Original Article
Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma
N Engl J Med 2009; 360:1487-1499April 9, 2009
- Abstract
Background
Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control.
Methods
In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries.
Results
Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17).
Conclusions
Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)
Media in This Article
Figure 1
Enrollment, Randomization, and Follow-up of Study Participants.Table 1
Baseline Characteristics of the Study Participants.Article Activity
- Article
Gastroesophageal reflux and asthma, both of which are common conditions, often coexist in the same patient. Persons with asthma are particularly prone to asymptomatic gastroesophageal reflux. Esophageal pH-monitoring studies have shown that 32 to 84% of persons with asthma have abnormal acid reflux,1-5 and about half of patients with asthma who have reflux have no symptoms.3,6-8 However, the role of gastroesophageal reflux in the development or persistence of asthma symptoms is not known. Symptoms of asthma — cough and chest discomfort — may overlap with those of gastroesophageal reflux, making it difficult to distinguish between the two conditions.9 Moreover, the causal relationship between asthma and gastroesophageal reflux is complex. Acid reflux causes bronchoconstriction through microaspiration into the airways, as well as through reflex-mediated effects of acid on the esophagus or upper airway.10-18– Conversely, asthma-related bronchoconstriction can induce acid reflux. Descent of the diaphragm with hyperinflation increases the pressure gradient between the abdomen and thorax and may cause the lower esophageal sphincter to herniate into the chest, where its barrier function is diminished.19,20, This process may be exacerbated by the accentuated negative inspiratory pleural pressure in acute asthma, which opposes the tone of the lower esophageal sphincter. Furthermore, beta-agonists and methylxanthine bronchodilators may decrease the tone of the lower esophageal sphincter, but it has been difficult to show that these agents actually worsen reflux. 21
Proton-pump inhibitors are effective in suppressing the production of gastric acid and reducing symptoms of gastroesophageal reflux, whether or not asthma is present.22,23 Previous trials have had conflicting results regarding the beneficial effects of treatment with proton-pump inhibitors in patients with asthma who have frequent symptoms of gastroesophageal reflux disease.23,24 Whether proton-pump inhibitors improve asthma control in patients with minimal or no symptoms of gastroesophageal reflux is unknown, and whether objective measurement of acid reflux can be used to tailor treatment with proton-pump inhibitors to individual patients has not been established.25,26 Current guidelines recommend that physicians consider evaluating patients who have poorly controlled asthma, especially those with nighttime symptoms, for gastroesophageal reflux disease, even in the absence of suggestive symptoms of the disease. If gastroesophageal reflux is present, treatment recommendations include the use of a proton-pump inhibitor.27 However, patients with asthma who are receiving treatment for gastroesophageal reflux incur substantially higher diagnostic and treatment costs than do patients with asthma of similar severity who are not receiving treatment for this diagnosis.28
We compared esomeprazole with placebo in patients with poorly controlled asthma. Our primary objective was to determine whether acid-suppression therapy would improve asthma symptoms. A secondary objective was to determine whether ambulatory esophageal pH monitoring would identify patients with minimal or no symptoms of gastroesophageal reflux who might have a response to treatment.
Methods
Participant Selection
We conducted a randomized, placebo-controlled, double-blind trial of esomeprazole (Nexium, AstraZeneca) in patients who had asthma that was inadequately controlled despite therapy with moderate or high doses of inhaled corticosteroids. Inclusion criteria were an age of 18 years or older; a diagnosis of asthma by a physician, with the diagnosis supported by either a positive methacholine challenge test or documentation of a 12% increase in the forced expiratory volume in 1 second (FEV1) after use of a bronchodilator; at least 8 weeks of stable use of an inhaled corticosteroid at a dose equivalent to 400 μg of fluticasone per day or more27; and poor asthma control as defined by either a score on the Juniper Asthma Control Questionnaire (JACQ) of 1.5 or higher29 (on a scale of 0 to 6, with lower scores indicating better control of symptoms and with 0.5 as the minimal clinically important difference between scores) or the occurrence of more than one acute episode of asthma requiring unscheduled medical care in the previous year. Participants were excluded if they had smoked cigarettes within the previous 6 months or had a history of 10 or more pack-years of smoking; had an FEV1 of less than 50% of their predicted value30; had undergone surgery for reflux or peptic ulcer; had clinical indications for acid-suppression treatment (i.e., two or more episodes per week of heartburn requiring antacids); had used antireflux medication within the previous month; or were taking drugs that could interact with proton-pump inhibitors, such as theophylline, iron supplements, warfarin, antifungal drugs, or digitalis. Participants were also excluded if they were pregnant, could not tolerate proton-pump inhibitors, or had any serious illness that would interfere with participation in the trial. The study was approved by the institutional review board at each participating center, and all participants provided written informed consent.
