BACKGROUND: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are genetically related viruses and major causes of medically attended acute respiratory illness in children. Research comparing the severity of illnesses resulting from these infections lacks consensus. METHODS: Children younger than 18 years with acute respiratory illness were enrolled through active, prospective surveillance from 2016 to 2020 at 7 US pediatric hospitals and emergency departments (EDs). Clinical information was obtained from parent interviews and medical records. Midturbinate nasal swabs were collected and tested for RSV and HMPV using molecular diagnostic assays at each site. We compared descriptive and clinical features of children with RSV or HMPV and calculated adjusted odds ratios (aOR) for severe outcomes comparing RSV with HMPV. Risk factors for severe outcomes were assessed in children with RSV or HMPV using logistic regression models. RESULTS: A total of 5329 children hospitalized with RSV (n = 4398) or HMPV (n = 931) and 3276 children with RSV-associated (n = 2371) or HMPV-associated (n = 905) ED visits were enrolled. The median age of children hospitalized with RSV was lower than that of children with HMPV (7 months vs 16 months, P < .0001). Children presenting to the ED with RSV-associated acute respiratory illness had higher odds of being hospitalized than children with HMPV (aOR, 1.68; 95% CI, 1.50-1.87), with the highest odds in infants younger than 6 months (aOR, 3.27; 95% CI, 2.53-4.23). Underlying conditions were more than twice as common among infants hospitalized with HMPV (26%) than those with RSV (11%). CONCLUSIONS: Children with HMPV-associated hospitalization tend to be older and more likely to have underlying medical conditions compared with children with RSV-associated hospitalization.

BACKGROUND: Influenza contributes to a high burden of pediatric emergency department (ED) visits annually. Guidelines recommend outpatient antiviral treatment for children at higher risk of severe influenza and recommend considering treatment for those who present within 2 days of symptom onset. We describe antiviral prescription in children with influenza presenting to the ED. METHODS: We analyzed data from the New Vaccine Surveillance Network (2016-2020), including children presenting to the ED and enrolled with confirmed influenza at one of seven pediatric academic centers. We compared characteristics of children prescribed antivirals to those who were not, using generalized estimating equations models to identify predictors of antiviral prescription. Children were considered at higher risk of severe influenza if they were < 5 years old or had an underlying condition. RESULTS: Overall, 2472 (15%) of 16,915 enrolled children tested positive for influenza virus. Among these, 1931 (78%) were at higher risk of severe influenza; only 622 (32%) received an antiviral. Among 233 (9%) children not at high risk with symptom onset ≤ 2 days, 62 (27%) were prescribed an antiviral. Children prescribed an antiviral had a shorter duration of illness prior to presenting to the ED. For children at higher risk of severe influenza, odds of antiviral prescription were higher for those clinically tested for influenza and with underlying conditions. CONCLUSION: Clinical testing and having an underlying condition were associated with antiviral prescription in children at higher risk of severe influenza. However, only 1/3 of those at higher risk were prescribed an antiviral. Strategies to increase antiviral use for children at higher risk for influenza in the ED are needed.

In this 2017-2019 community-based cohort, 245 healthy children were followed from birth to age two years. 46 EV-D68 infections were detected by nasal swabs, all between 08/2018-11/2018, with no detections in other study periods. 46% of infections met ARI criteria, of which 33% were medically attended; none required hospitalization.

BACKGROUND: Risk factors for severe respiratory syncytial virus (RSV) illness include early infancy, premature birth, and underlying medical conditions. However, the clinical significance of respiratory viral co-detection is unclear. We compared the clinical outcomes of young children with RSV-only detection and those with RSV viral co-detection. METHODS: We conducted active, population-based surveillance of children with medically attended fever or respiratory symptoms at 7 US medical centers (1 December 2016-31 March 2020). Demographic and clinical data were collected through parental interviews and chart abstractions. Nasal swabs, with or without throat swabs, were systematically tested for RSV and 6 other common respiratory virus groups. We compared clinical outcomes, including hospitalization, and among those hospitalized, length of stay, intensive care unit admission, supplemental oxygen use, and intubation, between children aged <2 years with RSV-only detection and those with RSV co-detection. RESULTS: We enrolled 18 008 children aged <2 years. Of 17 841 (99.1%) tested for RSV, 5099 (28.6%) were positive. RSV was singly detected in 3927 children (77.0%) and co-detected in 1172 (23.0%). RSV co-detection with parainfluenza virus or adenovirus was associated with significantly lower odds of hospitalization (adjusted odds ratio, 0.56; 95% confidence interval [CI]: .33-.95; P = .031) and supplemental oxygen use (adjusted odds ratio, 0.66; 95% CI: .46-.95; P = .026), respectively, than RSV-only detection. For all other comparisons, we did not identify a significant association between RSV co-detection and worse clinical outcomes. CONCLUSIONS: Co-detection of RSV with another respiratory virus was not significantly associated with worse clinical outcomes compared with RSV-only detection.

