvaccinated children. These findings suggest benefits of COVID-19 vaccination beyond those associated with protection against acute COVID-19 and may encourage increased pediatric uptake.

IMPORTANCE: Multisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness that occurs 2 to 6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severity differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes. OBJECTIVE: To characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, MIS-C phenotypic clusters were inferred using latent class analysis applied to the largest cohort to date of cases from US national surveillance data from 55 US public health jurisdictions. Cases reported to the Centers for Disease Control and Prevention MIS-C national surveillance program as of April 4, 2023, with symptom onset on or before December 31, 2022, were retrospectively analyzed. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with 20% or more missingness and 10% or less or 90% or more prevalence. A total of 389 cases missing 10 or more variables were excluded, and multiple imputation was conducted on the remaining cases. MAIN OUTCOMES AND MEASURES: Differences by cluster in prevalence of each clinical sign and symptom, percentage of patients admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time. RESULTS: Among 8944 included MIS-C cases (median [IQR] patient age, 8.7 [5.0-12.5] years; 5407 [60.5%] male), latent class analysis identified 3 clusters characterized by (1) frequent respiratory findings primarily affecting older children (respiratory cluster; 713 cases [8.0%]; median [IQR] age, 12.7 [6.3-16.5] years), (2) frequent shock and/or cardiac complications (shock and cardiac cluster; 3359 cases [37.6%]; median [IQR] age, 10.8 [7.7-14.0] years), and (3) remaining cases (undifferentiated cluster; 4872 cases [54.5%]; median [IQR] age, 6.8 [3.6-10.3] years). The percentage of patients with MIS-C admitted to the ICU was highest for the shock and cardiac cluster (82.3% [2765/3359]) followed by the respiratory (49.5% [353/713]) and undifferentiated clusters (33.0% [1609/4872]). Among patients with data on length of stay available, 129 of 632 hospitalizations (20.4%) and 54 of 281 ICU stays (19.2%) in the respiratory cluster lasted 10 or more days compared with 708 of 3085 (22.9%) and 157 of 2052 (7.7%), respectively, in the shock and cardiac cluster and 293 of 4467 (6.6%) and 19 of 1220 (1.6%), respectively, in the undifferentiated cluster. The proportion of cases in both the respiratory cluster and the shock and cardiac cluster decreased after emergence of the Omicron variant in the US. CONCLUSIONS AND RELEVANCE: In this cohort study, MIS-C cases clustered into 3 subgroups with distinct clinical phenotypes, severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and identify groups at highest risk for severe outcomes.

BACKGROUND: Pediatric respiratory syncytial virus (RSV)-related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. METHODS: We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 U.S. PICUs from October through December 2022. We assigned CPS-Ped (0=discharged home at respiratory baseline to 8=death) at admission, days 2-7,10, and 14. We identified predictors of clinical improvement (CPS-Ped≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). RESULTS: Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV). Of the 49 (8.4%) infants whose CPS-Ped score worsened by 2 points after admission, one died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2,031 for hospital LOS. CONCLUSIONS: CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV.

During 2023, the Centers for Disease Control and Prevention (CDC) recommended the first respiratory syncytial virus (RSV) immunizations intended for widespread use in the United States to prevent severe RSV illness in infants and older adults. CDC, in collaboration with federal, public health, and academic partners, is conducting evaluations of real-world effectiveness of recommended RSV immunization products in the United States. Similar frameworks for evaluation are being applied to RSV vaccines and nirsevimab, a long-acting preventative monoclonal antibody, to estimate product effectiveness. The overall goal of CDC's RSV immunization effectiveness program is to generate timely and robust evidence through observational studies to inform immunization product policy decisions and other measures related to RSV prevention and control. CDC is evaluating effectiveness through high-quality, well-controlled observational studies leveraging a variety of platforms that provide robust data to inform policy decisions.

