BACKGROUND: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are genetically related viruses and major causes of medically attended acute respiratory illness in children. Research comparing the severity of illnesses resulting from these infections lacks consensus. METHODS: Children younger than 18 years with acute respiratory illness were enrolled through active, prospective surveillance from 2016 to 2020 at 7 US pediatric hospitals and emergency departments (EDs). Clinical information was obtained from parent interviews and medical records. Midturbinate nasal swabs were collected and tested for RSV and HMPV using molecular diagnostic assays at each site. We compared descriptive and clinical features of children with RSV or HMPV and calculated adjusted odds ratios (aOR) for severe outcomes comparing RSV with HMPV. Risk factors for severe outcomes were assessed in children with RSV or HMPV using logistic regression models. RESULTS: A total of 5329 children hospitalized with RSV (n = 4398) or HMPV (n = 931) and 3276 children with RSV-associated (n = 2371) or HMPV-associated (n = 905) ED visits were enrolled. The median age of children hospitalized with RSV was lower than that of children with HMPV (7 months vs 16 months, P < .0001). Children presenting to the ED with RSV-associated acute respiratory illness had higher odds of being hospitalized than children with HMPV (aOR, 1.68; 95% CI, 1.50-1.87), with the highest odds in infants younger than 6 months (aOR, 3.27; 95% CI, 2.53-4.23). Underlying conditions were more than twice as common among infants hospitalized with HMPV (26%) than those with RSV (11%). CONCLUSIONS: Children with HMPV-associated hospitalization tend to be older and more likely to have underlying medical conditions compared with children with RSV-associated hospitalization.

IMPORTANCE: Enterovirus D68 (EV-D68) typically causes mild to severe acute respiratory illness (ARI). Testing and surveillance for EV-D68 in the US are limited, and important epidemiologic gaps remain. OBJECTIVE: To characterize the epidemiology and clinical severity of EV-D68 among US children seeking care for ARI from 2017 to 2022, using a multisite, active, systematic surveillance network. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study collected data from the New Vaccine Surveillance Network, an active, prospective, population-based surveillance system of emergency departments (EDs) and hospitals at 7 US academic medical centers. Children with ARI and EV-D68-positive results were enrolled during platform-wide EV-D68 testing periods (July to October 2017, July to November 2018, July to November 2020, and July 2021 to December 2022). Included children were aged younger than 18 years, reported 1 or more qualifying ARI symptoms, with a symptom duration less than 14 days at enrollment. Data were analyzed from in October 2024. EXPOSURES: Laboratory-confirmed EV-D68 infection, including overall infections or those without viral codetection. MAIN OUTCOMES AND MEASURES: Trends and characteristics of EV-D68, including demographics, underlying conditions, and clinical severity by health care setting, were explored. Among hospitalized children with EV-D68-positive results without viral codetection, multivariable logistic regression was used to examine factors associated with receipt of (1) supplemental oxygen or (2) intensive care. RESULTS: From 2017 to 2022, 976 children with EV-D68-positive results were identified (median [IQR] age, 47 [18-63] months; 391 [40.1%] female); most were enrolled in 2018 (382 children) and 2022 (533 children). Among these, 856 had no viral codetection, of which 320 were discharged home from the ED (median [IQR] age, 33 [16-59] months; 180 male [56.3%]; 237 [74.1%] with no reported underlying conditions) and 536 were hospitalized (median [IQR] age, 40 [19-69] months; 330 male [61.6%]; 268 [50.0%] with no reported underlying conditions). Among those hospitalized, 199 (37.1%) reported a history of asthma or reactive airway disease (RAD) and 77 (14.4%) reported a condition other than asthma or RAD. Having an underlying condition other than asthma or RAD was associated with increased odds of receiving supplemental oxygen (adjusted odds ratio, 2.72; 95% CI, 1.43-5.18) or intensive care admission (adjusted odds ratio, 3.09; 95% CI, 1.72-5.56); neither age group nor history of asthma or RAD were associated with oxygen receipt or intensive care admission. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of children with medically attended EV-D68 infections, EV-D68 was associated with severe disease in otherwise healthy children of all ages, and children with nonasthma or RAD comorbidities were at higher risk for severe outcomes when hospitalized.