Discussion

We have shown that significantly more cases of all phenotypes of wheeze occur in children that have had bronchiolitis in infancy compared with those who had a UTI, with the largest effects seen in long admissions with non-RSV bronchiolitis. This effect is most marked for the early wheeze phenotypes but persists for even late-onset wheeze.

While the link between RSV bronchiolitis and later respiratory pathology has been consistently demonstrated, the strength and details of the association vary between populations and has not been previously described in a UK cohort.7 Studies have also linked rhinovirus, human meta-pneumovirus and parainfluenzae as associated with later wheeze, with some suggesting a stronger effect for non-RSV bronchiolitis.8 The strongest form of evidence for assessing the association between bronchiolitis and wheeze is from randomised controlled trials (RCTs) of monoclonal antibodies against RSV. The Dutch MAKI RCT of paluvizumab in premature infants found that at 6 years, there was a significant reduction in parentally reported wheeze (11.6% vs 19.9%) but not in physician diagnosed (10.3% vs 9.9%), concluding that there was no clinically significant effect.9 The phase III RCT of motavizumab in 2170 term Navajo infants found an 87% relative reduction in RSV-related admissions but no effect on rates of medically attended wheezing (14.9% vs 14.0%) during 1–3 years of follow-up.10 In our cohorts, rates of bronchiolitis-associated late-onset wheeze were low (5% vs 3%), raising the possibility that with <1000 patients per arm and only a subset of these developing bronchiolitis, these trials were not adequately powered to detect this difference. Although a small percentage change, we would argue that on a population scale, a vaccine that prevented any cases of a chronic health condition such as asthma as a secondary gain would be significant.

The strengths of this paper are that it follows a whole English population birth cohort of 642 000 children over an 8-year period. Using a hard outcome of admission rather than parentally reported or clinician diagnosed wheeze, it characterises the burden of admissions due to different phenotypes of wheeze. Our primary analysis using all diagnostic fields found similar frequencies of wheezing during admission as in parentally reported community surveys,11 restricting analysis to the primary diagnostic code found reduced incidence of wheeze (7.8% post bronchiolitis vs 3.1% post UTI) but with a similar RR 2.4 (2.0–3.0) between the groups. Its limitations are that it is reliant on quality of diagnostic coding, rates of routine virological testing and could not assess the effects on mild non-admitted wheeze presentations. As a retrospective analysis of routine health data, we were not able to distinguish between different syndromic phenotypes of bronchiolitis as our dataset limited us to identifying patients by diagnostic clinical coding. Rates of routine virological testing carried out in the UK in 2007 meant we could only meaningfully compare RSV with non-RSV subgroups. Our cohort of hospitalised children represent a severe subgroup and thus our findings are likely to be an overestimate of true population effect. Our analysis was controlled for gender; in a sensitivity analysis, we also included the index of multiple deprivations, but this did not alter the RR estimates. There may be other biases that we were not able to identify. Fundamentally, as an observational study design, we cannot hope to prove causality and must be cautious that our findings are not a product of the phenotype categorisation.12

While the narrative that bronchiolitis leads to an inflammatory state, the start of the allergic march and predisposition to later wheeze is appealing; that all causes of bronchiolitis are associated with all phenotypes of wheeze suggests this interpretation is actually the cart leading the horse. Perhaps bronchiolitis is simply a marker of children who are likely to go on to wheeze in later life and represents the sentinel manifestation of those genetically or environmentally predisposed to wheeze. That the association for early wheeze is stronger implies that this is more complicated than the revealing of an innate state. It may be that different clinical phenotypes of bronchiolitis13 would be helpful in this prognostication, but we were not able to assess this using this dataset.

Fundamentally, these data highlight our inability to prospectively clinically distinguish between wheeze phenotypes. It is reassuring that 80% of children with even severe bronchiolitis do not go on to wheeze. Academic interest aside, the reason for this study is to be able to answer parents’ questions of ‘will this happen again?’ Although these data cannot elucidate the cause, they are helpful to describe likely respiratory trajectories for children. We now plan to expand this research by also examining wheeze attendances in the emergency department and primary care to see if the association still holds for the less severe cases of bronchiolitis.