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Review Article |

The Efficacy of Proton Pump Inhibitors for the Treatment of Asthma in Adults:  A Meta-analysis FREE

Walter W. Chan, MD, MPH; Eric Chiou, MD; Keith L. Obstein, MD, MPH; April S. Tignor, MD, MPH; Tom L. Whitlock, MD, MPH
[+] Author Affiliations

Author Affiliations: Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (Drs Chan, Obstein, Tignor, and Whitlock), and Center for Motility and Functional Gastrointestinal Disorders, Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital Boston, Harvard Medical School (Dr Chiou), Boston, Massachusetts.


Arch Intern Med. 2011;171(7):620-629. doi:10.1001/archinternmed.2011.116.
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Published online

Background  Gastroesophageal reflux disease occurs frequently among patients with asthma. Therapy with proton pump inhibitors (PPIs) to improve asthma control remains controversial. We sought to evaluate the efficacy of PPIs in treatment of asthma using objective and subjective outcome measures.

Methods  A literature search was undertaken using MEDLINE (1950-January 2010), PubMed (1950-January 2010), EMBASE (1980-January 2010), and Cochrane Central Register of Controlled Trials (through January 31, 2010). Randomized, placebo-controlled trials evaluating the efficacy of PPIs for treatment of asthma in adults were selected. The primary outcome of interest was morning peak expiratory flow (PEF) rate. Secondary outcomes included objective (evening PEF rate and forced expiratory volume in 1 second) and subjective (asthma symptoms score and Asthma Quality of Life Questionnaire score) measures. Influence of study characteristics on outcomes was examined by subgroup analyses and meta-regression.

Results  Eleven trials (2524 patients) met inclusion criteria. Overall, patients had a higher mean morning PEF rate after treatment with PPIs compared with placebo (mean difference, 8.68 L/min [95% confidence interval, 2.35-15.02]). No significant single large-study effect, temporal effect, or publication bias was seen. Subgroup analysis revealed a trend toward a larger improvement in morning PEF rate in studies enrolling only patients with gastroesophageal reflux disease (mean difference, 16.90 L/min [95% confidence interval, 0.85-32.95]). Analyses of secondary outcomes (asthma symptoms score, Asthma Quality of Life Questionnaire score, evening PEF rate, and forced expiratory volume in 1 second) showed no significant difference between PPIs and placebo.

Conclusions  Proton pump inhibitor therapy in adults with asthma results in a small, statistically significant improvement in morning PEF rate. The magnitude of this improvement, however, is unlikely to be of meaningful clinical significance. There is insufficient evidence to recommend empirical use of PPIs for routine treatment of asthma.

Figures in this Article

Asthma is a common disease, affecting approximately 7% of the population in the United States and 300 million people worldwide.1,2 It is defined as a chronic disorder of the airways characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation.1 Gastroesophageal reflux disease (GERD), the passage of gastric contents into the esophagus, is the most common digestive system disorder in the United States, affecting roughly one-third of the population.3 The association between asthma and GERD has been a topic of much investigation in recent decades. The 2 conditions often coexist, with GERD being reported in 40% to 80% of patients with asthma.46

Gastroesophageal reflux disease–associated respiratory symptoms include cough, dyspnea, and wheezing. Reflux is postulated to cause bronchoconstriction directly, through microaspiration into the airways, as well as indirectly, via vagally mediated effects of acid on the upper airway or esophagus.79 In addition, bronchial asthma may favor the development of reflux by several mechanisms, eg, changes in the pressure gradient between the thorax and the abdomen may cause displacement of the lower esophageal sphincter into the chest, asthma-induced pulmonary hyperinflation can exacerbate diaphragmatic dysfunction, and lower esophageal sphincter tone can be decreased by frequent use of bronchodilators.10,11 Because gastroesophageal reflux may act as a trigger for asthma, medical therapy has been a topic of much investigation.

The cornerstone of medical treatment for acid reflux is the proton pump inhibitor (PPI), which has proven efficacy in the treatment of GERD and esophagitis.12 Expert opinion guidelines13,14 on the management of GERD recommend empirical therapy for patients with typical esophageal symptoms, such as heartburn or regurgitation. In the absence of a concomitant esophageal syndrome, empirical therapy is more controversial. Several groups1520 have investigated the efficacy of different PPIs on asthma outcomes through randomized controlled trials (RCTs). Some studies17,2022 have indicated that symptoms, lung function, or both can be improved with treatment of acid reflux; others16,18,19,23 have not demonstrated measurable improvement with acid suppression. A Cochrane Library systematic review24 published in 2003 examined the effects of several antireflux treatments (medical and surgical) on asthma outcomes in children and adults. The most recent systematic review,25 published in 2009, studied whether treatment of GERD with PPIs improved asthma symptoms in children. Both studies were limited by small numbers of RCTs using PPIs with conflicting results and made no definitive recommendations regarding the use of PPIs for patients with asthma.

Since the Cochrane Library systematic review, to our knowledge no meta-analysis has been published examining the effects of PPI therapy in adults with asthma. Furthermore, several large RCTs1517,20,26 have been published in recent years. The objective of this meta-analysis was to evaluate the efficacy of PPI use on asthma control in adults with or without symptomatic GERD with respect to improvement in objective and subjective asthma outcome measures.

DATA SOURCES AND SEARCHES

A literature search was undertaken using MEDLINE (1950 to January 2010), EMBASE (1980 to January 2010), and the Cochrane Central Register of Controlled Trials for RCTs on the use of PPIs for asthma published through January 31, 2010. The following search terms were used as both keywords and medical subject heading terms as applicable: asthma, gastro-esophageal reflux, gastroesophageal reflux disease, gastro-oesophageal reflux, proton pump inhibitor, omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole. The titles, abstracts, and keywords of identified articles were evaluated for relevance, and the reference lists of these articles were reviewed for additional articles. No language restrictions were applied.