IMPORTANCE: Enterovirus D68 (EV-D68) typically causes mild to severe acute respiratory illness (ARI). Testing and surveillance for EV-D68 in the US are limited, and important epidemiologic gaps remain. OBJECTIVE: To characterize the epidemiology and clinical severity of EV-D68 among US children seeking care for ARI from 2017 to 2022, using a multisite, active, systematic surveillance network. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study collected data from the New Vaccine Surveillance Network, an active, prospective, population-based surveillance system of emergency departments (EDs) and hospitals at 7 US academic medical centers. Children with ARI and EV-D68-positive results were enrolled during platform-wide EV-D68 testing periods (July to October 2017, July to November 2018, July to November 2020, and July 2021 to December 2022). Included children were aged younger than 18 years, reported 1 or more qualifying ARI symptoms, with a symptom duration less than 14 days at enrollment. Data were analyzed from in October 2024. EXPOSURES: Laboratory-confirmed EV-D68 infection, including overall infections or those without viral codetection. MAIN OUTCOMES AND MEASURES: Trends and characteristics of EV-D68, including demographics, underlying conditions, and clinical severity by health care setting, were explored. Among hospitalized children with EV-D68-positive results without viral codetection, multivariable logistic regression was used to examine factors associated with receipt of (1) supplemental oxygen or (2) intensive care. RESULTS: From 2017 to 2022, 976 children with EV-D68-positive results were identified (median [IQR] age, 47 [18-63] months; 391 [40.1%] female); most were enrolled in 2018 (382 children) and 2022 (533 children). Among these, 856 had no viral codetection, of which 320 were discharged home from the ED (median [IQR] age, 33 [16-59] months; 180 male [56.3%]; 237 [74.1%] with no reported underlying conditions) and 536 were hospitalized (median [IQR] age, 40 [19-69] months; 330 male [61.6%]; 268 [50.0%] with no reported underlying conditions). Among those hospitalized, 199 (37.1%) reported a history of asthma or reactive airway disease (RAD) and 77 (14.4%) reported a condition other than asthma or RAD. Having an underlying condition other than asthma or RAD was associated with increased odds of receiving supplemental oxygen (adjusted odds ratio, 2.72; 95% CI, 1.43-5.18) or intensive care admission (adjusted odds ratio, 3.09; 95% CI, 1.72-5.56); neither age group nor history of asthma or RAD were associated with oxygen receipt or intensive care admission. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of children with medically attended EV-D68 infections, EV-D68 was associated with severe disease in otherwise healthy children of all ages, and children with nonasthma or RAD comorbidities were at higher risk for severe outcomes when hospitalized.

BACKGROUND: Human parainfluenza viruses (PIV) are a major cause of acute respiratory infection (ARI) leading to hospitalization in young children. In order to quantify the burden of PIV hospitalizations and to evaluate the characteristics of children hospitalized with PIV by virus type, we used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective population-based surveillance network, enrolling children hospitalized for ARI (defined as fever and/or respiratory symptoms) at 7 U.S. children's hospitals. METHODS: The study period included December 1, 2016 through March 31, 2020. Data captured included demographic characteristics, clinical presentation, underlying medical conditions, discharge diagnoses, and virus detection by RT-PCR. Linear and logistic regression were used to compare descriptive and clinical characteristics among children. Population-based PIV-associated hospitalization rates were calculated by age group and PIV-type. RESULTS: Of the 16,791 enrolled children with PIV virologic testing, 10,488 had only one respiratory virus detected, among whom 702 (7%) had positive testing for PIV without a co-detected virus (mean age [SD], 2.2 [3.2] years). Of these 702 children, 340 (48%) had underlying comorbidities, 139 (20%) had a history of prematurity, 121 (17%) were admitted to the ICU, and 23 (3%) required intubation. Overall, PIV hospitalization rates were highest in children aged 0-5 months (1.91 hospitalizations per 1,000 children per year [95% CI, 1.61-2.23], with PIV-3 contributing to the highest rates in that age group, followed by PIV-1 and PIV-4: 1.08 [0.84-1.21], 0.42 [0.28-0.58] and 0.25 [0.15-0.37] per 1,000 children per year, respectively. Seasonal distribution of PIV-associated hospitalizations varied by type. CONCLUSIONS: PIV infection was associated with a substantial number of ARI hospitalizations in children aged 0-5 months. Results suggest that future PIV prevention strategies in the US that focus on younger children and protection against PIV-3, PIV-1, and PIV-4 might have the greatest impact on reducing PIV hospitalization burden.

IMPORTANCE: Preterm infants are recommended to receive most vaccinations at the same postnatal age as term infants. Studies have inconsistently observed an increased risk for postvaccination apnea in preterm infants. OBJECTIVE: To compare the proportions of hospitalized preterm infants with apnea and other adverse events in the 48 hours after 2-month vaccinations vs after no vaccinations. DESIGN, SETTING, AND PARTICIPANTS: This randomized, open-label clinical trial took place at 3 US neonatal intensive care units between August 2018 and October 2021. Infants between 6 and 12 weeks' postnatal age who were born at less than 33 weeks' gestational age and were eligible to receive 2-month vaccines were included. INTERVENTION: Infants were randomized 1:1 to vaccinated (received vaccines within 12 hours of randomization) or unvaccinated (no vaccines received during the study period) groups. Cardiorespiratory data were collected during the 48 hours after vaccination or randomization (unvaccinated group). MAIN OUTCOMES AND MEASURES: The primary outcome was apnea, defined as a respiration pause greater than 20 seconds or a respiration pause greater than 15 seconds with associated bradycardia less than 80 beats per minute. Other outcomes included the number and duration of apnea episodes, serious adverse events, respiratory support escalation, and receipt of positive pressure ventilation. RESULTS: Of 223 randomized infants (117 female; median [range] gestational age, 27.6 [23.0-32.9] weeks), 107 (48%) were vaccinated, and 116 (52%) were unvaccinated. For 2 infants in the vaccinated group, the primary outcome was unable to be assessed. The proportion of infants with 1 or more apnea event was 25 of 105 (24%) in the vaccinated group vs 12 of 116 (10%) in the unvaccinated group (adjusted odds ratio, 2.70; 95% CI, 1.27 to 5.73; P = .01). The mean number of apneic episodes did not significantly differ (model point estimate of difference, 0.54; 95% CI, -0.12 to 1.21) between the vaccinated (2.72) and unvaccinated (2.00) groups. The mean duration of apneic episodes did not significantly differ (model point estimate of difference, 4.6; 95% CI, -5.4 to 14.7) between the vaccinated (27.7) and unvaccinated (32.3) groups. No serious adverse events occurred during the 48-hour monitoring period. Other outcomes were not significantly different between groups. CONCLUSIONS AND RELEVANCE: In hospitalized preterm infants, the odds of apnea within 48 hours were higher after 2-month vaccinations vs after no vaccinations. The similar number and duration of apneic events and lack of serious adverse events suggest that current vaccination recommendations for hospitalized preterm infants are appropriate. Neonatal clinicians should continue providing evidence-based anticipatory guidance about postvaccination apnea risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03530124.