Study Design
The study was conducted at 19 clinical centers from October 2004 through early May 2008. Data were analyzed at the coordinating center at Johns Hopkins University. The study was designed as a two-group, parallel-design, randomized clinical trial to test the hypothesis that esomeprazole was superior to placebo in improving asthma control. Participants who met the eligibility criteria were enrolled in a 2- to 8-week run-in period during which time they completed baseline daily asthma diaries and underwent pH testing. Participants were randomly assigned in a 1:1 ratio to receive either 40 mg of esomeprazole twice daily or a similar-appearing placebo. Participants and study staff were unaware of the group assignments. The randomization schedule was stratified according to clinic site with the use of a permuted block design with concealed allocation. After randomization, participants returned to the clinic for assessments of outcome measures every 4 weeks for 24 weeks.
Outcome Measures
For the duration of the trial, participants maintained diaries to record morning peak expiratory flow, asthma symptoms, nocturnal awakening, and use of beta-agonists. The primary outcome measure was the rate of episodes of poor asthma control. Such episodes were defined by a decrease of 30% or more in the morning peak expiratory flow rate on 2 consecutive days, as compared with the patient's best rate during the run-in period; an urgent visit, defined as an unscheduled health care visit for asthma symptoms; or the need for a course of oral prednisone for treatment of asthma. Use of a beta-agonist was not included as a criterion in this definition because of the possibility that participants might use beta-agonists for treatment of symptoms related to gastroesophageal reflux. In a secondary analysis, we added to the above definition the use of beta-agonists for asthma symptoms (four or more inhalations in 1 day at a dose above the baseline dose).31 The outcome measure we used — episodes of poor asthma control — incorporates key measures that are clinically relevant and are responsive to therapy such as inhaled corticosteroids. Other asthma symptoms recorded in daily diaries were considered to be secondary outcomes.
Secondary outcomes recorded at each visit were the results of spirometry before and after inhalation of 180 μg of albuterol,32 the score on the JACQ,29 the score on the Asthma Symptom Utility Index,33 the score on the Mini Asthma Quality of Life Questionnaire (MiniAQLQ),34 and the score on the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).35 Methacholine airway reactivity, expressed as the inhaled methacholine concentration causing a 20% reduction in FEV1 (PC20), was measured at baseline and at 24 weeks in participants with an FEV1 that was 70% or more of their predicted value.36
The presence or absence of esophageal reflux was ascertained with the use of ambulatory pH monitoring.37 Studies were reviewed for technical quality at a central reading center. To be considered technically satisfactory, a study had to have a total recording time of 16 hours or more and include at least one meal and 2 hours of monitoring while the patient was lying down. Reflux was considered to be present if the pH was less than 4.0 for more than 5.8% of the total time, more than 8.2% of the time the patient was upright, or more than 3.5% of the time the patient was lying down.38 Symptoms of gastroesophageal reflux were assessed with the use of the Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS)–Distress Version, which measures both the number and the severity of symptoms.39
Study Oversight
The study was designed and supervised by the steering committee of the American Lung Association Asthma Clinical Research Centers, which approved the publication of the study. The data were collected at the clinical centers and were analyzed at the data coordinating center (see Appendix). The writing committee wrote the manuscript and takes full responsibility for the accuracy and completeness of the article. Esomeprazole and matching placebo were donated by AstraZeneca, but AstraZeneca had no role in the design or conduct of the study or in the analysis or interpretation of the data. The American Lung Association Asthma Clinical Research Centers are not bound by any confidentiality agreement with respect to the study results.
Statistical Analysis
We calculated that with a sample size of 400 participants, the study would have 77 to 97% power, with a two-sided type I error rate of 5% and 10% loss of data, to show a relative difference of 33% in the proportion of participants having one or more episodes of poor asthma control, assuming a rate of 40 to 60% in the control group. The primary outcome was the rate of episodes of poor asthma control; by basing the power calculation on the proportion of participants in each group who had one or more events, rather than on the event rate, we obtained a conservative estimate of power. All analyses were performed according to treatment assignment, and all available data were included in the evaluations, regardless of whether or not they discontinued the assigned treatment (modified intention-to-treat analysis). Negative binomial regression models were used to evaluate differences in the rate of episodes of poor asthma control and in the rates of the individual components.40 Linear regression techniques were used to evaluate the mean differences from baseline; robust variance estimates were calculated with generalized estimating equations.41 Analyses of treatment-effect modification for key covariates such as pH-monitoring results, age, sex, race or ethnic group, asthma severity, GSAS distress score, and presence or absence of obesity; self-reported gastroesophageal reflux disease, sinusitis, or rhinitis; use of long-acting beta-agonists; and history of exposure to cigarette smoke were performed by creating an interaction term and evaluating the term's significance in a model with the main effects (study drug and covariate). The reported results were not adjusted for baseline covariates unless there was evidence of an imbalance across the treatment groups at baseline. P values of less than 0.05 (two-sided) were considered to indicate statistical significance. P values were not adjusted for multiple comparisons.
