Christopher J. Harrison

Background: Infants are at risk of severe respiratory syncytial virus (RSV) infection. We characterized the humoral immune response of infants with primary RSV infection. Methods: Term infants hospitalized for RSV acute respiratory infection (ARI) or non-RSV ARI (controls) were enrolled from November 2018 through March 2020 at 5 pediatric medical institutions. Adult controls were women aged 18–45 years without acute RSV infection. Acute and convalescent sera were tested for homologous and heterologous neutralizing antibodies (NtAbs), competitive antibodies (CAs) to sites Ø, II, IV, and I on the fusion (F) glycoprotein, and anti-postF and 27-amino acid peptide (p27) immunoglobulin G (IgG). Geometric mean titer or CA concentrations of acute and convalescent sera were compared between and within groups. Results: Sixty-six infants (49 RSV infected and 17 controls) were enrolled. Median age was 76 (interquartile range [IQR], 45–179) days and 151 (IQR, 72–207) days for the RSV and control groups, respectively. NtAb and CA at hospitalization were low among infant groups. Postinfection, RSV/A induced robust homologous and heterologous NtAb responses while RSV/B caused a robust NtAb response only to RSV/B. RSV/A infection generated significant CA rise to sites IV and II, while RSV/B infection resulted in only site II CA rise. Rises in postF and p27 IgG were not detected. Postinfection RSV antibody levels in infants were markedly lower compared to those in control adult women. Conclusions: RSV-infected infants had low preinfection levels of protective antibodies. Infants infected with RSV/A compared to RSV/B generated a more robust NtAb response, highlighted by a broader CA response to sites II and IV.

Background: In 1999, the Centers for Disease Control and Prevention established the New Vaccine Surveillance Network (NVSN) as a multisite pediatric infectious diseases active surveillance system. Methods: NVSN prospectively collects population-based clinical, epidemiologic, and laboratory information on children who seek medical care at hospitals, emergency departments, urgent care centers, and outpatient clinics with symptoms of acute respiratory infections (ARI) and acute gastroenteritis (AGE) in the United States. Results: These efforts have clearly established the significant burden of both ARI and AGE in US children, demonstrated the effectiveness of licensed pediatric vaccines, and helped guide their use. The surveillance platform also measures the real-world impact of preventive measures intended to avoid or ameliorate adverse child health outcomes within the US healthcare system. Furthermore, NVSN provides a platform for detecting and evaluating emerging infections (eg, enterovirus D-68 and severe acute respiratory syndrome coronavirus 2) and unexpected sequelae in children. Conclusions: For 25 years, NVSN has provided an evidence-based foundation for pediatric infectious disease policy decision-making through objective, empirical data. Sustained investment in disease surveillance guides the scientific principles and public health practices that prevent suffering and premature death, prepares us for new and existent pathogen threats, and enables wise economic decisions that improve the health of Americans.

Background: Human adenovirus (HAdV) is a common cause of pediatric acute respiratory illness (ARI), contributing to 5–13% of cases worldwide. Clinical manifestations vary by HAdV species and type; therefore, delineating type-specific disease presentations and understanding severity of specific HAdV types' disease may help develop targeted interventions. Methods: We conducted a multicenter, prospective study within the New Vaccine Surveillance Network to characterize HAdV types. Children <18 years old with ARI were enrolled in the emergency department or inpatient setting at 7 US children's hospitals from 1 December 2016 to 30 November 2019. Respiratory specimens were collected and tested for HAdV and other viruses. Subsequently, typing was conducted on HAdV specimens using single-plex real-time PCR assays targeting sequences in the hexon gene. Comparisons between HAdV types were performed to determine differences in characteristics and outcomes. Generalized linear mixed effects models were used to evaluate severity. Results: Among the 1843 HAdV-positive cases, 1402 specimens (76%) were typed. The most common types detected were HAdV-C1 (n = 439), HAdV-C2 (n = 393), and HAdV-B3 (n = 221). Children with HAdV-B7 (n = 78) had higher odds of severe outcomes compared to those with other HAdV types (aOR = 2.05; 95% CI: 1.24, 3.40). Symptom presentation varied across types within species B, C, and E; while all species had high frequency of upper respiratory symptoms, species B cases presented with a higher frequency of non-respiratory manifestations. Conclusions: Among children with HAdV-positive ARI, those with HAdV-B7 had higher odds of severe outcomes. These findings suggest heterogeneity in clinical presentation and severity among HAdV types, emphasizing the importance of HAdV type in future prevention and treatment strategies.

