Cause Of Acute Respiratory Illness Research Articles

P-670. Differences in Adenovirus Type Detection in Children with Acute Respiratory Illness versus Healthy Controls: New Vaccine Surveillance Network (NVSN) 2016-2019

Abstract Background Human adenovirus (HAdV) is a common cause of acute respiratory illness (ARI) in children, ranging from asymptomatic to life-threatening disease. While previous studies have examined asymptomatic vs HAdV ARI infections, few have analyzed HAdV species and type. We compared frequencies of common HAdV ARI types among children with ARI vs. healthy controls (HCs). Comparison of demographics and HAdV detection between children with ARI and healthy controls: New Vaccine Surveillance Network 12/01/2016–11/30/2019 (N=1,393). Methods Data were analyzed from the New Vaccine Surveillance Network, a multicenter, prospective surveillance network at 7 U.S. children’s hospitals that enrolled children < 18 years with ARI (fever and/or respiratory symptoms) from emergency departments or inpatient settings during 12/01/16–11/30/19. HCs (ARI symptom free ≥3 days and no vomiting/diarrhea ≥14 days) were matched by age and near date of enrollment, and enrolled from outpatient clinics. Nasal and/or throat swabs were tested using molecular assays for HAdV and other respiratory viruses. HAdV-positive specimens were tested by real-time PCR for 11 common respiratory HAdV types representing species B, C, and E based on unique sequences in the hexon gene. Demographics, HAdV species, and HAdV types from HAdV-positive children with ARI were compared to those from HAdV-positive HCs. Percent of HAdV species detections stratified by ARI cases and healthy controls: New Vaccine Surveillance Network 12/01/2016–11/30/2019 Results 1,330 HAdV detections from ARI cases and 63 from HCs were included. Children with HAdV ARI were older, more frequently attended daycare, had higher viral load (based on cycle threshold value), and had more frequent viral co-detection compared to HCs (Table 1). HAdV-C predominated in both ARI and HC groups (Fig. 1); HAdV-C2 was most common, followed by HAdV-C1 (Fig. 2). Among HAdV-positive patients, those with ARI more frequently had HAdV-B detection than HCs (22.3% vs. 1.6%, p< 0.001). HAdV-positive HCs more frequently had HAdV-C detected than HAdV-positive ARI cases (95.2% vs 73.8%, p< 0.001). HAdV-C1 was more likely to be detected in HCs than those with ARI (28.9% vs. 41.3%, p=0.03), and HAdV-B3 was only detected in those with ARI. Percent of HAdV type detections stratified by ARI cases and healthy controls: NVSN, 12/01/2016–11/30/2019. Conclusion While HAdV-C was most frequent in all children, HAdV-B was more often detected in those with ARI than HCs, suggesting that different HAdV species and types have different symptom phenotypes, including HAdV-B3. Further investigations into the identification of specific HAdV types responsible for ARI are necessary. Disclosures Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, FAAM, Abbott: Grant/Research Support|Abbott: Honoraria|BioMerieux: Grant/Research Support|Cepheid: Grant/Research Support|Diasorin: Grant/Research Support|GSK: Advisor/Consultant|Hologic: Grant/Research Support|Luminex: Grant/Research Support|Qiagen: Grant/Research Support Christopher J. Harrison, MD, GSK: Grant/Research Support|Medscape: Honoraria|Merck: Grant/Research Support|Pfizer: Grant/Research Support|UpToDate: Honoraria Pedro A. Piedra, MD, Merck: Grant/Research Support|Novavax: Grant/Research Support|Sanofi-Pasteur: Grant/Research Support|Shionogi: Grant/Research Support Mary A. Staat, MD, MPH, Cepheid: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Up-To-Date: Honoraria Elizabeth P. Schlaudecker, MD, MPH, Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Geoffrey A. Weinberg, MD, Inhalon: Advisor/Consultant|Merck & Company: Honoraria for textbook chapter preparation Janet A. Englund, MD, Abbvie: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Speaker at meeting|SanofiPasteur: Advisor/Consultant|Shinogi: Advisor/Consultant James Chappell, MD, PhD, Merck: Grant/Research Support Natasha B. Halasa, MD, MPH, Merck: Grant/Research Support