Results
Characteristics of the Participants
A total of 412 patients were randomly assigned to one of the two groups in the study (Figure 1Figure 1
Enrollment, Randomization, and Follow-up of Study Participants.). Because of Hurricane Katrina, data from 10 patients in New Orleans were incomplete and were not included in the analysis. The majority of the patients were women, and most had lung function that was at the low end of the normal range and very poor asthma control, as evidenced by a mean JACQ score of 1.9.29 Approximately 15% of the participants reported that they had a history of gastroesophageal reflux, but the mean symptom scores were low. Gastroesophageal reflux, as assessed by ambulatory pH monitoring, was present in 41% of the patients in the placebo group and 40% of the patients in the esomeprazole group. The asthma characteristics were similar in the two study groups (Table 1Table 1Baseline Characteristics of the Study Participants.).When we defined an adherent participant as one who took both doses of the drug or placebo on at least 80% of the days during the study period, the rate of adherence in the placebo group was similar to the rate in the esomeprazole group, as assessed by diary cards (86% and 84%, respectively; P=0.53) and as assessed by pill counts (82% in each group, P=0.91). Ninety-four percent of the participants in the placebo group and 91% of the participants in the esomeprazole group took one or more doses of the study drug on at least 80% of the days (P=0.21). Esomeprazole was generally very well tolerated, but a few more participants in the esomeprazole group than in the placebo group discontinued treatment because of adverse effects (nine vs. three participants). Few serious adverse events were reported in either the esomeprazole group or the placebo group (11 and 17 events, respectively, P=0.25); three hospitalizations for asthma exacerbations were reported in the esomeprazole group and four in the placebo group. One patient in the esomeprazole group died after surgery for a bronchial carcinoid that was discovered during the study (Table 2Table 2
Serious Adverse Events.).Episodes of Poor Asthma Control
Overall, the participants had persistent, poorly controlled symptoms of asthma. Approximately 42% of the participants had an episode of poor asthma control according to the definition that did not include the use of beta-agonists as a criterion, and 61% had an episode according to the definition that included the increased use of beta-agonists. Over the course of the 24 weeks of follow-up, about 18% of the patients required an urgent care visit or a course of prednisone. The annualized rates of episodes of poor asthma control and of the individual components (a fall in the peak expiratory flow rate, an urgent care visit, a course of corticosteroids, and increased use of beta-agonists) did not differ significantly between the treatment and placebo groups. Night awakening due to asthma occurred on one or more occasions in about half of the participants, and the rate did not differ significantly between the two groups (Table 3Table 3
Episodes of Poor Asthma Control and Component Events.).Secondary Outcomes
Pulmonary function as measured by spirometry, bronchodilator response, peak expiratory flow rate, and airway reactivity did not change during the study and did not differ significantly between the two groups. Asthma symptoms, asthma control, and quality of life, as assessed by questionnaires, all improved slightly during the trial but did not differ significantly according to the group assignment. Gastroesophageal-reflux-symptom scores, which were, by design, low at baseline, showed small improvements during the study, but did not differ significantly according to the group assignment (Table 4Table 4
Change in Secondary Outcomes from Baseline to 24 Weeks.).Subgroup Analyses
We performed prespecified subgroup analyses to determine whether we could identify a subgroup that was likely to benefit from esomeprazole therapy. For all outcomes, there was no significant interaction between abnormal gastroesophageal reflux, as assessed by pH monitoring, and the group assignment, indicating that patients with documented gastroesophageal reflux did not have a response to treatment with proton-pump inhibitors that differed from the response of patients without documented reflux. Neither the body-mass index nor the presence or absence of night awakening identified a group of patients who had a response to proton-pump inhibitors. In addition, there was no interaction of treatment effect with age; race or ethnic group; sex; obesity; former smoking status; asthma control or severity scores; use of long-acting beta-agonists; self-reported sinusitis, rhinitis, or gastroesophageal reflux; or the GSAS distress score.
Discussion
The purpose of this trial was to determine whether the use of a proton-pump inhibitor, esomeprazole, in doses large enough to suppress gastric acid, would improve asthma control in patients with inadequately controlled asthma who did not have frequent symptoms of gastroesophageal reflux. We used a dose of esomeprazole that was higher than that typically used to treat symptomatic gastroesophageal reflux in order to increase our confidence that there was adequate suppression of gastric acid.42 Moreover, we performed ambulatory esophageal pH-monitoring studies to establish whether persons with documented acid reflux might benefit more from therapy with a proton-pump inhibitor than persons without documented acid reflux. After following 402 patients for 6 months, we were not able to show any treatment benefit with respect to the primary outcome — the rate of episodes of poor asthma control — or with respect to secondary outcomes, including asthma symptoms, nocturnal awakening, quality of life, and lung function. Moreover, there was no significant difference in asthma-related outcomes between patients in whom reflux was documented and those in whom it was not.
