Antireflux Therapy in Asthma: Is There Any Role?

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American Lung Association Asthma Clinical Research Centers, Mastronarde JG, Anthonisen NR, Castro M, et al. (Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland). Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360:1487–1499.

Asthma and gastroesophageal reflux disease (GERD) are common conditions that frequently coexist in the same patient. Current practice guidelines suggest aggressively seeking out and treating GERD in patients with difficult to control asthma. However, studies examining the impact of aggressive GERD treatment on asthmatics with GERD symptoms are conflicting. Furthermore, some asthma patients have evidence of abnormal acid exposure by 24-hour pH monitoring despite the absence of any GERD symptoms. The effect of aggressive antisecretory therapy in this group is unknown. To address this question, the American Lung Association Asthma Clinical Research Centers performed a randomized clinical trial that examined the effect of esomeprazole 40 mg given twice daily for 24 weeks in 412 patients with inadequately controlled asthma despite moderate to high doses of inhaled steroids and minimal or no reflux symptoms (<2 episodes per week of heartburn requiring antacids). Reflux was measured by transnasal pH recordings at baseline and considered to be present if acid exposure time in the upright, supine, or combined positions was increased by standard criteria (Dig Dis Sci 1992;37:849–856). The primary end point was rate of episodes of poor asthma control, defined as either (a) a decrease of ≥30% in morning peak expiratory flow rate on 2 consecutive days compared with the patient's best rate during the 2- to 8-week run-in period; (b) unscheduled health care visit for asthma symptoms; or (c) need for a course of oral prednisone for asthma treatment. Secondary end points included spirometry before and after inhalation of 180 μg of albuterol, and a variety of symptom and quality-of-life questionnaires. Interestingly, despite minimal or absent GERD symptoms, abnormal pH studies were encountered in 41% of the placebo and 40% of the esomeprazole treatment groups. At the end of the study, there was no difference in the number of episodes of poor asthma control, as determined by any of the 3 criteria, between the treatment and placebo groups. Similarly, there were no differences in any of the secondary outcome measures between the 2 groups at 24 weeks. Finally, there was no difference between the placebo and treatment groups in the response of patients with abnormal 24-hour pH reflux parameters compared with individuals with normal reflux parameters.

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GERD and asthma are common clinical problems in both adults and children. Typical symptoms of heartburn and/or acid regurgitation are encountered in 52% to 82% of asthma patients (Chest 2004;126:1490–1494; Chest 1999;115:654–659; Chest 1996;109:316–322). Similarly, abnormal acid exposure by 24-hour pH recordings may be seen in 36% to 82% of asthma patients (Chest 2004;126:1490–1494; Chest 1999;115:654–659; Gastroenterology 1990;99:613–620). Sontag et al reported a strikingly high prevalence of esophageal mucosal damage in 186 consecutive asthmatics undergoing endoscopy regardless of the presence of reflux symptoms: erosive esophagitis was encountered in 39% and Barrett's esophagus in 13% (Gut 1992;33:872–876). Overall, 43% of the asthmatics studied had erosive esophagitis, Barrett's esophagus, or both. GERD has also been identified as an important contributing factor in patients with difficult to control asthma (Chest 1993;103:1662–1669). Approximately 50% of patients with difficult to control asthma have GERD by esophageal pH testing (Chest 2005;127:1227–1231; Aliment Pharmacol Ther 2006;23:1321–1327). Interestingly, GERD has now also been identified by pH recordings in a subgroup of asthmatics in the absence of any typical GERD symptoms, with the prevalence varying from 9.6% to 62% of asthmatics studied (Chest 2005;127:1227–1231; Chest 2004;126:1490–1494; Am J Respir Crit Care Med 2000;162:34–39; Chest 1999;115:654–659).

A variety of different mechanisms may explain the relationship between reflux and asthma. Microaspiration into the lungs has been demonstrated in asthmatics by simultaneous esophageal and tracheal pH recordings. Esophageal reflux episodes have been accompanied by a fall in both tracheal pH and peak expiratory flow rates in asthmatics (Ann Thorac Surg 1993;56:1029–1034; Thorax 1995;50:201–204). A vagally mediated esophagobronchial reflex may be triggered by acid in the esophagus. Wright et al demonstrated that infusion of 0.1 N hydrochloric acid into the esophagus reduced airway flow, arterial oxygen saturation, and heart rate (Gastroenterology 1990;99:71–73). These changes were all abolished by atropine. Others have also shown a decrease in peak expiratory flow after esophageal infusion of hydrochloric acid in asthmatics (Chest 1995;108:1220–1227). Other mechanisms whereby reflux may contribute to asthma include heightened bronchial reactivity, a local axonal reflex involving a direct neuronal connection between the esophagus and the lung, and neurogenic inflammation (Immunol Allergy Clin North Am 2005;25:131–148). However, asthma may also contribute to reflux because asthma attacks may increase the gastroesophageal pressure gradient, thereby facilitating the occurrence of reflux. Zerbib et al experimentally induced bronchial obstruction by administering methacholine to a group of healthy volunteers and asthmatics (Am J Respir Crit Care Med 2002;166:1206–1211). They found that the rate of transient lower esophageal sphincter relaxation and reflux episodes increased in the asthmatics but not in the control group of patients. Thus, it is possible that a vicious cycle exists whereby reflux triggers asthma and asthma triggers reflux.