P-687. Respiratory Syncytial Virus (RSV) Testing Patterns among Medically Attended Cases of Acute Respiratory Illness from 2016 to 2023

Abstract Background Historically, respiratory syncytial virus (RSV) has been an underrecognized cause of acute respiratory illness (ARI) in adults and patients have been infrequently tested for RSV. This study aimed to describe RSV testing patterns among adults over time and by setting of care. Methods This was a retrospective cohort study, analyzing the Optum de-identified Electronic Health Record data set (Optum EHR) from October 2015 to June 2023. Medically attended ARIs were identified (using ICD-10-CM codes) in adults aged ≥ 50 years with ≥ 12 months of activity in the Optum EHR. Individuals could have multiple ARIs included over the study period. ARIs were classified by epidemiological year (July 1 to June 30), RSV season, and by most intensive setting of care during the ARI (outpatient, emergency department [ED], or inpatient). The percentage of ARIs tested for RSV was reported by time period and other characteristics. Influenza and SARS-CoV-2 testing patterns were also reported for context. Results The study included 22,475,891 ARIs among adults aged ≥50 years. The mean age at the time of ARI was 67.3 years. Key baseline characteristics of ARI episodes are reported in Table 1. The percentage of ARIs tested for RSV generally increased each epidemiological year, from 1.3% in 2016-17 to 5.9% in 2022-23 (Table 2). RSV testing was higher during RSV seasons than outside of seasons prior to the COVID-19 pandemic period. Across epidemiological years, the percentages of medically attended ARIs tested for RSV was highest among ARIs that involved inpatient care (9.5-27.5%), followed by ED visits (1.4-17.9%), and outpatient visits (0.3-1.4%). Conclusion Despite increased awareness of the importance of RSV as a pathogen in older adults and adults with comorbidities, RSV testing remains infrequent. RSV testing has increased over time, particularly among ARIs involving inpatient care. These findings suggest that studies relying on recent real-world data could substantially underestimate RSV burden. Future research may further explore ARI or patient characteristics associated with RSV testing. FUNDING: GSK (study identifier: VEO-000617) Disclosures David Singer, PharmD, MS, GSK: employee|GSK: Stocks/Bonds (Public Company) Yan Wang, ScD, Analysis Group: Employee Aozhou Wu, PhD, Analysis Group: Employee Emily K. Horn, MSc, GSK: employee|GSK: Stocks/Bonds (Private Company) Elizabeth M. La, PhD, GSK: employee|GSK: Stocks/Bonds (Private Company) Susan Gerber, MD, GSK: Employee Joanna Boland, PhD, MS, Analysis Group: Employee Keith A. Betts, PhD, Analysis Group: Employee

Cost-effectiveness of the adjuvanted RSVPreF3 vaccine among adults aged ≥60 years in the United States

ABSTRACT Respiratory syncytial virus (RSV) is a common cause of acute respiratory illness in individuals of all ages, with adults aged ≥60 years and adults with certain chronic conditions at increased risk of severe RSV-related outcomes. This study evaluates the cost-effectiveness of the adjuvanted RSVPreF3 vaccine versus no vaccine in adults aged ≥60 years in the United States (US). A multi-cohort Markov model was developed with a 5-year time horizon and 1-month cycle length to compare outcomes for no vaccination and one-time adjuvanted RSVPreF3 vaccination (assuming the same vaccination as for influenza vaccines). Clinical parameters (e.g., vaccine efficacy) were based on phase 3 clinical trial data over 3 seasons, with all other inputs obtained from public US sources and scientific literature. Outcomes included total and incremental quality-adjusted life year (QALY) losses and costs, as well as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were conducted to evaluate the sensitivity of results to inputs. In the base case, the model estimated that vaccinating 52.7 million adults aged ≥60 years with the adjuvanted RSVPreF3 vaccine once would result in 244,424 fewer QALY losses and an incremental societal cost of $4.5 billion over 5 years, with vaccination costs partially offset by reduced disease-related costs. From the societal perspective, adjuvanted RSVPreF3 vaccination resulted in an ICER of $18,430 per QALY gained. Results were relatively robust across sensitivity analyses and indicate that adjuvanted RSVPreF3 vaccination is a cost-effective option for the prevention of RSV in US adults aged ≥ 60 years, reducing the substantial burden within this population.