A systematic review of 12 small trials concluded that, although most of the studies showed that asthma-related outcomes were better when the patients were treated with proton-pump inhibitors, some of the studies had design flaws and the studies did not show consistent improvement in the same asthma outcomes.25 More recently, Littner and colleagues reported the results of a 6-month placebo-controlled trial involving 207 patients with moderate-to-severe asthma and definite symptoms of gastroesophageal reflux.23 Treatment with 30 mg of lansoprazole twice daily did not improve the primary outcome of daily asthma symptoms, but it did result in a reduction in exacerbations and an improvement in asthma-related quality of life. The reduction in exacerbations was greatest among patients taking more than one class of medication for control of asthma. Kiljander and colleagues24 conducted a three-strata, 24-week, multicenter, international trial involving patients with asthma who had nocturnal asthma symptoms, symptoms of gastroesophageal reflux, or both, and who were treated with 40 mg of esomeprazole twice daily. Overall, there was no efficacy in terms of daily peak expiratory flow rate, exacerbations, or asthma symptoms. However, in the stratum of 350 patients who had both symptoms of gastroesophageal reflux and nocturnal asthma symptoms, the peak expiratory flow rate improved, but there was no benefit with respect to FEV1, rescue-inhaler use, symptom scores, or nocturnal awakening. The esomeprazole-related improvement was most pronounced among patients who were taking long-acting beta-agonists.
This study differs from previous trials in that we excluded patients who had symptoms of gastroesophageal reflux two or more times per week. Our rationale was that these patients already have an indication for acid-suppression treatment, irrespective of their asthma. In our study population, we found no benefit from proton-pump inhibitors with respect to any primary or secondary asthma-related outcome measure. Moreover, ambulatory pH-monitoring studies did not identify a subgroup that was likely to benefit from therapy with proton-pump inhibitors. We also did not find that patients taking long-acting beta-agonists were more likely to have a response to proton-pump inhibitors. Therefore, taken as a whole, the weight of evidence indicates that proton-pump inhibitors should not be routinely prescribed for asthma symptoms if the patient does not have symptoms of gastroesophageal reflux. It should be noted, however, that this trial was designed as a superiority trial rather than a noninferiority trial. Thus, we cannot exclude the possibility that there is a small beneficial or harmful treatment effect. Among patients with asthma who have symptoms of gastroesophageal reflux, treatment with proton-pump inhibitors reduces these symptoms but probably has little effect on the asthma. Because diagnostic tests for and drug treatment of gastroesophageal reflux in patients with asthma contribute substantially to the cost of asthma care, limited use of these measures seems warranted.28
The presence of asymptomatic gastroesophageal reflux, which was noted in nearly half of our study participants with poorly controlled asthma, was not predictive of a treatment effect, indicating that asymptomatic gastroesophageal reflux may not be a frequent cause of poor asthma control. In addition, the failure of proton-pump inhibitors to improve methacholine reactivity suggests that airway inflammation from microaspiration or esophageal reflexes is not a common contributing mechanism of poor asthma control in patients who have persistent asthma symptoms despite the use of inhaled corticosteroids.
Although the dose of esomeprazole used in this study is highly effective in suppressing gastric acid throughout the day, and is larger than the dose that is routinely prescribed for symptoms of gastroesophageal reflux, it does not prevent alkaline reflux, which may also trigger esophageal reflexes mediating neurogenic inflammation in the airways.43 On occasion, nocturnal gastric acid breakthrough may occur with even high-dose proton-pump inhibitors, though it does not necessarily lead to reflux in asymptomatic persons.44 Furthermore, asymptomatic gastroesophageal reflux may have other adverse health consequences, such as the development of Barrett's esophagus and a predisposition to esophageal cancer, that are not related to asthma. Accordingly, the use of ambulatory esophageal pH monitoring in patients with asthma ought to be based on the need to diagnose and treat esophageal disease rather than asthma.
In summary, we have found that there is no benefit of treatment with a proton-pump inhibitor in patients with poorly controlled asthma who have minimal or no symptoms of gastroesophageal reflux. Ambulatory pH monitoring and clinical characteristics do not identify a subgroup that is likely to benefit from such treatment.
Supported by grants from the National Heart, Lung, and Blood Institute (5U01HL072968) and the American Lung Association. The study drug and placebo were supplied by AstraZeneca.
Dr. Mastronade reports receiving lecture fees from GlaxoSmithKline and grant support from Pfizer; Dr. Anthonisen, consulting fees from GlaxoSmithKline; Dr. Castro, consulting fees from Genentech and lecture fees from AstraZeneca, Boehringer Ingelheim, Genentech, Cornerstone Therapeutics, Novartis, and Sepracor; and Dr. Wise, consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, MedImmune, and Schering-Plough and grant support from GlaxoSmithKline, Forest, and Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported.