BACKGROUND: Guidelines state that all hospitalized children with suspected or confirmed influenza receive prompt treatment with influenza-specific antivirals. We sought to determine the frequency of, and factors associated with, antiviral receipt among hospitalized children. METHODS: We conducted active surveillance of children presenting with fever or respiratory symptoms from 1 December 2016 to 31 March 2020 at 7 pediatric medical centers in the New Vaccine Surveillance Network. The cohort consisted of children hospitalized with influenza A or B confirmed by clinical or research testing. The primary outcome was frequency of antiviral receipt during hospitalization. We used logistic regression to obtain adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for factors associated with antiviral receipt. RESULTS: A total of 1213 children with laboratory-confirmed influenza were included. Overall, 652 children (53.8%) received an antiviral. Roughly 63.0% of children received clinical influenza testing. Among those with clinical testing, 67.4% received an antiviral. Factors associated with higher odds of antiviral receipt included hematologic (aOR = 1.76; 95% CI = 1.03-3.02) or oncologic/immunocompromising (aOR = 2.41; 95% CI = 1.13-5.11) disorders, prehospitalization antiviral receipt (aOR = 2.34; 95% CI = 1.49-3.67), clinical influenza testing (aOR = 3.07; 95% CI = 2.28-4.14), and intensive care unit admission (aOR = 1.53; 95% CI = 1.02-2.29). Symptom duration >2 days was associated with lower odds of antiviral treatment (aOR = 0.40; 95% CI = .30-.52). Antiviral receipt varied by site with a 5-fold difference across sites. CONCLUSIONS: Almost half of children hospitalized with influenza did not receive antivirals. Additional efforts to understand barriers to guideline adherence are crucial for optimizing care in children hospitalized with influenza.

Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention.

BACKGROUND: Previous investigations into clinical signs and symptoms associated with influenza types and subtypes have not definitively established differences in the clinical presentation or severity of influenza disease. METHODS: The study population included children 0 through 17 years old enrolled at 8 New Vaccine Surveillance Network sites between 2015 and 2020 who tested positive for influenza virus by molecular testing. Demographic and clinical data were collected for study participants via parent/guardian interview and medical chart review. Descriptive statistics were used to summarize demographic and clinical characteristics by influenza subtype. Multivariable logistic regression and Cox proportional hazard models were used to assess effects of age, sex, influenza subtype, and history of asthma on severity, including hospital admission, need for supplemental oxygen, and length of stay. RESULTS: Retractions, cyanosis, and need for supplemental oxygen were more frequently observed among patients with influenza A(H1N1)pdm09. Headaches and sore throat were more commonly reported among patients with influenza B. Children with influenza A(H1N1)pdm09 and children with asthma had significantly increased odds of hospital admission (adjusted odds ratio (AOR): 1.39, 95% CI: 1.14-1.69 and AOR: 2.14, 95% CI: 1.72-2.67, respectively). During admission, children with influenza A(H1N1)pdm09 had significantly increased use of supplemental oxygen compared to children with A(H3N2) (AOR: 0.60, 95% CI: 0.44-0.82) or B (AOR: 0.56, 95% CI: 0.41-0.76). CONCLUSIONS: Among children presenting to the emergency department and admitted to the hospital, influenza A(H1N1)pdm09 caused more severe disease compared to influenza A(H3N2) and influenza B. Asthma also contributed to severe influenza disease regardless of subtype.

Influenza C virus (ICV) is an orthomyxovirus related to influenza A and B, yet due to few commercial assays, epidemiologic studies may underestimate incidence of ICV infection and disease. We describe the epidemiology and characteristics of ICV within the New Vaccine Surveillance Network (NVSN), a Centers for Disease Control and Prevention (CDC)-led network that conducts population-based surveillance for pediatric acute respiratory illness (ARI). Nasal or/combined throat swabs were collected from emergency department (ED) or inpatient ARI cases, or healthy controls, between 12/05/2016-10/31/2019 and tested by molecular assays for ICV and other respiratory viruses. Parent surveys and chart review were used to analyze demographic and clinical characteristics of ICV+ children. Among 19,321 children tested for ICV, 115/17,668 (0.7 %) ARI cases and 8/1653 (0.5 %) healthy controls tested ICV+. Median age of ICV+ patients was 18 months and 88 (71.5 %) were ≤36 months. Among ICV+ ARI patients, 40 % (46/115) were enrolled in the ED, 60 % (69/115) were inpatients, with 15 admitted to intensive care. Most ICV+ ARI patients had fever (67.8 %), cough (94.8 %), or wheezing (60.9 %). Most (60.9 %) ARI cases had ≥1 co-detected viruses including rhinovirus, RSV, and adenovirus. In summary, ICV detection was rarely associated with ARI in children, and most ICV+ patients were ≤3 years old with co-detected respiratory viruses.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection(1,2), yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19.

