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Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complication that has disproportionately affected racial/ethnic minority children. We conducted a pilot study to investigate risk factors for MIS-C aiming to understand MIS-C disparities.This case-control study included MIS-C cases and SARS-CoV-2-positive outpatient controls less than 18 years old frequency-matched 4:1 to cases by age group and site. Patients hospitalized with MIS-C were admitted between March 16 and October 2, 2020, across 17 pediatric hospitals. We evaluated race, ethnicity, social vulnerability index (SVI), insurance status, weight-for-age and underlying medical conditions as risk factors using mixed effects multivariable logistic regression.We compared 241 MIS-C cases with 817 outpatient SARS-CoV-2-positive at-risk controls. Cases and controls had similar sex, age and U.S. census region distribution. MIS-C patients were more frequently previously healthy, non-Hispanic Black, residing in higher SVI areas, and in the 95th percentile or higher for weight-for-age. In the multivariable analysis, the likelihood of MIS-C was higher among non-Hispanic Black children [adjusted odds ratio (aOR): 2.07; 95% CI: 1.23-3.48]. Additionally, SVI in the 2nd and 3rd tertiles (aOR: 1.88; 95% CI: 1.18-2.97 and aOR: 2.03; 95% CI: 1.19-3.47, respectively) were independent factors along with being previously healthy (aOR: 1.64; 95% CI: 1.18-2.28).In this study, non-Hispanic Black children were more likely to develop MIS-C after adjustment for sociodemographic factors, underlying medical conditions, and weight-for-age. Investigation of the potential contribution of immunologic, environmental, and other factors is warranted.

Infants younger than 6 months of age are at high risk for complications of coronavirus disease 2019 (Covid-19) and are not eligible for vaccination. Transplacental transfer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after maternal Covid-19 vaccination may confer protection against Covid-19 in infants.We used a case-control test-negative design to assess the effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age. Between July 1, 2021, and March 8, 2022, we enrolled infants hospitalized for Covid-19 (case infants) and infants hospitalized without Covid-19 (control infants) at 30 hospitals in 22 states. We estimated vaccine effectiveness by comparing the odds of full maternal vaccination (two doses of mRNA vaccine) among case infants and control infants during circulation of the B.1.617.2 (delta) variant (July 1, 2021, to December 18, 2021) and the B.1.1.259 (omicron) variant (December 19, 2021, to March 8, 2022).A total of 537 case infants (181 of whom had been admitted to a hospital during the delta period and 356 during the omicron period; median age, 2 months) and 512 control infants were enrolled and included in the analyses; 16% of the case infants and 29% of the control infants had been born to mothers who had been fully vaccinated against Covid-19 during pregnancy. Among the case infants, 113 (21%) received intensive care (64 [12%] received mechanical ventilation or vasoactive infusions). Two case infants died from Covid-19; neither infant's mother had been vaccinated during pregnancy. The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants was 52% (95% confidence interval [CI], 33 to 65) overall, 80% (95% CI, 60 to 90) during the delta period, and 38% (95% CI, 8 to 58) during the omicron period. Effectiveness was 69% (95% CI, 50 to 80) when maternal vaccination occurred after 20 weeks of pregnancy and 38% (95% CI, 3 to 60) during the first 20 weeks of pregnancy.Maternal vaccination with two doses of mRNA vaccine was associated with a reduced risk of hospitalization for Covid-19, including for critical illness, among infants younger than 6 months of age. (Funded by the Centers for Disease Control and Prevention.).

Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated concern about immune evasion and the duration of protection from vaccines in children and adolescents.Using a case-control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age.We enrolled 1185 case patients (1043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, -25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days).BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.).

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the United States appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight US surveillance sites on 8- to 59-month olds with acute gastroenteritis symptoms. Children’s stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year–vaccination interaction, and the second including the annual percent of rotavirus-positive tests plus a percent positive–vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year–vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive–vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.

The increasing incidence of pediatric hospitalizations associated with coronavirus disease 2019 (Covid-19) caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States has offered an opportunity to assess the real-world effectiveness of the BNT162b2 messenger RNA vaccine in adolescents between 12 and 18 years of age.We used a case-control, test-negative design to assess vaccine effectiveness against Covid-19 resulting in hospitalization, admission to an intensive care unit (ICU), the use of life-supporting interventions (mechanical ventilation, vasopressors, and extracorporeal membrane oxygenation), or death. Between July 1 and October 25, 2021, we screened admission logs for eligible case patients with laboratory-confirmed Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2) in case patients as compared with two hospital-based control groups: patients who had Covid-19-like symptoms but negative results on testing for SARS-CoV-2 (test-negative) and patients who did not have Covid-19-like symptoms (syndrome-negative).A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated. Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated. The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% confidence interval [CI], 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls. The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support. All 7 deaths occurred in patients who were unvaccinated.Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19-related hospitalization and ICU admission or the receipt of life support. (Funded by the Centers for Disease Control and Prevention.).

COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from COVID-19.

BackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients7 days to1 year old hospitalized with symptomatic acute COVID-19.We report 232 infants7 days to1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients7 days to18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and1% died.Infants accounted for over a fifth of children18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.