Human Stimulator of Interferon Genes Promotes Rhinovirus C Replication in Mouse Cells In Vitro and In Vivo.

Rhinovirus C (RV-C) infects airway epithelial cells and is an important cause of acute respiratory disease in humans. To interrogate the mechanisms of RV-C-mediated disease, animal models are essential. Towards this, RV-C infection was recently reported in wild-type (WT) mice, yet, titers were not sustained. Therefore, the requirements for RV-C infection in mice remain unclear. Notably, prior work has implicated human cadherin-related family member 3 (CDHR3) and stimulator of interferon genes (STING) as essential host factors for virus uptake and replication, respectively. Here, we report that even though human (h) and murine (m) CDHR3 orthologs have similar tissue distribution, amino acid sequence homology is limited. Further, while RV-C can replicate in mouse lung epithelial type 1 (LET1) cells and produce infectious virus, we observed a significant increase in the frequency and intensity of dsRNA-positive cells following hSTING expression. Based on these findings, we sought to assess the impact of hCDHR3 and hSTING on RV-C infection in mice in vivo. Thus, we developed hCDHR3 transgenic mice, and utilized adeno-associated virus (AAV) to deliver hSTING to the murine airways. Subsequent challenge of these mice with RV-C15 revealed significantly higher titers 24 h post-infection in mice expressing both hCDHR3 and hSTING-compared to either WT mice, or mice with hCDHR3 or hSTING alone, indicating more efficient infection. Ultimately, this mouse model can be further engineered to establish a robust in vivo model, recapitulating viral dynamics and disease.

Burden of respiratory syncytial virus infections in older adults with acute respiratory infection in Japan: An epidemiological study among outpatients

BackgroundRespiratory syncytial virus (RSV) is a leading cause of acute respiratory illness, with severe outcomes in older adults. Information on the prevalence, hospitalization rate, and impact on the health-related quality of life (HRQoL) of RSV in older adults with acute respiratory infections (ARI) in outpatient settings in Japan is limited. MethodsThis multi-center epidemiological study included outpatients aged ≥60 years presenting with ARI between August 2021 and February 2023. Nasal and throat swabs were collected and tested by reverse transcription polymerase chain reaction (RT-PCR). The prevalence of RT-PCR-confirmed RSV (cRSV)-ARI, cRSV-lower respiratory tract disease (LRTD), and other respiratory viruses was calculated by season, region, age group, and RSV subtype. HRQoL was assessed via patient-reported outcomes. ResultsThe study included 923 ARI episodes (cRSV-ARI: N = 24; non-cRSV-ARI: N = 899). In years 1 and 2 (August 2021–July 2022 and August 2022–February 2023), the prevalence of cRSV-ARI was 2.5% and 2.8%, respectively. There was a predominance of RSV-B and RSV-A subtypes in years 1 and 2, respectively. In years 1 and 2 combined, 37.5% of cRSV-ARI cases had lower respiratory tract infection; all cRSV-LRTD cases occurred in those aged 60–74 years. RSV-ARI cases reported throat, chest, and respiratory symptoms, leading to impaired functioning and HRQoL. ConclusionsDuring the observed study period, RSV was circulating among older adults in Japan. RSV was a leading cause of ARI and LRTD. More data are needed to fully clarify the burden of RSV among older adults in Japan.

