Geoffrey A. Weinberg

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: Comprehensive data are needed to guide the use and interpretation of molecular respiratory viral testing in evaluating infants 0 to ≤90 days old for invasive bacterial infections (IBIs). We aimed to describe the frequency and severity of respiratory viral infections in febrile and nonfebrile infants 0 to ≤90 days of age with emergency department visits or hospitalizations for acute respiratory illness and to quantify the occurrence of IBI (bacteremia and bacterial meningitis) in these groups. Methods: The New Vaccine Surveillance Network conducts acute respiratory illness surveillance at 7 US pediatric medical institutions in the United States. We conducted a cross-sectional analysis of febrile and nonfebrile infants 0 to ≤90 days of age enrolled in the emergency department or inpatient hospital settings. Respiratory viral detection from research respiratory samples in the context of clinical severity and IBI was examined. Results: Three thousand seven hundred and eighty febrile and nonfebrile infants 0 to ≤90 days of age enrolled from December 1, 2016, to March 31, 2020. Respiratory syncytial virus was the most common virus detected regardless of febrile status. IBIs were significantly more frequent in febrile infants without a respiratory virus compared with those with a respiratory virus detected (4.9% vs. 1.3%; P < 0.001). IBIs were not detected in infants with respiratory syncytial virus (n = 259), parainfluenza virus (n = 66), human metapneumovirus (n = 13), influenza virus (n = 67), or adenovirus (n = 11) alone. IBI and respiratory viral coinfections were found in infants with endemic coronaviruses (5.8%, 3/52), rhinovirus/enterovirus (2.2%, 7/324) and viral coinfections (2.0%, 2/99). Conclusions: These data suggest that febrile infants 0 to ≤90 days old with certain respiratory viruses are at lower risk of IBI.

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.

G8 rotaviruses are primarily associated with animals and infrequently cause infections in humans. The first detection of G8 strains in humans occurred around 1979, and since then, their presence has been sporadic, particularly in the United States (U.S.). During the 2016–2017 rotavirus surveillance season, the New Vaccine Surveillance Network (NVSN) identified 36 G8P[8] rotavirus strains across four sites in the U.S. This study presents the whole-genome characterization of these G8P[8] strains, along with comparative sequence analyses against the current vaccine strains, Rotarix and RotaTeq. Each strain exhibited a DS-1-like backbone with a consensus genotype constellation of G8P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 and exhibited high genetic similarities to G8P[8] strains previously detected in Europe and Asia. Clinical analysis revealed no significant differences in hospitalization rates, length of stay, or severity scores between G8P[8] RVA-positive and non-G8P[8] RVA-positive subjects. Additionally, phylodynamic analysis determined the evolutionary rates and the most recent common ancestor for these strains, highlighting the importance of ongoing monitoring of rotavirus genotypes to assess the spread of these emerging G8P[8] strains.

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%).

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

Background: Human parainfluenza viruses (PIV) are a major cause of acute respiratory infection (ARI) leading to hospitalization in young children. In order to quantify the burden of PIV hospitalizations and to evaluate the characteristics of children hospitalized with PIV by virus type, we used data from the New Vaccine Surveillance Network, a multicenter, active, prospective population-based surveillance network, enrolling children hospitalized for ARI (defined as fever and/or respiratory symptoms) at 7 U.S. children’s hospitals. Methods: The study period included December 1, 2016 through March 31, 2020. Data captured included demographic characteristics, clinical presentation, underlying medical conditions, discharge diagnoses, and virus detection by RT-PCR. Linear and logistic regression were used to compare descriptive and clinical characteristics among children. Population-based PIV-associated hospitalization rates were calculated by age group and PIV-type. Results: Of the 16,971 enrolled children with PIV virologic testing, 10,488 had only one respiratory virus detected, among whom 702 (7%) had positive testing for PIV without a co-detected virus (mean age [SD], 2.2 [3.2] years). Of these 702 children, 340 (48%) had underlying comorbidities, 139 (20%) had a history of prematurity, 121 (17%) were admitted to the ICU, and 23 (3%) required intubation. Overall, PIV hospitalization rates were highest in children aged 0-5 months, 1.91 hospitalizations per 1,000 children per year [95% CI, 1.61-2.23]; PIV-3 contributed to the highest rates in that age group, followed by PIV-1 and PIV-4: 1.08 [0.84-1.21], 0.42 [0.28-0.58] and 0.25 [0.15-0.37] per 1,000 children per year, respectively. Seasonal distribution of PIV-associated hospitalizations varied by type. Conclusions: PIV infection was associated with a substantial number of ARI hospitalizations in children aged 0-5 months. Results suggest that future PIV prevention strategies in the US that focus on younger children and protection against PIV-3, PIV-1, and PIV-4 might have the greatest impact on reducing PIV hospitalization burden.