Enterovirus D68 (EV-D68) is associated with a broad spectrum of illnesses, including mild to severe acute respiratory illness (ARI) and acute flaccid myelitis (AFM). Enteroviruses, including EV-D68, are typically detected in the United States during late summer through fall, with year-to-year fluctuations. Before 2014, EV-D68 was infrequently reported to CDC (1). However, numbers of EV-D68 detection have increased in recent years, with a biennial pattern observed during 2014-2018 in the United States, after the expansion of surveillance and wider availability of molecular testing. In 2014, a national outbreak of EV-D68 was detected (2). EV-D68 was also reported in 2016 via local (3) and passive national (4) surveillance. EV-D68 detections were limited in 2017, but substantial circulation was observed in 2018 (5). To assess recent levels of circulation, EV-D68 detections in respiratory specimens collected from patients aged18 years* with ARI evaluated in emergency departments (EDs) or admitted to one of seven U.S. medical centers

Background As of 2017 (WHO, 2017), diarrheal disease ranked second as a cause of worldwide mortality for children under five years of age. Approximately 50-70% of acute gastroenteritis (AGE) is viral in etiology, with commonly detected viruses including norovirus, rotavirus, and adenovirus. However, the epidemiology of less commonly detected viruses, specifically enterovirus (EV) and parechovirus A (PeV-A), associated AGE in the United States is not well described. The purpose of our study was to determine the prevalence of EV and PeV-A in children with AGE vs. healthy controls (HC) over a 7-year period. Methods From December 2011 – November 2018, we screened stool samples from children less than 18 years of age prospectively enrolled in Children’s Mercy-Kansas City’s (CM-KC) site for the CDC’s New Vaccine Surveillance Network; 3005 samples from subjects presenting with AGE and 1097 from HC. Samples from 2011 – 2016 (AGE: 2453; HC:752) and 2017 – 2018 (AGE:552; HC:344) were tested at CDC and CM-KC respectively by a real-time-PCR assay using specific EV and PeV-A primers targeting the highly conserved 5’ untranslated region. Demographic data were collected from EMR. Results Among 3005 AGE samples, EV was detected in 12.5% (n=386/3004), and PeV-A in 10.3% (n=252/3005). Among 1097 HC samples, EV was detected in 9.0% (99/1096), and PeV-A in 11.9% (130/1097). In 2014-2015 EV detection in AGE was highest (17.9%) among all years and significantly higher (p=0.004) than in HC samples (9.1%), whereas PeV-A detection in AGE was 9.5% vs. 15.6% in HC samples, p=0.008 (Table 1). Co-infections with EV and PeV-A were seen in 55 AGE and 21 HC. Most EV detections (45.1%) were in 1- to 2-year-olds, whereas PeV-A detections (47.3%) were in children < 1 year old (Table 2). Both EV (58.3%) and PeV-A (48.4%) detections were significantly more frequent in male children (p=0.006). The highest frequency of EV detections was in summer to fall months, and for PeV-A in late summer through early winter. Conclusion We report a higher prevalence of EV infections in AGE, and PeV-A infections in HC during 2011 to 2018, plus their seasonal and age distributions. Although our data do not currently demonstrate an association between detection of EV or PeV-A types and AGE, additional data could provide more clarity into a potential association. Disclosures Brian R. Lee, PhD, MPH, CDC: Grant/Research Support|Merck: Grant/Research Support Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Mary E. Moffatt, M.D., Becton and Dickinson and Company: Stocks/Bonds|Biogen: Stocks/Bonds|Coloplast B: Stocks/Bonds|Express Scripts: Stocks/Bonds|Novo Nordisk A/S Spons ADR: Stocks/Bonds|Novo Nordisk A/S-B: Stocks/Bonds|Steris PLC: Stocks/Bonds|Stryker Corp: Stocks/Bonds|Thermo Fisher Scientific: Stocks/Bonds Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support.