IMPORTANCE: Increasing the understanding of vaccine effectiveness (VE) against levels of severe influenza in children could help increase uptake of influenza vaccination and strengthen vaccine policies globally. OBJECTIVE: To investigate VE in children by severity of influenza illness. DESIGN, SETTING, AND PARTICIPANTS: This case-control study with a test-negative design used data from 8 participating medical centers located in geographically different US states in the New Vaccine Surveillance Network from November 6, 2015, through April 8, 2020. Participants included children 6 months through 17 years of age who were hospitalized or presented to an emergency department (ED) with acute respiratory illness. EXPOSURES: Receipt of at least 1 dose of the current season's influenza vaccine. MAIN OUTCOMES AND MEASURES: Demographic and clinical characteristics of patients presenting to the hospital or ED with or without influenza were recorded and grouped by influenza vaccination status. Estimated VE against severe influenza illness was calculated using multiple measures to capture illness severity. Data were analyzed between June 1, 2022, and September 30, 2023. RESULTS: Among 15 728 children presenting for care with acute respiratory illness (8708 [55.4%] male; 13 450 [85.5%] 6 months to 8 years of age and 2278 [14.5%] 9-17 years of age), 2710 (17.2%) had positive influenza tests and 13 018 (82.8%) had negative influenza tests (controls). Of the influenza test-positive cases, 1676 children (61.8%) had an ED visit, 896 children (33.1%) required hospitalization for noncritical influenza, and 138 children (5.1%) required hospitalization for critical influenza. About half (7779 [49.5%]) of the children (both influenza test positive and test negative) were vaccinated. Receiving at least 1 influenza vaccine dose was estimated to have a VE of 55.7% (95% CI, 51.6%-59.6%) for preventing influenza-associated ED visits or hospitalizations among children of all ages. The estimated VE was similar across severity levels: 52.8% (95% CI, 46.6%-58.3%) for ED visits, 52.3% (95% CI, 44.8%-58.8%) for noncritical hospitalization, and 50.4% (95% CI, 29.7%-65.3%) for critical hospitalization. CONCLUSIONS AND RELEVANCE: Findings from this case-control study with a test-negative design involving children with a spectrum of influenza severity suggest that influenza vaccination protects children against all levels of severe influenza illness.

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.

IMPORTANCE: During the 2023-2024 respiratory syncytial virus (RSV) season in the United States, 2 new RSV prevention products were recommended to protect infants in their first RSV season: nirsevimab and Pfizer's maternal RSV vaccine. Postlicensure studies are needed to assess prevention product impact and effectiveness. OBJECTIVE: To compare the epidemiology and disease burden of medically attended RSV-associated acute respiratory illness (ARI) among children younger than 5 years during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020), estimate nirsevimab effectiveness against medically attended RSV-associated ARI, and compare nirsevimab binding site mutations among circulating RSV in infants with and without nirsevimab receipt. DESIGN, SETTING, AND PARTICIPANTS: This study included a prospective population-based surveillance for medically attended ARI with systematic molecular testing for RSV and whole-genome sequencing of RSV positive samples, as well as a test-negative case-control design to estimate nirsevimab effectiveness. The study was conducted in 7 academic pediatric medical centers in the United States with data from RSV seasons (September 1 through April 30) in 2017 through 2024. Participants were children younger than 5 years with medically attended ARI. EXPOSURE: For the nirsevimab effectiveness analyses, nirsevimab receipt among infants younger than 8 months as of or born after October 1, 2023. MAIN OUTCOME AND MEASURE: Medically attended RSV-associated ARI. RESULTS: Overall, 28 689 children younger than 5 years with medically attended ARI were enrolled, including 9536 during September 1, 2023, through April 30, 2024, and 19 153 during the same calendar period of 2017-2020. Of these children, 16 196 (57%) were male, and 12 444 (43.4) were female; the median (IQR) age was 15 (6-29) months. During 2023-2024, the proportion of children with RSV was 23% (2199/9490) among all medically attended episodes, similar to 2017-2020. RSV-associated hospitalization rates in 2023-2024 were similar to average 2017-2020 seasonal rates with 5.0 (95% CI, 4.6-5.3) per 1000 among children younger than 5 years; the highest rates were among children aged 0 to 2 months (26.6; 95% CI, 23.0-30.2). Low maternal RSV vaccine uptake precluded assessment of effectiveness. Overall, 10 of 765 case patients (1%) who were RSV positive and 126 of 851 control patients (15%) who were RSV negative received nirsevimab. Nirsevimab effectiveness was 89% (95% CI, 79%-94%) against medically attended RSV-associated ARI and 93% (95% CI, 82%-97%) against RSV-associated hospitalization. Among 229 sequenced specimens, there were no differences in nirsevimab binding site mutations by infant nirsevimab receipt status. CONCLUSIONS AND RELEVANCE: This analysis documented the continued high burden of medically attended RSV-associated ARI among young children in the US. There is a potential for substantial public health impact with increased and equitable prevention product coverage in future seasons.

