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(Chest. 1999;116:1257-1264.)
© 1999 American College of Chest Physicians

Gastroesophageal Reflux in Asthmatics*

A Double-Blind, Placebo-Controlled Crossover Study With Omeprazole

Toni O. Kiljander, MD; Eija-Riitta M. Salomaa, MD; Eino K. Hietanen, MD and Erkki O. Terho, MD

* From the Departments of Respiratory Medicine and Clinical Allergology (Drs. Kiljander, Salomaa, and Terho) and Clinical Physiology (Dr. Hietanen), Turku University Central Hospital, Finland.

Correspondence to: Toni Kiljander, MD, Department of Respiratory Medicine and Clinical Allergology, Turku University Central Hospital, Alvar Aallon tie 275, 21540 Preitila, Finland; e-mail: toni.kiljander{at}utu.fi


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To investigate the prevalence of gastroesophageal reflux (GER) among patients with asthma and to determine the effect of omeprazole on the outcome of asthma in patients with GER.

Design: A double-blind, placebo-controlled crossover study.

Setting: Asthmatic patients who attended the pulmonary outpatient clinic of Turku University Central Hospital, Finland.

Patients: One hundred seven asthmatic patients.

Interventions: The patients who were found to have GER in ambulatory esophageal pH monitoring were randomized to receive either omeprazole, 40 mg qd, or placebo for 8 weeks. After a 2-week washout period, the patients were crossed over to the other treatment. Spirometry was performed at baseline and immediately after both treatment periods. Peak expiratory values, use of sympathomimetics, and pulmonary and gastric symptoms were recorded daily in a diary.

Results: Pathologic GER was found in 53% of the asthmatic patients. One third of these patients had no typical reflux symptoms. Daytime pulmonary symptoms did not improve significantly (p = 0.14), but a reduction in nighttime asthma symptoms (p = 0.04) was found during omeprazole treatment. In the patients with intrinsic asthma, there was an improvement in FEV1 values (p = 0.049). Based on symptom scores, 35% of the patients were regarded as responders to 8-week omeprazole treatment. The reflux (time [percent] of pH < 4) was found to be more severe (p = 0.002) in the responders.

Conclusions: There is a high prevalence of GER in the asthmatic population. This reflux is often clinically "silent." After an 8-week omeprazole treatment, there was a reduction in nocturnal asthma symptoms, whereas daytime asthma outcome did not improve. There seems to be a subgroup of asthma patients who benefit from excessive antireflux therapy.

Key Words: asthma • gastroesophageal reflux • omeprazole


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Gastroesophageal reflux (GER) has been found to occur in 32 to 80% of asthmatic patients.1 2 Although the association is evident, it has been difficult to establish a causal relationship between asthma and GER. Asthma is known to promote reflux by increasing the pressure gradient between the thorax and the abdomen.3 4 On the other hand, two mechanisms by which GER can aggravate or even cause asthma have been proposed, namely microaspiration of gastric contents,5 6 7 and vagally mediated esophagobronchial reflex.8 9 10 11 The hypothesis that GER can trigger or exacerbate asthma is supported by several clinical trials that have shown an amelioration in asthma symptoms and/or an improvement in pulmonary function after antireflux therapy.12 13 14 15 16 17 18 19 20 Not all clinical trials have been able to confirm such results,21 22 23 and even those that have, have only been able to show minor improvement in asthma symptoms and/or pulmonary function,12 14 16 17 18 19 or have not been placebo controlled.13 15 20

It has been shown that after antireflux therapy is started, a duration of up to 2 to 3 months is required before asthma symptoms are relieved.13 15 Harding et al15 have shown that 27% of GER patients require > 20 mg of omeprazole to stop acidic reflux. Most studies so far have not met all of the following criteria (which the present study did): adequate antireflux therapy, a treatment period of sufficient duration, and placebo control.