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: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 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 = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection 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.

BACKGROUND AND OBJECTIVES: In June 2022, the mRNA COVID-19 vaccination was recommended for young children. We examined clinical characteristics and factors associated with vaccination status among vaccine-eligible young children hospitalized for acute COVID-19. METHODS: We enrolled inpatients aged 8 months to <5 years with acute community-acquired COVID-19 across 28 US pediatric hospitals from September 20, 2022 to May 31, 2023. We assessed demographic and clinical factors, including the highest level of respiratory support, and vaccination status defined as unvaccinated, incomplete, or complete primary series [at least 2 (Moderna) or 3 (Pfizer-BioNTech) mRNA vaccine doses ≥14 days before hospitalization]. RESULTS: Among 597 children, 174 (29.1%) patients were admitted to the intensive care unit and 75 (12.6%) had a life-threatening illness, including 51 (8.5%) requiring invasive mechanical ventilation. Children with underlying respiratory and neurologic/neuromuscular conditions more frequently received higher respiratory support. Only 4.5% of children hospitalized for COVID-19 (n = 27) had completed their primary COVID-19 vaccination series and 7.0% (n = 42) of children initiated but did not complete their primary series. Among 528 unvaccinated children, nearly half (n = 251) were previously healthy, 3 of them required extracorporeal membrane oxygenation for acute COVID-19 and 1 died. CONCLUSIONS: Most young children hospitalized for acute COVID-19, including most children admitted to the intensive care unit and with life-threatening illness, had not initiated COVID-19 vaccination despite being eligible. Nearly half of these children had no underlying conditions. Of the small percentage of children who initiated a COVID-19 primary series, most had not completed it before hospitalization.

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.

Infants aged <6 months are not eligible for COVID-19 vaccination. Vaccination during pregnancy has been associated with protection against infant COVID-19-related hospitalization. The Overcoming COVID-19 Network conducted a case-control study during March 9, 2022-May 31, 2023, to evaluate the effectiveness of maternal receipt of a COVID-19 vaccine dose (vaccine effectiveness [VE]) during pregnancy against COVID-19-related hospitalization in infants aged <6 months and a subset of infants aged <3 months. VE was calculated as (1 - adjusted odds ratio) x 100% among all infants aged <6 months and <3 months. Case-patients (infants hospitalized for COVID-19 outside of birth hospitalization and who had a positive SARS-CoV-2 test result) and control patients (infants hospitalized for COVID-19-like illness with a negative SARS-CoV-2 test result) were compared. Odds ratios were determined using multivariable logistic regression, comparing the odds of receipt of a maternal COVID-19 vaccine dose (completion of a 2-dose vaccination series or a third or higher dose) during pregnancy with maternal nonvaccination between case- and control patients. VE of maternal vaccination during pregnancy against COVID-19-related hospitalization was 35% (95% CI = 15%-51%) among infants aged <6 months and 54% (95% CI = 32%-68%) among infants aged <3 months. Intensive care unit admissions occurred in 23% of all case-patients, and invasive mechanical ventilation was more common among infants of unvaccinated (9%) compared with vaccinated mothers (1%) (p = 0.02). Maternal vaccination during pregnancy provides some protection against COVID-19-related hospitalizations among infants, particularly those aged <3 months. Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19.

We analyzed multisystem inflammatory syndrome in children cases by reported COVID-19 vaccination status (2-dose primary series vs. no vaccination). A total of 46% vaccinated versus 58% unvaccinated persons received intensive care unit-level care (P = 0.02); the risk of intensive care unit admission was 23% higher (adjusted relative risk: 1.23; 95% confidence interval: 1.03-1.48) among unvaccinated patients; 21 unvaccinated persons died. Multisystem inflammatory syndrome in children occurs after SARS-CoV-2 infection in vaccinated persons, but may be less severe.