Annually, tens of thousands of U.S. children and adolescents are hospitalized with seasonal influenza virus infection. Both influenza vaccination and early initiation of antiviral treatment can reduce complications of influenza. Using data from two U.S. influenza surveillance networks for children and adolescents aged <18 years with medically attended, laboratory-confirmed influenza for whom antiviral treatment is recommended, the percentage who received treatment was calculated. Trends in antiviral treatment of children and adolescents hospitalized with influenza from the 2017-18 to the 2023-2024 influenza seasons were also examined. Since 2017-18, when 70%-86% of hospitalized children and adolescents with influenza received antiviral treatment, the proportion receiving treatment notably declined. Among children and adolescents with influenza during the 2023-24 season, 52%-59% of those hospitalized received antiviral treatment. During the 2023-24 season, 31% of those at higher risk for influenza complications seen in the outpatient setting in one network were prescribed antiviral treatment. These findings demonstrate that influenza antiviral treatment is underutilized among children and adolescents who could benefit from treatment. All hospitalized children and adolescents, and those at higher risk for influenza complications in the outpatient setting, should receive antiviral treatment as soon as possible for suspected or confirmed influenza.

IMPORTANCE: Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines. OBJECTIVE: To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4). DESIGN, SETTING, AND PARTICIPANTS: This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines. INTERVENTIONS: Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2. MAIN OUTCOMES AND MEASURES: The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups. RESULTS: A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05028361.

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.

A modified Vesikari severity score (MVSS) is a useful research tool for assessing severity of acute gastroenteritis. We present a MVSS for studies in which a follow-up assessment of symptoms cannot be obtained. The MVSS significantly correlated with other markers of severity, including illness duration and work and school absenteeism.

BACKGROUND: The coronavirus disease 2019 pandemic disrupted respiratory syncytial virus (RSV) seasonality resulting in early, atypical RSV seasons in 2021 and 2022, with an intense 2022 peak overwhelming many pediatric healthcare facilities. METHODS: We conducted prospective surveillance for acute respiratory illness during 2016-2022 at 7 pediatric hospitals. We interviewed parents, reviewed medical records, and tested respiratory specimens for RSV and other respiratory viruses. We estimated annual RSV-associated hospitalization rates in children aged <5 years and compared hospitalization rates and characteristics of RSV-positive hospitalized children over 4 prepandemic seasons (2016-2020) to those hospitalized in 2021 or 2022. RESULTS: There was no difference in median age or age distribution between prepandemic and 2021 seasons. Median age of children hospitalized with RSV was higher in 2022 (9.6 months vs 6.0 months, P < .001). RSV-associated hospitalization rates were higher in 2021 and 2022 than the prepandemic average across age groups. Comparing 2021 to 2022, RSV-associated hospitalization rates were similar among children <2 years of age; however, children aged 24 to 59 months had significantly higher rates of RSV-associated hospitalization in 2022 (rate ratio 1.68 [95% confidence interval 1.37-2.00]). More RSV-positive hospitalized children received supplemental oxygen and there were more respiratory virus codetections in 2022 than in prepandemic seasons (P < .001 and P = .003, respectively), but there was no difference in the proportion hypoxemic, mechanically ventilated, or admitted to intensive care. CONCLUSIONS: The atypical 2021 and 2022 RSV seasons resulted in higher hospitalization rates with similar disease severity to prepandemic seasons.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illnesses in children. RSV can be broadly categorized into 2 major subtypes: A and B. RSV subtypes have been known to cocirculate with variability in different regions of the world. Clinical associations with viral subtype have been studied among children with conflicting findings such that no conclusive relationships between RSV subtype and severity have been established. METHODS: During 2016-2020, children aged <5 years were enrolled in prospective surveillance in the emergency department or inpatient settings at 7 US pediatric medical centers. Surveillance data collection included parent/guardian interviews, chart reviews, and collection of midturbinate nasal plus/minus throat swabs for RSV (RSV-A, RSV-B, and untyped) using reverse transcription polymerase chain reaction. RESULTS: Among 6398 RSV-positive children aged <5 years, 3424 (54%) had subtype RSV-A infections, 2602 (41%) had subtype RSV-B infections, and 272 (5%) were not typed, inconclusive, or mixed infections. In both adjusted and unadjusted analyses, RSV-A-positive children were more likely to be hospitalized, as well as when restricted to <1 year. By season, RSV-A and RSV-B cocirculated in varying levels, with 1 subtype dominating proportionally. CONCLUSIONS: Findings indicate that RSV-A and RSV-B may only be marginally clinically distinguishable, but both subtypes are associated with medically attended illness in children aged <5 years. Furthermore, circulation of RSV subtypes varies substantially each year, seasonally and geographically. With introduction of new RSV prevention products, this highlights the importance of continued monitoring of RSV-A and RSV-B subtypes.