Background Mycoplasma pneumoniae (MP), a common pediatric pneumonia pathogen, has 2 subtypes based on P1 adhesin gene variation. Macrolide-resistant MP (MRMP), seen since 2000 in many countries, has been subtype associated. Limited U.S. pediatric data exist on MP subtype or MRMP frequency and their clinical importance. Methods During 2015–2020, mid-turbinate nasal swab (MTNS) specimens and/or throat swabs were collected from children with acute respiratory illness (ARI) enrolled in emergency department (ED) or outpatient and inpatient settings at 4 CDC-funded New Vaccine Surveillance Network sites (Cincinnati, Seattle, Houston, and Kansas City). Specimens were tested for MP and common respiratory viruses by singleplex or multiplex polymerase chain reaction assay (PCR). P1-subtyping for MP positive specimens used multiplex TaqMan real-time PCR while MR was assessed by real time PCR with melt curve analysis (Lightmix®, TIBMolbiol). Select demographic/clinical data were analyzed by P1 subtype (P1–1 vs. P1–2). Results Of 208 MTNS specimens from 208 children (median age 5.5 years), 110 (53%) were P1–1, 89 (43%) P1–2, and 9 (4%) untypeable. Of 199 typeable specimens, 111 (56%) came from inpatients while 88 (44%) came from ED/outpatients.Overall MRMP prevalence during 2015–2020 was low (3/208,1.4%); all MRMP (Houston: 1 each in 2016–2017 and 2019–2020, Seattle: 1 in 2018–2019) were P1–1. Differences in P1–2 vs. P1–1 proportions were significant in 2 years: P1–2 dominated in 2015–2016; P1-1 in 2019–2020 (Figure 1). Common clinical symptoms for 199 MP-positive patients were fever (84%, mean 102.5±1.5oF), shortness of breath (82%), wheezing (67%), and cough (60%). Clinical manifestations, hospitalization, and antibiotic use did not differ in P1-1 vs. P1-2 patients. Antibiotics were used in 59/199 (30%) patients overall; amoxicillin was most frequent (48/199, 24%), followed by cefdinir (9/199, 5%) and azithromycin (5/199, 3%). Conclusion MP subtypes co-circulated during 2015–2020; P1-2 dominated in 2015–2016, P1-1 in 2018–2019. Signs/symptoms were similar for P1-1 and P1-2. MRMP detection was uncommon among our pediatric subjects. Ongoing surveillance is important to assess potential changes in MR prevalence and temporal subtype variation. Disclosures Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Brian R. Lee, PhD, MPH, CDC: Grant/Research Support|Merck: Grant/Research Support Mary E. Moffatt, M.D., Becton and Dickinson and Company: Stocks/Bonds|Biogen: Stocks/Bonds|Coloplast B: Stocks/Bonds|Express Scripts: Stocks/Bonds|Novo Nordisk A/S Spons ADR: Stocks/Bonds|Novo Nordisk A/S-B: Stocks/Bonds|Steris PLC: Stocks/Bonds|Stryker Corp: Stocks/Bonds|Thermo Fisher Scientific: Stocks/Bonds Janet A. Englund, MD, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccine: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support|SanofiPasteur: Advisor/Consultant.

Background Adenovirus (AdV) is a common cause of acute respiratory illness (ARI). Multiple respiratory AdV types have been identified in humans, but it remains unclear which are the most common in U.S. children with ARI. Methods We conducted a multicenter, prospective viral surveillance study at seven U.S. children’s hospitals, the New Vaccine Surveillance Network, during 12/1/16–11/30/19, prior to the COVID-19 pandemic. Children < 18 years of age seen in the emergency department or hospitalized with fever and/or respiratory symptoms were enrolled, and mid-turbinate nasal +/- throat swabs were tested using multiplex respiratory pathogen assays or real time polymerase chain reaction (PCR) test for AdV, respiratory syncytial virus (RSV), human metapneumovirus, rhinovirus/enterovirus (RV), influenza, parainfluenza viruses, and endemic coronaviruses. AdV-positive specimens were subsequently typed using single-plex qPCR assays targeting sequences in the hexon gene specific for types 1-7, 11, 14, 16 and 21. Demographics, clinical characteristics, and outcomes were compared between AdV types. Results Of 29,381 enrolled children, 2,106 (7.2%) tested positive for AdV. The distribution of types among the 1,330 (63.2%) successfully typed specimens were as follows: 31.7% AdV-2, 28.9% AdV-1, 15.3% AdV-3, 7.9% AdV-5, 5.9% AdV-7, 1.4% AdV-4, 1.2% AdV-6, 0.5% AdV-14, 0.2% AdV-21, 0.1% AdV-11, and 7.0% ≥1 AdV type. Most children with AdV-1 or AdV-2 detection were < 5 years of age (Figure 1a). Demographic and clinical characteristics varied by AdV types, including age, race/ethnicity, smoke exposure, daycare/school attendance, and hospitalization (Table 1). Co-detection with other viruses was common among all AdV types, with RV and RSV being the most frequently co-detected (Figure 1b). Fever and cough were the most common symptoms for all AdV types (Figure 2). Children with AdV-7 detected as single pathogen had higher odds of hospitalization (adjusted odds ratio 6.34 [95% CI: 3.10, 12.95], p= 0.027). Conclusion AdV-2 and AdV-1 were the most frequently detected AdV types among children over the 3-year study period. Notable clinical heterogeneity of the AdV types warrants further surveillance studies to identify AdV types that could be targeted for pediatric vaccine development. Disclosures Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support John Williams, MD, GlaxoSmithKline: Advisor/Consultant|Quidel: Advisor/Consultant Mary A. Staat, MD, MPH, Centers for Disease Control and Prevention: Grant/Research Support|Cepheid: Grant/Research Support|National Institute of Health: Grant/Research Support|Uptodate: Royalties Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Mary E. Moffatt, M.D., Becton and Dickinson and Company: Stocks/Bonds|Biogen: Stocks/Bonds|Coloplast B: Stocks/Bonds|Express Scripts: Stocks/Bonds|Novo Nordisk A/S Spons ADR: Stocks/Bonds|Novo Nordisk A/S-B: Stocks/Bonds|Steris PLC: Stocks/Bonds|Stryker Corp: Stocks/Bonds|Thermo Fisher Scientific: Stocks/Bonds Geoffrey A. Weinberg, MD, Merck & Co.: Honoraria|Merck & Co.: Honoraria for composing and reviewing textbook chapters, Merck Manual of Therapeutics Janet A. Englund, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation.

