HRV is recognized as a virus of older children associated primarily with URI,6, 9, 51
but the role of HRV in term, non low birth weight, previously healthy infants who are not selected to be at high risk for atopy has not been as well studied. We detected HRV in 18% of bronchiolitis cases and 47% of URI among infants enrolled over four respiratory viral seasons. Thus, HRV appears to be an important cause of infant bronchiolitis. Kusel et al. reported that among 263 infants with ARI during the first year of life, half were associated with HRV with HRV being the most common virus detected in children with upper and lower respiratory illness.52
However, this finding has not been consistent. Another group identified HRV in only 9% of infants with bronchiolitis,14
and others have detected HRV in 7-17% of bronchiolitis in children <2 years of age53, 54
. This variability in apparent HRV burden may depend on both the study population and the years of study, as suggested by the differential circulation of HRV in each of the seasons studied in this investigation.
Infants with HRV alone were more likely to be older, black, attend daycare, and have a maternal asthma history, compared with infants with respiratory illness associated with other viruses or with no virus detected. Maternal atopy conferred over twice the risk of more severe HRV-associated respiratory illness as determined by the bronchiolitis severity score, independent of age, race, smoking, and gender. Korppi et al. compared infants <24 months of age with HRV vs. RSV-associated wheezing and reported that infants with HRV were older and more often had atopic dermatitis and eosinophilia.55
These data are consistent with our findings that infants with HRV-associated respiratory illness are older and that an atopic profile in the mother may be an important risk factor for more severe HRV-associated infant disease. Other cohort studies, such as the COAST study, have elegantly described risk factors for infant virus-associated wheezing and subsequent early childhood wheezing/asthma; however, all infants in those cohorts had one or both parents with atopy or asthma and thus constituted a high-risk population.11, 12, 20
In contrast, our study included infants with no history of maternal atopy as defined by the ISAAC questionnaire; 56% (354/630) of the infants enrolled did not have a history of maternal atopy. While there are not immediate clinical implications from our study for asthma development, children in this cohort are being followed until the sixth year of life and the outcomes of asthma and allergic rhinitis. This is the first study, to our knowledge, to find that maternal atopy is an independent risk factor for HRV disease severity among term non low birth weight infants who are not selected to be at high risk for atopy, suggesting that there is a genetic predisposition to HRV severity, and that risk factors for atopy may be linked with risk factors for innate immunity to HRV. Airway epithelial cells from asthmatic subjects have been shown to exhibit aberrant responses to HRV infection in vitro56, 57
; our findings suggest that these mechanisms may affect clinical disease.
We found a large proportion of HRV to be the newly described group HRVC. The diversity seen amongst HRVC strains was greater than that seen amongst HRVA strains, consistent with other studies.1, 2
All of the recently described HRV for which the VP4/VP2 sequences are available fell into the same group, including the QPM strains from Queensland that were originally classified as a subgroup of HRVA 21, 23, 31, 50, 58-63
. Infants with HRVB were more likely to require supplemental oxygen and have a longer duration of hospitalization compared to infants with HRVA or HRVC. Consistent with these findings, infants with HRVB tended to have higher bronchiolitis severity scores, although the number of HRVB strains was small as in other studies,1, 2, 64
. HRVC was more commonly seen in black infants, compared with HRVA or HRVB. Our prior study also found HRVC to be significantly more common in black children <5 years of age who were hospitalized with ARI or fever during one year and in one study site, but this effect was not significant during both study years and in both sites in that investigation.2
One cannot assume ethnic differences in predisposition to HRVC infection based on these limited data, as the effects could have merely been seen based on viral circulation patterns amongst different geographic or socioeconomic regions, but these findings suggest that both host and viral genetic factors may be important in disease pathogenesis.
A recent multi-year population-based study of HRVC in two U.S. locations found that HRVC was associated with medically diagnosed wheezing and asthma more frequently than other HRV species. 50
Other reports also suggest that viruses in the HRVC group are more likely to be associated with wheezing 21, 23, 31, 58, 61, 62
. However, we did not find a significant association between HRVC and bronchiolitis severity in the current study. It is possible that clinical features amongst children who are ill with certain strains or species of HRV differ based on age or other demographic or epidemiologic factors, and we only enrolled children <12 months of age. In addition, specific genotypes within species A, B, or C may be more likely to be associated with increased disease severity. Further studies are required to address these possibilities.
When examining frequency and proportions of HRV species by year in our study, there are clearly annual variations and alternation of the two major species during a single year, and sometimes recurrence at certain times of the year. Of the studies that have tested for HRVC to date, data on seasonality of HRVC is not conclusive. While many studies have detected HRVC as the predominant HRV species in the fall, suggesting it may play a role in the so-called September asthma epidemic21-23
, other studies in different regions and years have found otherwise. Han et al reported HRVC to be more common in the spring and HRVA in the fall in South Korea in 2006, but co-circulation occurred during both seasons28
. Consistent with our studies, Lau et al found HRVA and HRVC to alternate as the most common HRV species at different times during the peak seasons65
. Alternate disease activity by species and seasons suggests possible viral interference or serological cross-protection between HRVA and HRVC65
. While one study reported HRVC year-round without peaks in the spring and fall 25
, most studies do suggest that HRV species vary by season, year, and geographic location. This variation underscores the importance of studies over multiple years and seasons to understand fully the geographical and seasonal HRV epidemiology.
Despite the strengths of our prospective cohort study, there are limitations that should be noted. First, we did not test concurrent healthy controls to determine the prevalence of asymptomatic HRV infection, which is well described. 52,53,24
Since HRV can cause asymptomatic infection, our data suggest but do not prove that HRV infection was the etiologic agent for the respiratory illnesses, bronchiolitis and URI. However, we performed highly sensitive molecular testing for the spectrum of viruses known to cause infant respiratory viral illness, including influenza, RSV, HMPV, PIV1-3 and HCoV including OC43, 229E, and NL63 (data not shown) with no other virus detected in 73.5% of the HRV-positive children, strongly suggesting that HRV was the causative pathogen. Other studies support these findings.54-55
In addition, this study cannot delineate population-based rates of HRV-associated LRI and URI, as the cohort did not equally enroll hospitalized and non-hospitalized infants, with nearly two-thirds of the cohort being hospitalized infants, thus over representing infants with bronchiolitis. A final limitation was that we evaluated only one geographic site. However, we report a comprehensive study over 4 years in a site that captures over 90% of Nashville Davidson county infant hospitalizations.