The objectives of the present study are as follows: (1) to investigate the prevalence of GER in the outpatient asthmatic population, and (2) to determine the effect of omeprazole on asthma symptoms and pulmonary function.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
In order to get as heterogeneous a group of asthmatic patients as possible, the only inclusion criteria was a diagnosis of asthma, which was made according to the guidelines defined by the American Thoracic Society.24 The patients were considered to have asthma if they had reversible bronchial obstruction, documented by a 15% increase in FEV1 after sympathomimetic inhalation, or a 20% decrease in FEV1 after methacholine challenge, or >= 20% diurnal variation in peak expiratory flow (PEF) values. Asthma was considered to be extrinsic if at least one positive reaction was found in skin prick tests with common allergens. One hundred seven asthmatic patients from the pulmonary outpatient department of the Turku University Central Hospital participated in the study. Thirty-five of the patients (33%) were male and 72 (67%) were female. The mean age was 49 years old (range, 21 to 76). The results of the skin prick tests were positive in 43 patients (40%), negative in 44 patients (41%), and not available in 20 patients (19%). Twenty of the patients (19%) were smokers.

Study Design
Ambulatory esophageal pH monitoring was performed on all 107 patients. The patients whose pH recordings were abnormal were randomized in a double-blind fashion to receive either omeprazole, 40 mg qd, or placebo for 8 weeks. The patients were advised to take the study medication just before breakfast. After a 2-week washout period, the patients were crossed over to the other treatment for 8 weeks. Treatment was preceded by a 1-week pretreatment phase, during which the baseline data were collected. Drugs were provided by Astra Finland (Masala, Finland), who was also responsible for randomization. Compliance with the trial medication was measured by tablet counts after both treatment periods. An attempt was made to maintain asthma medication unchanged, but in case of a deterioration of asthma, attending physicians were allowed to change medication when required. Oral steroid courses that were needed were counted.

All treated patients underwent flow-volume spirometry before the first treatment period and immediately after both treatment periods. PEF values, the use of sympathomimetics, and the following variables were recorded daily in a diary: cough, dyspnea, wheezing, heartburn, regurgitation, chest pain, and nighttime asthma symptoms. A scoring system used previously13 15 was utilized: symptoms were recorded on a scale of 0 (no symptoms) to 3 (severe symptoms). Afterwards, the weekly pulmonary (cough, dyspnea, wheezing) and gastric (heartburn, regurgitation, chest pain) symptom scores (both 0 to 63) and nighttime asthma symptom score (0 to 21) were calculated by summing the daily scores.

The patients were considered to be free of typical GER symptoms if they had heartburn, regurgitation, chest pain, and dysphagia less than once a week.

The patients were regarded as responders to the antireflux therapy if their pulmonary symptom score or PEF or FEV1 values improved on omeprazole from the baseline, and if the improvement was >= 20% when compared to placebo therapy.15 18

The study was approved by the Ethics Committee of the Turku University Central Hospital, and every patient gave written informed consent.

Ambulatory pH Monitoring
pH recordings were made using semidisposable monocrystant antimony pH catheters (Synectics Medical; Stockholm, Sweden) that have two channels for pH monitoring and a built-in water-perfused channel for manometric identification of the lower esophageal sphincter (LES). pH electrodes, which were 15 cm apart, were calibrated before each procedure.

A pH probe was passed transnasally into the stomach and then slowly withdrawn, and a distal pH electrode was positioned 5 cm above the LES, as determined by the change in pH between the stomach and the esophagus.25 In 78 patients (73%), the LES location was also checked manometrically by using the slow-pull-through technique. An external reference electrode was attached to the skin of the chest wall. pH was monitored 5 and 20 cm above the LES, and was stored at 4 s intervals using a portable recorder (Digitrapper Mk III; Synectics Medical). The parameters measured were those described by Johnson and DeMeester.26 After ambulatory recording, the data was downloaded into an IBM-compatible computer using appropriate analysis software (EsopHogram; Gastrosoft; Irving, Tx). pH monitoring was considered to be abnormal if total time pH < 4 was > 4.5% or if the DeMeester score was > 14.7.27

During pH monitoring, the patients carried on their normal daily routines. They were instructed to keep a diary, noting respiratory and gastric symptoms, meals, and recumbent times. All patients were asked to stop possible antacid, H2-blocker, prokinetic, or proton pump inhibitor medications at least 3 days before pH monitoring, and they were also told to avoid these drugs during the monitoring.

