This study confirms that there is a strong association between symptoms of gastro-oesophageal reflux and symptoms of asthma in this population-based cohort of young adults. These associations were independent of BMI and smoking. Acid regurgitation tended to be a stronger predictor of respiratory symptoms than heartburn, but those with both heartburn and acid regurgitation had the highest risk of respiratory symptoms. The association of reflux symptoms with objective indicators of respiratory function was different for men and women. In women both bronchodilator responsiveness and a lower FEV1/FVC ratio were associated with reflux symptoms, whereas in men there was little evidence of an association. The reasons for these sex differences are unclear.
Although this study provides longitudinal follow-up of asthma, wheeze and airway responsiveness since childhood, data on gastro-oesophageal reflux symptoms were not collected during childhood or adolescence and we are unable to establish the temporal sequence between respiratory symptoms and airway responsiveness and gastro-oesophageal reflux. However, symptomatic gastro-oesophageal reflux is uncommon in children and adolescents after infancy [25
]. We hypothesised that if asthma precipitates gastro-oesophageal reflux, there would be strong associations between childhood persistent asthma and reflux symptoms. Although childhood wheeze (but not asthma) did significantly predict adult reflux symptoms (figures and ), teenage-onset asthma and wheeze were better predictors of adult reflux symptoms suggesting that the association between airway and oesophageal dysfunction emerges or strengthens during adolescence. This is supported by the association between airway hyperresponsiveness to methacholine from age 11 onwards and adult reflux symptoms. The strongest association between diagnosed asthma and reflux symptoms was in those with adult-onset asthma, but the findings for wheeze and airway responsiveness are consistent with the hypothesis that longstanding wheeze contributes to the development of reflux, even though it may not have been diagnosed as "asthma".
Perhaps the most striking finding was that airway hyperresponsiveness to methacholine at age 11 years and older predicted the combination of heartburn and acid regurgitation symptoms 15 years later (table ). These associations were generally similar in males and females (data not shown). By contrast, there was no association between bronchodilator responsiveness at age 18 and adult reflux, while the cross-sectional association between bronchodilator responsiveness and reflux at age 26 was significant in women only. The association between methacholine responsiveness at age 9 and adult reflux was not statistically significant. Methacholine responsiveness was more common at this age and often asymptomatic. For many, this was a self-limiting phenomenon, and long-term associations would not be expected.
Why methacholine responsiveness in later childhood and adolescence predicts gastro-oesophageal reflux symptoms years later is unknown. Episodes of airway narrowing may lead to increased pressure swings in the thorax during the respiratory cycle and promote failure of the gastro-oesophageal sphincter [26
]. However, the association was independent of both diagnosed asthma and wheezing symptoms, which suggests that frequent episodes of bronchoconstriction were an unlikely cause of the association. Alternatively, the two phenomena may be linked by altered vagal function, since the vagus nerve controls lower oesophageal tone as well as airway calibre and responsiveness. Autonomic function tests in patients with both asthma and gastro-oesophageal reflux have demonstrated heightened vagal tone, but it is unclear if this was a primary abnormality or a consequence of either asthma, gastro-oesophageal reflux or their treatment [27
It is possible that the long-term association between teenage methacholine responsiveness and adult reflux symptoms is due to persistence of gastro-oesophageal reflux since adolescence. Although gastro-oesophageal reflux is thought to be uncommon in children and adolescents [25
], this may be because it is poorly recognised. In a recent cross-sectional survey, 6% of 13 and 14 year-olds reported having either heartburn or regurgitation symptoms at least once a week in the previous month [28
]. Consistent with our findings, reflux symptoms were much more common in the children with asthma. Moreover gastro-oesophageal reflux is often asymptomatic and even "silent" reflux is associated with asthma [29
]. Several studies have reported improvements in asthma symptoms or lung function after medical or surgical treatment for gastro-oesophageal reflux. Although a recent systematic review found that the evidence was inconsistent and concluded that there was no overall benefit, sub-groups of patients may benefit [31
The finding that the association between wheeze, waking with a cough, and bronchodilator responsiveness and reflux symptoms tended to be stronger in those who were not atopic would support a hypothesis that gastro-oesophageal reflux causes these symptoms by a mechanism which is distinct from the classic atopic/immunological model of asthma.
The associations between reflux symptoms and asthma were independent of BMI, confirming the finding from the European Community Respiratory Health Survey [13
]. This is an important observation since gastro-oesophageal reflux has been suggested as a plausible mechanism for the association between asthma and obesity, particularly since the associations between obesity and both asthma and reflux are stronger in women and because oestrogen has been implicated in both [10
]. We have previously identified an association between asthma and BMI in women in this cohort [9
]. This association between asthma and BMI was not materially altered by including reflux symptoms in the model indicating that reflux does not mediate the asthma-obesity association (data not shown). Perhaps this is not surprising since reflux symptoms in this young adult cohort were only weakly associated with obesity [32
We found little evidence of an association between asthma and irritable bowel syndrome, which suggests that the association between asthma and gastro-intestinal symptoms is specific for gastro-oesophageal reflux and not a more generalised functional gastro-intestinal disorder. This finding contrasts with results from the postal survey by Kennedy et al
which found that symptoms of bronchial hyperresponsiveness, irritable bowel syndrome and gastro-oesophageal reflux were all significantly and independently associated with each other [12
]. The survey by Kennedy et al
used a randomly selected sample of adults with a mean age of 38, 12 years older than the participants of this cohort. Moreover, they did not measure lung function but used symptoms to predict bronchial responsiveness.
Strengths of this study include a high rate of follow-up in a population based cohort, prospectively collected data on asthma since childhood, measurements of lung function and airway responsiveness, and directly measured rather than self-reported height and weight. Our findings are coherent across a range of indicators of asthma including a reported diagnosis, wheezing symptoms, and methacholine responsiveness, as well as the symptom of nocturnal cough which could be caused by either asthma or gastro-oesophageal reflux. For women there is also coherence with spirometry and salbutamol-responsiveness. Weaknesses of this study include the fact that detailed information on reflux symptoms was only collected at age 26, and that a subjective measure of "bothersome" symptoms was used to indicate clinically significant reflux. Hence we do not know when these symptoms first occurred, nor do we have data on symptom frequency. However, these factors would reduce the likelihood of identifying significant associations and therefore it is unlikely that these limitations have biased our findings.