BACKGROUND: The long-term effects of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) or acute COVID-19 are not well known. Our objective was to determine long-term outcomes. METHODS: Children hospitalized with MIS-C or COVID-19 at 3 US hospitals from March 2020, through February 2021 were followed to assess health through 2 years post-hospitalization using medical records and patient surveys. RESULTS: Medical record abstraction was performed for 183 patients hospitalized with MIS-C, 53 of whom participated in surveys, and 97 patients hospitalized with COVID-19, 35 of whom participated in surveys. Patients with MIS-C were younger (median, 9 vs. 14 years of age for COVID-19 patients; P = 0.004), more frequently male (62% vs. 39%; P < 0.001) and had more cardiac (14% vs. 2%; P = 0.001) and neurologic sequelae (8% vs. 1%; P = 0.023). Children with COVID-19 more often had other comorbidities (59% vs. 19%; P < 0.001). Full mental recovery at the time of survey 2 (median, 16 months post-hospitalization for patients with MIS-C and 20 months for patients with COVID-19) was 85% and 88%, respectively; full physical recovery was 87% and 81%, respectively; and nearly all had resumption of normal activities. Patients with MIS-C reported more frequent headache at 1 month (45% vs. 20%; P = 0.037). Patients with COVID-19 were more likely to report cough at 1 month (37% vs. 17%; P = 0.045). Fatigue persisted >1 year in 15%-20% of patients in both groups. CONCLUSIONS: Approximately 20% of children with MIS-C and COVID-19 continued to have symptoms including fatigue and headache >1 year after hospital discharge. The duration of these findings emphasizes the importance of providers following patients until sequelae have resolved.

IMPORTANCE: 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.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of MIS-C patient samples (n=199) to identify a distinct set of host proteins that are differentially targeted by patient autoantibodies relative to matched controls. We identified an autoreactive epitope within SNX8, a protein expressed primarily in immune cells which regulates an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed the SARS-CoV-2 proteome-wide MIS-C patient antibody response and found it to be differentially reactive to a distinct domain of the SARS-CoV-2 nucleocapsid (N) protein relative to controls. This viral N region and the mapped SNX8 epitope bear remarkable biochemical similarity. Furthermore, we find that many children with anti-SNX8 autoantibodies also have T-cells cross-reactive to both SNX8 and this distinct domain of the SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients develop a distinct immune response against the SARS-CoV-2 N protein that is associated with cross reactivity to the self-protein SNX8, demonstrating a link from the infection to the inflammatory syndrome. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition associated with antecedent SARS-CoV-2 infection. In the United States, reporting of MIS-C after vaccination is required under COVID-19 vaccine emergency use authorizations. This case series describes persons aged 12-20 years with MIS-C following COVID-19 vaccination reported to passive surveillance systems or through clinician outreach to CDC. Method(s): We investigated potential cases of MIS-C after COVID-19 vaccination reported to CDC's health department-based national MIS-C surveillance, the Vaccine Adverse Event Reporting System (VAERS, co-administered by CDC and the U.S. FDA), and CDC's Clinical Immunization Safety Assessment Project (CISA) from December 14, 2020, to August 31, 2021. We describe cases meeting the CDC MIS-C case definition. Any positive SARS-CoV-2 serology test satisfied the case criteria although anti-nucleocapsid antibody indicates SARS-CoV-2 infection, while anti-spike protein antibody indicates either infection or COVID-19 vaccination. Finding(s): We identified 21 persons with MIS-C after COVID-19 vaccination. Of these 21 persons, median age was 16 years (range, 12-20 years); 13 (62%) were male. All were hospitalized; 12 (57%) had intensive care unit admission, and all were discharged home. Fifteen (71%) of the 21 had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. Through August 2021, 21,335,331 persons aged 12-20 years had received >=1 dose of COVID-19 vaccine, making the overall reporting rate for MIS-C following vaccination 1.0 case per million persons receiving >=1 vaccine dose in this age group. The reporting rate for those without evidence of SARS-CoV-2 infection was 0.3 cases per million vaccinated persons. Interpretation(s): In our case series, we describe a small number of persons with MIS-C who had received >=1 COVID-19 vaccine dose before illness onset. Continued reporting of potential cases and surveillance for MIS-C illnesses after COVID-19 vaccination is warranted. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Objective Studies suggest infants may be at increased risk of severe COVID-19 relative to older children, but few data exist regarding the incidence of COVID-19 episodes and associated risk factors. We estimate incidence rates and describe characteristics associated with medically attended COVID-19 episodes among infants younger than 6 months of age. Methods We analyzed electronic medical record data from a cohort of infants born March 1, 2020-February 28, 2021. Data from three health care delivery systems included demographic characteristics, maternal and infant outpatient visit and hospitalization diagnoses, and SARSCoV-2 test results. Medically attended COVID-19 episodes were defined by positive SARSCoV-2 clinical tests and/or COVID-19 diagnosis codes during medical care visits. Unadjusted and site-adjusted incidence rates by infant month of age, low and high SARS-CoV-2 circulation periods and maternal COVID-19 diagnosis were calculated. Results Among 18,192 infants aged <6 months whose mothers received prenatal care within the three systems, 173 (1.0%) had medically attended COVID-19 episodes. Incidence rates were highest among infants aged under 1 month (2.0 per 1,000 person-weeks) and 1 month (2.0 per 1,000 person-weeks) compared with older infants. Incidence rates were also higher for infants born to women with postpartum COVID-19 compared with women without known COVID-19 and women diagnosed with COVID-19 during pregnancy. Conclusion Most medically attended COVID-19 episodes in infants aged <6 months were outpatient care encounters. Infants of women with postpartum COVID-19 had a higher risk of medically attended COVID-19 than infants born to mothers who were diagnosed during pregnancy or never diagnosed underscoring the importance of COVID-19 prevention measures for their household members and caregivers to prevent infections in infants. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

