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Background Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. Methods We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. Results Common variants in DDX58, encoding the retinoic acid–inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants’ impact on RIG-I and IFN immunity. Conclusions We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.

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.

We used daily real-time reverse-transcription polymerase chain reaction (RT-PCR) results from 67 cases of SARS-CoV-2 infection in a household transmission study, conducted April 2020–May 2021, to examine the trajectory of cycle threshold (Ct) values, an inverse correlate of viral RNA concentration. Ct values varied across RT-PCR platforms and by participant age. Specimens collected from children and adolescents had higher Ct values and adults aged ≥50 years showed lower Ct values than adults aged 18–49 years. Ct values were lower on days when participants reported experiencing symptoms, with the lowest Ct value occurring 2–6 days after symptom onset.

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.

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.

From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals

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 Risk factors for MIS-C, a rare but serious hyperinflammatory syndrome associated with SARS-CoV-2 infection, remain unclear. We evaluated household, clinical, and environmental risk factors potentially associated with MIS-C. Methods This investigation included MIS-C cases hospitalized in 14 US pediatric hospitals in 2021. Outpatient controls were frequency-matched to case-patients by age group and site and had a positive SARS-CoV-2 viral test within 3 months of the admission of their matched MIS-C case (Figure 1). We conducted telephone surveys with caregivers and evaluated potential risk factors using mixed effects multivariable logistic regression, including site as a random effect. We queried regarding exposures within the month before hospitalization for MIS-C cases or the month after a positive COVID-19 test for controls. Figure.Patient enrollment timeline. Enrollment scheme for MIS-C case-patients and SARS-CoV-2-positive outpatient controls. MIS-C case-patients were identified through hospital electronic medical records, while two outpatient controls per case were identified through registries of outpatient SARS-CoV-2 testing logs at facilities affiliated with that medical center. Caregivers of outpatient controls were interviewed at least four weeks after their positive test to ensure they did not develop MIS-C after their infection. Results We compared 275 MIS-C case-patients with 494 outpatient SARS-CoV-2-positive controls. Race, ethnicity and social vulnerability indices were similar. MIS-C was more likely among persons who resided in households with >1 resident per room (aOR=1.6, 95% CI: 1.1–2.2), attended a large (≥10 people) event with little to no mask-wearing (aOR=2.2, 95% CI: 1.4–3.5), used public transportation (aOR=1.6, 95% CI: 1.2–2.1), attended school >2 days per week with little to no mask wearing (aOR=2.1, 95% CI: 1.0–4.4), or had a household member test positive for COVID-19 (aOR=2.1, 95% CI: 1.3–3.3). MIS-C was less likely among children with comorbidities (aOR=0.5, 95% CI: 0.3–0.9) and in those who had >1 positive SARS-CoV-2 test at least 1 month apart (aOR=0.4, 95% CI: 0.2–0.6). MIS-C was not associated with a medical history of recurrent infections or family history of underlying rheumatologic disease. Conclusion Household crowding, limited masking at large indoor events or schools and use of public transportation were associated with increased likelihood of developing MIS-C after SARS-CoV-2 infection. In contrast, decreased likelihood of MIS-C was associated with having >1 SARS-CoV-2 positive test separated by at least a month. Our data suggest that additional studies are needed to determine if viral load, and/or recurrent infections in the month prior to MIS-C contribute to MIS-C risk. Medical and family history were not associated with MIS-C in our analysis. Disclosures Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation Mark Hall, MD, Abbvie: Service on a Data Safety Monitoring Board|Kiadis: Licensing income unrelated to the current submission 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 Pia S. Pannaraj, MD, MPH, AstraZeneca: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi-Pasteur: Advisor/Consultant|Seqirus: Advisor/Consultant Charlotte V. Hobbs, MD, Biofire (Biomerieux): Advisor/Consultant.

