Bronchiolitis is an important public health problem in the United States. Indeed, bronchiolitis is the leading cause of infant hospitalizations, accounting for 130,000 hospitalizations with a direct cost of at least $550 million each year.1 Respiratory syncytial virus (RSV) is the most common causative pathogen of bronchiolitis and has been used to define bronchiolitis cohorts for decades.2 In recent years, the advent of molecular techniques has revealed a diverse group of respiratory pathogens related to severe bronchiolitis (ie, bronchiolitis that requires hospitalization).2
Understanding the epidemiology of respiratory pathogens in infants with severe bronchiolitis is essential for developing effective prophylactic (eg, immunoprophylaxis) and treatment (eg, antiviral agents) strategies. Prior active and passive surveillance efforts have reported temporal patterns of common respiratory viruses in the general population3–6 and children (<5 years of age) with acute respiratory infections (ARIs).7–9 However, most studies have focused on a single pathogen (eg, RSV) and had a limited geographic diversity. Furthermore, no study has comprehensively investigated the geographic and temporal patterns of respiratory pathogens in infants with bronchiolitis, including infants with severe bronchiolitis—a population with high morbidity.
To address this knowledge gap, we analyzed data from 2 prospective cohort studies of the US children hospitalized with bronchiolitis. Specifically, we examined the epidemiology of respiratory pathogens among infants with severe bronchiolitis and investigated potential differences between these pathogens according to the US region and hospitalization month.
The present analysis combines data from 2 multicenter, multiyear prospective cohort studies of infants with severe bronchiolitis. Using a similar protocol, one study enrolled subjects at 16 sites during 3 consecutive bronchiolitis season (from November 1 to March 31) in 2007–2010—the 30th Multicenter Airway Research Collaboration (MARC-30), while the other enrolled subjects at 17 sites from November 1 to April 30 in 2011–2014—MARC-35. The details of study design, setting, participants and methods of data collection are described in Supplemental Digital Content 1, https://links.lww.com/INF/D458. The institutional review board at each of the participating hospitals approved the studies. Written informed consent was obtained from the parent or guardian.
In brief, investigators collected clinical data and nasopharyngeal aspirates within 24 hours of hospitalization by using a standardized protocol. Identification of respiratory pathogens was performed by using singleplex or duplex 2-step real-time polymerase chain reaction (rtPCR) at Baylor College of Medicine (Houston, TX). Real-time reverse transcriptase-PCR was used for the detection of RNA respiratory viruses, including RSV (types A and B), rhinovirus, coronaviruses (NL-63, OC-43, HKU1 and 229E), human metapneumovirus (hMPV), parainfluenza viruses (types 1, 2 and 3), enteroviruses and influenza viruses (types A and B, and 2009 novel H1N1). rtPCR was also used for the detection of DNA pathogens which included adenovirus, human bocavirus type 1, Mycoplasma pneumoniae and Bordetella pertussis.
In the current analysis, we analyzed the data of infants (<1 year of age) from MARC-30 and MARC-35. We compared the likelihood of having each of the five most common pathogens (with a detection likelihood of >5%) between the US census regions (Northeast, Midwest, South, West) by using χ2 test. To examine the region-×-month (compilation of study years) interactions with regard to the likelihood of having each virus, we used random-effects model adjusting for hospitalization year and patient clustering within hospitals, and likelihood ratio test.
In MARC-30, of 3910 children with severe bronchiolitis eligible to the study, 2207 children (age <2 years) were enrolled (56.4%). In MARC-35, of 1228 infants with severe bronchiolitis eligible to the study, 1016 infants were enrolled (82.7%). In both studies, the enrolled and nonenrolled children were not significantly different in age and sex (both P > 0.05). The overall analytic cohort comprised 2912 infants (age <1 year) with severe bronchiolitis from all the 4 US regions: 1896 infants from MARC-30 and 1016 infants from MARC-35. The median age was 3.2 (interquartile range 1.6–6.1) months, 40.5% were female, and 39.4% were non-Hispanic white. Of these, 16.9% were admitted to an intensive care unit and 7.1% underwent mechanical ventilation (Table, Supplemental Digital Content 2, https://links.lww.com/INF/D459). Overall, 66.2% had a single respiratory pathogen infection, while 28.9% had a coinfection by ≥2 respiratory pathogens; no respiratory pathogens were detected in 4.9%. Among infants with coinfection, RSV plus rhinovirus infection was most common [46.2% (13.3% of analytic cohort)]. The 5 most common respiratory pathogens were detected in 92.8% of the analytic cohort. Specifically, RSV was the most commonly detected pathogen (overall 76.5%; RSV-A 48.6%; RSV-B 28.5%), followed by rhinovirus (23.8%), coronavirus (6.9%), adenovirus (6.4%) and hMPV (6.0%) (Figure, Supplemental Digital Content 3, https://links.lww.com/INF/D460). Approximately two-thirds of RSV-A and RSV-B bronchiolitis were caused by single respiratory pathogen (Figure, Supplemental Digital Content 4, https://links.lww.com/INF/D461). The likelihood of infection with RSV-A and -B, 4 species of coronavirus and hMPV significantly varied across the study years (all P < 0.05; Table, Supplemental Digital Content 5, https://links.lww.com/INF/D462).
