Impact of Human Adenovirus Co-detection on Disease Severity in Children with Medically Attended Acute Respiratory Infections

Abstract

Human Adenovirus (HAdV) is frequently identified as a cause of acute respiratory infections (ARIs) in children and often co-detected with other common respiratory viruses. However, the effect of co-detection on disease severity is not well understood. This study aimed to describe the spectrum and frequency of other respiratory viruses co-detected with HAdV and define the impact of co-detection on HAdV disease severity. Children admitted to the hospital or seen in the emergency department with fever and/or respiratory symptoms <14 days duration were enrolled at 7 sites across the US, from 12/01/2016 through 08/31/2023, as part of the CDC-sponsored New Vaccine Surveillance Network (NVSN). Respiratory specimens were systematically obtained and tested for HAdV and other common viral etiologies of ARI. Demographics, clinical characteristics, and disease severity (hospitalization and in-hospital oxygen use) were compared among children with HAdV single detection, HAdV co-detection with other respiratory viral pathogens, and single detection of a non-HAdV virus. Of 68,004 children enrolled with a respiratory specimen tested, 4,292 (6.3%) were positive for HAdV; 1,779 (41.4%) of these were HAdV single detections. Human rhinovirus/enterovirus (HRV/EV) (43.1%), respiratory syncytial virus (RSV) (14.7%), and parainfluenza virus (PIV) (7.6%) were the most common viruses co-detected with HAdV and selected for further analysis. HAdV co-detection with these 3 viruses was associated with increased odds of hospitalization and in-hospital oxygen use when compared to HAdV single detection. However, the odds of hospitalization and in-hospital oxygen use with HRV/EV, RSV, and PIV single detection were also increased compared to HAdV single detection. HAdV co-detection with HRV/EV, RSV, or PIV was associated with increased disease severity when compared to HAdV single detection. However, HRV/EV, RSV, and PIV single detections were also associated with increased severity in comparison to HAdV single detection with these pathogens. Additionally, the increased odds of severe disease seen in HRV/EV, RSV, and PIV single detections was often greater than the increase seen with HAdV co-detection with HRV/EV, RSV, or PIV. This could suggest that the overall severity of these ARIs is being driven primarily by the co-detected viruses, HRV/EV, RSV, and PIV. These results could help guide interpretation of viral testing by clinicians, when multiple viruses are detected. Further research involving asymptomatic and mild HAdV ARI cases, as well as longitudinal studies to determine timing of co-infections, are needed to fully understand the role of HAdV in pediatric ARI of mixed viral etiology.