In this retrospective cohort study of children born at ≥32 weeks GA, we found that three important risk factors (RSV disease in the first year of life, moderate prematurity, and exposure to supplemental oxygen in the neonatal period) had statistically significant associations with the development of RW5. This is consistent with our previous report, [14
] where these predictors were associated with RW in the third year of life. Our study is concordant with and expands upon the study by Carroll et al. [13
]. As was the case with that study, ours is a very large cohort, but ours had the advantage of including children born at <37 weeks gestation as well as actually documenting RSV infection, rather than just using the presence of a bronchiolitis diagnosis. Our study also found that other pathogens did not show a strong association. We also found that, consistent with the known epidemiology of asthma and RW, prevalence decreases over time, but among infants with certain risk factors including RSV infection, the prevalence of RW remained high in the fifth year. We found that these relationships persisted when we employed a more lenient definition of RW (accepting any instance of an asthma diagnosis). Future studies may be needed to better characterize the burden of these infants on the healthcare system and determine whether other strategies for mitigating the effects of RSV are possible. It is important to stress that our study is not in concordance with another very large study conducted in Finland, where Dunder et al. did not find an association between RSV epidemics and subsequent use of asthma medication [26
]. The study by Dunder et al. is important because, like us, electronic scanning of asthma medications was employed for ascertainment.
In our previous report [14
], we pointed out a number of limitations to our findings, of which the most important was that not all infants in our cohort were tested for RSV. Nonetheless, the presence of a severity gradient, the fact that the RSV effect observed in the third year of life persists into the fifth year, and the fact that other pathogens do not show this association, strongly support the notion that RSV infection in infancy is associated with asthma in childhood. This notion has been suggested by others [5
]. However, it is important to note that some of our findings could be interpreted differently. For example, while it is true that our analyses clearly show a specific effect of documented RSV infection, it is striking that the relative contribution of this variable to the overall predictive ability of our model is small (6.6%), while the contribution of non-modifiable risk factors such as sex, race, and family history was far greater. In this context, we must note that our lack of data on tobacco exposure is a significant limitation.
The presence of an association, however strong, does not constitute evidence of causality, and it is important to consider a number of possible causal paths, which are not mutually exclusive, that could explain our findings. The relationship of lower respiratory tract RSV disease to asthma is under investigation, particularly the role of genetic susceptibility for eventual asthma and the interaction of genetic susceptibility with the environment [27
]. It remains unclear whether RSV infection disrupts neural control of bronchiolar smooth muscle setting the stage for sensitized airways or whether RSV disease serves as an additional insult to a host with pre-existing genetic susceptibility for eventual asthma [27
]. One possibility is that infection with RSV causes lung damage that ultimately leads to the development of asthma. Such damage could be accentuated by oxygen exposure, prematurity, bronchopulmonary dysplasia, and/or environmental exposures (e.g., air pollution, secondhand smoke). Another possibility is that a set of genes exists that is preferentially expressed following infection with RSV. Such genes, which could also be affected by environmental factors, could lead to the occurrence of wheezing and asthma. It is also possible that a set of genes that are not identical to, but are related to, the development of asthma also code for a more exaggerated response to RSV infection, thus explaining the severity gradient noted by us and others. Lastly, one cannot exclude the possibility that a subset of the population requires a severe RSV infection in order to develop asthma.
Given conflicting findings in the literature, with different studies and study types (e.g., twin studies) coming to different conclusions [28
], a definitive explanation of the relationship of RSV infection to the development of asthma remains elusive [36
]. What is clear is that future studies need to include more detail with respect to direct capture of genetic information. It is instructive to outline the components of what could be considered an optimal prospective study to explore the relationship between RSV infection in infancy and the development of asthma. Ideally, infants should be enrolled immediately after birth, and the initial intake process should include non-invasive collection of infant and parental DNA and a detailed history that includes special attention to family smoking history, history of atopy in parents and grandparents, and other possible environmental and allergen exposures (e.g., pets in the home). Subsequent follow-up should include frequent testing for respiratory pathogens [37
], careful attention to the development of atopy, and an objective assessment of whether or not a child develops wheezing. The setting for such a study should be in an ethnically diverse population with a relatively high baseline prevalence of asthma.