Inferring enterovirus D68 transmission dynamics from the genomic data of two 2022 North American outbreaks

Enterovirus D68 (EV-D68) has emerged as a significant cause of acute respiratory illness in children globally, notably following its extensive outbreak in North America in 2014. A recent outbreak of EV-D68 was observed in Ontario, Canada, from August to October 2022. Our phylogenetic analysis revealed a notable genetic similarity between the Ontario outbreak and a concurrent outbreak in Maryland, USA. Utilizing Bayesian phylodynamic modeling on whole genome sequences (WGS) from both outbreaks, we determined the median peak time-varying reproduction number (Rt) to be 2.70, 95% HPD (1.76, 4.08) in Ontario and 2.10, 95% HPD (1.41, 3.17) in Maryland. The Rt trends in Ontario closely matched those derived via EpiEstim using reported case numbers. Our study also provides new insights into the median infection duration of EV-D68, estimated at 7.94 days, 95% HPD (4.55, 12.8) in Ontario and 10.8 days, 95% HPD (5.85, 18.6) in Maryland, addressing the gap in the existing literature surrounding EV-D68’s infection period. We observed that the estimated Time since the Most Recent Common Ancestor (TMRCA) and the epidemic’s origin coincided with the easing of COVID-19 related social contact restrictions in both areas. This suggests that the relaxation of non-pharmaceutical interventions, initially implemented to control COVID-19, may have inadvertently facilitated the spread of EV-D68. These findings underscore the effectiveness of phylodynamic methods in public health, demonstrating their broad application from local to global scales and underscoring the critical role of pathogen genomic data in enhancing public health surveillance and outbreak characterization.

Relative Contribution of Diagnostic Testing to the Diagnosis of Respiratory Syncytial Virus in Hospitalized Adults in the United States.

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illness (ARI) in older adults. Optimizing diagnosis could improve understanding of RSV burden. We enrolled adults ≥50 years of age hospitalized with ARI and adults of any age hospitalized with congestive heart failure or chronic obstructive pulmonary disease exacerbations at 2 hospitals during 2 respiratory seasons (2018-2020). We collected nasopharyngeal (NP) and oropharyngeal (OP) swabs (n = 1558), acute and convalescent sera (n = 568), and expectorated sputum (n = 153) from participants, and recorded standard-of-care (SOC) NP results (n = 805). We measured RSV antibodies by 2 immunoassays and performed BioFire testing on respiratory specimens. Of 1558 eligible participants, 92 (5.9%) tested positive for RSV by any diagnostic method. Combined NP/OP polymerase chain reaction (PCR) testing yielded 58 positives, while separate NP and OP testing identified 11 additional positives (18.9% increase). Compared to study NP/OP PCR alone, the addition of paired serology increased RSV detection by 42.9% (28 vs 40) among those with both specimen types, while the addition of SOC swab PCR increased RSV detection by 25.9% (47 vs 59). The addition of paired serology testing, SOC swab results, and separate testing of NP and OP swabs improved RSV diagnostic yield in hospitalized adults.

Seasonality, Clinical Characteristics, and Outcomes of Respiratory Syncytial Virus Disease by Subtype Among Children Aged

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

2608. Circulating Respiratory Syncytial Virus Genotypes in Hospitalized Children with Bronchiolitis in the United Arab Emirates