IMPORTANCE: Studies of influenza in children commonly rely on coded diagnoses, yet the ability of International Classification of Diseases, Ninth Revision codes to identify influenza in the emergency department (ED) and hospital is highly variable. The accuracy of newer International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to identify influenza in children is unknown. OBJECTIVE: To determine the accuracy of ICD-10 influenza discharge diagnosis codes in the pediatric ED and inpatient settings. DESIGN, SETTING, AND PARTICIPANTS: Children younger than 18 years presenting to the ED or inpatient settings with fever and/or respiratory symptoms at 7 US pediatric medical centers affiliated with the Centers for Disease Control and Prevention-sponsored New Vaccine Surveillance Network from December 1, 2016, to March 31, 2020, were included in this cohort study. Nasal and/or throat swabs were collected for research molecular testing for influenza, regardless of clinical testing. Data, including ICD-10 discharge diagnoses and clinical testing for influenza, were obtained through medical record review. Data analysis was performed in August 2023. MAIN OUTCOMES AND MEASURES: The accuracy of ICD-10-coded discharge diagnoses was characterized using molecular clinical or research laboratory test results as reference. Measures included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Estimates were stratified by setting (ED vs inpatient) and age (0-1, 2-4, and 5-17 years). RESULTS: A total of 16 867 children in the ED (median [IQR] age, 2.0 [0.0-4.0] years; 9304 boys [55.2%]) and 17 060 inpatients (median [IQR] age, 1.0 [0.0-4.0] years; 9798 boys [57.4%]) were included. In the ED, ICD-10 influenza diagnoses were highly specific (98.0%; 95% CI, 97.8%-98.3%), with high PPV (88.6%; 95% CI, 88.0%-89.2%) and high NPV (85.9%; 95% CI, 85.3%-86.6%), but sensitivity was lower (48.6%; 95% CI, 47.6%-49.5%). Among inpatients, specificity was 98.2% (95% CI, 98.0%-98.5%), PPV was 82.8% (95% CI, 82.1%-83.5%), sensitivity was 70.7% (95% CI, 69.8%-71.5%), and NPV was 96.5% (95% CI, 96.2%-96.9%). Accuracy of ICD-10 diagnoses varied by patient age, influenza season definition, time between disease onset and testing, and clinical setting. CONCLUSIONS AND RELEVANCE: In this large cohort study, influenza ICD-10 discharge diagnoses were highly specific but moderately sensitive in identifying laboratory-confirmed influenza; the accuracy of influenza diagnoses varied by clinical and epidemiological factors. In the ED and inpatient settings, an ICD-10 diagnosis likely represents a true-positive influenza case.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.

BACKGROUND: The endemic coronaviruses OC43, HKU1, NL63 and 229E cause cold-like symptoms and are related to SARS-CoV-2, but their natural histories are poorly understood. In a cohort of children followed from birth to 4 years, we documented all coronavirus infections, including SARS-CoV-2, to understand protection against subsequent infections with the same virus (homotypic immunity) or a different coronavirus (heterotypic immunity). METHODS: Mother-child pairs were enrolled in metropolitan Cincinnati during the third trimester of pregnancy in 2017-18. Mothers reported their child's socio-demographics, risk factors, and weekly symptoms. Mid-turbinate nasal swabs were collected weekly. Blood was collected at 6 weeks, 6, 12, 18, 24 months and annually thereafter. Infections were detected by testing nasal swabs by an RT-PCR multi-pathogen panel and by serum IgG responses. Health care visits were documented from pediatric records. Analysis was limited to 116 children with high sample adherence. Re-consent for monitoring SARS-CoV-2 infections from June 2020 through November 2021 was obtained for 74 (64%) children. RESULTS: We detected 345 endemic coronavirus infections (1.1 infections/child-year) and 21 SARS-CoV-2 infections (0.3 infections/child-year). Endemic coronavirus and SARS-CoV-2 infections were asymptomatic or mild. Significant protective homotypic immunity occurred after a single infection with OC43 (77%) and HKU1 (84%), and after two infections with NL63 (73%). No heterotypic protection against endemic coronaviruses or SARS-CoV-2 was identified. CONCLUSIONS: Natural coronavirus infections were common and resulted in strong homotypic immunity but not heterotypic immunity against other coronaviruses, including SARS-CoV-2. Endemic coronavirus and SARS-CoV-2 infections in this US cohort were typically asymptomatic or mild.