Background According to the 2018 Infectious Diseases Society of America (IDSA) clinical practice guidelines and Centers for Disease Control and Prevention (CDC) guidance, clinicians should start antiviral treatment as soon as possible for children who are hospitalized with suspected or confirmed influenza. We assessed the use of influenza-specific antiviral therapy in children hospitalized with symptoms of acute respiratory illness and laboratory-confirmed influenza. Methods We conducted active, population-based surveillance of children hospitalized with fever and/or respiratory symptoms (12/01/2016–02/28/2020) at the seven U.S. medical centers that comprise the CDC New Vaccine Surveillance Network. We excluded children who did not undergo clinical testing (by rapid antigen testing or nucleic acid amplification test [NAAT]) or research testing (by NAAT) for influenza, those who presented out of influenza season (site- and season-specific), and those whose date of antiviral therapy or whether antiviral therapy was given was unknown. We assessed the use of influenza-specific antiviral therapy in this cohort and defined timely antiviral therapy as administration within 2 days of hospitalization. Results Of 11,275 eligible children, 1,149 (10.2%) tested positive for influenza by clinical and/or research assays (Table 1). Overall, 154 influenza cases (13.4%) were detected by clinical testing only, 428 (37.2%) by research testing only, and 567 (49.3%) by both. During their influenza-associated hospitalization, 620 children (54.0%) received influenza-specific antivirals, and therapy was timely in 572 cases (92.3%). Of those who tested positive clinically, 445/721 (61.7%) received timely antiviral therapy, 38 (5.3%) received delayed antiviral therapy, and 238 (33.0%) received no antiviral therapy. Oseltamivir was the antiviral used in all treated cases. The distribution of antiviral-treated cases varied by race and Hispanic origin and study site, but not by age at presentation or influenza season (Figure 1). Table 1 Demographic characteristics of 1,149 children with influenza enrolled in the New Vaccine Surveillance Network over four influenza seasons between December 1, 2016, and February 28, 2020. Figure 1Proportions of children with influenza enrolled in the New Vaccine Surveillance Network who received timely, delayed, or no antiviral therapy by age at presentation, race and Hispanic origin, study site, and influenza season (N=1,149). Conclusion Although antiviral therapy is recommended for all influenza-associated hospitalizations in children, antiviral prescribing remains suboptimal. Further studies would help identify and address barriers to antiviral therapy in children with influenza. Disclosures John Williams, MD, GlaxoSmithKline: Advisor/Consultant|Quidel: Advisor/Consultant Janet A. Englund, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support Mary A. Staat, MD, MPH, Centers for Disease Control and Prevention: Grant/Research Support|Cepheid: Grant/Research Support|National Institute of Health: Grant/Research Support|Uptodate: Royalties Geoffrey A. Weinberg, MD, Merck & Co.: Honoraria|Merck & Co.: Honoraria for composing and reviewing textbook chapters, Merck Manual of Therapeutics Flor M. Munoz, MD, MSc, Gilead: Grant/Research Support|Moderna: DSMB|Pfizer: DSMB Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation.

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

Autoantibodies against type I interferons (IFNs) occur in approximately 10% of adults with life-threatening COVID-19. The frequency of anti-IFN autoantibodies in children with severe sequelae of SARS-CoV-2 infection is unknown.To quantify anti-Type I IFN autoantibodies in a multi-center cohort of children with severe COVID-19, Multisystem Inflammatory Syndrome in Children (MIS-C), and mild SARS-CoV-2 infections.Circulating anti-IFNa2 antibodies were measured by a radioligand binding assay. Whole exome sequencing (WES), RNA-sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFNα2 autoantibodies exceeding the assay's positive control.Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only one had high levels of anti-IFNα2 antibodies. Anti-IFNα2 autoantibodies were not detected in patients treated with intravenous immunoglobulin prior to sample collection. WES identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of NF-kB essential for non-canonical NF-kB signaling. Her peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity.High levels of anti-IFNα2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare, but can occur in patients with inborn errors of immunity.Anti-IFNα2 autoantibodies should prompt diagnostic evaluation for inborn errors of immunity if identified in children or adolescents.

Hospitalization for severe influenza infection in childhood may result in postdischarge sequelae.To evaluate inpatient management and postdischarge sequelae in children with critical respiratory illness owing to influenza with or without preexisting asthma.This was a prospective, observational multicenter study of children (aged 8 months to 17 years) admitted to a pediatric intensive care or high-acuity unit (in November 2019 to April 2020) for influenza. Results were stratified by preexisting asthma. Prehospital status, hospital treatments, and outcomes were collected. Surveys at approximately 90 days after discharge evaluated postdischarge health resource use, functional status, and respiratory symptoms.A total of 165 children had influenza: 56 with preexisting asthma (33.9%) and 109 without it (66.1%; 41.1% and 39.4%, respectively, were fully vaccinated against influenza). Fifteen patients with preexisting asthma (26.7%) and 34 without it (31.1%) were intubated. More patients with versus without preexisting asthma received pharmacologic asthma treatments during hospitalization (76.7% vs 28.4%). Of 136 patients with 90-day survey data (82.4%; 46 with preexisting asthma [33.8%] and 90 without it [66.1%]), a similar proportion had an emergency department/urgent care visit (4.3% vs 6.6%) or hospital readmission (8.6% vs 3.3%) for a respiratory condition. Patients with preexisting asthma more frequently experienced asthma symptoms (78.2% vs 3.3%) and had respiratory specialist visits (52% vs 20%) after discharge. Of 109 patients without preexisting asthma, 10 reported receiving a new diagnosis of asthma (11.1%).Respiratory health resource use and symptoms are important postdischarge outcomes after influenza critical illness in children with and without preexisting asthma. Less than half of children were vaccinated for influenza, a tool that could mitigate critical illness and its sequelae.