Abstract Background Respiratory syncytial virus (RSV) is a major cause of acute respiratory illness in young children and elderly people worldwide. It has a complex molecular epidemiology with multiple strains cocirculating during a single epidemic. Whole genome sequencing is a valuable tool for monitoring genetic diversity and providing genomic information essential for antiviral and vaccine development. In the United Arab Emirates (UAE), little is known about the RSV circulating genotypes, their evolution, and transmission dynamics. Using next-generation sequencing, this study aims to identify RSV genotypes circulating among young children with bronchiolitis in Al Ain City, UAE. Methods This cross-sectional study involved 100 children under two years of age who were hospitalized at a tertiary care facility between April and December 2021 with RSV-positive bronchiolitis. Nasopharyngeal samples were obtained, within 24 hours of hospitalization, for RSV genotyping. MinION nanopore sequencer was used to analyze the whole viral genome. We only sequenced samples with cycle threshold (Ct) &amp;lt; 30 (n=70). After sequencing, 7 samples were not analyzed due to long gaps and small lengths. The remaining 63 samples included 59 RSV-A and 4 RSV-B isolates. Results The median age of the studied children was 4.3 months, interquartile range (2.1-10.4), with 56% below the age of 6 months. There was no significant difference in the clinical characteristics of children having RSV-A compared to those infected with RSV-B. Phylogenetic analysis showed that out of the 59 RSV-A sequences, 58 clustered with the NA1 genotype, and 1 sequence clustered with the GA1 genotype. All RSV-B sequences were classified as BA2 genotypes. The amino acid sequence alignment of the G gene revealed that all 58 NA1 genotypes had 24 amino acid duplication regions from 247 to 282 amino acid positions. We also found four substitutional changes at L248I, H258Q, L274P, and P276Q. Conclusion Phylogenetic analysis revealed that the subtype A NA1 genotype was the dominant strain among the studied children in Al Ain, UAE during the 2021 season. As vaccine development advances, further sequencing of RSV is needed to better understand viral origin, transmission, and genetic recombination, particularly in under-studied populations. Disclosures All Authors: No reported disclosures

Clinical Presentation and Outcome of Acute Respiratory Illnesses in South African Children During the COVID-19 Pandemic.

Data from low- and middle-income countries (LMICs) show higher morbidity and mortality in children with acute respiratory illness (ARI) from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, whether SARS-CoV-2 infection is distinct from other causes of ARI in this regard is unclear. We describe clinical characteristics and outcomes of South African children with SARS-CoV-2 and non-SARS-CoV-2 ARIs. We performed a cross-sectional study including 0-13 years old children admitted to Tygerberg Hospital between May and December 2020 with an ARI. Routine clinical data were collected by the attending clinicians. All children underwent SARS-CoV-2 polymerase chain reaction testing. For severity of disease, the need for respiratory support and duration of support was considered. Multivariable logistic regression models were built to determine the factors associated with SARS-CoV-2 infection and severity. Data for 176 children were available, 38 (22%) children were SARS-CoV-2 polymerase chain reaction positive and 138 (78%) were negative. SARS-CoV-2 positive children were more likely to be female (OR: 2.68, 95% CI: 1.18-6.07), had lower weight-for-age Z score (OR: 0.76, 95% CI: 0.63-0.93), presented more frequently with fever (OR: 3.56, 95% CI: 1.54-8.24) and less often with cough (OR: 0.27, 95% CI: 0.11-0.66). SARS-CoV-2 infection was associated with significantly longer duration of oxygen treatment (median 8 vs. 3 days; OR: 1.1, 95% CI: 1.01-1.20). Overall, 66% of children had viral coinfection, with no significant difference between the groups. In total, 18% of SARS-CoV-2 positive children were readmitted within 3 months for a respiratory reason, compared with 15% SARS-CoV-2 negative children ( P = 0.64). Our data show that ARIs from SARS-CoV-2 cannot be easily differentiated, but were associated with a higher morbidity compared with ARIs from other causes. Overall outcomes were good. The long-term implications of severe SARS-CoV-2 pneumonia in young children in low- and middle-income countries require further study.

Fungal Pathogens as Causes of Acute Respiratory Illness in Hospitalized Veterans: Frequency of Fungal Positive Test Results Using Rapid Immunodiagnostic Assays.