The 2007 National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma recommends that medical management of GERD be instituted for patients who have asthma and complain of frequent heartburn or pyrosis, particularly those who have frequent episodes of nocturnal asthma (available: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln). Furthermore, for patients who have poorly controlled asthma, particularly with a nocturnal component, investigation for GERD may be warranted even in the absence of suggestive symptoms. The goal of both of these recommendations is to improve asthma control and lessen requirements for asthma medications. Thus, it comes as no surprise that a number of studies have examined the impact of antireflux therapy in the treatment of asthma. The results are decidedly mixed. A recent Cochrane review examined all randomized, controlled clinical trials of the effect of GERD treatment on asthma in individuals with either GERD symptoms or evidence of GERD on 24-hour pH monitoring (Cochrane Database Syst Rev 2009;2:CD001290). Twelve studies were identified, including 6 with proton pump inhibitors (PPIs), 5 with histamine H₂-receptor antagonists, and 1 with surgery. GERD therapy did not consistently improve lung function, asthma symptoms, nocturnal asthma, or use of asthma medications. Nevertheless, this systematic review concluded that subgroups of patients may benefit from GERD therapy; however, identification of these subgroups is difficult at present. Important methodologic problems identified in these studies included the wide variation of treatment measures examined, differing duration and dosages of therapy and, importantly, the wide variety of outcome measures used. Furthermore, it was unclear from these studies if reflux was adequately controlled by the interventions used. The issue of adequacy of acid control in asthmatics was highlighted by Harding et al in an open-label study of omeprazole in 30 adults with asthma and GERD symptoms in conjunction with abnormal 24-hour pH monitoring. Eight patients (27%) required more than the standard 20 mg daily of omeprazole to control esophageal acid exposure.

Given the problems with medical therapy of GERD in asthmatics, is there any role for surgery? Case series suggest that antireflux surgery can result in a decrease in asthma symptoms (Am J Gastroenterol 1987;82:119–126; Am Surg 2006;72:207–212). A clinical trial by Sontag et al reported on 16 asthmatic patients who underwent antireflux surgery. They found that 1 patient was completely cured of asthma, 6 patients were markedly improved, and 5 were improved (Am J Gastroenterol 2003;98:987–999). Larrain et al compared antireflux therapy with cimetidine and placebo in 90 asthmatics with reflux disease and found comparable improvements in asthma parameters in both the cimetidine and surgical groups, which were superior to placebo (Chest 1991;99:1330–1335).

Taken together, all these data suggest that antireflux therapy is not a panacea in asthmatics as a whole. However, it is clear that a difficult to define a priori subset of asthmatics will improve with antireflux therapy. The work by the American Lung Association Asthma Clinical Research Centers described is another chapter in this area. The group examined the effect of aggressive acid suppression therapy in asthmatics with inadequate control of symptoms despite the use of inhaled steroids and minimal, if any, symptoms of GERD. Two key findings emerged. First, in this large well characterized cohort, approximately 40% had abnormal acid exposure on pH testing. Second, prolonged (24 weeks) aggressive acid suppression was not superior to placebo for any primary or secondary outcome measure regardless of the presence or absence of pathologic acid exposure. Although well executed, this study does have some limitations. First, we do not have the actual data on acid exposure on these patients. Despite the limitations of transnasal pH testing, there is a gradation of abnormal acid exposure. If acid exposure was only minimally elevated in these patients, the lack of efficacy of PPIs should not be surprising at all. This study did not confirm the elimination of pathologic reflux by a second pH test. Furthermore, it did not determine whether nonacid reflux, as measured by impedance pH technology, was a contributing factor in these patients. In fact, the use of impedance pH testing is probably the last frontier for sorting out the relationship between reflux and asthma.

What is one to do in the asthmatic patient with a possibility of GERD in 2009? It is clear that many asthmatics have classic GERD symptoms and these should be treated with aggressive medical therapy as they would be in any patient with GERD alone. A subset of asthmatics will have objective detection of GERD without typical symptoms. The work by the American Lung Association Asthma Clinical Research Centers suggests that twice daily PPI therapy will not be helpful in these patients. However, given the implications of difficult to control asthma and the simplicity and rapidly decreasing cost of PPI therapy along with a favorable adverse event profile, an aggressive course of bid PPI therapy for a period of time, perhaps 3–6 months, may still be reasonable until we can accurately identify subgroups of patients who may respond. However, any such treatment should not be continued indefinitely. Surgery should only be considered in asthmatics with well-defined reflux disease, preferably with volume regurgitation or a sizable hiatal hernia if done by a skilled, high-volume surgeon. Surgery should not be the treatment of last resort for difficult to control asthma given the well-recognized morbidity and even mortality of the operation.