The members of the writing committee of the American Lung Association Asthma Clinical Research Centers (John G. Mastronarde, M.D., Ohio State University Medical College, Columbus; Nicholas R. Anthonisen, M.D., Faculty of Medicine, University of Manitoba, Winnipeg, Canada; Mario Castro, M.D., Washington University School of Medicine, St. Louis; Janet T. Holbrook, M.P.H., Ph.D., Bloomberg School of Public Health, Johns Hopkins University, Baltimore; Frank T. Leone, M.D., University of Pennsylvania School of Medicine, Philadelphia; W. Gerald Teague, M.D., Emory University School of Medicine, Atlanta; and Robert A. Wise, M.D., Johns Hopkins University School of Medicine, Baltimore) take responsibility for the scientific content and integrity of the article.
Source Information
Address reprint requests to Dr. Wise at the Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Cir., Baltimore, MD 21212, or at rwise@jhmi.edu.
Members of the research group of the American Lung Association Asthma Clinical Research Centers are listed in the Appendix.
Appendix
The members of the research group for the trial were as follows: Baylor College of Medicine, Houston — N.A. Hanania (principal investigator), M. Sockrider (coprincipal investigator), L. Giraldo (principal clinic coordinator), R. Valdez, E. Flores (coordinators); Columbia University–New York University Consortium, New York — J. Reibman (principal investigator), E. DiMango, L. Rogers (coprincipal investigators), C. Cammarata, K. Carapetyan (clinic coordinators at New York University), J. Sormillon, E. Simpson (clinic coordinators at Columbia University); Duke University Medical Center, Durham, NC — L. Williams (principal investigator), J. Sundy (coprincipal investigator), G. Dudek (principal clinic coordinator), R. Newton, A. Dugdale (coordinators); Emory University School of Medicine, Atlanta — W.G. Teague (principal investigator), A. Fitzpatrick, S. Khatri (coprincipal investigators), R. Patel (principal clinic coordinator), J. Peabody, E. Hunter, D. Whitlock (coordinators); Illinois Consortium, Chicago — L. Smith (principal investigator), J. Moy, E. Naureckas, C.S. Olopade (coprincipal investigators), J. Hixon (principal clinic coordinator), A. Brees, G. Rivera, S. Sietsema, V. Zagaja (coordinators); Indiana University, Asthma Clinical Research Center, Indianapolis — M. Busk (principal investigator), C. Williams (coprincipal investigator), P. Puntenney (principal clinic coordinator), N. Busk (coordinator); University of Pennsylvania, Philadelphia — F. Leone (principal investigator), M. Hayes-Hampton (principal clinic coordinator); Louisiana State University Health Sciences Center, Ernest N. Morial Asthma, Allergy, and Respiratory Disease Center, New Orleans — W.R. Summer (principal investigator), G. Meyaski (principal clinic coordinator); National Jewish Medical and Research Center, Denver — S. Wenzel, R. Katial (principal investigators), L. Lopez (principal clinic coordinator); Nemours Children's Clinic–University of Florida Consortium, Jacksonville — J. Lima (principal investigator), K. Blake (coprincipal investigator), A. Santos (principal clinic coordinator), K. Vega, L. Lambiase, T. Langford, D. Schaeffer, J. Lang, M. McRae (coordinators); North Shore–Long Island Jewish Health System, New Hyde Park, NY — J. Karpel (principal investigator), R. Cohen (coprincipal investigator), R. Ramdeo (principal clinic coordinator); Northern New England Consortium (formerly Vermont Lung Center at the University of Vermont), Colchester, VT — C.G. Irvin (principal investigator), A.E. Dixon, D.A. Kaminsky (coprincipal investigators), R. Colletti (GI consultant), S.M. Burns, L.M. Bourassa, S.E. Lang, L.V. Griffes (coordinators), R. Pratt, K.B. Nakos, K.J. Girard; Ohio State University Medical Center–Nationwide Children's Hospital, Columbus — J. Mastronarde (principal investigator), K. McCoy (coprincipal investigator), J. Parsons (coinvestigator), J. Drake (principal clinic coordinator), R. Compton, L. Raterman, D. Cosmar (coordinators); University of Alabama at Birmingham, Birmingham — L.B. Gerald (principal