IMPORTANCE: Acute neurological involvement occurs in some patients with multisystem inflammatory syndrome in children (MIS-C), but few data report neurological and psychological sequelae, and no investigations include direct assessments of cognitive function 6 to 12 months after discharge. OBJECTIVE: To characterize neurological, psychological, and quality of life sequelae after MIS-C. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional cohort study was conducted in the US and Canada. Participants included children with MIS-C diagnosed from November 2020 through November 2021, 6 to 12 months after hospital discharge, and their sibling or community controls, when available. Data analysis was performed from August 2022 to May 2023. EXPOSURE: Diagnosis of MIS-C. MAIN OUTCOMES AND MEASURES: A central study site remotely administered a onetime neurological examination and in-depth neuropsychological assessment including measures of cognition, behavior, quality of life, and daily function. Generalized estimating equations, accounting for matching, assessed for group differences. RESULTS: Sixty-four patients with MIS-C (mean [SD] age, 11.5 [3.9] years; 20 girls [31%]) and 44 control participants (mean [SD] age, 12.6 [3.7] years; 20 girls [45%]) were enrolled. The MIS-C group exhibited abnormalities on neurological examination more frequently than controls (15 of 61 children [25%] vs 3 of 43 children [7%]; odds ratio, 4.7; 95% CI, 1.3-16.7). Although the 2 groups performed similarly on most cognitive measures, the MIS-C group scored lower on the National Institutes of Health Cognition Toolbox List Sort Working Memory Test, a measure of executive functioning (mean [SD] scores, 96.1 [14.3] vs 103.1 [10.5]). Parents reported worse psychological outcomes in cases compared with controls, particularly higher scores for depression symptoms (mean [SD] scores, 52.6 [13.1] vs 47.8 [9.4]) and somatization (mean [SD] scores, 55.5 [15.5] vs 47.0 [7.6]). Self-reported (mean [SD] scores, 79.6 [13.1] vs 85.5 [12.3]) and parent-reported (mean [SD] scores, 80.3 [15.5] vs 88.6 [13.0]) quality of life scores were also lower in cases than controls. CONCLUSIONS AND RELEVANCE: In this cohort study, compared with contemporaneous sibling or community controls, patients with MIS-C had more abnormal neurologic examinations, worse working memory scores, more somatization and depression symptoms, and lower quality of life 6 to 12 months after hospital discharge. Although these findings need to be confirmed in larger studies, enhanced monitoring may be warranted for early identification and treatment of neurological and psychological symptoms.