Background Pediatric solid organ transplant (SOT) recipients are at high risk of complications from influenza and those with documented or suspected influenza should receive antivirals as soon as possible. We aimed to compare outcomes between pediatric SOT recipients who did or did not receive timely antiviral therapy for an influenza-associated hospitalization (IAH). Methods We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR) databases and queried the merged database for single SOT recipients < 18 years old who were transplanted between 1/1/2006 and 6/1/2016 and had at least one IAH within 3 years. We excluded children who contracted influenza or died during the transplant encounter and those who did not have follow-up data. We defined “timely” antiviral therapy as the receipt of antivirals no more than 2 days after hospitalization and compared the outcomes of children who did or did not receive timely antiviral therapy using Pearson’s χ2 test or the two-sample t-test with unequal variances, as appropriate. Results Of 12,419 children, 379 (3.1%) had at least one IAH. The most common organ transplant was kidney (n=133 [35.1%]). Of 270 children (71.2%) who received antivirals, 225 (83.3%) received them within 2 days of hospitalization. Oseltamivir was the most frequently administered influenza-specific antiviral (n=268 [99.3%]). The outcomes of children who received timely antiviral therapy and those who did not are compared in Table 1. The proportion of children who received timely antiviral therapy increased over the study period from 33.3% in 2007 to 100% in 2019 (Figure 1). Table 1Outcomes of pediatric SOT recipients who did or did not receive timely antiviral therapy.Figure 1Proportions of pediatric SOT recipients who did or did not receive timely antiviral therapy. Conclusion Timely influenza-specific antiviral therapy was associated with better outcomes in pediatric SOT recipients with IAH. Importantly, more than one-third of children did not receive timely antiviral therapy. Further studies are needed to identify and address barriers to timely antiviral therapy. Disclosures Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation Daniel Dulek, MD, Eurofins/Viracor: Grant/Research Support.

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare sequela that typically develops 2–6 weeks after SARS-CoV-2 infection. According to CDC recommendations, children who recover from MIS-C should be vaccinated 90 days after diagnosis, but safety and immunogenicity data are lacking. Our aim was to evaluate the safety and immunogenicity of one dose of the BNT162b2 vaccine in children with a history of MIS-C. Methods We conducted a longitudinal study of children with MIS-C admitted to Monroe Carell Jr. Children's Hospital at Vanderbilt from 7/11/2020 to 3/23/2022. Children were eligible if they met CDC’s MIS-C criteria and had blood collected before and after SARS-CoV-2 vaccination. Clinical data were obtained from medical records and injection site and systemic reactions were recorded for a week following SARS-CoV-2 vaccination via memory aids. IgG against SARS-CoV-2 nucleocapsid (N), spike receptor-binding domain (RBD), and spike extracellular domain (ECD) was detected using an enzyme-linked immunosorbent assay. The first anti-RBD and anti-ECD levels prevaccination and postvaccination were compared using the paired-samples t-test. Results Seven children were included, of whom five were male and five were non-Hispanic White. The first blood sample was collected 3–44 days following admission. The median age at admission was 15.8 years (IQR, 10.5–14.7 years), and the median time from admission to vaccination was 7 months (IQR, 6–8 months). Five children each had injection site or systemic reactions (Figure 1); the majority were mild or moderate and occurred within 2 days of vaccination. Children were followed for a median of 5.6 months (4.3–6.2 months) postvaccination; none developed MIS-C recurrence. Following vaccination, mean anti-RBD and anti-ECD levels increased by 2.0 (1.2–2.9; p < 0.001) and 1.9 (1.2–2.6; p < 0.001) absorbance units, respectively (Figure 2). A sensitivity analysis excluding children with antibody evidence of reinfection (increase in anti-N level ≥ 0.5) showed similar results. Figure 1Safety of SARS-CoV-2 vaccination in children with a history of MIS-C. Figure 2 Immunogenicity of SARS-CoV-2 vaccination in children with a history of MIS-C. The best-fit lines (LOESS) are indicated in black. The dashed line indicates the day of vaccination. Conclusion SARS-CoV-2 vaccination is safe and immunogenic in children with a history of MIS-C, with no documented recurrence of MIS-C–like illness. Further studies are needed to determine the optimal timing, safety, and immunogenicity of vaccination following MIS-C. Disclosures Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation.

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 Children can present with overlapping symptoms of acute respiratory illness (ARI) and acute gastroenteritis (AGE). In these cases, it is unclear if the etiologic agent is a respiratory pathogen, gastrointestinal pathogen, or both. Methods We analyzed data collected in Nashville, TN (12/01/2016–2/28/2020) as part of the New Vaccine Surveillance Network, a prospective ARI/AGE surveillance study. Children (< 18 years old) who presented to the emergency department or were admitted with fever and/or respiratory symptoms for < 14 days were enrolled as ARI subjects and had mid-turbinate nasal ± throat swabs collected, while children with ≥1 episode of vomiting and/or ≥3 episodes of diarrhea in 24 hours were enrolled as AGE subjects and had stool collected. Children who met both sets of criteria were dually enrolled. Respiratory specimens were tested for common respiratory viruses by molecular testing and stool specimens were tested for common gastrointestinal (GI) pathogens by Luminex GI Pathogen Panel. We compared detection groups using Pearson’s χ2 test. C. difficile detection in children < 2 years old was considered asymptomatic carriage (n=32). Results We identified 501 dual enrollees, among whom 279 (55.7%) had both a respiratory and stool specimen tested. Overall, 127 (45.5%) had only a respiratory virus detected, 33 (11.8%) had only a GI pathogen detected, 39 (14.0%) had both, and 77 (27.6%) had no detection (Table 1). Vomiting and diarrhea were frequently reported ( >50%) in all dual enrollees whether or not a pathogen was detected (Figure 1). Cough was detected in high frequency in all groups with pathogen detection. Children with respiratory-only or dual detection had a higher frequency of wheezing and shortness of breath than those with GI-only or no detection. The distribution of pathogens did not significantly differ between single and co-detected cases (Figure 2). Table 1Demographic characteristics of N=279* children presenting with symptoms of acute respiratory illness and acute gastroenteritis in Nashville, TN, stratified by detection status.Figure 1Distribution of signs and symptoms in N=279 children presenting with symptoms of acute respiratory illness and acute gastroenteritis in Nashville, TN, stratified by detection status. p values represent omnibus comparisons of all four groups.Figure 2Distribution of pathogens detected in N=279 children presenting with symptoms of acute respiratory illness and acute gastroenteritis in Nashville, TN, stratified by detection status. Conclusion Children presenting with overlapping symptoms of ARI and AGE were more likely to have an ARI-associated virus. Lower respiratory symptoms (namely, wheezing and shortness of breath) were more specific for ARI-associated viral detection compared with other signs and symptoms. Disclosures 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.

Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children.Hospitalized children18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment.Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95]).Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment.

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN inpatient (i.e., hospital) surveillance began in 2015, expanded to emergency departments (EDs) in 2016, and to outpatient clinics in 2018. This report describes demographic characteristics of enrolled children who received care in these settings, and yearly circulation of influenza, RSV, HMPV, HPIV1-3, adenovirus, human rhinovirus and enterovirus (RV/EV),* and SARS-CoV-2 during December 2016-August 2021. Among 90,085 eligible infants, children, and adolescents (children) aged18 years

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.

Background Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in young children worldwide. Multiple factors affect RSV disease severity, and data regarding differences between RSV subtypes severity are controversial. This study aimed to evaluate the clinical characteristics, seasonality and severity of RSV subtypes in children. Methods As part of a prospective ARI surveillance study conducted from March 2010 to March 2013 in Amman, Jordan, children less than 2 years with fever and/or respiratory symptoms were enrolled. Demographic and clinical characteristics were collected through parental interviews and medical chart review. The treating physician collected severity score data at admission. Nasal and throat swabs were collected and tested. Multivariable regression models were used to compare the odds of increased disease severity across a priori selected predictors of interest. Results Overall, 1397/3168 (44%) children were RSV positive, with a mean age of 5.3 months (±4.8 SD), 59.7% were male, 6.4% had an underlying medical condition (UMC), 63.6% were RSV-A positive, 25.2% were RSV-B positive, 0.6% were positive for both, and 10.6% could not be typed. Both RSV subtypes peaked in January-March of each year. RSV A-positive children were more likely to present with decreased appetite but less likely to have viral co-detection than RSV B-positive children. Independent factors associated with RSV disease severity included cycle threshold value, vitamin D level, age, UMC, prematurity and severity score, but not RSV subtypes. Conclusion RSV subtypes co-circulated and had similar severity profiles; future preventive and treatment measures should target both subtypes.

Background Influenza vaccine effectiveness (VE) against a spectrum of severe disease, including critical illness and death, remains poorly characterized. Methods We conducted a test-negative study in an intensive care unit (ICU) network at 10 US hospitals to evaluate VE for preventing influenza-associated severe acute respiratory infection (SARI) during the 2019–2020 season, which was characterized by circulation of drifted A/H1N1 and B-lineage viruses. Cases were adults hospitalized in the ICU and a targeted number outside the ICU (to capture a spectrum of severity) with laboratory-confirmed, influenza-associated SARI. Test-negative controls were frequency-matched based on hospital, timing of admission, and care location (ICU vs non-ICU). Estimates were adjusted for age, comorbidities, and other confounders. Results Among 638 patients, the median (interquartile) age was 57 (44–68) years; 286 (44.8%) patients were treated in the ICU and 42 (6.6%) died during hospitalization. Forty-five percent of cases and 61% of controls were vaccinated, which resulted in an overall VE of 32% (95% CI: 2–53%), including 28% (−9% to 52%) against influenza A and 52% (13–74%) against influenza B. VE was higher in adults 18–49 years old (62%; 95% CI: 27–81%) than those aged 50–64 years (20%; −48% to 57%) and ≥65 years old (−3%; 95% CI: −97% to 46%) (P = .0789 for interaction). VE was significantly higher against influenza-associated death (80%; 95% CI: 4–96%) than nonfatal influenza illness. Conclusions During a season with drifted viruses, vaccination reduced severe influenza-associated illness among adults by 32%. VE was high among young adults.