investigator), W.C. Bailey (coprincipal investigator), S. Erwin (principal clinic coordinator), A. Kelley, D. Laken (coordinators); University of Miami at Miami–University of South Florida, Tampa — A. Wanner (principal investigator, Miami), R. Lockey (principal investigator, Tampa), E. Mendes (principal clinic coordinator for University of Miami), S. McCullough (principal clinic coordinator for University of South Florida), B. Fimbel, M. Grandstaff (coordinators); University of Minnesota, Minneapolis — M.N. Blumenthal (principal investigator), G. Brottman, J. Hagen (coprincipal investigators), A. Decker, D. Lascewski, S. Kelleher (principal clinic coordinators), K. Bachman, C. Quintard, C. Sherry (coordinators); University of Missouri–Kansas City School of Medicine, Kansas City — G. Salzman (principal investigator), D. Pyszczynski (coprincipal investigator), P. Haney (principal clinic coordinator); St. Louis Asthma Clinical Research Center of Washington University, St. Louis — M. Castro (principal investigator), L. Bacharier, K. Sumino (coinvestigators), M.E. Scheipeter, J. Tarsi (coordinators); University of California, San Diego, San Diego — S. Wasserman (principal investigator), J. Ramsdell (coprincipal investigator), J. Vitin, T. Tucker (clinic coordinators); Respiratory Hospital, Winnipeg, MB, Canada — N. Anthonisen (research group chair); Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore — R. Wise (center director), J. Holbrook (deputy director), E. Brown (principal coordinator), D. Amend-Libercci, K. Barry, M. Daniel, A. Lears, G. Leatherman, C. Levine, R. Masih, S. Modak, D. Nowakowski, N. Prusakowski, D. Shade, C. Shiflett, E. Sugar; Esophageal pH Probe Quality Control Center, Temple University School of Medicine, Philadelphia — J. Richter (center director); Steering Committee — N. Anthonisen (chair), E. Lancet, A. Santos, V. Taggart, N. Edelman, R. Wise, J. Holbrook, N. Hanania, L. Williams, G. Teague, L. Smith, M. Busk, F. Leone, J. Karpel, W. Summer, M. Blumenthal, J. Lima, R. Katial, C. Irvin, J. Reibman, A. Dozor, J. Mastronarde, M. Castro, L. Gerald, G. Salzman, A. Wanner, S. Wasserman; Data and Safety Monitoring Board — S. Lazarus (chair), W. Calhoun, P. Kahrilas, B. McWilliams, A. Rogatko, C. Sorkness; Project Office, American Lung Association, New York — E. Lancet, R. Vento (project officers), N. Edelman (scientific consultant), S. Rappaport, G. Pezza; Project Office, National Heart Lung and Blood Institute, Bethesda, MD — V. Taggart (project officer), G. Weinmann (data safety and monitoring board secretary, airway branch chief); American Lung Association Scientific Advisory Committee — G. Snider (chair), N. Anthonisen, M. Castro, J. Fish, D. Ingbar, S. Jenkinson, D. Mannino, H. Perlstadt, L. Rosenwasser, J. Samet, D. Schraufnagel, J. Smith, L. Smith, T. Standiford, A. Wanner, T. Weaver.
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- Citing Articles (45)
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Karna Dev Bardhan, Vicki Strugala, Peter W. Dettmar. (2012) Reflux Revisited: Advancing the Role of Pepsin. International Journal of Otolaryngology 2012, 1-13
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S. Grassin-Delyle, P.-O. Girodet. (2012) Exacerbations dans l’asthme : prévention pharmacologique. Revue des Maladies Respiratoires
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Christian Bime, Jessica Nguyen, Robert A. Wise. (2012) Measures of asthma control. Current Opinion in Pulmonary Medicine 18:1, 48-56
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Alex D. Hakim, Michael R. Littner. 2012. Sleep-Related Disorders in Chronic Pulmonary Disease. , 270-285.
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Harly Greenberg, Rubin I. Cohen. (2012) Nocturnal asthma. Current Opinion in Pulmonary Medicine 18:1, 57-62
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Richard B. Berry. 2012. Sleep and Obstructive Lung Disease. , 409-428.
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Richard B. Berry. 2012. Sleep and Nonrespiratory Physiology—Impact on Selected Medical Disorders. , 615-630.