BACKGROUND: The diagnosis of SARS-CoV-2-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute COVID-19 and may impact clinical management. METHODS: In this retrospective cohort study, we applied the U.S. Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at six academic medical centers during March 1, 2020-December 31, 2021. MIS-A patients were matched on age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts. RESULTS: Through medical record review of 10,223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched COVID-19 patients, MIS-A patients were more likely to be non-Hispanic Black and less likely to be non-Hispanic White. MIS-A patients more likely had laboratory-confirmed COVID-19 ≥ 14 days prior to hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, MIS-A patients had higher neutrophil-to-lymphocyte ratio, C-reactive protein, ferritin, procalcitonin and D-dimer, compared with COVID-19 patients. MIS-A patients had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. Mortality was 6% in both cohorts. CONCLUSIONS: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

Pfizer-BioNTech COVID-19 vaccine is authorized for use in children and adolescents aged 12-15 years and is licensed by the Food and Drug Administration (FDA) for persons aged ≥16 (1). A randomized placebo-controlled trial demonstrated an efficacy of 100% (95% confidence interval [CI] = 75.3%-100%) in preventing outpatient COVID-19 in persons aged 12-15 years (2); however, data among adolescents on vaccine effectiveness (VE) against COVID-19 in real-world settings are limited, especially among hospitalized patients. In early September 2021, U.S. pediatric COVID-19 hospitalizations reached the highest level during the pandemic (3,4). In a test-negative, case-control study at 19 pediatric hospitals in 16 states during June 1-September 30, 2021, the effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was assessed among children and adolescents aged 12-18 years. Among 464 hospitalized persons aged 12-18 years (179 case-patients and 285 controls), the median age was 15 years, 72% had at least one underlying condition, including obesity, and 68% attended in-person school. Effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was 93% (95% CI = 83%-97%), during the period when B.1.617.2 (Delta) was the predominant variant. This evaluation demonstrated that 2 doses of Pfizer-BioNTech vaccine are highly effective at preventing COVID-19 hospitalization among persons aged 12-18 years and reinforces the importance of vaccination to protect U.S. youths against severe COVID-19.

BACKGROUND: Despite the disproportionate morbidity and mortality expeHealth Equity and Health Disparitiesrienced by American Indian and Alaska Native (AI/AN) persons during the coronavirus disease 2019 (COVID-19) pandemic, few studies have reported vaccine effectiveness (VE) estimates among these communities. METHODS: We conducted a test-negative case-control analysis among AI/AN persons aged ≥12 years presenting for care from January 1, 2021, through November 30, 2021, to evaluate the effectiveness of mRNA COVID-19 vaccines against COVID-19-associated outpatient visits and hospitalizations. Cases and controls were patients with ≥1 symptom consistent with COVID-19-like illness; cases were defined as those test-positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and controls were defined as those test-negative for SARS-CoV-2. We used unconditional multivariable logistic regression to estimate VE, defined as 1 minus the adjusted odds ratio for vaccination among cases vs controls. RESULTS: The analysis included 207 cases and 267 test-negative controls. Forty-four percent of cases and 78% of controls received 2 doses of either BNT162b2 or mRNA-1273 vaccine. VE point estimates for 2 doses of mRNA vaccine were higher for hospitalized participants (94.6%; 95% CI, 88.0-97.6) than outpatient participants (86.5%; 95% CI, 63.0-95.0), but confidence intervals overlapped. CONCLUSIONS: Among AI/AN persons, mRNA COVID-19 vaccines were highly effective in preventing COVID-associated outpatient visits and hospitalizations. Maintaining high vaccine coverage, including booster doses, will reduce the burden of disease in this population.

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.