Fungal respiratory illnesses caused by endemic mycoses can be nonspecific and are often mistaken for viral or bacterial infections. We performed fungal testing on serum specimens from patients hospitalized with acute respiratory illness (ARI) to assess the possible role of endemic fungi as etiologic agents. Patients hospitalized with ARI at a Veterans Affairs hospital in Houston, Texas, during November 2016-August 2017 were enrolled. Epidemiologic and clinical data, nasopharyngeal and oropharyngeal samples for viral testing (PCR), and serum specimens were collected at admission. We retrospectively tested remnant sera from a subset of patients with negative initial viral testing using immunoassays for the detection of Coccidioides and Histoplasma antibodies (Ab) and Cryptococcus, Aspergillus, and Histoplasma antigens (Ag). Of 224 patient serum specimens tested, 49 (22%) had positive results for fungal pathogens, including 30 (13%) by Coccidioides immunodiagnostic assays, 19 (8%) by Histoplasma immunodiagnostic assays, 2 (1%) by Aspergillus Ag, and none by Cryptococcus Ag testing. A high proportion of veterans hospitalized with ARI had positive serological results for fungal pathogens, primarily endemic mycoses, which cause fungal pneumonia. The high proportion of Coccidioides positivity is unexpected as this fungus is not thought to be common in southeastern Texas or metropolitan Houston, though is known to be endemic in southwestern Texas. Although serological testing suffers from low specificity, these results suggest that these fungi may be more common causes of ARI in southeast Texas than commonly appreciated and more increased clinical evaluation may be warranted.

Identifying Cross-Utilization of RSV Vaccine Inventions across the Human and Veterinary Field.

The respiratory syncytial virus (RSV) has two main variants with similar impact, a human and a bovine variant. The human respiratory syncytial virus (HRSV) is the most frequent cause of acute respiratory disease (pneumonia) in children, leading to hospitalization and causing premature death. In Europe, lower respiratory tract infections caused by HRSV are responsible for 42-45 percent of hospital admissions in children under two. Likewise, the bovine respiratory syncytial virus (BRSV) is a significant cause of acute viral broncho-pneumonia in calves. To date no licensed HRSV vaccine has been developed, despite the high burden of the disease. In contrast, BRSV vaccines have been on the market since the 1970s, but there is still an articulated unmet need for improved BRSV vaccines with greater efficacy. HRSV/BRSV vaccine development was chosen as a case to assess whether collaboration and knowledge-sharing between human and veterinary fields is taking place, benefiting the development of new vaccines in both fields. The genetic relatedness, comparable pathogeneses, and similar severity of the diseases suggests much can be gained by sharing knowledge and experiences between the human and veterinary fields. We analyzed patent data, as most of pharmaceutical inventions, such as the development of vaccines, are protected by patents. Our results show only little cross-utilization of inventions and no collaborations, as in shared IP as an exchange of knowledge. This suggests that, despite the similarities in the genetics and antigenicity of HRSV and BRSV, each fields follows its own process in developing new vaccines.

2196. Frequencies of Adenovirus Types in U.S. Children with Acute Respiratory Illness, 2016–2019

Abstract 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 &amp;lt; 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 &amp;lt; 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 &amp; Co.: Honoraria|Merck &amp; 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.