STUDY SELECTION

Two authors (E.C. and K.L.O.) independently reviewed the results of the search and selected all randomized placebo-controlled trials of any PPI used for treatment of asthma in adults (>18 years). For study inclusion, all patients needed to have an asthma diagnosis established by clinical history, physician's diagnosis, or evidence of variable expiratory airflow obstruction such as change in peak expiratory flow (PEF) rate or forced expiratory volume in 1 second (FEV1). Studies also needed to report at least 1 clinical asthma outcome measure (eg, PEF rate, FEV1, asthma symptoms score, or quality-of-life assessment). We considered 4 weeks of daily therapy as the minimum duration, based on previous GERD studies12,27 that demonstrated stable symptom improvement after 4 to 6 weeks of PPI therapy. We excluded studies if they were published only in abstract form, did not report posttreatment asthma outcome measures, did not demonstrate adequate randomization, or did not include a placebo or PPI monotherapy arm.

DATA EXTRACTION AND QUALITY ASSESSMENT

Two independent reviewers (W.W.C. and T.L.W.) extracted data and assessed the quality of the selected studies. Discrepancies between the reviewers were adjudicated by a third reviewer (A.S.T.). We extracted clinical data for each trial: setting, number of centers, country, PPI dosage and duration of treatment, definition of asthma used, severity of asthma at enrollment, primary and secondary asthma outcomes used to define improvement, definition of GERD used, type and total number of adverse events, method of randomization, method of allocation concealment, level of blinding, and duration of follow-up. Data were extracted as intention-to-treat analyses, in which all withdrawals are assumed to be treatment failures, whenever this was allowed by trial reporting. Formal methodologic quality was assessed using the Jadad system,28 with a maximum score of 5; RCTs with a Jadad score of less than 3 were excluded.

OUTCOME MEASURES

Our primary outcome measure was the mean difference in morning PEF rate after treatment between participants receiving PPIs vs placebo. Morning PEF rate is a commonly used objective indicator for airway obstruction. It is inexpensive, widely available, and often included in asthma clinical research. Studies29 have shown that PEF rate indices, especially the morning prebronchodilator PEF, correlate strongly with airway hyperresponsiveness. Secondary objective measures of lung function included evening PEF rate and FEV1. Secondary subjective measures of asthma outcome included the standardized Asthma Quality of Life Questionnaire (AQLQ[S]) score and asthma symptoms score (scale, 0-3).30 The overall quality-of-life score on AQLQ(S) is derived from calculating the mean across a 32-item questionnaire in which patients are asked to respond to each item on a 7-point Likert scale, with 1 indicating maximal impairment and 7 indicating no impairment.

DATA SYNTHESIS AND STATISTICAL ANALYSIS

For continuous outcomes, the weighted mean difference and 95% confidence interval (CI) were calculated. The primary metameter for this meta-analysis was the mean difference in morning PEF rate between the placebo and study groups at the end of the trial. Because of the anticipated variability in patient population and study design, we used the random-effects models, with significance accepted at P < .05. Pooled trial results were evaluated with the I2 statistic, with cut-off points of 25%, 50%, and 75% to quantify low, moderate, and high degrees of heterogeneity between studies.31 Potential sources for clinical heterogeneity among studies were specified a priori, including a planned subgroup analysis according to whether studies required a diagnosis of GERD for inclusion and meta-regression analyses based on weeks of PPI therapy and cumulative PPI dosage used to examine the effect of different lengths of treatment and drug dosage. One-study-removed analysis was performed on the pooled trial results to examine the effect of single large studies; a cumulative analysis was conducted to explore time trends by publication year. Finally, we assessed the possibility of publication bias with a funnel plot and the Duval and Tweedie32 trim and fill method. All analyses were conducted using meta-analysis software (Comprehensive Meta-Analysis, Version 2; Biostat, Englewood, New Jersey). The meta-analysis was carried out in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines.33

STUDY SELECTION

The search strategy yielded 777 articles, 25 of which were complete reports on RCTs published in English. The 752 excluded articles included duplicate citations, non–peer-reviewed abstracts, animal studies, case reports, observational studies, editorials, letters, reviews, meta-analyses, and practice guidelines. Of the 25 clinical trials identified, 11 RCTs1523,26,34 that investigated PPI use in patients with asthma were included. Fourteen studies were excluded because the sample included children or adolescents,3537 the patients did not have a diagnosis of asthma,38 the trials were not randomized or not placebo-controlled,3947 or the treatment included medications in addition to PPIs to treat GERD.48Figure 1 shows the flowchart for study inclusion.

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Figure 1.

Flow diagram depicting search and selection processes. CCRT indicates Cochrane Central Register of Controlled Trials; PPI, proton pump inhibitor.

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Eleven RCTs investigated the effects of treatment with PPI on asthma (2524 patients) (Table 1).1523,26,34,49 Seven studies used a parallel design and 4 were crossover trials.17,19,21,34 Asthma was diagnosed most often in accordance with American Thoracic Society guidelines50 and/or by pulmonary function testing indicating expiratory airflow obstruction with or without bronchodilator reversibility. One study22 included patients with exercise-triggered asthma that had been clinically diagnosed by a pulmonologist. A diagnosis of GERD was required for inclusion in 8 studies.15,1719,21,23,26,34 The criteria for GERD varied among studies and included history of symptoms, endoscopy-proved esophagitis, and/or 24-hour pH monitoring. Three studies16,20,22 did not require patients to have a diagnosis of GERD for inclusion. All 11 studies had a Jadad score of 5 and were of acceptable methodologic quality for inclusion in the meta-analysis.

Table Graphic Jump LocationTable 1. RCTs Included in Meta-analysis

Treatment protocols contained moderate variation. Included studies used omeprazole, lansoprazole, pantoprazole, esomeprazole, or rabeprazole, with an equivalent daily dosing range of 20 mg to 80 mg. Treatment duration ranged from 4 weeks to 26 weeks. Asthma outcomes were reported inconsistently among the studies and therefore not all studies were included in all analyses. Objective measures of lung function, such as evening PEF rate and FEV1, were reported in several studies. Subjective outcomes, such as asthma symptoms scores and AQLQ(S) scores, were not consistently reported (Table 2).