BACKGROUND: In a 2020 pilot case-control study using medical records, we reported that non-Hispanic Black children were more likely to develop multisystem inflammatory syndrome in children (MIS-C) after adjustment for sociodemographic factors and underlying medical conditions. Using structured interviews, we investigated patient, household, and community factors underlying MIS-C likelihood. METHODS: MIS-C case patients hospitalized in 2021 across 14 US pediatric hospitals were matched by age and site to outpatient controls testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the admission date. Caregiver interviews queried race/ethnicity, medical history, and household and potential community exposures 1 month before MIS-C hospitalization (case-patients) or after SARS-CoV-2 infection (controls). We calculated adjusted odds ratios (aOR) using mixed-effects multivariable logistic regression. RESULTS: Among 275 case patients and 496 controls, race/ethnicity, social vulnerability and patient or family history of autoimmune/rheumatologic disease were not associated with MIS-C. In previously healthy children, MIS-C was associated with a history of hospitalization for an infection [aOR: 4.8; 95% confidence interval (CI): 2.1-11.0]. Household crowding (aOR: 1.7; 95% CI: 1.2-2.6), large event attendance (aOR: 1.7; 95% CI: 1.3-2.1), school attendance with limited masking (aOR: 2.6; 95% CI: 1.1-6.6), public transit use (aOR: 1.8; 95% CI: 1.4-2.4) and co-resident testing positive for SARS-CoV-2 (aOR: 2.2; 95% CI: 1.3-3.7) were associated with increased MIS-C likelihood, with risk increasing with the number of these factors. CONCLUSIONS: From caregiver interviews, we clarify household and community exposures associated with MIS-C; however, we did not confirm prior associations between sociodemographic factors and MIS-C.

OBJECTIVE: Evidence regarding effectiveness of interleukin-1 receptor antagonism in Multisystem Inflammatory Syndrome in Children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy. METHODS: We conducted a retrospective cohort study of MIS-C cases in a U.S. surveillance registry November 2020-December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids vs. anakinra plus IVIG and/or glucocorticoids (days 0-1), using inverse probability weighting to balance severity. Primary outcomes were vasopressor requirement (day 3) and impaired left ventricular ejection fraction (days 3-4). The secondary outcome was 50% reduction in C-reactive protein (day 3). RESULTS: Among 1516 MIS-C cases (44 sites), 193 (13%) received anakinra alone or with other immunomodulators as initial treatment (range 0-74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (N=121) vs. IVIG and glucocorticoids (N=389) was not associated with significant differences in vasopressor requirement (25.6% vs. 20.1%; RR 1.27, 95% CI [0.88-1.84]), ventricular dysfunction (33.7% vs. 25.7%; RR 1.31, 95% CI [0.98-1.75]), or C-reactive protein reduction. CONCLUSIONS: We identified substantial variation in initial anakinra use in a real-world population of children with MIS-C, but no average short-term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone.

Aseptic meningitis is a rare but potentially serious complication of intravenous immunoglobulin (IVIG) treatment. In this case series, meningitic symptoms following IVIG initiation in patients with multisystem inflammatory syndrome were rare (7/2,086 [0.3%]). However, they required the need for additional therapy and/or readmission.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a multiorgan hyperinflammatory condition following SARS-CoV-2 infection. Data on COVID-19 vaccine adverse events and vaccine attitudes in children with prior MIS-C are limited. We described characteristics associated with COVID-19 vaccination, vaccine adverse events and vaccine attitudes in children with a history of MIS-C or COVID-19 and their parents/guardians. METHODS: We enrolled children previously hospitalized for MIS-C or COVID-19 from 3 academic institutions. We abstracted charts and interviewed children and parents/guardians regarding vaccine adverse events and acceptability. RESULTS: Of 163 vaccine-eligible children enrolled with a history of MIS-C and 70 with history of COVID-19, 51 (31%) and 34 (49%), respectively, received mRNA COVID-19 vaccine a median of 10 (Interquartile Range 6-13) months after hospital discharge. Among 20 children with MIS-C and parents/guardians who provided interviews, local injection site reaction of brief duration (mean 1.8 days) was most commonly reported; no children required medical care within 2 weeks postvaccination. Vaccine survey results of interviewed, vaccinated children and their parents/guardians: of 20 children with MIS-C and 15 children with COVID-19, 17 (85%) and 13 (87%), respectively, listed doctors in the top 3 most trusted sources for vaccine information; 13 (65%) and 9 (60%) discussed vaccination with their doctor. CONCLUSIONS: COVID-19 vaccination was well tolerated in children with prior MIS-C or COVID-19 participating in our investigation. Parents/guardians regarded their children's doctors as a trusted source of information for COVID-19 vaccines, and most vaccinated children's parents/guardians had discussed COVID-19 vaccination for their child with their doctor.