OBJECTIVES To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C). METHODS Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients RESULTS Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04–1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06–1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55–6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35–4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C). CONCLUSIONS Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening testing is a recommended mitigation strategy for schools, although few descriptions of program implementation are available.MethodsKindergarten through 12th grade (K–12) students and staff practicing universal masking during the delta and omicron variant waves from five schools in Durham, North Carolina and eight schools in Kansas City, Missouri participated; Durham’s program was structured as a public health initiative facilitated by school staff, and Kansas City’s as a research study facilitated by a research team. Tests included school-based rapid antigen or polymerase chain reaction testing, at-home rapid antigen testing, and off-site nucleic acid amplification testing.ResultsWe performed nearly 5700 screening tests on more than 1600 K–12 school students and staff members. The total cost for the Durham testing program in 5 public charter K–12 schools, each with 500–1000 students, was $246 587 and approximately 752 h per semester; cost per test was $70 and cost per positive result was $7076. The total cost for the Kansas City program in eight public K–12 schools was $292 591 and required approximately 537 h in personnel time for school-based testing; cost per test was $132 and cost per positive result was $4818. SARS-CoV-2 positivity rates were generally lower (0–16.16%) than rates in the community (2.7–36.47%) throughout all testing weeks.Conclusions and RelevanceVoluntary screening testing programs in K–12 schools are costly and rarely detect asymptomatic positive persons, particularly in universally masked settings.Clinical Trial RegistrationNCT04831866.

Background Pfizer-BioNTech COVID-19 vaccine received emergency use authorization for persons ≥ 16 years in December 2020 and for adolescents 12–15 years in May 2021. Despite the clear benefits and favorable safety profile, vaccine uptake in adolescents has been suboptimal. We sought to assess factors associated with COVID-19 non-vaccination in adolescents 12–18 years of age. Methods Between June 1, 2021 and April 29, 2022, we assessed factors associated with COVID-19 non-vaccination in hospitalized adolescents ages 12–18 years enrolled in the Overcoming COVID-19 vaccine effectiveness network. Demographic characteristics and clinical information were captured through parent interviews and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of the COVID-19 vaccine and demographic and clinical factors using univariate and multivariable logistic regression and estimated adjusted odds ratios (aOR) for each factor associated with non-vaccination. Results Among 1665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p Conclusions Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination.

A suboptimal response to the 2-dose COVID-19 vaccine series in the immunocompromised population prompted recommendations for a 3rd primary dose. We aimed to determine the humoral and cellular immune response to the 3rd COVID-19 vaccine in immunocompromised children.Prospective cohort study of immunocompromised participants, 5-21 years old, who received 2 prior doses of an mRNA COVID-19 vaccine. Humoral and CD4/CD8 T-cell responses were measured to SARS-CoV-2 spike antigens prior to receiving the 3rd vaccine dose and 3-4 weeks after the 3rd dose was given.Of the 37 participants, approximately half were solid organ transplant recipients. The majority (86.5%) had a detectable humoral response after the 2nd and 3rd vaccine doses, with a significant increase in antibody levels after the 3rd dose. Positive T-cell responses increased from being present in 86.5% to 100% of the cohort after the 3rd dose.Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This supports the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in this population.Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This is the first prospective cohort study to analyze both the humoral and T-cell immune response to the 3rd COVID-19 primary vaccine dose in children who are immunocompromised. The results of this study support the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in the immunosuppressed pediatric population.

Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood.In a multicenter case-control public health investigation of children ages 5-18 years hospitalized from July 1, 2021 to April 7, 2022, we compared the odds of being fully vaccinated (two doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, and periods of Delta and Omicron variant predominance using multivariable logistic regression.We compared 304 MIS-C case-patients (280 [92%] unvaccinated) with 502 controls (346 [69%] unvaccinated). MIS-C was associated with decreased likelihood of vaccination (aOR, 0.16 95% CI, 0.10-0.26), including among children ages 5-11 years (aOR, 0.22 95% CI, 0.10-0.52), ages 12-18 years (aOR, 0.10 95% CI, 0.05-0.19), and during the Delta (aOR, 0.06 95% CI, 0.02-0.15) and Omicron (aOR, 0.22 95% CI, 0.11-0.42) variant-predominant periods. This association persisted beyond 120 days after the second dose (aOR, 0.08, 95% CI, 0.03-0.22) in 12-18 year-olds. Among all MIS-C case-patients, 187 (62%) required intensive care unit admission and 280 (92%) vaccine-eligible patients were unvaccinated.Vaccination with two doses of BNT162b2 is associated with reduced likelihood of MIS-C in children ages 5-18 years. Most vaccine eligible hospitalized patients with MIS-C were unvaccinated.