IMPORTANCE: Influenza virus infection during pregnancy is associated with severe maternal disease and may be associated with adverse birth outcomes. Inactivated influenza vaccine during pregnancy is safe and effective and can protect young infants, but recent evidence, particularly after the 2009 novel influenza A (H1N1) pandemic, is limited. OBJECTIVE: To evaluate the effectiveness of influenza vaccination during pregnancy against laboratory-confirmed influenza-associated hospitalizations and emergency department (ED) visits in infants younger than 6 months. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, test-negative case-control study using data from the New Vaccine Surveillance Network from the 2016 to 2017 through 2019 to 2020 influenza seasons. Infants younger than 6 months with an ED visit or hospitalization for acute respiratory illness were included from 7 pediatric medical institutions in US cities. Control infants with an influenza-negative molecular test were included for comparison. Data were analyzed from June 2022 to September 2023. EXPOSURE: Maternal influenza vaccination during pregnancy. MAIN OUTCOMES AND MEASURES: We estimated maternal vaccine effectiveness against hospitalizations or ED visits in infants younger than 6 months, those younger than 3 months, and by trimester of vaccination. Maternal vaccination status was determined using immunization information systems, medical records, or self-report. Vaccine effectiveness was estimated by comparing the odds of maternal influenza vaccination 14 days or more before delivery in infants with influenza vs those without. RESULTS: Of 3764 infants (223 with influenza and 3541 control infants), 2007 (53%) were born to mothers who were vaccinated during pregnancy. Overall vaccine effectiveness in infants was 34% (95% CI, 12 to 50), 39% (95% CI, 12 to 58) against influenza-associated hospitalizations, and 19% (95% CI, -24 to 48) against ED visits. Among infants younger than 3 months, effectiveness was 53% (95% CI, 30 to 68). Effectiveness was 52% (95% CI, 30 to 68) among infants with mothers who were vaccinated during the third trimester and 17% (95% CI, -15 to 40) among those with mothers who were vaccinated during the first or second trimesters. CONCLUSIONS AND RELEVANCE: Maternal vaccination was associated with reduced odds of influenza-associated hospitalizations and ED visits in infants younger than 6 months. Effectiveness was greatest among infants younger than 3 months, for those born to mothers vaccinated during the third trimester, and against influenza-associated hospitalizations.

SARS-CoV-2 infection in young children is often mild or asymptomatic; however, some children are at risk for severe disease. Data describing the protective effectiveness of COVID-19 mRNA vaccines against COVID-19-associated emergency department (ED) visits and hospitalization in this population are limited. Data from the New Vaccine Surveillance Network, a prospective population-based surveillance system, were used to estimate vaccine effectiveness using a test-negative, case-control design and describe the epidemiology of SARS-CoV-2 in infants and children aged 6 months-4 years during July 1, 2022-September 30, 2023. Among 7,434 children included, 5% received a positive SARS-CoV-2 test result, and 95% received a negative test result; 86% were unvaccinated, 4% had received 1 dose of any vaccine product, and 10% had received ≥2 doses. When compared with receipt of no vaccines among children, receipt of ≥2 COVID-19 mRNA vaccine doses was 40% effective (95% CI = 8%-60%) in preventing ED visits and hospitalization. These findings support existing recommendations for COVID-19 vaccination of young children to reduce COVID-19-associated ED visits and hospitalization.

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.

BACKGROUND: Adjuvanted inactivated influenza vaccine (aIIV) and high-dose inactivated influenza vaccine (HD-IIV) are U.S.-licensed for adults aged ≥ 65 years. This study compared serum hemagglutination inhibition (HAI) antibody titers for the A(H3N2) and A(H1N1)pdm09 and B strains after trivalent aIIV3 and trivalent HD-IIV3 in an older adult population. RESULTS: The immunogenicity population included 342 participants who received aIIV3 and 338 participants who received HD-IIV3. The proportion of participants that seroconverted to A(H3N2) vaccine strains after allV3 (112 participants [32.8%]) was inferior to the proportion of participants that seroconverted after HD-IIV3 (130 participants [38.5%]) at day 29 after vaccination (difference, - 5.8%; 95%CI, - 12.9% to 1.4%). There were no significant differences between the vaccine groups in percent seroconversion to A(H1N1)pdm09 or B vaccine strains, in percent seropositivity for any of the strains, or in post-vaccination GMT for the A(H1N1)pdm09 strain. The GMTs for the post-vaccination A(H3N2) and B strains were higher after HD-IIV than after aIIV3. CONCLUSIONS: Overall immune responses were similar after aIIV3 and HD-IIV3. For the primary outcome, the aIIV3 seroconversion rate for H3N2 did not meet noninferiority criteria compared with HD-IIV3, but the HD-IIV3 seroconversion rate was not statistically superior to the aIIV3 seroconversion rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03183908.

Multisystem inflammatory syndrome in children (MIS-C) is a complication of SARS-CoV-2 infection; in the U.S., reporting of MIS-C after COVID-19 vaccination is required for vaccine safety monitoring. Pfizer-BioNTech COVID-19 vaccine was authorized for children aged 5-11 years on October 29, 2021. Covering a period when ∼7 million children received vaccine, surveillance for MIS-C ≤90 days post-vaccination using passive systems identified 58 children with MIS-C and laboratory evidence of past/recent SARS-CoV-2 infection, and 4 without evidence. During a period with extensive SARS-CoV-2 circulation, MIS-C illness in children after COVID-19 vaccination who lacked evidence of SARS-CoV-2 infection was rare (<1 per million vaccinated children).

