Human rhinovirus, wheezing illness, and the primary prevention of childhood asthma.

Although human rhinovirus (HRV) is widely recognized as a major cause of upper respiratory infections, the development of molecular diagnostics has demonstrated the important role of HRV in lower respiratory infections and led to the discovery of new species and subtypes (1, 2). In recent years, investigators from around the world have found that HRV-related wheezing illness in early childhood is associated with a markedly increased risk of future wheezing and incident asthma (3–5). The magnitude of this association (with relative risks up to 10) appears larger than that of respiratory syncytial virus (RSV), the classic respiratory pathogen of infancy (6, 7). These impressive HRV–asthma associations are, at least in some research groups, starting to push RSV into the background. However, several decades of RSV bronchiolitis research hold valuable lessons for HRV researchers, if only by reminding us of several familiar (and vexing) questions. Most notably, is HRV-related wheezing illness an actual etiologic factor for asthma, or is it simply a marker of someone who was prone to develop asthma anyway, regardless of the HRV-related acute respiratory infection (ARI)? In the latter situation, we might consider HRV-related wheezing akin to a positive “stress test” that simply brings the child’s elevated asthma risk to our attention. Then again, it is possible that HRV plays both roles—that is, that HRV-related wheezing may identify people predisposed to asthma, but HRV infection may also increase risk of developing asthma. These questions have been debated for literally decades for RSV bronchiolitis, and I suspect that we will have a similar debate about HRV in the years ahead. With the emergence of HRV as an epidemiologic risk factor for asthma, additional permutations are emerging—for example, might RSV be an etiologic factor, whereas HRV is more of a stress test? If the converse is true (i.e., HRV is causally related to future wheezing and asthma), does the relatively high frequency of RSV–HRV coinfection in severe bronchiolitis (8) contribute to at least part of the RSV–asthma association? The recent trial by Blanken and colleagues (9) provides an elegant example of how we can begin to disentangle this web of potential etiologic factors, confounders, intermediates, and effect modifiers. In this randomized, double-blind, placebo-controlled trial of 429 preterm infants, investigators examined the effect of monthly palivizumab during the RSV season on total number of wheezing days during the first year of life. Palivizumab treatment resulted in a significant reduction in wheezing days (even after the end of treatment), and the proportion of infants with recurrent wheeze was approximately half that in the placebo group (11 vs. 21%, respectively; P = 0.01). Clearly, this infancy trial does not address the impact of RSV prophylaxis in the primary prevention of asthma, but the findings are encouraging. Further follow-up of these children is likely to shed light on the RSV–asthma debate—at least for the subset of children who were enrolled into this Dutch trial. Given the plethora of HRV subtypes, and the considerable challenge of developing a vaccine or medication to prevent HRV-related ARIs, it is currently infeasible to do a similar trial to address the etiologic role of HRV in wheezing illness and childhood asthma. In this issue of the Journal, Cox and colleagues (pp. 1358–1364) report on the association between three HRV species (A, B, and C) and their link to emergency department (ED) presentations due to ARI (10). All participants were under 5 years of age and recruited during an ED presentation with an acute wheezing episode. Although almost all (97%) of these ED patients were hospitalized at their index visit, roughly half were admitted to the overnight observation ward and thereby provided a larger spectrum of ARI severity. Approximately two-thirds of the children had HRV identified at enrollment, and among this subset, approximately two-thirds had HRV-C. Compared with the other viruses, the children with HRV-C were more likely to have had a prior hospital admission for ARI, and they also were at higher risk of a subsequent hospital admission for ARI. Risk of subsequent ARI admission appeared to be highest among children with atopy. The authors concluded that their results were consistent with HRV-C being “more pathogenic than other HRV species in children with more severe wheezing illness.” Although the study was relatively small (with wide 95% confidence intervals), and the single-center design might raise questions about generalizability, the results support the idea that wheezing illness related to HRV-C (rather than HRV-A or HRV-B) accounts for the increased risk of hospital admission for ARI. These novel data fit nicely into the larger story that implicates HRV as an important cause of wheezing illness, incident asthma, and asthma exacerbations (11). On the other hand, and as acknowledged by the authors, the fact that the association between HRV-C and ARI was present both before and after the index event (where HRV-C was identified) suggests that the index event may not have changed the child but rather that child may have already have had this increased propensity for ARI. Deja vu? Notwithstanding this uncertainty, the identification of HRV-C as the primary culprit in the association between HRV infection and serious childhood ARIs is an important advance. Together with other evidence, it seems likely that this HRV-C finding will extend to the link between HRV infection, more generally, and future risk of wheezing illness and asthma. Although causal inferences remain premature, the possibility of focusing on HRV-C (as compared with all species of HRV) has exciting implications for the development of more targeted interventions and their potential role in asthma prevention. Promising areas for such research include the interaction between early-life atopy and viral ARIs and its role in asthma pathogenesis (12); the relation of vitamin D status with wheezing illness and incident asthma (13); and the role of genetic factors, such as polymorphisms in 17q21 genes (14). Concurrent with this clinical/epidemiologic research, basic scientists may focus now on what makes HRV-C so harmful (e.g., in comparison to HRV-B), and on the development of tailored interventions to prevent HRV-C infection or to mitigate infection-related effects. Ideally, this future research would consider the impact of the respiratory microbiome (15), given its likely role in how viruses contribute to asthma pathogenesis. By focusing our attention on the HRV-C species, the study by Cox and colleagues provides valuable guidance on how to refine our approach to the primary prevention of wheezing illness and childhood asthma.