OBJECTIVES Throughout the COVID-19 pandemic, masking has been a widely used mitigation practice in kindergarten through 12th grade (K–12) school districts to limit within-school transmission. Prior studies attempting to quantify the impact of masking have assessed total cases within schools; however, the metric that more optimally defines effectiveness of mitigation practices is within-school transmission, or secondary cases. We estimated the impact of various masking practices on secondary transmission in a cohort of K–12 schools. METHODS We performed a multistate, prospective, observational, open cohort study from July 26, 2021 to December 13, 2021. Districts reported mitigation practices and weekly infection data. Districts that were able to perform contact tracing and adjudicate primary and secondary infections were eligible for inclusion. To estimate the impact of masking on secondary transmission, we used a quasi-Poisson regression model. RESULTS A total of 1 112 899 students and 157 069 staff attended 61 K–12 districts across 9 states that met inclusion criteria. The districts reported 40 601 primary and 3085 secondary infections. Six districts had optional masking policies, 9 had partial masking policies, and 46 had universal masking. In unadjusted analysis, districts that optionally masked throughout the study period had 3.6 times the rate of secondary transmission as universally masked districts; and for every 100 community-acquired cases, universally masked districts had 7.3 predicted secondary infections, whereas optionally masked districts had 26.4. CONCLUSIONS Secondary transmission across the cohort was modest (

OBJECTIVES:Echocardiography performed under sedation allows for better coronary artery visualization in children with Kawasaki disease. We sought to describe hospital-level variability in the percentage of sedated echocardiography (SE) among children with nonrefractory Kawasaki disease (NRKD) and then test its association with repeat echocardiography, length of stay (LOS), and costs.METHODS:We identified children in the Pediatric Health Information System RESULTS:There were 2887 NRKD hospitalizations from 40 children’s hospitals. Initial SE varied from 0.0% to 87.0% (median 5.9%; interquartile range 1.4%–21.1%). Of initial echocardiographies, 22.4% were sedated and 10.1% of all hospitalizations had a repeat echocardiography. Use of SE at the hospital level was associated with a lower likelihood for repeat echocardiography (r = −0.32; 95% confidence interval −0.58 to −0.01; P = .042). Absolute risk reduction was 3.5% and the number needed to sedate was 29. Initial SE was not associated with LOS or hospital-level costs but was associated with increased patient-level costs.CONCLUSIONS:Significant variation exists in the use of SE for children

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Clinical differences between critical illness from influenza infection versus coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.We compared U.S. children (8 months to 17 years) admitted to the intensive care or high acuity unit with influenza (17 hospitals, 12/19/2019-3/9/2020) or COVID-19 (52 hospitals, 3/15/2020-12/31/2020). We compared demographics, underlying conditions, clinical presentation, severity, and outcomes. Using mixed-effects models, we assessed the odds of death or requiring life-support for influenza versus COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median 5.2 vs. 13.8 years), less likely to be non-Hispanic black (14.5% vs. 27.6%) or Hispanic (24.0% vs. 36.2%), and less likely to have ≥1 underlying condition (66.4% vs. 78.5%) or be obese (21.4% vs. 42.2%). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life-support in children with influenza vs. COVID-19 were similar (adjusted odds ratio, 1.30 [95% CI: 0.78-2.15; P = 0.32]). Median duration of hospital stay was shorter for influenza than COVID-19 (5 versus 7 days).Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

Background Human adenovirus (HAdV) is commonly associated with acute respiratory illnesses (ARI) in children and is also frequently co-detected with other viral pathogens. We compared clinical presentation and outcomes in young children with HAdV detected alone vs co-detected with other respiratory viruses. Methods We used data from a multicenter, prospective, viral surveillance study of children seen in the emergency department and inpatient pediatric settings at seven US sites. Children less than 18 years old with fever and/or respiratory symptoms were enrolled between 12/1/16 and 10/31/18 and tested by molecular methods for HAdV, human rhinovirus/enterovirus (HRV/EV), respiratory syncytial virus (RSV), parainfluenza (PIV, types 1–4), influenza (flu, types A-C), and human metapneumovirus (HMPV). Our primary measure of illness severity was hospitalization; among hospitalized children, secondary severity outcomes included oxygen support and length of stay (LOS). Results Of the 18,603 children enrolled, HAdV was detected in 1,136 (6.1%), among whom 646 (56.9%) had co-detection with at least one other respiratory virus. HRV/EV (n = 293, 45.3%) and RSV (n = 123, 19.0%) were the most frequent co-detections. Children with HRV/EV (aOR = 1.61; 95% CI = [1.11–2.34]), RSV (aOR = 4.48; 95% CI = [2.81–7.14]), HMPV (aOR = 3.39; 95% CI = [1.69–6.77]), or ≥ 2 co-detections (aOR = 1.95; 95% CI = [1.14–3.36]) had higher odds of hospitalization compared to children with HAdV alone. Among hospitalized children, HAdV co-detection with RSV or HMPV was each associated with higher odds of oxygen support, while co-detection with PIV or influenza viruses was each associated with higher mean LOS. Conclusions HAdV co-detection with other respiratory viruses was associated with greater disease severity among children with ARI compared to HAdV detection alone.

The coronavirus disease 2019 (COVID-19) pandemic forced the suspension of in-person education in schools serving students in kindergarten through 12th grade (K–12) across the United States. As time passed, teachers, students, and parents struggled with remote education. With limited guidance at the federal level, physicians and school leaders across the country collaborated to develop local solutions for schools. This article describes the lessons learned from the development of 4 academic-community partnerships and collaboration among these partnerships to provide national leadership on managing COVID-19 mitigation in the K–12 environment. In addition, we describe a pathway forward for using academic-community partnerships to improve child health.