Pulmonary Function Tests
Patients were advised to measure their PEF values (Spira Peak Flowmeter; Spira; Helsinki, Finland) three times every morning within an hour after awakening, and to write the best result down in a diary. All spirometric measurements were made using Flowscreen spirometry (Jaeger GmbH; Würzburg, Germany) that was calibrated according to instructions before each procedure. The normal values used were made especially for the Finnish population.28

Statistical Analysis
The statistical analysis was performed using methodology developed for crossover design with two periods and two treatments.29 When comparing diary information, the average scores for the 3 last weeks at the end of both treatment periods were used. Because the outcome variables were discrete and/or not normally distributed, the analyses were conducted with a nonparametric Mann-Whitney U test using appropriate statistical software (SAS Release 6.12; SAS Institute; Cary, NC). When mentioned, the {chi}2 test was utilized. Before testing the treatment effect, carryover effect was tested using 0.10 as a level of significance.30 In other tests, p values < 0.05 were interpreted as statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty-seven of 107 asthma patients (53%) were found to have pathologic GER in the ambulatory esophageal pH recording and were randomized. A comparison of the patients who had GER with those patients who did not have GER is shown in Table 1 . Of the 57 patients with GER, 20 patients (35%) had no typical reflux symptoms.


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  		Table 1. Comparison of Patients With and Without Pathologic GER in Ambulatory Esophageal pH Monitoring*

 
Fifty-two patients completed both treatment periods. Three patients dropped out while receiving placebo treatment (two because of intense gastric symptoms), and two dropped out while receiving the active drug. Eighteen of these 52 patients (35%) were male and 34 (65%) were female. Their mean age was 50 years (range, 21 to 75); PEF, 455 L/min (range, 250 to 700); and FEV1 % of predicted, 81 (range, 31 to 114). Eight patients (15%) were smokers, and all but three used regular inhaled steroids. No patients had to be excluded from the final analysis because of poor compliance with the trial medication.

No carryover effect was detected after the washout period. The variables that were followed and their p values are shown in Table 2 . There was a significant improvement in the gastric symptom score with omeprazole treatment compared to placebo treatment (p = 0.0001). Also, the pulmonary symptom score improved (Fig 1 , 2 ), but this was not statistically significant (p = 0.14). There was a small but statistically significant relief in nighttime asthma symptoms (p = 0.04). Pulmonary function did not improve; on the contrary, there was a statistically significant decline in FEV1 values. With 95% confidence, this decline was <= 0.15 L. Seven oral steroid courses were used during omeprazole treatment, nine were used during placebo treatment, and two were used during the washout period.


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  		Table 2. Weekly Pulmonary (Cough, Dyspnea, and Wheezing), Gastric (Regurgitation, Heartburn, and Chest Pain; 0–63), and Nighttime Asthma Symptom Scores (0–21), Use of Rescue Sympathomimetics, and PEF and FEV1 Values at the Baseline and at the End of Each Treatment Period (Average of the 3 Last Weeks at the End of the Period)*

 


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  		Figure 1. Weekly pulmonary (cough, dyspnea, and wheezing) and gastric (regurgitation, heartburn, and chest pain) symptom scores (0 to 63; medians) of the patients (n = 27) who received omeprazole, 40 mg/d, during weeks 1 through 8 and placebo treatment during weeks 11 through 18. Weeks 9 through 10 were the washout period. The score at week 0 is the baseline value.