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S. Hashimoto, E. H. Bel. (2012) Current treatment of severe asthma. Clinical & Experimental Allergyn/a-n/a
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A. J. Wang, M. J. Liang, A. Y. Jiang, J. K. Lin, Y. L. Xiao, S. Peng, J. Chen, W. P. Wen, M. H. Chen. (2012) Predictors of acid suppression success in patients with chronic laryngitis. Neurogastroenterology & Motilityno-no
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(2011) Azithromycin for Prevention of Exacerbations of COPD. New England Journal of Medicine 365:23, 2234-2237
Full Text11
David Price, Alison Chisholm, Thys Molen, Nicolas Roche, Elizabeth V. Hillyer, Jean Bousquet. (2011) Reassessing the Evidence Hierarchy in Asthma: Evaluating Comparative Effectiveness. Current Allergy and Asthma Reports 11:6, 526-538
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Rodolfo M. Pascual, Stephen P. Peters. (2011) Asthma. Medical Clinics of North America 95:6, 1115-1124
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SHOAIB FARUQI, IAN D. MOLYNEUX, HOSNIEH FATHI, CAROLINE WRIGHT, RACHAEL THOMPSON, ALYN H. MORICE. (2011) Chronic cough and esomeprazole: A double-blind placebo-controlled parallel study. Respirology 16:7, 1150-1156
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Anne E. Dixon, Emmanuelle M. Clerisme-Beaty, Elizabeth A. Sugar, Rubin I. Cohen, Jason E. Lang, Ellen D. Brown, Joel E. Richter, Charles G. Irvin, John G. Mastronarde. (2011) Effects of Obstructive Sleep Apnea and Gastroesophageal Reflux Disease on Asthma Control in Obesity. Journal of Asthma 48:7, 707-713
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Adalberto Pacheco-Galván, Simon P. Hart, Alyn H. Morice. (2011) La relación entre el reflujo gastroesofágico y las enfermedades de la vía aérea: el paradigma del reflujo a vía aérea. Archivos de Bronconeumología 47:4, 195-203
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Amir A. Zeki, Nicholas J. Kenyon, Ken Yoneda, Samuel Louie. (2011) The Adult Asthmatic. Clinical Reviews in Allergy & Immunology
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Edward L. Korn, Boris Freidlin. (2011) Inefficacy Interim Monitoring Procedures in Randomized Clinical Trials: The Need to Report. The American Journal of Bioethics 11:3, 2-10
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S. Kunsch, V. Gross, A. Neesse, K. Sohrabi, C. Nell, T. M. Gress, V. Ellenrieder, U. Koehler. (2011) Combined lung-sound and reflux-monitoring: a pilot study of a novel approach to detect nocturnal respiratory symptoms in gastro-oesophageal reflux disease. Alimentary Pharmacology & Therapeutics 33:5, 592-600
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Stacy Raviv, Anne E. Dixon, Ravi Kalhan, David Shade, Lewis J. Smith. (2011) Effect of Obesity on Asthma Phenotype is Dependent upon Asthma Severity. Journal of Asthma 48:1, 98-104
CrossRef20
Adalberto Pacheco-Galván, Simon P. Hart, Alyn H. Morice. (2011) Relationship Between Gastro-Oesophageal Reflux and Airway Diseases: The Airway Reflux Paradigm. Archivos de Bronconeumología (English Edition) 47:4, 195-203
CrossRef21
N. J. Shaheen, S. D. Crockett, S. D. Bright, R. D. Madanick, R. Buckmire, M. Couch, E. S. Dellon, J. A. Galanko, G. Sharpless, D. R. Morgan, M. B. Spacek, P. Heidt-Davis, D. Henke. (2011) Randomised clinical trial: high-dose acid suppression for chronic cough - a double-blind, placebo-controlled study. Alimentary Pharmacology & Therapeutics 33:2, 225-234
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Yun Bin Lee, Joo Hyun Lim, Yoon Jin Choi, Ji Yeon Kim, Jun Hyuk Son, Sun Mi Choi, Hyun Jin Jo, Cheol Min Shin, Sang Hyup Lee, Young Soo Park, Jin-Hyeok Hwang, Jin-Wook Kim, Sook-Hyang Jeong, Nayoung Kim, Dong Ho Lee, Hyun Chae Jung, In Sung Song. (2011) Effects of Proton Pump Inhibitors in Asthmatics with Gastroesophageal Reflux Disease. The Korean Journal of Gastroenterology 58:4, 178
CrossRef23
Sanghoon Park, Eun Joo Lee, Hoon Jai Chun, Bora Keum, Yeon Seok Seo, Yong Sik Kim, Yoon-Tae Jeen, Hong Sik Lee, Soon Ho Um, Chang Duck Kim, Ho Sang Ryu, Kwang Ho In, Chang-Sub Uhm, Sung Joon Lee. (2011) Electron microscopic study of intercellular space: Correlation analysis of bronchial asthma and gastroesophageal reflux disease. Journal of Gastroenterology and Hepatology 26:1, 104-107
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Ahmed Madisch, Joachim Labenz. (2011) Extraösophageale Manifestationen der Refluxkrankheit: Fakt oder Fiktion?. Viszeralmedizin 27:2, 1-1
CrossRef25