Table Graphic Jump LocationTable 2. Summary of Results of PPI Therapy on Asthma Outcomes
META-ANALYSIS

In the analysis of the primary end point, 8 of 9 included studies15,16,1921,23,26,34 showed improved morning PEF rate in the PPI arm, although the 95% CI of 6 of these studies15,16,19,20,26,34 crossed the neutral (zero) line. The overall meta-analysis demonstrated a small but statistically significant improvement (8.68 L/min; [95% CI, 2.35-15.02]; P = .007) in morning PEF rate in participants who received PPI therapy (Figure 2A). The I2 index was 30.09%, suggesting moderate heterogeneity.31 In the 1-study-removed analysis, the outcomes of pooled analysis remained the same, without significant deviation from the overall result when individual studies were removed, suggesting no significant effect from single large studies. Cumulative analysis showed consistent results, with the outcomes favoring a small benefit of PPI use as more studies were added. Publication bias was evaluated with a funnel plot, which demonstrated balanced study results without the need for study imputation. The Duval and Tweedie trim and fill analysis32 further supported the lack of publication bias, with no studies trimmed and no significant change in the point estimate (Figure 3, Figure 4, and Figure 5).

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Figure 2.

Meta-analysis of morning peak expiratory flow rate. A, The forest plot of the meta-analysis that includes all patients with asthma. B, Subgroup analysis of patients with asthma based on GERD diagnosis. CI indicates confidence interval; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.

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Figure 3.

One-study-removed analysis of morning peak expiratory flow rate for single large study effect. CI indicates confidence interval; PPI, proton pump inhibitor.

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Figure 4.

Cumulative analysis of morning peak expiratory flow rate for consistency of results. CI indicates confidence interval; PPI proton pump inhibitor.

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Figure 5.

Funnel plot of standard error by difference in means in morning peak expiratory flow rate outcome.

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A subgroup analysis was carried out based on studies that required GERD diagnosis for inclusion15,18,19,21,23,26,34 vs studies that did not16,20 (Figure 2B). Both subgroups showed small but statistically significant improvements in morning PEF rate with PPI therapy, although a larger benefit was seen in the subgroup of studies containing only patients with GERD (16.90 L/min; [95% CI, 0.85-32.95] vs 6.21 L/min [0.71-11.71]). The difference in morning PEF rate improvement between the 2 subgroups was statistically significant (P = .006), according to analysis of variance. Meta-regression analyses were carried out on the basis of treatment duration and cumulative PPI dosage. There was no evidence of any significant relationship between treatment length (β = −0.007; P = .35) or cumulative PPI dosage (β = −0.001; P = .05) and morning PEF rate outcome (Figure 6 and Figure 7).

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Figure 6.

Meta-regression of treatment length (in weeks) by difference in means in morning peak expiratory flow rate outcome.

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Figure 7.

Meta-regression of cumulative PPI dosage (in milligrams) by difference in means in morning peak expiratory flow rate outcome. PPI indicates proton pump inhibitor.

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Six studies included in the analysis1921,23,26,34 reported data on evening PEF rate, with 5 showing a mean difference favoring PPI use. One study26 displayed no treatment effect, with a mean difference in evening PEF rate of zero. The overall meta-analysis revealed a trend toward benefit with PPI therapy in patients with asthma (9.865 L/min [95% CI, −1.294 to 21.015]; P = .08) that did not reach statistical significance (Figure 8A). Mean change in FEV1 was reported in 6 studies15,16,18,20,21,26 as another objective asthma outcome after treatment (Figure 8B). Five of those studies showed no significant change in FEV1 level between the PPI and placebo groups, and 1 study15 demonstrated a small but statistically significant improvement. The outcome of the meta-analysis demonstrated no significant benefit of PPIs on FEV1 (0.056 L [95% CI, −0.023 to 0.134]; P = .17).

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Figure 8.

Meta-analysis of secondary outcomes, including (A) evening PEF rate, (B) FEV1, (C) asthma symptoms score, and (D) AQLQ(S). AQLQ(S) indicates standardized Asthma Quality of Life Questionnaire; CI, confidence interval; FEV1, forced expiratory volume in 1 second; PEF, peak expiratory flow; PPI, proton pump inhibitor.

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Subjective treatment outcomes were evaluated using the asthma symptoms score and the AQLQ(S) score. The 3 studies18,19,26 that reported the asthma symptoms score found no significant difference in symptom improvements with PPIs vs placebo (Figure 8C). The overall meta-analysis similarly demonstrated no treatment benefits with PPI use (0.109 [95% CI, −0.042 to 0.026]; P = .16). Four studies15,16,20,21 used AQLQ(S) to measure quality of life before and after treatment (Figure 8D). Three studies15,20,21 showed a difference in means favoring PPI use, although one of them20 failed to achieve statistical significance. Meta-analysis of the 4 studies revealed no significant difference in mean AQLQ(S) after therapy between the 2 treatment arms (0.197 [95% CI, −0.078 to 0.472]; P = .16).

ADVERSE EVENTS

Data on the total number of adverse events were reported in only 4 RCTs (2154 patients).15,16,20,26 Overall, 34 of 1216 patients (2.8%) who received a PPI experienced serious adverse events compared with 31 of 938 patients (3.3%) who received a placebo. The most commonly reported adverse events were asthma exacerbation, nasopharyngitis, bronchitis, pneumonia, headache, nausea, and back pain. None of the studies reported a statistically significant difference in the rate of serious adverse events between the PPI and placebo arms. The overall relative risk of experiencing serious adverse events with PPIs compared with placebo was 0.85 (95% CI, 0.52-1.37).

For our primary outcome of interest, morning PEF rate, we evaluated 9 RCTs (2167 patients) and found a small, statistically significant improvement in patients with asthma treated with PPI vs placebo. Stratification of studies based on whether GERD was an inclusion criterion demonstrated an incremental benefit for patients diagnosed as having GERD. Although statistically significant, physiologic benefits of PPI therapy for asthma were noted, these improvements were small and likely represent minimal clinical benefit. Furthermore, PPI therapy appeared to have little effect on evening PEF rate, FEV1, asthma symptoms, or quality of life.

To our knowledge, the present study is the largest meta-analysis to date exploring the relationship between PPI therapy and asthma, an area that continues to remain controversial. The largest previous analysis on PPIs in asthma was published in 2003 by the Cochrane Collaboration.24 The Cochrane Collaboration study also found no overall improvement in asthma outcomes after treatment with PPIs, but it was limited by the low number of studies and small sample sizes, as only 3 studies involving PPIs could be analyzed for our primary outcome, morning PEF rate. With several large, multicenter RCTs published in recent years, the present meta-analysis is able to provide a 20-fold greater number of patients for measurement of this outcome. The larger sample of studies also allowed us to conduct a more robust analysis of secondary outcomes, evaluation of possible sources of heterogeneity, and assessment for publication bias.