Introduction: Bronchiolitis, pneumonia, and croup account for a substantial burden of pediatric hospitalizations. We aim to provide an updated, multi-center, multi-pathogen evaluation of viral detections seen with these acute respiratory illness (ARI) syndromes before and after the COVID-19 pandemic. Methods: We included children 80% had one or more respiratory virus detected. Respiratory syncytial virus (RSV) was the most frequent virus detected in bronchiolitis (41%) and pneumonia (26%), with a similar distribution across the COVID-19 onset periods. Parainfluenza virus (PIV) was the most frequent virus detected in croup (28%), but detections fell in the post-COVID-19 onset period by 8.4%; there was a comparable proportion of SARS-CoV-2 detections (7.6%) that emerged among croup cases. Rhinoviruses/enteroviruses (RV/EV) were the second most frequently detected virus across all three ARI syndromes and were the predominant virus in children <6 months and children with an underlying medical condition diagnosed with croup. Codetections were present in 17%-19% of bronchiolitis, pneumonia, and croup cases. Discussion: We found a high proportion of respiratory viral detections in children <5 years with bronchiolitis, pneumonia, or croup, particularly with RSV, RV/EV, and PIV. Most viruses were identified in similar proportions before and after the emergence of SARS-CoV-2, except for PIV and influenza virus. In our cohort, there was a high proportion of viral detection across all three ARI syndromes, with RV/EV frequently detected in certain age groups and among children with underlying conditions.

Background: Non-pharmaceutical interventions to mitigate the spread of SARS-CoV-2 were implemented across the United States in 2020. These public health measures might influence pneumococcal colonization in younger children and their subsequent risk of invasive pneumococcal disease. Our objective was to evaluate pneumococcal colonization rates in children ≤ 5 years of age with and without respiratory symptoms during the first 12 months of SARS-CoV-2 pandemic (April 2020 – March 2021). Study design: This is a retrospective cross-sectional study evaluating pneumococcal colonization rates, density and serotype distribution across three study periods (April-July [Period 1], August-November [Period 2] and December-March [Period 3]) after implementation of non-pharmaceutical interventions in Kansas City, Missouri. Children aged ≤5 years with and without respiratory symptoms seeking care at Children’s Mercy Kansas City hospital system with a residual standard of care nasal mid-turbinate sample were included. The odds of pneumococcal colonization across study periods were calculated using multivariable logistic regression. Results: A total of 311 children met inclusion criteria (126 symptomatic and 185 asymptomatic). The overall pneumococcal colonization (23% vs. 13%, p = 0.03) and SARS-CoV-2 positivity (34.1% vs. 17.8%, p = 0.001) rates were higher in symptomatic children than in asymptomatic children. The odds of pneumococcal colonization of symptomatic (Period 2: OR 1.09; 95% CI 0.33–3.64, and Period 3: OR 0.46; 95% CI 0.13–1.59) and asymptomatic (Period 2: OR 0.55; 95% CI 0.18–1.7, and Period 3: OR 0.37; 95% CI 0.11–1.2) children did not statistically differ across study periods. Pneumococcal colonization density was also not different across study periods among study groups. Overall, non-PCV15, non-PCV20 serotypes were the most frequently identified serotypes (56.8%). Conclusions: Pneumococcal colonization rates and density did not significantly change across study periods as adherence to non-pharmaceutical interventions gradually relaxed during the first year of the SARS-CoV-2 pandemic.

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

Background: Human adenovirus (HAdV) is a common cause of pediatric acute respiratory illness (ARI). HAdV-B, -C, and -E species have been associated with ARI, though relative detection frequencies in United States (U.S.) and respective roles in symptomatic respiratory infections remain unclear. Methods: We conducted a multicenter, prospective viral surveillance study at 7 U.S. children’s hospitals comprising the New Vaccine Surveillance Network from January 12, 2016 to November 30, 2019. Children <18 years old in the emergency department or hospitalized with fever and/or respiratory symptoms were enrolled, and respiratory specimens were tested for HAdV and other viral pathogens. HAdV-positive specimens were subsequently typed using single-plex real-time PCR assays targeting sequences in the hexon gene. Demographics, clinical characteristics, and outcomes (hospitalization and supplemental oxygen use as severity indicators) were compared between HAdV-B and HAdV-C species. Results: Of the 29 381 children with ARI, 1843 (6.3%) had HAdV detected, with 1402 specimens (76.0%) successfully typed. HAdV-C was the most frequently detected species (73.0%), followed by HAdV-B (22.3%). Children with HAdV-C were younger than those with HAdV-B and more likely to have another respiratory pathogen. Among children without other detected respiratory pathogens, those with HAdV-C had lower odds of hospitalization compared with children with HAdV-B (aOR: 0.44, 95% CI, 0.27-0.73, P =.001). Conclusions: In our study among children seen in the emergency department or hospitalized with ARI, those with HAdV-C had lower odds of hospitalization compared with HAdV-B. These findings warrant further assessment to identify which HAdV types contribute to illness severity.

Norovirus-associated acute gastroenteritis (AGE) in children <11 years resulted in substantial AGE illness among household contacts (HHCs). Vomiting (≥5 episodes in 24 hours) was the greatest risk factor (aOR, 2.85, [95% CI, 1.91-4.26]) for AGE symptoms among HHCs of norovirus-positive index cases. HHCs age 0-4 years had the highest attack rates (22%).