 
There were 18 patients (35%) whose pulmonary symptom scores improved >= 20% while receiving omeprazole, and they were thus regarded as responders. No PEF or FEV1 responders were found. The pulmonary symptom scores of the responders and the nonresponders are shown in Figure 3 . Reflux (time [percent] pH < 4) was more severe (p = 0.002) in the patients who responded to the omeprazole therapy than in the patients who did not respond (Fig 4 ).



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  		Figure 3. Medians of the weekly pulmonary (cough, dyspnea, and wheezing) symptom scores (0 to 63) of the patients who responded (n = 18; >= 20% improvement) to the omeprazole treatment and the patients who did not respond (n = 34). For this representation, the omeprazole and the placebo groups were combined regardless of the order in which they received the drugs.

 


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  		Figure 4. Medians (75 to 25% quartiles) of pH < 4 (percent) of the total time and in the supine and upright positions in the patients who responded (n = 18); >= 20% improvement in the pulmonary symptom score) to the omeprazole treatment and in the patients who did not respond (n = 34). The Mann-Whitney U test was used. * = statistically significant.

 
GER was more common among patients with intrinsic asthma (27/44; 61%) than in patients with extrinsic asthma (19/43; 44%). However, the difference was not statistically significant (p = 0.11). In patients with extrinsic asthma, the only variable that improved with omeprazole treatment was the gastric symptom score (p = 0.002). In patients with intrinsic asthma, there was also an amelioration in the gastric symptom score (p = 0.01) and, in addition, a statistically significant improvement in FEV1 (p = 0.049).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found a high prevalence (53%) of GER in the asthmatic population. This is in accordance with previous studies, which have shown GER in 32 to 80% of asthmatic patients.1 2 It is of interest that 35% of the patients who had GER in pH monitoring were free of typical reflux symptoms. Irwin et al31 have similarly shown GER to be clinically "silent" in 24% of asthmatic patients.

Although theophylline has been shown to reduce the pressure of the LES and thus potentially promote GER,32 it has been shown that the influence of theophylline or other asthma medication on the prevalence of GER in asthmatic patients is minor.2 We did not find any difference in the use of any asthma medication between patients with or without GER.

Our study showed some improvement in asthma symptoms after 8-week omeprazole treatment; however, the improvement was not statistically significant. This is in accordance with several studies with H2 blockers and proton pump inhibitors,19 21 22 23 which have failed to significantly reduce asthma symptoms in asthmatic patients with GER. On the other hand, Harper et al,13 who studied 15 nonallergic asthma patients with symptomatic GER, were able to achieve a statistically significant improvement in daytime asthma symptoms after 8-week ranitidine therapy. Unfortunately, their study was not placebo controlled. Similarly to Harper et al,13 we were also able to show a statistically significant improvement in the pulmonary function of patients with intrinsic asthma after 2 months of omeprazole treatment. In another study with nonallergic asthmatic patients, both medical (cimetidine) and surgical antireflux therapy were found to be significantly more effective in reducing asthma symptoms than placebo therapy. In this study, pulmonary function did not improve significantly after antireflux therapy.14

Recently Levin et al,33 who studied nine asthmatic patients with symptomatic GER, have shown that omeprazole, 20 mg qd for 8 weeks, significantly improves PEF values and quality of life when compared to placebo therapy. Furthermore, two groups15 18 have shown that some asthmatic patients with GER respond to omeprazole therapy. Meier et al18 administered omeprazole, 20 mg bid for 6 weeks, to 15 asthmatic patients with esophagitis and symptoms of pyrosis in a placebo-controlled crossover study. They found an improvement of >= 20% in FEV1 in four patients (27%). All responders and only 6 of 11 nonresponders had a complete healing of esophagitis. This has raised a discussion as to whether they would have been able to get more responders with longer treatment. Harding et al15 studied 30 asthmatic patients with symptomatic GER. They found that 20 patients (67%) responded to 3 months of omeprazole treatment with >= 20% decrease in asthmatic symptoms and 6 patients (20%) responded with >=20% increase in PEF values.

