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Early life origins of the Asthma–COPD Overlap Syndrome?

Chronic persistent asthma and tobacco smoking are the two most prominent risk factors for chronic airflow limitation. In many patients these factors overlap and in such circumstances the relative contribution of each risk factor and the underlying diagnosis among older adults with irreversible airflow obstruction may be difficult to determine. How smoking and asthma combine and interact to result in airflow obstruction and what other host and environmental factors influence this interaction is poorly understood. The conceptual framework of ‘causal pies’ encourages us to think about necessary and sufficient causes of disease (Fig. 1). Although smoking is regarded as the most important cause of COPD, it is not a sufficient cause because not everyone who smokes heavily will develop COPD. Nor is smoking a necessary cause, because COPD can occur in people who have never smoked. Similarly, chronic asthma is neither a sufficient nor a necessary cause for developing chronic airflow obstruction. Hence each of these major contributors must combine or interact with other risk factors to result in COPD. It is clear that there must be several combinations of factors (‘pies’) that constitute sufficient causes for COPD, but we are a long way from understanding how many different pathways to COPD there might be or identifying many of the other risk factors that make up these pies. To a great extent our progress in understanding these interactions has been limited by a lack of longitudinal research documenting lung function across the life course. The recent report by Perret et al. in Respirology suggests that childhood measles may be another part of an asthma and smoking pie (the fourth pie in Fig. 1). The Tasmanian Longitudinal Health Study (TAHS) first measured spirometry at age 7 among a cohort of participants born in 1961. Spirometry was repeated nearly four decades later in a subgroup of 1389 participants when they were in their mid-40s. A history of parentreported childhood measles was obtained from school medical records. Childhood measles on its own did not increase the risk of airflow obstruction in mid-adult life, but did appear to influence the impact of asthma and smoking. A three-way interaction between measles, asthma and smoking found that the combination of heavy smoking (over 10 pack years) and asthma was associated with airflow obstruction only among participants with a history of childhood measles. This observation may help to explain the discrepancy between an earlier report from the TAHS suggesting an interaction between smoking and asthma leading to enhanced lung function decline and findings from the Dunedin cohort, which did not, because the Dunedin participants were born after measles vaccination had been introduced. The mechanism by which childhood measles might predispose people to be more susceptible to the combined effect of smoking and asthma is undetermined. Childhood respiratory infections have previously been found to increase the susceptibility to smoking-related airway damage, but the observation that childhood measles modified the combined effects of smoking and asthma is novel. It has been hypothesized that multiple inflammatory ‘hits’ are necessary for the development of chronic airways disease, but how do early childhood infections increase susceptibility to smoking many years later? The authors speculate that measlesrelated damage of the small airways, inflammation and remodelling predispose to symptomatic asthma and increased susceptibility to future insults. However, measles was not associated with an increased risk of adult asthma in the TAHS. The findings are unlikely to be explained by tracking of airflow obstruction from the time of measles because the analyses adjusted for childhood lung function at age 7. Is it possible that the measles virus has long-lasting effects on immune function, or is it more likely that developing clinical measles reflects underlying pre-existing immune function, which subsequently influenced the response to smoking and asthma? There are other findings from this report that are hard to explain. The finding that measles was almost statistically significantly associated with lower risk of atopy (unadjusted P = 0.052) may be compatible with Strachan’s hypothesis that children with more infections are less likely to develop allergies. A lower prevalence of atopy among children with a history of measles has been observed before, although the evidence is inconsistent. However, the finding that childhood measles appeared to protect against developing obstruction in asthmatic adults who did not smoke is puzzling. These novel findings need to be tested in other cohorts: we cannot be sure that the interactions are not due to residual confounding or chance associations arising from the complexity of the regression models. We also need to investigate whether other childhood infections have similar three-way interactions. Other host or environmental factors must also be involved— not all smokers with asthma and a history of measles developed airflow obstruction, so the combination of these three risk factors do not make up a sufficient cause on their own—there are more pieces of the pie to be discovered. Nevertheless, the findings suggest that complex interactions between childhood infections, environmental exposures, immune function and asthma may comprise a ‘causal pie’ for COPD.