Given the large patient population analyzed in this study, we believe that it contributes to scientific knowledge and clinical care of patients with asthma. Although our analysis did not find any statistically significant difference in the rate of serious adverse events between patients receiving PPIs and those receiving placebo, chronic acid suppression has become increasingly linked to complications such as pneumonia, bone loss, enteric infections, and bacterial overgrowth.5154 Within this context, establishing clear benefits of chronic PPI use on objective asthma outcomes has gained considerable importance. The relatively small improvements in morning PEF rate after treatment with PPIs demonstrated by our analysis should be weighed against the lack of improvement among other objective and subjective asthma outcomes as well as the risk of complications associated with chronic acid suppression. Furthermore, other literature suggests that greater improvements in PEF rate are necessary to affect clinical outcomes. Santanello et al55 demonstrated the average minimal patient perceivable improvement for PEF rate to be 18.79 L/min (95% CI, 0.7-36.9). Randomized controlled trials5659 involving inhaled corticosteroids, bronchodilators, and leukotriene inhibitors generally demonstrate PEF rate improvements in the range of 25 to 40 L/min. Our results fall below the range of minimal patient perceivable improvement for PEF rate as well as improvements seen with other medical therapies, suggesting minimal clinical benefit for routine asthma care.

Subgroup analysis from our study demonstrated an incremental improvement in PEF rate (16.9 L/min) in the subpopulation of patients with asthma and GERD. This improvement was also small; however, it approached the minimal patient perceivable improvement and fell within the range of PEF rate (15-20 L/min) traditionally used as target and deemed effective in clinical trials for asthma therapies.60 Although the clinical significance of this added benefit remains unclear, it does raise the possibility of a physiological mechanism between GERD and asthma. In addition, it suggests that a subpopulation of patients with asthma and GERD may receive clinically significant benefit from PPI therapy. Within the limitations of this meta-analysis, however, we were not able to identify the specific clinical features of this subpopulation.

The association between asthma and GERD has been well established in clinical studies, and several causal relationships have been proposed, including microaspiration, vagal reflex, and airway hyperresponsiveness.61,62 There are some possible explanations for the small improvement with PPIs observed in our meta-analysis. First, the primary mechanism of action of PPI therapy is acid suppression. Proton pump inhibitors may have less benefit if nonacidic reflux is a contributor to asthma severity and symptoms. Suppression of acid secretion does not protect against reflux and aspiration of the other components of gastric contents. In studies63,64 of lung transplant recipients with GERD, higher levels of both pepsin and bile acids were found in the bronchoalveolar lavage fluid obtained from patients with signs of graft failure compared with those without such signs, suggesting that acidic secretions from the stomach may be only one of many irritants aspirated during reflux. Second, it is possible that PPI therapy is beneficial only in certain subpopulations of patients with asthma, particularly those with pathologic vs physiologic acid reflux. Our study suggests that routine use of PPIs in most patients with asthma is unlikely to result in significant clinical benefit. Future investigations should focus on the effect of minimizing reflux and the optimal identification of subgroups of patients with asthma and GERD who may benefit the most from PPI therapy. In a study conducted by Harding et al,65 most patients with asthma and no reflux symptoms (62%) had abnormal findings during 24-hour esophageal pH monitoring. Furthermore, participants with asymptomatic GERD had higher amounts of proximal esophageal acid exposure compared with those with symptomatic GERD. Therefore, the role of tests such as manometry, intraesophageal impedance, and proximal pH monitoring in the care of patients with asthma should be further explored.

There are several limitations to our study. Of 11 RCTs, 2 reported the primary outcome of interest in a form that could not be extracted and combined. However, we do not believe that these excluded trials would have significantly affected our conclusions. The 1999 study by Kiljander et al,17 which reported medians and quartiles, was relatively small. Similarly, the study by Peterson et al,22 in which PEF rate was not measured, was small, with 31 participants randomized to 3 arms. Another problem was that significantly fewer studies could be combined to evaluate some of our secondary outcome measures. This led to decreased power for these outcomes; however, results between studies have been generally consistent.

Heterogeneity among studies could also be a limitation. Asthma diagnoses were based on a range of methods from clinical guidelines to spirometry. Asthma severity in the various studies ranged from typical to treatment refractory. Similarly, GERD diagnoses were based on varied criteria ranging from clinical symptoms to endoscopy to pH probe results. In 2 of the 9 RCTs, GERD was not a prerequisite for inclusion. Finally, the duration of PPI therapy varied. Our analysis demonstrated only moderate statistical heterogeneity across studies (I2 = 30.09%). In the studies that did not specify GERD as an inclusion criterion, postenrollment testing revealed a GERD prevalence of 33% to 75%, which is consistent with observational data.4,6669 We evaluated the role of GERD as an inclusion criterion by dichotomizing the studies into those requiring GERD for enrollment vs those that did not and noted a modest improvement with PPI therapy in the studies requiring a GERD diagnosis. This suggests a small, but measurable benefit for patients with asthma and GERD. Finally, our meta-regression did not demonstrate any relationship between the duration of PPI therapy or cumulative PPI dosage and asthma outcomes.

Our results show that the empirical use of PPI therapy for adults with asthma results in a small, statistically significant improvement in morning PEF rate. However, these small benefits are unlikely to be clinically significant. The increase in morning PEF rate was greater among participants enrolled in studies that had GERD as an inclusion criterion. Analyses of secondary outcomes (other signs and symptoms of asthma and quality of life) showed no significant difference between PPIs and placebo. There is insufficient evidence to support the routine use of PPIs in the treatment of asthma. Further studies should focus on clarifying the pathologic roles of symptomatic and silent GERD in patients with concurrent asthma, exploring the clinical utility of physiological studies such as esophageal impedance and pH monitoring, and identifying patients who may receive benefits from PPI therapy.

Correspondence: Walter W. Chan, MD, MPH, Division of Gastroenterology, Brigham and Women's Hospital, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (wwchan@partners.org).

Accepted for Publication: September 29, 2010.

