The main finding of this study is that there are no clear clinical or demographic characteristics that can be used to differentiate between poorly controlled patients with asthma with or without ambulatory pH probe–documented acid reflux. These results indicate that although asymptomatic GER frequently accompanies poorly controlled asthma, it is not associated with lower lung function, worse asthma control, or increased airway responsiveness, but is associated with significantly worse asthma quality of life. In addition, the concordance between lower (distal) esophageal reflux and upper (proximal) reflux was only moderate; 25% of subjects had one without the other. Discordance between proximal and distal reflux measurements are likely due to the established normal values used for presence of acid at each of these sites. Because the distal esophagus is more frequently exposed to gastric acid, a normal total time with pH less than 4 is 5.5% in the distal esophagus, compared with less than 1% in the proximal esophagus (21
). In patients who are undergoing esophageal pH probe monitoring for evaluation of disorders such as chronic cough, it seems a reasonable extrapolation to suggest that dual-probe studies are necessary to exclude proximal acid reflux.
Previously published studies have shown lack of association between probe-documented GER and asthma outcomes (6
). However, because of small sample size, these studies had limited ability to identify asthma characteristics associated with reflux. The present study is the largest to use ambulatory pH probe monitoring and confirms these findings in a larger group of patients with asthma without significant symptoms of GER.
The 2007 National Asthma Education and Prevention Program Guidelines for the diagnosis and management of asthma recommend that clinicians consider treatment of reflux to improve asthma control in patients with poorly controlled asthma (7
). In our study of 304 subjects with asthma who had ambulatory pH probe monitoring performed, we have demonstrated no effect of reflux on lung function, airway hyperresponsiveness, acute care visits for asthma, asthma symptoms, nocturnal symptoms, dose of asthma maintenance therapy, or need for rescue therapy. Subjects with GER did report significantly worse Asthma Quality of Life, though the clinical significance of this modest effect is uncertain. Our finding of greater previous use of oral corticosteroids among subjects with GER may suggest that patients with GER have more acute episodes of worsening of asthma, which may affect quality of life.
Individuals with proximal reflux did not demonstrate worse asthma symptoms, lower lung function, increased airway responsiveness, or rescue bronchodilator use, but did have substantially poorer asthma quality of life and generic health-related quality of life compared with those participants without proximal GER. Specifically, there was a trend toward increase in feeling bothered by cough on the mini-AQLQ in subjects with proximal GER and the SF-36 showed a significantly worse physical activity score. This finding suggests that proximal reflux may be more relevant to subjective evaluation of asthma symptoms rather than physiologic impairment of lung function. In this regard, Ferrari and colleagues studied 17 patients with asthma and proximal reflux. They found that omeprazole reduced the cough sensitivity to capsaicin but did not alter airways reactivity to methacholine (28
). Interestingly, previous studies have demonstrated that proximal acid reflux is predictive of a favorable response to acid suppressor therapy, although we did not find this in our trial (2
Nocturnal asthma symptoms are frequently present in patients with difficult-to-control asthma, raising the suggestion that GER contributes to both nocturnal symptoms and poor asthma control. Kiljander and colleagues reported that in patients with asthma with combined symptoms of GER and nocturnal asthma, treatment with esomeprazole resulted in a modest improvement in morning and evening peak flow (10
). One may speculate that nocturnal asthma symptoms are a marker of proximal esophageal reflux, which in our study is associated with worsened asthma quality of life. In support of this, Tomonaga and colleagues demonstrated that nocturnal cough was associated with proximal, but not distal, esophageal reflux (30
). Our study however, did not demonstrate a difference in nocturnal asthma symptoms between those individuals with and without proximal reflux. It is possible that asymptomatic GER may disrupt sleep in more subtle ways, thus leading to impaired quality of life without significant differences in asthma control. In a large study from Taiwan, Chen and colleagues found that asymptomatic esophagitis was associated with poorer sleep quality and shorter sleep duration (31
The present study confirms and extends prior work that has emphasized the high prevalence of silent proximal and distal GER in patients with asthma. This is the first large-scale study to use pH probe monitoring to compare severity of asthma symptoms and asthma control in patients with and without documented evidence of acid GER. Because the present study enrolled only patients with minimal or absent GER symptoms, we cannot address the question whether in patients with symptomatic GER, reflux does contribute to asthma symptoms, asthma exacerbations, and poorer lung function. Furthermore, nonacid esophageal reflux (e.g., pepsin, bile acids) has been recognized as a cause of respiratory symptoms such as cough and wheeze (32
) and is not detectable with the pH monitoring performed in our study. Our findings therefore cannot be extrapolated to the effect of nonacid reflux on asthma control. Several studies have demonstrated that in patients not taking acid suppressor therapy, combined pH and impedance testing for detection of both acid and nonacid reflux has demonstrated that only 6.3% of reflux events are nonacid. Nonacid reflux appears to play a more significant role in patients who have persistent reflux symptoms despite PPI therapy (34
Our study does not support the idea that asymptomatic reflux is associated with lower lung function, worse asthma control, increased airway hyperresponsiveness, or increased asthma symptoms. Evaluation for GER using ambulatory pH probes in individuals with poorly controlled asthma with no reflux symptoms is therefore not usually warranted unless atypical symptoms, such as cough or unexplained chest symptoms, might suggest the diagnosis.