IMPORTANCE: Rhinoviruses and/or enteroviruses, which continued to circulate during the COVID-19 pandemic, are commonly detected in pediatric patients with acute respiratory illness (ARI). Yet detailed characterization of rhinovirus and/or enterovirus detection over time is limited, especially by age group and health care setting. OBJECTIVE: To quantify and characterize rhinovirus and/or enterovirus detection before and during the COVID-19 pandemic among children and adolescents seeking medical care for ARI at emergency departments (EDs) or hospitals. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective surveillance platform, for pediatric patients who sought medical care for fever and/or respiratory symptoms at 7 EDs or hospitals within NVSN across the US between December 2016 and February 2021. Persons younger than 18 years were enrolled in NVSN, and respiratory specimens were collected and tested for multiple viruses. MAIN OUTCOMES AND MEASURES: Proportion of patients in whom rhinovirus and/or enterovirus, or another virus, was detected by calendar month and by prepandemic (December 1, 2016, to March 11, 2020) or pandemic (March 12, 2020, to February 28, 2021) periods. Month-specific adjusted odds ratios (aORs) for rhinovirus and/or enterovirus-positive test results (among all tested) by setting (ED or inpatient) and age group (<2, 2-4, or 5-17 years) were calculated, comparing each month during the pandemic to equivalent months of previous years. RESULTS: Of th 198 children and adolescents who were enrolled and tested, 11 303 (29.6%; mean [SD] age, 2.8 [3.7] years; 6733 boys [59.6%]) had rhinovirus and/or enterovirus-positive test results. In prepandemic and pandemic periods, rhinoviruses and/or enteroviruses were detected in 29.4% (9795 of 33 317) and 30.9% (1508 of 4881) of all patients who were enrolled and tested and in 42.2% (9795 of 23 236) and 73.0% (1508 of 2066) of those with test positivity for any virus, respectively. Rhinoviruses and/or enteroviruses were the most frequently detected viruses in both periods and all age groups in the ED and inpatient setting. From April to September 2020 (pandemic period), rhinoviruses and/or enteroviruses were detectable at similar or lower odds than in prepandemic years, with aORs ranging from 0.08 (95% CI, 0.04-0.19) to 0.76 (95% CI, 0.55-1.05) in the ED and 0.04 (95% CI, 0.01-0.11) to 0.71 (95% CI, 0.47-1.07) in the inpatient setting. However, unlike some other viruses, rhinoviruses and/or enteroviruses soon returned to prepandemic levels and from October 2020 to February 2021 were detected at similar or higher odds than in prepandemic months in both settings, with aORs ranging from 1.47 (95% CI, 1.12-1.93) to 3.01 (95% CI, 2.30-3.94) in the ED and 1.36 (95% CI, 1.03-1.79) to 2.44 (95% CI, 1.78-3.34) in the inpatient setting, and in all age groups. Compared with prepandemic years, during the pandemic, rhinoviruses and/or enteroviruses were detected in patients who were slightly older, although most (74.5% [1124 of 1508]) were younger than 5 years. CONCLUSIONS AND RELEVANCE: Results of this study show that rhinoviruses and/or enteroviruses persisted and were the most common respiratory virus group detected across all pediatric age groups and in both ED and inpatient settings. Rhinoviruses and/or enteroviruses remain a leading factor in ARI health care burden, and active ARI surveillance in children and adolescents remains critical for defining the health care burden of respiratory viruses.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) rarely involves delayed giant coronary aneurysms, multiple readmissions or occurrence after COVID-19 vaccination. METHODS: We describe a child with all 3 of these unusual features. We discuss his clinical presentation, medical management, review of the current literature and CDC guidance recommendations regarding further vaccinations. RESULTS: A 5-year-old boy had onset of MIS-C symptoms 55 days after COVID-19 illness and 15 days after receiving his first BNT162b2 COVID-19 vaccination. He was admitted 3 times for MIS-C, and twice after his steroid dose was tapered. On his initial admission, he was given intravenous immunoglobulin and steroids. During his second admission, new, moderate coronary dilation was noted, and he was treated with intravenous immunoglobulin and steroids. At his last admission, worsening coronary dilation was noted, and he was treated with infliximab and steroids. During follow-up, he had improvement in his coronary artery dilatation. However, his inflammatory markers increased after steroid wean, and his steroid taper was further extended, after which time his inflammatory markers improved. This is the only such reported case of a patient who was admitted 3 times for MIS-C complications after COVID-19 vaccination. CONCLUSION: MIS-C rarely involves delayed giant coronary aneurysms, multiple readmissions, or occurrence after COVID-19 vaccination. Whether our patient's COVID-19 vaccine 6 weeks after COVID-19 illness contributed to his MIS-C is unknown. After consultation with the CDC-funded Clinical Immunization Safety Assessment Project, the patient's care team decided against further COVID-19 vaccination until at least 3 months post normalization of inflammatory markers.

BACKGROUND: Adult studies have demonstrated within-season declines in influenza vaccine effectiveness (VE); data in children are limited. METHODS: We conducted a prospective, test-negative study of children 6 months-17 years hospitalized with acute respiratory illness at 7 pediatric medical centers during the 2015-2016 through 2019-2020 influenza seasons. Case-patients were children with an influenza-positive molecular test matched by illness onset to influenza-negative control-patients. We estimated VE [100% x (1 - odds ratio)] by comparing the odds of receipt of ≥1 dose of influenza vaccine ≥14 days before illness onset among influenza-positive children to influenza-negative children. Changes in VE over time between vaccination date and illness onset date were estimated using multivariable logistic regression. RESULTS: Of 8,430 children, 4,653 (55%) received ≥1 dose of influenza vaccine. On average, 48% were vaccinated through October and 85% through December each season. Influenza vaccine receipt was lower in case-patients than control-patients (39% vs. 57%, p < 0.001); overall VE against hospitalization was 53% (95% CI: 46%-60%). Pooling data across 5 seasons, the odds of influenza-associated hospitalization increased 4.2% (-3.2%-12.2%) per month since vaccination, with an average VE decrease of 1.9% per month (n = 4,000, p = 0.275). Odds of hospitalization increased 2.9% (95% CI: -5.4%-11.8%) and 9.6% (95% CI: -7.0%-29.1%) per month in children ≤8 years (n = 3,084) and 9-17 years (n = 916), respectively. These findings were not statistically significant. CONCLUSIONS: We observed minimal, not statistically significant within-season declines in VE. Vaccination following current ACIP guidelines for timing of vaccine receipt remains the best strategy for preventing influenza-associated hospitalizations in children.