OBJECTIVES To identify factors associated with the decision to provide in-person, hybrid, and remote learning in kindergarten through 12th grade school districts during the 2020–2021 school year. METHODS We performed a retrospective study evaluating school district mode of learning and community coronavirus 2019 (COVID-19) incidence and percentage positivity rates at 3 time points during the pandemic: (1) September 15, 2020 (the beginning of the school year, before Centers for Disease Control and Prevention guidance); (2) November 15, 2020 (midsemester after the release of Centers for Disease Control and Prevention guidance and an increase of COVID-19 cases); and (3) January 15, 2021 (start of the second semester and peak COVID-19 rates). Five states were included in the analysis: Michigan, Missouri, North Carolina, Ohio, and Wisconsin. The primary outcome was mode of learning in elementary, middle, and high schools during 3 time points. The measures included community COVID-19 incidence and percentage positivity rates, school and student demographics, and county size classification of school location. RESULTS No relationship between mode of learning and community COVID-19 rates was observed. County urban classification of school location was associated with mode of learning with school districts in nonmetropolitan and small metropolitan counties more likely to be in-person. CONCLUSIONS Community COVID-19 rates did not appear to influence the decision of when to provide in-person learning. Further understanding of factors driving the decisions to bring children back into the classroom are needed. Standardizing policies on how schools apply national guidance to local decision-making may decrease disparities in emergent crises.

Evidence suggests that coronavirus disease 2019 (COVID-19) testing in schools can add a layer of protection to reduce the spread of Severe Acute Respiratory Syndrome Coronavirus 2 and facilitate a safer return to in-person learning. Despite this evidence, implementation of testing in school settings has been challenging initially because of a lack of funding and limited availability of testing, but, as the pandemic has progressed and more funding and resources have been devoted to testing, other implementation challenges have arisen. We describe key implementation barriers and strategies that have been operationalized across 5 projects working to help schools with predominantly underserved populations who have faced significant COVID-19–related health disparities. We leveraged a key framework from the implementation science field to identify the challenges and used a matching tool to align implementation strategies to these challenges. Our findings suggest that the biggest obstacles to COVID-19 testing were the perceived relative advantages versus burden of COVID-19 testing, limited engagement with the target beneficiaries (eg, families, students, staff), and innovation complexity. Common strategies to overcome these challenges included identifying and preparing testing champions, altering incentive and allowance structures, assessing for readiness, and identifying barriers and facilitators. We aim to augment existing implementation guidance for schools by describing common barriers and recommended solutions from the implementation science field. Our results indicate a clear need to provide implementation support to schools to facilitate COVID-19 testing as an added layered mitigation strategy.

Multisystem inflammatory syndrome in children (MIS-C) is a severe postinfectious hyperinflammatory condition, which generally occurs 2-6 weeks after a typically mild or asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19 (1-3). In the United States, the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine is currently authorized for use in children and adolescents aged 5-15 years under an Emergency Use Authorization and is fully licensed by the Food and Drug Administration for persons aged ≥16 years (4). Prelicensure randomized trials in persons aged ≥5 years documented high vaccine efficacy and immunogenicity (5)

BackgroundDetection of SARS-CoV-2 antigens in blood has high sensitivity in adults with acute COVID-19, but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery).MethodsPlasma was collected from inpatients (ResultsSpecificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity, respectively; sensitivity in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤ 35 were 93%/63%. Antigen concentrations ranged from 1.28-3,844 pg/mL (N) and 1.65-1,071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw.ConclusionsUltrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.Key pointsIn a U.S. pediatric cohort tested with ultrasensitive immunoassays, SARS-CoV-2 nucleocapsid antigens were detectable in most patients with acute COVID-19, and spike antigens were commonly detectable. Both antigens were undetectable in almost all MIS-C patients.

Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). Methods Plasma was collected from inpatients ( Results Specificities of N and S assays were 95–97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28–3844 pg/mL (N) and 1.65–1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. Conclusions Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

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: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians)

Background Predominance of 2 antigenically drifted influenza viruses during the 2019–2020 season offered an opportunity to assess vaccine effectiveness against life-threatening pediatric influenza disease from vaccine-mismatched viruses in the United States. Methods We enrolled children aged Results We enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, –21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. Conclusions During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.

OBJECTIVES Nonpharmaceutical interventions against coronavirus disease 2019 likely have a role in decreasing viral acute respiratory illnesses (ARIs). We aimed to assess the frequency of respiratory syncytial virus (RSV) and influenza ARIs before and during the coronavirus disease 2019 pandemic. METHODS This study was a prospective, multicenter, population-based ARI surveillance, including children seen in the emergency departments and inpatient settings in 7 US cities for ARI. Respiratory samples were collected and evaluated by molecular testing. Generalized linear mixed-effects models were used to evaluate the association between community mitigation and number of eligible and proportion of RSV and influenza cases. RESULTS Overall, 45 759 children were eligible; 25 415 were enrolled and tested; 25% and 14% were RSV-positive and influenza-positive, respectively. In 2020, we noted a decrease in eligible and enrolled ARI subjects after community mitigation measures were introduced, with no RSV or influenza detection from April 5, 2020, to April 30, 2020. Compared with 2016–2019, there was an average of 10.6 fewer eligible ARI cases per week per site and 63.9% and 45.8% lower odds of patients testing positive for RSV and influenza, respectively, during the 2020 community mitigation period. In all sites except Seattle, the proportions of positive tests for RSV and influenza in the 2020 community mitigation period were lower than predicted. CONCLUSIONS Between March and April 2020, rapid declines in ARI cases and the proportions of RSV and influenza in children were consistently noted across 7 US cities, which could be attributable to community mitigation measures against severe acute respiratory syndrome coronavirus 2.