Author Contributions:Study concept and design: Chan, Chiou, Obstein, Tignor, and Whitlock. Acquisition of data: Chan, Chiou, Obstein, Tignor, and Whitlock. Analysis and interpretation of data: Chan, Chiou, Obstein, Tignor, and Whitlock. Drafting of the manuscript: Chan, Chiou, Obstein, Tignor, and Whitlock. Critical revision of the manuscript for important intellectual content: Chan, Chiou, Obstein, Tignor, and Whitlock. Statistical analysis: Chan, Chiou, Obstein, Tignor, and Whitlock. Administrative, technical, and material support: Chan. Study supervision: Chan.

Financial Disclosure: None reported.

Additional Contributions: Michael Stoto, PhD, Adjunct Professor of Biostatistics (Harvard School of Public Health) and Professor of Health Services Administration and Population Health (Georgetown University School of Nursing & Health Studies) provided support and guidance in the design and statistical analysis of this study. He did not receive compensation for his assistance.

This article was corrected for typographical errors in the "Comment" section on April 11, 2011.

Fanta  CH Asthma. N Engl J Med 2009;360 (10) 1002- 1014
PubMed
National Asthma Education and Prevention Program, Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma—Summary Report 2007. J Allergy Clin Immunol 2007;120 (5) ((suppl)) S94- S138
PubMed
Camilleri  MDubois  DCoulie  B  et al.  Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol 2005;3 (6) 543- 552
PubMed
Sontag  SJO’Connell  SKhandelwal  S  et al.  Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990;99 (3) 613- 620
PubMed
Allen  CJNewhouse  MT Gastroesophageal reflux and chronic respiratory disease. Am Rev Respir Dis 1984;129 (4) 645- 647
PubMed
Ducoloné  AVandevenne  AJouin  H  et al.  Gastroesophageal reflux in patients with asthma and chronic bronchitis. Am Rev Respir Dis 1987;135 (2) 327- 332
PubMed
Richter  JE Asthma and gastroesophageal reflux disease: the truth is difficult to define. Chest 1999;116 (5) 1150- 1152
PubMed
Kiljander  TOLaitinen  JO The prevalence of gastroesophageal reflux disease in adult asthmatics. Chest 2004;126 (5) 1490- 1494
PubMed
Wu  DNTanifuji  YKobayashi  H  et al.  Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest 2000;118 (6) 1553- 1556
PubMed
Harding  SMSchan  CAGuzzo  MRAlexander  RWBradley  LARichter  JE Gastroesophageal reflux–induced bronchoconstriction: is microaspiration a factor? Chest 1995;108 (5) 1220- 1227
PubMed
Zerbib  FGuisset  OLamouliatte  HQuinton  AGalmiche  JPTunon-De-Lara  JM Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med 2002;166 (9) 1206- 1211
PubMed
Khan  MSantana  JDonnellan  CPreston  CMoayyedi  P Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007; (2) CD003244
PubMed
DeVault  KRCastell  DOAmerican College of Gastroenterology, Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100 (1) 190- 200
PubMed
Kahrilas  PJShaheen  NJVaezi  MF  et al. American Gastroenterological Association, American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135 (4) 1383- 1391, 1391.e1-5
PubMed10.1053/j.gastro.2008.08.045
Kiljander  TOJunghard  OBeckman  OLind  T Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2010;181 (10) 1042- 1048
PubMed
Mastronarde  JGAnthonisen  NRCastro  M  et al. American Lung Association Asthma Clinical Research Centers, Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360 (15) 1487- 1499
PubMed
Kiljander  TOSalomaa  ERHietanen  EKTerho  EO Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999;116 (5) 1257- 1264
PubMed
Boeree  MJPeters  FTPostma  DSKleibeuker  JH No effects of high-dose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux. Eur Respir J 1998;11 (5) 1070- 1074
PubMed
Ford  GAOliver  PSPrior  JSButland  RJWilkinson  SP Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastro-oesophageal reflux: a placebo-controlled cross-over study. Postgrad Med J 1994;70 (823) 350- 354
PubMed
Kiljander  TOHarding  SMField  SK  et al.  Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173 (10) 1091- 1097
PubMed
Levin  TRSperling  RMMcQuaid  KR Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998;93 (7) 1060- 1063
PubMed
Peterson  KASamuelson  WMRyujin  DT  et al.  The role of gastroesophageal reflux in exercise-triggered asthma: a randomized controlled trial. Dig Dis Sci 2009;54 (3) 564- 571
PubMed
dos Santos  LHRibeiro  IOSánchez  PGHetzel  JLFelicetti  JCCardoso  PF Evaluation of pantoprazol treatment response of patients with asthma and gastroesophageal reflux: a randomized prospective double-blind placebo-controlled study. J Bras Pneumol 2007;33 (2) 119- 127
PubMed
Gibson  PGHenry  RLCoughlan  JL Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev 2003; (2) CD001496
PubMed
Sopo  SMRadzik  DCalvani  M Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? a systematic review. J Investig Allergol Clin Immunol 2009;19 (1) 1- 5
PubMed
Littner  MRLeung  FWBallard  ED  IIHuang  BSamra  NKLansoprazole Asthma Study Group, Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005;128 (3) 1128- 1135
PubMed
Salas  MWard  ACaro  J Are proton pump inhibitors the first choice for acute treatment of gastric ulcers? a meta analysis of randomized clinical trials. BMC Gastroenterol 2002;217
PubMed
Moher  DJadad  ARNichol  GPenman  MTugwell  PWalsh  S Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials 1995;16 (1) 62- 73
PubMed
Reddel  HKSalome  CMPeat  JKWoolcock  AJ Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995;151 (5) 1320- 1325
PubMed
Juniper  EFBuist  ASCox  FMFerrie  PJKing  DR Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115 (5) 1265- 1270
PubMed
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed
Duval  STweedie  R Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56 (2) 455- 463
PubMed
Stroup  DFBerlin  JAMorton  SC  et al. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group, Meta-analysis of Observational Studies in Epidemiology: a proposal for reporting. JAMA 2000;283 (15) 2008- 2012
PubMed
Teichtahl  HKronborg  IJYeomans  NDRobinson  P Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma. Aust N Z J Med 1996;26 (5) 671- 676