BACKGROUND AND OBJECTIVES: Asthma is considered a precaution for use of quadrivalent live attenuated influenza vaccine (LAIV4) in persons aged ≥5 years because of concerns for wheezing events. We evaluated the safety of LAIV4 in children with asthma, comparing the proportion of children with asthma exacerbations after LAIV4 or quadrivalent inactivated influenza vaccine (IIV4). METHODS: We enrolled 151 children with asthma, aged 5 to 17 years, during 2 influenza seasons. Participants were randomly assigned 1:1 to receive IIV4 or LAIV4 and monitored for asthma symptoms, exacerbations, changes in peak expiratory flow rate (PEFR), and changes in the asthma control test for 42 days after vaccination. RESULTS: We included 142 participants in the per-protocol analysis. Within 42 days postvaccination, 18 of 142 (13%) experienced an asthma exacerbation: 8 of 74 (11%) in the LAIV4 group versus 10 of 68 (15%) in the IIV4 group (LAIV4-IIV4 = -0.0390 [90% confidence interval -0.1453 to 0.0674]), meeting the bounds for noninferiority. When adjusted for asthma severity, LAIV4 remained noninferior to IIV4. There were no significant differences in the frequency of asthma symptoms, change in PEFR, or childhood asthma control test/asthma control test scores in the 14 days postvaccination between LAIV4 and IIV4 recipients. Vaccine reactogenicity was similar between groups, although sore throat (P = .051) and myalgia (P <.001) were more common in the IIV4 group. CONCLUSIONS: LAIV4 was not associated with increased frequency of asthma exacerbations, an increase in asthma-related symptoms, or a decrease in PEFR compared with IIV4 among children aged 5 to 17 years with asthma.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition associated with antecedent SARS-CoV-2 infection. In the USA, reporting of MIS-C after vaccination is required under COVID-19 vaccine emergency use authorisations. We aimed to investigate reports of individuals aged 12-20 years with MIS-C after COVID-19 vaccination reported to passive surveillance systems or through clinician outreach to the US Centers for Disease Control and Prevention (CDC). METHODS: In this surveillance activity, we investigated potential cases of MIS-C after COVID-19 vaccination reported to CDC's MIS-C national surveillance system, the Vaccine Adverse Event Reporting System (co-administered by CDC and the US Food and Drug Administration), and CDC's Clinical Immunization Safety Assessment Project. A multidisciplinary team adjudicated cases by use of the CDC MIS-C definition. Any positive SARS-CoV-2 serology test satisfied case criteria; although anti-nucleocapsid antibodies indicate previous SARS-CoV-2 infection, anti-spike protein antibodies indicate either past or recent infection or COVID-19 vaccination. We describe the demographic and clinical features of cases, stratified by laboratory evidence of SARS-CoV-2 infection. To calculate the reporting rate of MIS-C, we divided the count of all individuals meeting the MIS-C case definition, and of those without evidence of SARS-CoV-2 infection, by the number of individuals aged 12-20 years in the USA who received one or more COVID-19 vaccine doses up to Aug 31, 2021, obtained from CDC national vaccine surveillance data. FINDINGS: Using surveillance results from Dec 14, 2020, to Aug 31, 2021, we identified 21 individuals with MIS-C after COVID-19 vaccination. Of these 21 individuals, median age was 16 years (range 12-20); 13 (62%) were male and eight (38%) were female. All 21 were hospitalised: 12 (57%) were admitted to an intensive care unit and all were discharged home. 15 (71%) of 21 individuals had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. As of Aug 31, 2021, 21 335 331 individuals aged 12-20 years had received one or more doses of a COVID-19 vaccine, making the overall reporting rate for MIS-C after vaccination 1·0 case per million individuals receiving one or more doses in this age group. The reporting rate in only those without evidence of SARS-CoV-2 infection was 0·3 cases per million vaccinated individuals. INTERPRETATION: Here, we describe a small number of individuals with MIS-C who had received one or more doses of a COVID-19 vaccine before illness onset; the contribution of vaccination to these illnesses is unknown. Our findings suggest that MIS-C after COVID-19 vaccination is rare. Continued reporting of potential cases and surveillance for MIS-C illnesses after COVID-19 vaccination is warranted. FUNDING: US Centers for Disease Control and Prevention.

Studies have shown egg-adaptive mutations in influenza vaccine strains that might have impaired protection against circulating A(H3N2) influenza viruses during the 2016-17 and 2017-18 seasons. We employed the test-negative design and multivariable models to assess vaccine effectiveness against influenza-associated hospitalization and emergency department visits among children <18 years during the 2016-17 and 2017-18 seasons. Effectiveness was 71% (95% CI:59%-79%), 46% (95% CI:35%-55%), and 45% (95% CI:33%-55%) against A(H1N1)pdm09, A(H3N2), and B viruses respectively, across both seasons. During high-severity seasons with concerns for vaccine mismatch, vaccination offered substantial protection against severe influenza outcomes requiring hospitalization or emergency department visits among children.