- Top of page
Background: Recent studies have suggested that rhinovirus-associated early wheezing is a greater risk factor for development of recurrent wheezing in children than is early wheezing associated with respiratory syncytial virus (RSV). We determined the development of recurrent wheezing in young children within 3 years after hospitalization for RSV or non-RSV bronchiolitis.
Methods: We identified retrospectively all children <2 years of age who were admitted to Turku University Hospital because of bronchiolitis in the months of August–December during 1988–2001. The primary outcome was recurrent wheezing that required long-term asthma medication. Data on asthma medications of the individual children were derived from the Social Insurance Institution of Finland.
Results: Within the first year after hospitalization, 36 of 217 (16.6%) children with non-RSV bronchiolitis developed recurrent wheezing, compared with five of 199 (2.5%) children with RSV bronchiolitis [relative risk (RR) 6.6; 95% confidence interval (CI) 2.6–16.5]. The rates of recurrent wheezing were significantly increased in the non-RSV group also within 2 years (RR 2.9; 95% CI 1.7–5.1) and 3 years (RR 3.4; 95% CI 2.0–5.7) after hospitalization. The increased risk of recurrent wheezing in children with non-RSV-associated bronchiolitis was observed both in boys and girls at all time points of the 3-year follow-up, and it was not explained by the age difference between the RSV and non-RSV groups or any confounding seasonal factors.
Conclusion: Children hospitalized with bronchiolitis caused by other viruses than RSV develop recurrent wheezing at substantially higher rates during a 3-year follow-up period than do children with RSV-induced bronchiolitis.
Bronchiolitis is a frequent illness and one of the main causes of hospitalization in infants and young children. In the US, approximately 3% of children <1 year of age with no underlying medical conditions are hospitalized for bronchiolitis during respiratory syncytial virus (RSV) epidemics (1). Several viruses are known as causative agents of bronchiolitis. In infants, RSV is clearly the primary cause, although other viruses, e.g. rhinoviruses, enteroviruses, human metapneumovirus and human bocavirus, are also frequently found in infants hospitalized with this condition (2–5). In children with 1 year of age or older, the relative importance of RSV in the etiology of bronchiolitis is substantially lower, and the predominant viruses detected in these children are rhinoviruses and enteroviruses (3).
Many children who experience bronchiolitis in infancy develop recurrent wheezing later in life. RSV infection has been recognized as an important risk factor for recurrent wheezing in several studies (6–10). The pathogenetic mechanisms that lead to recurrent wheezing after RSV bronchiolitis are still unknown but there is evidence to suggest that both genetic and environmental factors contribute to the host immune response to RSV infection and that this response, in turn, may adversely affect the development of lungs and the control mechanisms of the lower airways (11–13).
Recent studies have suggested that children with bronchiolitis associated with other viruses than RSV, especially rhinovirus, have a greater risk of developing recurrent wheezing than do those with RSV-induced wheezing (14–20). In a large prospective study in the US, rhinovirus-associated wheezing in infancy was determined as the strongest predictor of subsequent wheezing during the third year of life and the development of asthma at the age of 6 years (16, 20).
The purpose of our study was to assess the development of recurrent wheezing in young children who had been hospitalized for bronchiolitis caused by RSV or other viruses. In Finland, RSV epidemics follow a distinct 2-year cycle (21), with small outbreaks occurring in the spring and early summer of each odd-numbered year, followed by large outbreaks during the subsequent autumn and winter (Fig. 1). During the autumn of every even-numbered year, RSV is virtually undetectable in Finland, and during this time acute wheezing illnesses in children are caused by other viruses than RSV. This well-established epidemiologic pattern of RSV infection provided us with a unique opportunity to compare the impact of RSV and other viruses on the development of recurrent wheezing.
Figure 1. Monthly occurrence of laboratory-confirmed respiratory syncytial virus (RSV) infections in children seen at Turku University Hospital during 1988–2001. Source of data: Department of Virology, University of Turku, Finland.
Download figure to PowerPoint
- Top of page
Our results indicate that bronchiolitis caused by other viruses than RSV is associated with a substantially increased risk of recurrent wheezing when compared with an RSV-associated primary wheezing episode. This effect was sustained during a follow-up period of 3 years after hospitalization for bronchiolitis. Our main finding was further strengthened by several subgroup analyses that demonstrated that the observed differences in the development of recurrent wheezing were not explained by age differences between the groups or any potential confounding seasonal factors between the odd- and even-numbered years.
Our findings provide strong, albeit indirect, support for recent studies suggesting that rhinovirus-induced early wheezing is a major risk factor for recurrent wheezing later in life (14–20). In one of the first studies challenging the primary role of RSV in the development of asthma, Reijonen et al. (14) followed infants hospitalized for wheezing and reported that the identification of RSV as the etiologic agent was surprisingly associated with a decreased occurrence of asthma during a 3-year period after the hospitalization when compared with RSV-negative children. In subsequent reports of that cohort of children, hospitalization for rhinovirus-induced wheezing was demonstrated as an important risk factor for the development of asthma, and the increased risk persisted at least until late teenage years (15, 17, 19). In a prospective study of children from birth to 6 years of age in the US, Lemanske et al. (16) and Jackson et al. (20) concluded that the most significant risk factor for the development of preschool childhood wheezing and asthma was the occurrence of rhinovirus-associated wheezing during infancy. In contrast, children who wheezed only with RSV during their first 2 years of life were not at increased risk for asthma at the age of 6 years (20). Recently, Dunder et al. (23) reported that exposure to RSV in early infancy did not increase the consumption of asthma medicines at the population level.