Background Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease (KD), the most common cause of acquired heart disease in children, 10–20% of patients are IVIG-resistant and require additional therapy. This group has an increased risk of coronary artery aneurysms (CAA) and there has been no adequately powered, randomized clinical trial in a multi-ethnic population to determine the optimal therapy for IVIG-resistant patients. Objectives The primary outcome is duration of fever in IVIG-resistant patients randomized to treatment with either infliximab or a second IVIG infusion. Secondary outcomes include comparison of inflammatory markers, duration of hospitalization, and coronary artery outcome. An exploratory aim records parent-reported outcomes including signs, symptoms and treatment experience. Methods The KIDCARE trial is a 30-site randomized Phase III comparative effectiveness trial in KD patients with fever ≥36 h after the completion of their first IVIG treatment. Eligible patients will be randomized to receive either a second dose of IVIG (2 g/kg) or infliximab (10 mg/kg). Subjects with persistent or recrudescent fever at 24 h following completion of the first study treatment will cross-over to the other treatment arm. Subjects will exit the study after their first outpatient visit (5–18 days following last study treatment). The parent-reported outcomes, collected daily during hospitalization and at home, will be compared by study arm. Conclusion This trial will contribute to the management of IVIG-resistant patients by establishing the relative efficacy of a second dose of IVIG compared to infliximab and will provide data regarding the patient/parent experience of these treatments.

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

Key Points Question Among children with a COVID-19 diagnosis, what conditions are common, and which are associated with severe COVID-19 illness? Findings In this cross-sectional study of 43 465 patients aged 18 years or younger with COVID-19, more than one-quarter had 1 or more underlying condition; asthma, obesity, neurodevelopmental disorders, and certain mental health conditions were most common. Certain conditions as well as medical complexity were associated with a higher risk of severe COVID-19 illness. Meaning These findings expand the knowledge available regarding children with COVID-19 and could inform pediatric clinical practice and public health priorities, such as prevention and mitigation of COVID-19., This cross-sectional study examines the risk of severe COVID-19 illness among children associated with underlying medical conditions and medical complexity., Importance Information on underlying conditions and severe COVID-19 illness among children is limited. Objective To examine the risk of severe COVID-19 illness among children associated with underlying medical conditions and medical complexity. Design, Setting, and Participants This cross-sectional study included patients aged 18 years and younger with International Statistical Classification of Diseases, Tenth Revision, Clinical Modification code U07.1 (COVID-19) or B97.29 (other coronavirus) during an emergency department or inpatient encounter from March 2020 through January 2021. Data were collected from the Premier Healthcare Database Special COVID-19 Release, which included data from more than 800 US hospitals. Multivariable generalized linear models, controlling for patient and hospital characteristics, were used to estimate adjusted risk of severe COVID-19 illness associated with underlying medical conditions and medical complexity. Exposures Underlying medical conditions and medical complexity (ie, presence of complex or noncomplex chronic disease). Main Outcomes and Measures Hospitalization and severe illness when hospitalized (ie, combined outcome of intensive care unit admission, invasive mechanical ventilation, or death). Results Among 43 465 patients with COVID-19 aged 18 years or younger, the median (interquartile range) age was 12 (4-16) years, 22 943 (52.8%) were female patients, and 12 491 (28.7%) had underlying medical conditions. The most common diagnosed conditions were asthma (4416 [10.2%]), neurodevelopmental disorders (1690 [3.9%]), anxiety and fear-related disorders (1374 [3.2%]), depressive disorders (1209 [2.8%]), and obesity (1071 [2.5%]). The strongest risk factors for hospitalization were type 1 diabetes (adjusted risk ratio [aRR], 4.60; 95% CI, 3.91-5.42) and obesity (aRR, 3.07; 95% CI, 2.66-3.54), and the strongest risk factors for severe COVID-19 illness were type 1 diabetes (aRR, 2.38; 95% CI, 2.06-2.76) and cardiac and circulatory congenital anomalies (aRR, 1.72; 95% CI, 1.48-1.99). Prematurity was a risk factor for severe COVID-19 illness among children younger than 2 years (aRR, 1.83; 95% CI, 1.47-2.29). Chronic and complex chronic disease were risk factors for hospitalization, with aRRs of 2.91 (95% CI, 2.63-3.23) and 7.86 (95% CI, 6.91-8.95), respectively, as well as for severe COVID-19 illness, with aRRs of 1.95 (95% CI, 1.69-2.26) and 2.86 (95% CI, 2.47-3.32), respectively. Conclusions and Relevance This cross-sectional study found a higher risk of severe COVID-19 illness among children with medical complexity and certain underlying conditions, such as type 1 diabetes, cardiac and circulatory congenital anomalies, and obesity. Health care practitioners could consider the potential need for close observation and cautious clinical management of children with these conditions and COVID-19.

Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.