Unlike Meier et al18 and Harding et al,15 we did not reach a 20% increase in FEV1 or PEF values with any of the patients; unlike Levin et al,33 we were not able to show a significant improvement in daytime asthma symptoms after 2 months of omeprazole treatment. There are at least two possible explanations. Firstly, we feel that our patients’ asthma was in good control already at the baseline (all but three patients used regular inhaled steroids, and the mean FEV1 was 81% of predicted), and thus it was difficult to reach a 20% increase in the pulmonary function or a statistically significant improvement in the asthma symptoms. Secondly, in the present study, we have shown that GER is relatively severe in the asthmatic patients who respond to omeprazole treatment. Since our inclusion criteria did not include the presence of typical reflux symptoms, it is probable that reflux in our patients was milder and the prevalence of esophagitis was probably lower than in the previous studies 15 18 33 .

We found 18 patients (35%) to be asthma symptom responders to 2 months of omeprazole treatment. Our finding is less than 67% what Harding et al found.15 This could be due to the fact that their study was not placebo controlled, whereas the present study was. Although it has been shown that even mild GER without esophagitis is sufficient to cause pulmonary symptoms,14 we found GER to be more severe in patients whose pulmonary symptoms were relieved with the omeprazole treatment than in patients whose pulmonary symptoms did not improve with omeprazole (Fig 4) . Of interest is that even those patients who were regarded as responders showed improvement in their pulmonary symptoms only after several weeks of omeprazole treatment (Fig 3) . This is in accordance with previous studies13 15 that have shown that asthma symptom improvement lags behind the typical reflux symptom improvement.

An interesting study was made by Ekström and Tibbling.34 They studied 37 patients with nocturnal asthma and found significantly lower morning PEF values in those patients who had pathologic nocturnal GER compared to patients with no GER at night, suggesting a relationship between GER and nocturnal asthma. Similarly to our study, some previously published placebo-controlled studies with H2 blockers have been able to show an amelioration in nighttime asthma symptoms.12 16 17 Conversely, Ford et al22 were not able to show a significant improvement in patients with nocturnal asthma and GER after omeprazole treatment. There may be several explanations for this: they studied only 11 patients, the length of treatment was only 4 weeks, and the dose of omeprazole was perhaps not sufficient (20 mg). A retrospective study of a surgical treatment of GER in asthmatic patients also showed a marked relief in asthma symptoms in patients with intrinsic asthma having a predominance of nocturnal symptoms.35 There is evidence that especially asthmatic patients with excessive proximal esophageal reflux might benefit from antireflux therapy,15 36 although contradictory reports have been published.37

In conclusion, there is a high prevalence of GER in the asthmatic population. This reflux is often clinically "silent." In this study, we have shown that daytime asthma outcome did not improve with 8-week omeprazole therapy. However, there seems to be a subgroup of asthmatic patients who benefit from excessive antireflux therapy. These responders seem to have relatively severe reflux, and they possibly are patients with intrinsic asthma having predominantly nighttime asthmatic symptoms.



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  		Figure 2. Weekly pulmonary (cough, dyspnea, and wheezing) and gastric (regurgitation, heartburn, and chest pain) symptom scores (0 to 63; medians) of the patients (n = 25) who received placebo treatment during weeks 1 through 8 and omeprazole, 40 mg/d, during weeks 11 through 18. Weeks 9 through 10 were the washout period. The score at week 0 is the baseline value.

 

   Footnotes
 
For editorial comment see page 1150.

Abbreviations: GER = gastroesophageal reflux; LES = lower esophageal sphincter; PEF = peak expiratory flow

This study was supported by the Finnish Anti-Tuberculosis Association Foundation, the Väinö and Laina Kivi Foundation, and the Research Foundation of Respiratory Diseases.

Received for publication January 5, 1999. Accepted for publication May 25, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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