Michael F. Vaezi, David D. Hagaman, James C. Slaughter, S. Bobo Tanner, James A. Duncavage, Christine T. Allocco, Christy Sparkman, Lynn E. Clement, Cynthia M. Wasden, Dana Wirth, Marion Goutte, Barbara A. McCafferty, Donald C. Lanza. (2010) Proton Pump Inhibitor Therapy Improves Symptoms in Postnasal Drainage. Gastroenterology 139:6, 1887-1893.e1
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Ajay Bansal, Peter J. Kahrilas. (2010) Treatment of GERD complications (Barrett’s, peptic stricture) and extra-oesophageal syndromes. Best Practice & Research Clinical Gastroenterology 24:6, 961-968
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Stanislas Bruley des Varannes, Emmanuel Coron, Jean-Paul Galmiche. (2010) Short and long-term PPI treatment for GERD. Do we need more-potent anti-secretory drugs?. Best Practice & Research Clinical Gastroenterology 24:6, 905-921
CrossRef28
J. Labenz. (2010) Facts and fantasies in extra-oesophageal symptoms in GORD. Best Practice & Research Clinical Gastroenterology 24:6, 893-904
CrossRef29
Jean Bousquet, Eva Mantzouranis, Alvaro A. Cruz, Nadia Aït-Khaled, Carlos E. Baena-Cagnani, Eugene R. Bleecker, Chris E. Brightling, Peter Burney, Andrew Bush, William W. Busse, Thomas B. Casale, Moira Chan-Yeung, Rongchang Chen, Badrul Chowdhury, Kian Fan Chung, Ronald Dahl, Jeffrey M. Drazen, Leonardo M. Fabbri, Stephen T. Holgate, Francine Kauffmann, Tari Haahtela, Nikolaï Khaltaev, James P. Kiley, Mohammad R. Masjedi, Yousser Mohammad, Paul O'Byrne, Martyn R. Partridge, Klaus F. Rabe, Alkis Togias, Christiaan van Weel, Sally Wenzel, Nanshan Zhong, Torsten Zuberbier. (2010) Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma. Journal of Allergy and Clinical Immunology 126:5, 926-938
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Luis Alejandro Pérez De Llano, Francisco Carballada González, Olalla Castro Añón, Marlies Pizarro Perea, Manuel Vázquez Caruncho, Adolfo Baloira Villar. (2010) Relationship Between Comorbidity and Asthma Control. Archivos de Bronconeumología (English Edition) 46:10, 508-513
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Luis Alejandro Pérez De Llano, Francisco Carballada González, Olalla Castro Añón, Marlies Pizarro Perea, Manuel Vázquez Caruncho, Adolfo Baloira Villar. (2010) Relación entre presencia de comorbilidad y control del asma. Archivos de Bronconeumología 46:10, 508-513
CrossRef32
A. Gillman, Jo A. Douglass. (2010) What do asthmatics have to fear from food and additive allergy?. Clinical & Experimental Allergy 40:9, 1295-1302
CrossRef33
Alison Ting, Clare S Murray. (2010) Treatment-resistant asthma: options and decision making. Pediatric Health 4:4, 433-446
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John M Moore, Michael F Vaezi. (2010) Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined?. Current Opinion in Gastroenterology 26:4, 389-394
CrossRef35
Tmirah Haselkorn, Hubert Chen, Dave P. Miller, James E. Fish, Stephen P. Peters, Scott T. Weiss, Craig A. Jones. (2010) Asthma control and activity limitations: insights from the Real-world Evaluation of Asthma Control and Treatment (REACT) Study. Annals of Allergy, Asthma & Immunology 104:6, 471-477
CrossRef36
Jonathan P. Parsons, Cathy Benninger, Miles P. Hawley, Gary Philips, L. Arick Forrest, John G. Mastronarde. (2010) Vocal cord dysfunction: Beyond severe asthma. Respiratory Medicine 104:4, 504-509
CrossRef37
M.V. Malfertheiner, A. Kandulski, P. Malfertheiner, J. Schreiber. (2010) Bronchopulmonale Manifestationen der gastroösophagealen Refluxerkrankung. Der Internist 51:S1, 246-254
CrossRef38
Roberto Gomez, John Fortunato. (2010) Dysphagia, Esophagitis, and Lung Disease. Clinical Pulmonary Medicine 17:2, 96-102
CrossRef39
Jaclyn A Smith. (2010) Interrupting the cough reflex in asthma. Current Opinion in Allergy and Clinical Immunology 10:1, 77-81
CrossRef40
Jonathan P Parsons, John G Mastronarde. (2010) Gastroesophageal reflux disease and asthma. Current Opinion in Pulmonary Medicine 16:1, 60-63
CrossRef41
Luke Carlstrom, Mario Castro. (2009) Severe asthma: What makes it so hard to manage?. Current Allergy and Asthma Reports 9:5, 393-400
CrossRef42
Jose R. Cortes, Maria D. Rivas, Javier Molina-Infante, Maria A. Gonzalez-Nuñez, Moises Perez-G, Juan F. Masa, Juan F. Sanchez, Jose Zamorano. (2009) Omeprazole inhibits IL-4 and IL-13 signaling signal transducer and activator of transcription 6 activation and reduces lung inflammation in murine asthma. Journal of Allergy and Clinical Immunology 124:3, 607-610.e1
CrossRef43
(2009) Esomeprazole for Asthma. New England Journal of Medicine 361:2, 206-208
Full Text44
D. Schiff. (2009) PPIs for Adults with Poorly Controlled Asthma Not Beneficial. AAP Grand Rounds 22:1, 2-2
CrossRef45
Asano, Koichiro, Suzuki, Hidekazu, . (2009) Silent Acid Reflux and Asthma Control. New England Journal of Medicine 360:15, 1551-1553
Full Text
- Letters