Because rhinoviruses and enteroviruses were not routinely searched for at our hospital during the period of this study, we were unable to determine the viral etiology of most children who had a non-RSV illness. It is most likely, however, that the majority of non-RSV-associated cases were caused by rhinoviruses or enteroviruses. This assumption is based on a recent 2-year study of the viral etiology of acute expiratory wheezing at our hospital, in which the causative viral agent could be detected in 95% of the cases (3, 5). In infants younger than 1 year of age, RSV accounted for 54% and picornaviruses for 42% of all wheezing illnesses, which left only a minor role for any other viruses in the etiology of this illness. In children aged 12–35 months, picornaviruses were detected in 65% and RSV in 22% of the cases (3).
It is important to emphasize that the increasing recognition of rhinovirus-associated primary wheezing as a major risk factor for the development of asthma does not necessarily imply that primary wheezing caused by RSV infection would not run an increased risk of asthma. In an 11-year follow-up of infants hospitalized for wheezing, the risk of teenage asthma was 10-fold after rhinovirus-induced wheezing but also fivefold after RSV-induced wheezing (17).
In our study, 8% of children hospitalized with RSV-associated bronchiolitis developed recurrent wheezing within the following 3 years. This rate is much lower than the rates observed for RSV-infected children in many previous studies with varying durations of follow-up (8, 9, 20). While the threshold of admitting children to hospital may differ between different settings and countries, the most likely explanation for the apparent discrepancy between our results and those of the previous studies is the stringent criteria that we used in defining our primary outcome. In the present study, children were classified as recurrent wheezers only if they were granted reimbursement for their long-term asthma medication by the Social Insurance Institution, which practically excluded all children with less severe wheezing who might have used asthma medications on a temporary basis. Although our rates of recurrent wheezing are thus not comparable with those observed in other studies, there is no reason to assume that the criteria for granting reimbursement would have been different for children with previous RSV or non-RSV bronchiolitis. It should be noted, however, that even recurrent wheezing during the first years of life does not automatically lead to persistent asthma later in life.
Recent studies assessing the efficacy of systemic corticosteroids in the management of wheezing have provided additional evidence for the concept that there are distinct differences between infants hospitalized with rhinovirus and RSV-associated wheezing (18, 24, 25). As observed also in the present study, infants with rhinovirus illnesses are generally older than those hospitalized with RSV infection (24, 26). Moreover, infants hospitalized with rhinovirus-induced wheezing seem to have a different response to anti-inflammatory treatment when compared with RSV-infected infants. In studies where children were followed up to 1 year after hospitalization for wheezing, prednisolone treatment was associated with a significantly decreased risk of recurrent wheezing in infants hospitalized with rhinovirus infection, but not in infants hospitalized with RSV-induced wheezing (18, 24).
Male gender is a well-established risk factor for recurrent wheezing (27). In our study, two-thirds of children initially admitted for bronchiolitis were boys. In the development of recurrent wheezing, however, it appears that the viral etiology of the primary wheezing episode is a more important factor than gender. The risk of recurrent wheezing was significantly increased after non-RSV bronchiolitis in both girls and boys during all time periods analyzed. Although there was a tendency for boys to develop recurrent wheezing at a relatively higher rate than in girls, the difference did not reach statistical significance in a group of 416 children.
Our study has some limitations. Most important, we could not determine the viral etiology of bronchiolitis in most children in the non-RSV group because rhinoviruses and enteroviruses were not routinely searched for during the study period. Because of the retrospective nature of the study, we were unable to retrieve comprehensive information on various environmental and genetic factors, such as the presence of atopy or maternal asthma, that are known as strong predictors of persistent wheezing in children. We also studied only hospitalized children. On the other hand, a major strength of our study was the meticulous examination of all medical records to rule out any previous wheezing episodes, which largely excluded the possibility that children hospitalized for non-RSV illnesses had previously had an RSV illness that could have predisposed them to the non-RSV illness. Other strengths of the study included the utilization of a reliable and comprehensive register of reimbursement for asthma medications, a study period of 14 consecutive years to diminish the potential effect of any season-to-season variation, and the well-established seasonal pattern of RSV epidemics in Finland.
In conclusion, our results demonstrate that bronchiolitis caused by other viruses than RSV confers a substantially greater risk of recurrent wheezing during a 3-year period after hospitalization than in RSV-induced bronchiolitis. These data provide indirect support for the recent recognition of rhinovirus as a major risk factor for the development of recurrent wheezing in children. Further studies are needed to determine whether primary rhinovirus-associated wheezing during a critical period of life induces a long-lasting ‘innate imprint’ on the child’s immune response (28), or whether it just serves as a sensitive indicator of children who are at increased risk of developing recurrent wheezing and asthma later in life.