Respiratory syncytial virus and asthma: still no final answer.

During the past two decades, a large number of studies have addressed the association of viral respiratory events in early life and the subsequent development of recurrent wheezing and asthma later in life. Investigations performed both in animal models and in humans have provided new insights into potential pathogenetic mechanisms discernible during acute and convalescent stages of viral events and their potential association with the long-term consequences of these events. 6 Retrospective analysis of clinical trials has suggested that the use of antirespiratory syncytial virus (RSV) antibodies may decrease the incidence of subsequent asthma-like symptoms, but prospective data are lacking. The strongest data for the association between early RSV events and asthma comes from longitudinal studies. The Tucson Children’s Respiratory Study was based on a healthy and representative population, and its results, if not automatically applicable to all communities given the peculiarities of the Arizona desert, have been replicated in other population-based studies. The main findings from the Tucson study indicated that RSV, independent of other known risk factors for asthma, was significantly associated with recurrent wheeze in the first decade of life. The results of a larger birth cohort, also population based, the ALSPAC study from Bristol points in the same direction as the Tucson study: children with a RSV bronchiolitis admission in the first year of life were more likely to have asthma at age 7 years, compared with controls and there was no relation with RSV infection and the development of atopy at this age. The issue of a possible relation between early life RSV bronchiolitis and the later development of atopy has been entertained by a series of studies, and the disparities of findings seem to be related to the methodology used in selecting the subjects. A major strength of these two abovementioned birth cohort studies is that they are population based, and are powered adequately enough to study asthma and atopy as main outcomes, in a scenario in which a great number of other independent risk factors were also ascertained. Valuable information comes from a subset of children in the Tucson study who had infant lung function testing before any viral event was detected; these children were more likely to wheeze with lower respiratory illnesses if they had lower lung function values as measured by maximal expiratory flow at functional residual capacity [V9maxFRC]. Infant lung function data were not evaluated in relation to severe bronchiolitis or RSV bronchiolitis in the Tucson study, but this was done in birth cohort from Perth, in which 253 healthy infants were followed from birth and had lung function measured at 1, 6 and 12 months of life. Similarly to the Tucson findings, infants in Perth who had bronchiolitis were in the lowest quartile for premorbid lung function values. When this cohort was re-evaluated years later, children with bronchiolitis were shown to be at an increased risk of wheezing and, more interestingly, their expiratory flows at age 11 years were significantly lower compared with the rest of the cohort, and these levels tracked with the lower expiratory flows observed in the first months of life. These findings indicate that premorbid lung function predicts low lung function that may not (at least not significantly) be affected by the acute viral bronchiolitis event. In this issue of Thorax, Sigurs and collaborators (see page 1045) offer new insights into mechanisms relating early life severe viral bronchiolitis and later asthma. These investigators revisit their cohort, for which almost 18 years ago they originally enrolled two groups of children: one admitted to hospital and diagnosed with severe RSV bronchiolitis and another consisting of healthy controls. A series of previous publications by the same group has established not only that children in the bronchiolitis group were at greater risk of subsequent wheeze in later years, when compared with healthy controls, but that they were also at greater risk of atopy. This latter finding has not been confirmed by most other studies, perhaps due to specific characteristics of the Swedish population, or a bias that might have been introduced in the selection of cases and controls at the beginning of the study. In the current study, Sigurs and colleagues confirm their earlier findings now at age 18 years, indicating, as the long-term prospective studies mentioned previously, that the combination of RSV bronchiolitis and early sensitisation is a major risk factor for persistent wheeze. They also report that children with RSV bronchiolitis, independently of asthma at age 18 years, but not the asthmatic controls, had lower levels of lung function, thus suggesting that severe RSV may directly affect lung development. It is worth mentioning again that the main limitation of these conclusions is that no premorbid data are available for these children. The observation that small airway dysfunction, as measured by the lung clearance index, at age 18 years was associated with current asthma, enhanced airway responsiveness, and Fraction of exhaled nitric oxide (FeNO) but not with bronchiolitis points to the need for sensitive measures of small airways function and markers of inflammation to detect changes in children with milder disease. All these conclusions are based on the evaluation of a small number of subjects (after stratification for subgroups), with functional differences that may not mean much clinically. More data are needed, especially considering that the lung clearance index is a new method with some limitations, especially when used on the evaluation of children with asthma. Recent twin studies further support the idea of a shared heritability between asthma and RSV bronchiolitis. Using a large registry of twins in Denmark and sophisticated statistical modelling, Thomsen and coworkers concluded that severe RSV bronchiolitis is an early indicator of a shared genetic predisposition for asthma, and not that asthma is the consequence of having had RSV bronchiolitis. We take a step further to suggest that, for most children presenting with severe RSV bronchiolitis, the most frequent risk factor is premorbid low lung function and that, in the absence of Pediatric Respirology, Deparment of Pediatrics, Pontifı́cia Universidade Católica RGS, Rio Grande do Sul, Brazil; Arizona Respiratory Center and BIO5 Institute, University of Arizona Health Sciences Center, Arizona, USA