PubMed
Størdal  KJohannesdottir  GBBentsen  BS  et al.  Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease. Arch Dis Child 2005;90 (9) 956- 960
PubMed
Khorasani  ENFallahi  GHMansouri  FRezaei  N The effect of omeprazole on asthmatic adolescents with gastroesophageal reflux disease. Allergy Asthma Proc 2008;29 (5) 517- 520
PubMed
Khoshoo  VHaydel  R  Jr Effect of antireflux treatment on asthma exacerbations in nonatopic children. J Pediatr Gastroenterol Nutr 2007;44 (3) 331- 335
PubMed
Ours  TMKavuru  MSSchilz  RJRichter  JE A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999;94 (11) 3131- 3138
PubMed
Meier  JHMcNally  PRPunja  M  et al.  Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? a double-blind, placebo-controlled crossover study. Dig Dis Sci 1994;39 (10) 2127- 2133
PubMed
Bucknall  CStanton  AMiller  GRajoriya  NBabu  SMackenzie  J The impact of normalization of esophageal acid profile by incremental protein pump inhibitors dosing in difficult asthma patients with proven gastro-esophageal acid reflux. J Asthma 2009;46 (5) 506- 511
PubMed
Shimizu  YDobashi  KKobayashi  S  et al.  A proton pump inhibitor, lansoprazole, ameliorates asthma symptoms in asthmatic patients with gastroesophageal reflux disease. Tohoku J Exp Med 2006;209 (3) 181- 189
PubMed
Calabrese  CFabbri  AAreni  AScialpi  CZahlane  DDi Febo  G Asthma and gastroesophageal reflux disease: effect of long-term pantoprazole therapy. World J Gastroenterol 2005;11 (48) 7657- 7660
PubMed
Jiang  SPLiang  RYZeng  ZYLiu  QLLiang  YKLi  JG Effects of antireflux treatment on bronchial hyper-responsiveness and lung function in asthmatic patients with gastroesophageal reflux disease. World J Gastroenterol 2003;9 (5) 1123- 1125
PubMed
Kiljander  TSalomaa  ERHietanen  EHelenius  HLiippo  KTerho  EO Asthma and gastro-oesophageal reflux: can the response to anti-reflux therapy be predicted? Respir Med 2001;95 (5) 387- 392
PubMed
Tsugeno  HMizuno  MFujiki  S  et al.  A proton-pump inhibitor, rabeprazole, improves ventilatory function in patients with asthma associated with gastroesophageal reflux. Scand J Gastroenterol 2003;38 (5) 456- 461
PubMed
Harding  SMRichter  JEGuzzo  MRSchan  CAAlexander  RWBradley  LA Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996;100 (4) 395- 405
PubMed
Wong  CHChua  CJLiam  CKGoh  KL Gastro-oesophageal reflux disease in “difficult-to-control” asthma: prevalence and response to treatment with acid suppressive therapy. Aliment Pharmacol Ther 2006;23 (9) 1321- 1327
PubMed
Sharma  BSharma  MDaga  MKSachdev  GKBondi  E Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007;13 (11) 1706- 1710
PubMed
Juniper  EFBousquet  JAbetz  LBateman  ED Identifying “well-controlled” and “not well-controlled” asthma using the Asthma Control Questionnaire. Respir Med 2006;100616- 621
American Thoracic Society, Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 1962;85762- 768
Eurich  DTSadowski  CASimpson  SHMarrie  TJMajumdar  SR Recurrent community-acquired pneumonia in patients starting acid-suppressing drugs. Am J Med 2010;123 (1) 47- 53
PubMed
Targownik  LELix  LMMetge  CJPrior  HJLeung  SLeslie  WD Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179 (4) 319- 326
PubMed
Leonard  JMarshall  JKMoayyedi  P Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102 (9) 2047- 2057
PubMed
Lombardo  LFoti  MRuggia  OChiecchio  A Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010;8 (6) 504- 508
PubMed
Santanello  NCZhang  JSeidenberg  BReiss  TFBarber  BL What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999;14 (1) 23- 27
PubMed
Bateman  EDBritton  MCarrillo  JAlmeida  JWixon  C Salmeterol/fluticasone combination inhaler: a new, effective and well tolerated treatment for asthma. Clin Drug Investig 1998;16 (3) 193- 201
PubMed
Chapman  KRRingdal  NBacker  VPalmqvist  MSaarelainen  SBriggs  M Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Can Respir J 1999;6 (1) 45- 51
PubMed
Aubier  MPieters  WRSchlösser  NJSteinmetz  KO Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999;93 (12) 876- 884
PubMed
Perng  DWHuang  HYLee  YCPerng  RP Leukotriene modifier vs inhaled corticosteroid in mild-to-moderate asthma: clinical and anti-inflammatory effects. Chest 2004;125 (5) 1693- 1699
PubMed
Reddel  HKTaylor  DRBateman  ED  et al. American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations, An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180 (1) 59- 99
PubMed
Mansfield  LEStein  MR Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978;41 (4) 224- 226
PubMed
Field  SK Gastroesophageal reflux and asthma: can the paradox be explained? Can Respir J 2000;7 (2) 167- 176
PubMed
Stovold  RForrest  IACorris  PA  et al.  Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 2007;175 (12) 1298- 1303
PubMed
D’Ovidio  FMura  MTsang  M  et al.  Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005;129 (5) 1144- 1152
PubMed
Harding  SMGuzzo  MRRichter  JE The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000;162 (1) 34- 39
PubMed
Hogan  WJ Spectrum of supraesophageal complications of gastroesophageal reflux disease. Am J Med 1997;103 (5) ((suppl 1)) 77S- 83S
PubMed
Harding  SM Gastroesophageal reflux, asthma, and mechanisms of interaction. Am J Med 2001;111 (8) ((suppl 1)) 8S- 12S
PubMed
Field  SKUnderwood  MBrant  RCowie  RL Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996;109 (2) 316- 322
PubMed
Simpson  WG Gastroesophageal reflux disease and asthma: diagnosis and management. Arch Intern Med 1995;155 (8) 798- 803
PubMed

Figures

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Figure 1.

Flow diagram depicting search and selection processes. CCRT indicates Cochrane Central Register of Controlled Trials; PPI, proton pump inhibitor.

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Figure 2.

Meta-analysis of morning peak expiratory flow rate. A, The forest plot of the meta-analysis that includes all patients with asthma. B, Subgroup analysis of patients with asthma based on GERD diagnosis. CI indicates confidence interval; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.

