Discussion
In our large prospective study investigating the burden of multiple respiratory viruses in hospitalized Jordanian children under two years, more than half of the subjects presented with wheezing, and the vast majority of subjects had virus detected. The most frequently detected viruses in wheezing subjects in order of highest frequency were RSV, HRV, AdV and HMPV.
Other studies have demonstrated a similar relative proportion of RSV and HRV detected in subjects hospitalized with wheezing illness; in a Japanese study of children under three years hospitalized with lower respiratory tract infections, among wheezing subjects, 33% had RSV, 14% HRV, and 2% HMPV20. In a 4-year study of infants <12 months hospitalized with bronchiolitis in Greece, 79% had RSV, 17% HRV, 2% HMPV, 10% influenza, 3% coronaviruses, and 1% PIV21. In contrast with our cohort, a Finnish cohort of children 3 months-16 years (median age 2 years) admitted with acute wheezing, they detected a lower frequency of subjects with RSV (14%), but more subjects had HRV (27%) and 9% had HMPV. The older cohort may explain more HRV detected compared with RSV, as studies have shown that HRV-associated LRTI becomes more common as children age 21. This study also excluded children with severe wheezing and ICU treatment, but noted that RSV-positive children tend to have more severe manifestations of LRTIs than those with HRV21.
We also found that RSV and HMPV were detected in a significantly higher percentage of subjects with wheezing than in those without wheezing, and this persisted after adjusting for multiple variables. Supporting our findings, RSV has been reported to be the leading cause of LRTIs requiring hospitalization in young infants3,5,22,23. HMPV has also been identified as an important pathogen in upper and lower respiratory tract infections8. Studies of children with acute LRTIs reported HMPV frequency similar to our cohort, ranging from 2-13%3,5,10,20,21,24, including hospitalized children in the Middle East17. Given that HMPV resembles RSV infection cytopathologically, clinically and epidemiologically, it is not surprising that it was found to be an important contributor to wheezing illness in our study.
While HRV was identified in a significant proportion of young, hospitalized patients in our study, we did not observe a significant difference in HRV among those with wheezing versus those without wheezing. Possible reasons for this observation include the fact that the median age of our wheezing subjects was five months, a minority had atopic mothers, relatively few of the children themselves were atopic, and all patients presented with severe symptoms requiring hospitalization. The prevalence of HRV in patients with wheezing and/or bronchiolitis increases with age and is more common in children with recurrent wheezing2,7,21. A Finnish study 7 of hospitalized children found that those with HRV infection were older than those with RSV infection; this is supported by our finding that RSV was detected more frequently in younger subjects with wheezing than older subjects. Studies have also shown that HRV-associated wheezing is observed more frequently in atopic children7,25and that maternal atopic asthma is a risk factor for HRV-associated wheezing 7. An outpatient study of patients with an atopic parent found that HRV was the most frequently detected infection in LRTIs (40.7%) and contributed to three times the number of LRTI and wheezing LRTIs than RSV3. Our young cohort with less predominant personal and parental atopic history may explain the predominant effect of RSV (and not HRV) on wheezing.
In our cohort, personal history of RAD or family history of asthma were associated with higher OR of wheezing, but maternal atopy and asthma were not associated with wheezing. According to the Tucson Children’s Respiratory Study, there are four patterns of wheezing in early childhood: never wheeze, transient early wheeze, late-onset wheeze and persistent wheeze 26. Although the current study was not a longitudinal study that would allow us to accurately determine the ultimate wheezing phenotype of our subjects, since most children who wheeze before two years of age do not develop recurrent wheeze or asthma later in childhood2,27, it is likely that a significant proportion of children in our cohort were of the transient early wheeze phenotype. Such children do not tend to have history of maternal asthma or personal history of atopy2,26. Alternatively, a potential impact of maternal asthma on development of childhood wheeze may not have been detected due to the low frequency of maternal asthma in our cohort. A follow-up study of these children could provide insight regarding whether or not they developed asthma.
This study has both strengths and limitations. Given the large cohort, we were able to compare differences among multiple viruses and the association of wheezing. However, since this was not a longitudinal study and there was no follow-up of subjects to determine if they developed recurrent wheezing or asthma beyond the age of five, we are unable to directly ascertain the link between virus-induced wheezing and recurrent wheeze or asthma. While epidemiological studies are often limited by difficulty in accurately diagnosing wheezing in young children, particularly through clinical assessment by parents28, in our study wheezing was diagnosed by both clinical assessment and physical exam by a physician, making the diagnosis more reliable. This study investigated wheezing illness specifically in hospitalized children, which provides useful information for patients with potentially more severe disease. This is a year-round surveillance study conducted over a period of three years, and therefore allows us to capture viruses during several seasons. It also is one of the few studies in Jordan/Middle East that used highly a sensitive molecular diagnostic technique for detection of viruses in such a large cohort of hospitalized patients29.
In summary, this investigation demonstrates that wheezing in children under two years is associated with RSV and HMPV. Although HRV is a known important risk factor for wheezing, particularly in older children with atopic parental or personal history, an association between HRV and wheezing was not seen in our cohort. This study provides useful data on the burden of respiratory viruses with clinical and demographic factors for wheezing illness. These data can be used to design future longitudinal studies to evaluate the association between early childhood viral acute respiratory infections and recurrent wheezing later in childhood, and to determine which virus interventions, such as vaccination or antiviral therapy that would be most effective at preventing development of wheezing illness.