92. Incidence of Adenovirus Respiratory Infection and Coinfection in a Longitudinal Birth Cohort

Abstract Background Adenoviruses (AdVs) are a common cause of acute respiratory illness (ARI) in children and are often detected with other viruses (coinfection). However, the community incidence of AdV infections is poorly understood due to a lack of prospective studies outside the hospital setting. Here, we aim to characterize respiratory AdV infections and coinfections in a prospective birth cohort of children. Methods The PREVAIL cohort is a CDC-funded, 2-year birth cohort, conducted from 2017–2020 in Cincinnati, OH. ARI was defined as the presence of cough or fever identified with weekly maternal text surveys and medical chart review. Mid-turbinate nasal swabs were collected weekly. Swabs were tested using Luminex Respiratory Pathogen Panel. AdV infection was defined as a swab positive for AdV and included subsequent positives &amp;lt; 30 days apart. Coinfection was defined as detection of any other virus(es) during an AdV infection. Children who submitted at least 70% of weekly samples were included in our analysis. Results 101 children met inclusion criteria, representing 165 child-years. 137 distinct AdV infections were identified (incidence 0.84 infections per child year), with 98 (97%) children having ≥1 AdV infection. Only 40% (n=55) of AdV infections were symptomatic. Of those with symptomatic infections, 51% (n=28) sought medical care, with 42% (n=23) presenting to a primary care provider and 9% (n=5) resulting in an ED visit or hospital admission. Coinfections were detected in 67% (n=92) of AdV infections, with 45% (n=62) coinfected with 1 virus, 19% (n=26) with 2 viruses, and 3% (n=4) with ≥3 viruses. 77% of coinfections (n=71) were rhino/enterovirus. The number of coinfections or the specific coinfection virus was not associated with an increase in symptom prevalence or symptom severity (all p &amp;gt; 0.05). Viral Coinfection Frequency with Adenovirus Infection in the PREVAIL Cohort. Adenovirus Infection and Coinfection in the PREVAIL Cohort. Conclusion In this cohort of healthy children, AdVs were a common cause of respiratory infection. Most infections were asymptomatic or resulted in mild symptoms. Two-thirds of AdV infections involved viral coinfections, but coinfection was not associated with more frequent or severe symptoms. Our findings suggest studies that only include symptomatic or hospitalized patients may overestimate AdVs disease severity. Disclosures All Authors: No reported disclosures.

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship. To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI. This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc. The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection. In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Next-generation sequencing of human respiratory syncytial virus subgroups A and B genomes

Human respiratory syncytial virus (HRSV) is a leading cause of acute respiratory illness in young children worldwide. Whole genome sequencing of HRSV offers enhanced resolution of strain variability for epidemiological surveillance and provides genomic information essential for antiviral and vaccine development. A 10-amplicon one-step RT-PCR assay and a 20-amplicon nested RT-PCR assay with enhanced sensitivity were developed to amplify whole HRSV genomes from samples containing high and low viral loads, respectively. Ninety-six HRSV-positive samples comprised of 58 clinical specimens and 38 virus isolates with Ct values ≤ 24 were amplified successfully using the 10-amplicon one-step RT-PCR method and multiplexed in a single MiSeq run. Genome coverage exceeded 99.3% for all 96 samples. The 20-amplicon nested RT-PCR NGS method was used to generate >99.6% HRSV full-length genome for 72 clinical specimens with Ct values ranging from 24 to 33. Phylogenetic analysis of the genome sequences obtained from the 130 clinical specimens revealed a wide diversity of HRSV genotypes demonstrating methodologic robustness.

Respiratory syncytial virus acute respiratory infections in ≥ 65-year-old adults in long-term care facilities in the Czech Republic.

Due to immunosenescence and presence of comorbidities, respiratory syncytial virus (RSV) disease burden is a major health concern in older adults, which is expected to increase with the life expectancy rise. Data on RSV burden are scarce in older adults residing in long-term care facilities, a vulnerable population living in crowded settings. Therefore, two independent prospective studies were conducted during the 2003-2004 and 2004-2005 RSV seasons to assess RSV acute respiratory illnesses (ARIs) and lower respiratory tract infections (LRTIs) in ≥ 65-year-old adults residing in long-term care facilities in the Czech Republic. RSV ARI episodes were confirmed by polymerase chain reaction in nasal swabs collected within 3 days of symptoms onset. The mortality and morbidity of RSV-confirmed ARIs, as well as the risk factors associated with RSV-confirmed ARIs were evaluated. Among 1,251 participants in the 2003-2004 season (ARI surveillance between October and March), there were no RSV-positive cases in 255 ARI and 105 LRTI episodes. Among 1,280 participants in the 2004-2005 season (ARI surveillance between October and April), there were 39 and 26 RSV-positive cases in 335 ARI and 217 LRTI episodes, respectively, and RSV-positive ARI and LRTI episode incidence rates were 45.82 and 30.40 per 1,000 person-years. Among 290 RSV-negative and 39 RSV-positive ARI cases in the 2004-2005 season, 15 and 4 hospitalizations, 188 and 26 LRTIs, and 11 and 3 deaths were reported. Risk factors associated with RSV-positive ARI were female gender (odds ratio: 4.98), chronic heart failure class II (odds ratio: 2.31) and diabetes requiring insulin treatment (odds ratio: 9.82). These studies showed that RSV was an important cause of ARI in older adults living in long-term care facilities in the 2004-2005 season, with fluctuating yearly incidences.

Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain′s pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed.

Clinical features of parainfluenza infections among young children hospitalized for acute respiratory illness in Amman, Jordan

BackgroundParainfluenza virus (PIV) is a leading cause of acute respiratory illness (ARI) in children. However, few studies have characterized the clinical features and outcomes associated with PIV infections among young children in the Middle East.MethodsWe conducted hospital-based surveillance for ARI among children < 2 years of age in a large referral hospital in Amman, Jordan. We systematically collected clinical data and respiratory specimens for pathogen detection using reverse transcription polymerase chain reaction. We compared clinical features of PIV-associated ARI among individual serotypes 1, 2, 3, and 4 and among PIV infections compared with other viral ARI and ARI with no virus detected. We also compared the odds of supplemental oxygen use using logistic regression.ResultsPIV was detected in 221/3168 (7.0%) children hospitalized with ARI. PIV-3 was the most commonly detected serotype (125/221; 57%). Individual clinical features of PIV infections varied little by individual serotype, although admission diagnosis of ‘croup’ was only associated with PIV-1 and PIV-2. Children with PIV-associated ARI had lower frequency of cough (71% vs 83%; p < 0.001) and wheezing (53% vs 60% p < 0.001) than children with ARI associated with other viruses. We did not find a significant difference in supplemental oxygen use between children with PIV-associated infections (adjusted odds ratio [aOR] 1.12, 95% CI 0.66–1.89, p = 0.68) and infections in which no virus was detected.ConclusionsPIV is frequently associated with ARI requiring hospitalization in young Jordanian children. Substantial overlap in clinical features may preclude distinguishing PIV infections from other viral infections at presentation.

Incidence of Medically Attended Acute Respiratory Illnesses Due to Respiratory Viruses Across the Life Course During the 2018/19 Influenza Season.

BackgroundWhile multiple respiratory viruses circulate in humans, few studies have compared the incidence of different viruses across the life course. We estimated the incidence of outpatient illness due to 12 different viruses during November 2018 through April 2019 in a fully enumerated population.MethodsWe conducted active surveillance for ambulatory care visits for acute respiratory illness (ARI) among members of Kaiser Permanente Washington (KPWA). Enrolled patients provided respiratory swab specimens which were tested for 12 respiratory viruses using RT-PCR. We estimated the cumulative incidence of infection due to each virus overall and by age group.ResultsThe KPWA population under surveillance included 202,562 individuals, of whom 2,767 (1.4%) were enrolled in the study. Influenza A(H3N2) was the most commonly detected virus, with an overall incidence 21 medically attended illnesses per 1,000 population; the next most common viruses were influenza A(H1N1) (18 per 1,000), coronaviruses (13 per 1,000), respiratory syncytial virus (RSV, 13 per 1,000), and rhinovirus (9 per 1,000). RSV was the most common cause of medically attended ARI among children aged 1-4 years; coronaviruses were the most common among adults aged ≥65 years.ConclusionsConsistent with other studies focused on single viruses, we found that influenza and RSV were major causes of acute respiratory illness in persons of all ages. In comparison, coronaviruses and rhinovirus were also important pathogens. Prior to the emergence of SARS-CoV-2, coronaviruses were the second-most common cause of medically attended ARI during the 2018/19 influenza season.