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Figure 3.

One-study-removed analysis of morning peak expiratory flow rate for single large study effect. CI indicates confidence interval; PPI, proton pump inhibitor.

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Figure 4.

Cumulative analysis of morning peak expiratory flow rate for consistency of results. CI indicates confidence interval; PPI proton pump inhibitor.

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Figure 5.

Funnel plot of standard error by difference in means in morning peak expiratory flow rate outcome.

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Figure 6.

Meta-regression of treatment length (in weeks) by difference in means in morning peak expiratory flow rate outcome.

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Figure 7.

Meta-regression of cumulative PPI dosage (in milligrams) by difference in means in morning peak expiratory flow rate outcome. PPI indicates proton pump inhibitor.

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Place holder to copy figure label and caption
Figure 8.

Meta-analysis of secondary outcomes, including (A) evening PEF rate, (B) FEV1, (C) asthma symptoms score, and (D) AQLQ(S). AQLQ(S) indicates standardized Asthma Quality of Life Questionnaire; CI, confidence interval; FEV1, forced expiratory volume in 1 second; PEF, peak expiratory flow; PPI, proton pump inhibitor.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. RCTs Included in Meta-analysis
Table Graphic Jump LocationTable 2. Summary of Results of PPI Therapy on Asthma Outcomes

References

Fanta  CH Asthma. N Engl J Med 2009;360 (10) 1002- 1014
PubMed
National Asthma Education and Prevention Program, Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma—Summary Report 2007. J Allergy Clin Immunol 2007;120 (5) ((suppl)) S94- S138
PubMed
Camilleri  MDubois  DCoulie  B  et al.  Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol 2005;3 (6) 543- 552
PubMed
Sontag  SJO’Connell  SKhandelwal  S  et al.  Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990;99 (3) 613- 620
PubMed
Allen  CJNewhouse  MT Gastroesophageal reflux and chronic respiratory disease. Am Rev Respir Dis 1984;129 (4) 645- 647
PubMed
Ducoloné  AVandevenne  AJouin  H  et al.  Gastroesophageal reflux in patients with asthma and chronic bronchitis. Am Rev Respir Dis 1987;135 (2) 327- 332
PubMed
Richter  JE Asthma and gastroesophageal reflux disease: the truth is difficult to define. Chest 1999;116 (5) 1150- 1152
PubMed
Kiljander  TOLaitinen  JO The prevalence of gastroesophageal reflux disease in adult asthmatics. Chest 2004;126 (5) 1490- 1494
PubMed
Wu  DNTanifuji  YKobayashi  H  et al.  Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest 2000;118 (6) 1553- 1556
PubMed
Harding  SMSchan  CAGuzzo  MRAlexander  RWBradley  LARichter  JE Gastroesophageal reflux–induced bronchoconstriction: is microaspiration a factor? Chest 1995;108 (5) 1220- 1227
PubMed
Zerbib  FGuisset  OLamouliatte  HQuinton  AGalmiche  JPTunon-De-Lara  JM Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med 2002;166 (9) 1206- 1211
PubMed
Khan  MSantana  JDonnellan  CPreston  CMoayyedi  P Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007; (2) CD003244
PubMed
DeVault  KRCastell  DOAmerican College of Gastroenterology, Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100 (1) 190- 200
PubMed
Kahrilas  PJShaheen  NJVaezi  MF  et al. American Gastroenterological Association, American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135 (4) 1383- 1391, 1391.e1-5
PubMed10.1053/j.gastro.2008.08.045
Kiljander  TOJunghard  OBeckman  OLind  T Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2010;181 (10) 1042- 1048
PubMed
Mastronarde  JGAnthonisen  NRCastro  M  et al. American Lung Association Asthma Clinical Research Centers, Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360 (15) 1487- 1499
PubMed
Kiljander  TOSalomaa  ERHietanen  EKTerho  EO Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999;116 (5) 1257- 1264
PubMed
Boeree  MJPeters  FTPostma  DSKleibeuker  JH No effects of high-dose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux. Eur Respir J 1998;11 (5) 1070- 1074
PubMed
Ford  GAOliver  PSPrior  JSButland  RJWilkinson  SP Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastro-oesophageal reflux: a placebo-controlled cross-over study. Postgrad Med J 1994;70 (823) 350- 354
PubMed
Kiljander  TOHarding  SMField  SK  et al.  Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173 (10) 1091- 1097
PubMed
Levin  TRSperling  RMMcQuaid  KR Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998;93 (7) 1060- 1063
PubMed
Peterson  KASamuelson  WMRyujin  DT  et al.  The role of gastroesophageal reflux in exercise-triggered asthma: a randomized controlled trial. Dig Dis Sci 2009;54 (3) 564- 571
PubMed
dos Santos  LHRibeiro  IOSánchez  PGHetzel  JLFelicetti  JCCardoso  PF Evaluation of pantoprazol treatment response of patients with asthma and gastroesophageal reflux: a randomized prospective double-blind placebo-controlled study. J Bras Pneumol 2007;33 (2) 119- 127
PubMed
Gibson  PGHenry  RLCoughlan  JL Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev 2003; (2) CD001496
PubMed
Sopo  SMRadzik  DCalvani  M Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? a systematic review. J Investig Allergol Clin Immunol 2009;19 (1) 1- 5
PubMed
Littner  MRLeung  FWBallard  ED  IIHuang  BSamra  NKLansoprazole Asthma Study Group, Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005;128 (3) 1128- 1135
PubMed
Salas  MWard  ACaro  J Are proton pump inhibitors the first choice for acute treatment of gastric ulcers? a meta analysis of randomized clinical trials. BMC Gastroenterol 2002;217
PubMed
Moher  DJadad  ARNichol  GPenman  MTugwell  PWalsh  S Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials 1995;16 (1) 62- 73
PubMed
Reddel  HKSalome  CMPeat  JKWoolcock  AJ Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995;151 (5) 1320- 1325
PubMed
Juniper  EFBuist  ASCox  FMFerrie  PJKing  DR Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115 (5) 1265- 1270