Across the 4 US regions, while there was no significant difference in the likelihood of overall RSV infection (P = 0.72), there were significant between-region differences in that of RSV-A and -B infection (both P < 0.001 (Table, Supplemental Digital Content 6, https://links.lww.com/INF/D463). For example, infants in the West region had a lower likelihood of RSV-A infection and higher likelihood of RSV-B infection compared with the other regions. In contrast, the other common pathogens—except for coronavirus NL63—had no significant regional differences (P ≥ 0.10).
Overall, the likelihood of infection significantly differed between the hospitalization months for the most common pathogens (all P ≤ 0.01), except for coronavirus (P = 0.30). For example, rhinovirus was the dominant pathogen in November and April, while RSV-A was dominant in all other months. hMPV had a peak in March and April. Figure 1 shows the temporal changes in the likelihood of having each of 5 most common pathogens by the US region. The random-effects models demonstrated significant interactions between regions and hospitalization months with regard to the likelihood of RSV-A and -B infection (both P < 0. 001) indicating heterogeneity in the temporal patterns by region. For example, infants in the South region had a peak of RSV-A in December, while those in the Northeast and Midwest regions had a peak in February.
In this analysis based on 2 multicenter, multiyear prospective cohorts of the US infants with severe bronchiolitis, the 5 most common pathogens—RSV, rhinovirus, coronavirus, adenovirus and hMPV—accounted for >90% of cases. Our data demonstrated that these viruses (except for coronavirus) had different temporal patterns and that there is a regional heterogeneity in the temporal pattern in RSV-A and -B infections. In agreement with our finding, the National Respiratory and Enteric Virus Surveillance System—a passive laboratory surveillance system—reported that the overall incidence of RSV infection varies across the US regions and seasons in the general population.5 While it did not specifically evaluate children with bronchiolitis or RSV subtypes, it reported that the onset of RSV season is earlier in the South compared with the Midwest region. As for the non-RSV pathogens, another surveillance effort in 3 US counties (Cincinnati, OH; Nashville, TN and Rochester, NY)—the New Vaccine Surveillance Network—reported that, in children (<5 years of age) with ARI, the peak of rhinovirus infection was nonwinter seasons (eg, fall, spring).7,8 National Respiratory and Enteric Virus Surveillance System also reported the temporal patterns in coronavirus,3 adenovirus4 and hMPV6 in the general populations. Our geographically diverse, multicenter data—with comprehensive respiratory pathogen characterization—corroborate these earlier reports and extend them by demonstrating, for the first time, different regional and temporal patterns for the common respiratory pathogens, including non-RSV pathogens, in infants with severe bronchiolitis.
Our study has potential limitations. First, this study is not a random sampling of all infants with severe bronchiolitis. However, as causative pathogens were not tested at initial recruitment and are unlikely to be related to enrollment, our study samples were likely representative of severe bronchiolitis population at the study sites. Second, as the studies focused on infants with severe bronchiolitis and enrolled infants in the bronchiolitis season, the results should be cautiously generalized to broader ARI populations that may have different virus epidemiology patterns (eg, higher frequencies of rhinovirus ARI in spring and fall). Nonetheless, our findings are directly relevant, at least, to 130,000 children with severe bronchiolitis each year.1 Finally, the current American Academy of Pediatrics guidelines of bronchiolitis10 do not recommend routine virologic testing and the potential benefit of testing at the clinical setting remains to be determined. Yet, recent studies have demonstrated the association of specific viruses (eg, RSV plus rhinovirus coinfection) and high RSV genomic load with higher acute severity of bronchiolitis11 and beneficial effects of anti-RSV agents on acute severity.12 Furthermore, the literature has reported not only the association of severe viral respiratory infections (eg, RSV and rhinovirus) in the first year of life with differential risks of developing recurrent wheeze and asthma in childhood2,13,14 but also potential prophylactic strategies—for example, palivizumab on recurrent wheezing15 and omalizumab on rhinovirus infection.16 These emerging evidence indicate the role of different viruses in the acute and chronic morbidities of bronchiolitis.
In summary, on the basis of data from 2 large, multicenter, multiyear prospective cohorts of the US infants with severe bronchiolitis, we observed that the major viruses (RSV-A, RSV-B, rhinovirus, adenovirus and hMPV) had different temporal patterns and that there is a regional heterogeneity in the temporal pattern in RSV-A and -B infections. For clinicians, our data provide guidance for optimal timing of RSV immunoprophylaxis by the US region in infants at higher risk for severe illness. For researchers, our data should facilitate further investigations into the development of treatment strategies for the acute (eg, antiviral agents for bronchiolitis) and chronic (eg, immunomodulators for incident asthma) morbidities of bronchiolitis.
A list of the investigators is available in the appendix, https://links.lww.com/INF/D464.
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