PubMed
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed
Duval  STweedie  R Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56 (2) 455- 463
PubMed
Stroup  DFBerlin  JAMorton  SC  et al. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group, Meta-analysis of Observational Studies in Epidemiology: a proposal for reporting. JAMA 2000;283 (15) 2008- 2012
PubMed
Teichtahl  HKronborg  IJYeomans  NDRobinson  P Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma. Aust N Z J Med 1996;26 (5) 671- 676
PubMed
Størdal  KJohannesdottir  GBBentsen  BS  et al.  Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease. Arch Dis Child 2005;90 (9) 956- 960
PubMed
Khorasani  ENFallahi  GHMansouri  FRezaei  N The effect of omeprazole on asthmatic adolescents with gastroesophageal reflux disease. Allergy Asthma Proc 2008;29 (5) 517- 520
PubMed
Khoshoo  VHaydel  R  Jr Effect of antireflux treatment on asthma exacerbations in nonatopic children. J Pediatr Gastroenterol Nutr 2007;44 (3) 331- 335
PubMed
Ours  TMKavuru  MSSchilz  RJRichter  JE A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999;94 (11) 3131- 3138
PubMed
Meier  JHMcNally  PRPunja  M  et al.  Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? a double-blind, placebo-controlled crossover study. Dig Dis Sci 1994;39 (10) 2127- 2133
PubMed
Bucknall  CStanton  AMiller  GRajoriya  NBabu  SMackenzie  J The impact of normalization of esophageal acid profile by incremental protein pump inhibitors dosing in difficult asthma patients with proven gastro-esophageal acid reflux. J Asthma 2009;46 (5) 506- 511
PubMed
Shimizu  YDobashi  KKobayashi  S  et al.  A proton pump inhibitor, lansoprazole, ameliorates asthma symptoms in asthmatic patients with gastroesophageal reflux disease. Tohoku J Exp Med 2006;209 (3) 181- 189
PubMed
Calabrese  CFabbri  AAreni  AScialpi  CZahlane  DDi Febo  G Asthma and gastroesophageal reflux disease: effect of long-term pantoprazole therapy. World J Gastroenterol 2005;11 (48) 7657- 7660
PubMed
Jiang  SPLiang  RYZeng  ZYLiu  QLLiang  YKLi  JG Effects of antireflux treatment on bronchial hyper-responsiveness and lung function in asthmatic patients with gastroesophageal reflux disease. World J Gastroenterol 2003;9 (5) 1123- 1125
PubMed
Kiljander  TSalomaa  ERHietanen  EHelenius  HLiippo  KTerho  EO Asthma and gastro-oesophageal reflux: can the response to anti-reflux therapy be predicted? Respir Med 2001;95 (5) 387- 392
PubMed
Tsugeno  HMizuno  MFujiki  S  et al.  A proton-pump inhibitor, rabeprazole, improves ventilatory function in patients with asthma associated with gastroesophageal reflux. Scand J Gastroenterol 2003;38 (5) 456- 461
PubMed
Harding  SMRichter  JEGuzzo  MRSchan  CAAlexander  RWBradley  LA Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996;100 (4) 395- 405
PubMed
Wong  CHChua  CJLiam  CKGoh  KL Gastro-oesophageal reflux disease in “difficult-to-control” asthma: prevalence and response to treatment with acid suppressive therapy. Aliment Pharmacol Ther 2006;23 (9) 1321- 1327
PubMed
Sharma  BSharma  MDaga  MKSachdev  GKBondi  E Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007;13 (11) 1706- 1710
PubMed
Juniper  EFBousquet  JAbetz  LBateman  ED Identifying “well-controlled” and “not well-controlled” asthma using the Asthma Control Questionnaire. Respir Med 2006;100616- 621
American Thoracic Society, Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 1962;85762- 768
Eurich  DTSadowski  CASimpson  SHMarrie  TJMajumdar  SR Recurrent community-acquired pneumonia in patients starting acid-suppressing drugs. Am J Med 2010;123 (1) 47- 53
PubMed
Targownik  LELix  LMMetge  CJPrior  HJLeung  SLeslie  WD Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179 (4) 319- 326
PubMed
Leonard  JMarshall  JKMoayyedi  P Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102 (9) 2047- 2057
PubMed
Lombardo  LFoti  MRuggia  OChiecchio  A Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010;8 (6) 504- 508
PubMed
Santanello  NCZhang  JSeidenberg  BReiss  TFBarber  BL What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999;14 (1) 23- 27
PubMed
Bateman  EDBritton  MCarrillo  JAlmeida  JWixon  C Salmeterol/fluticasone combination inhaler: a new, effective and well tolerated treatment for asthma. Clin Drug Investig 1998;16 (3) 193- 201
PubMed
Chapman  KRRingdal  NBacker  VPalmqvist  MSaarelainen  SBriggs  M Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Can Respir J 1999;6 (1) 45- 51
PubMed
Aubier  MPieters  WRSchlösser  NJSteinmetz  KO Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999;93 (12) 876- 884
PubMed
Perng  DWHuang  HYLee  YCPerng  RP Leukotriene modifier vs inhaled corticosteroid in mild-to-moderate asthma: clinical and anti-inflammatory effects. Chest 2004;125 (5) 1693- 1699
PubMed
Reddel  HKTaylor  DRBateman  ED  et al. American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations, An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180 (1) 59- 99
PubMed
Mansfield  LEStein  MR Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978;41 (4) 224- 226
PubMed
Field  SK Gastroesophageal reflux and asthma: can the paradox be explained? Can Respir J 2000;7 (2) 167- 176
PubMed
Stovold  RForrest  IACorris  PA  et al.  Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 2007;175 (12) 1298- 1303
PubMed
D’Ovidio  FMura  MTsang  M  et al.  Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005;129 (5) 1144- 1152
PubMed
Harding  SMGuzzo  MRRichter  JE The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000;162 (1) 34- 39
PubMed
Hogan  WJ Spectrum of supraesophageal complications of gastroesophageal reflux disease. Am J Med 1997;103 (5) ((suppl 1)) 77S- 83S
PubMed
Harding  SM Gastroesophageal reflux, asthma, and mechanisms of interaction. Am J Med 2001;111 (8) ((suppl 1)) 8S- 12S
PubMed
Field  SKUnderwood  MBrant  RCowie  RL Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996;109 (2) 316- 322
PubMed
Simpson  WG Gastroesophageal reflux disease and asthma: diagnosis and management. Arch Intern Med 1995;155 (8) 798- 803
PubMed

Correspondence

CME


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