What is the effect of documented acid suppression on asthma symptoms? On expiratory flow rates?
S.M. Harding (Birmingham)
Asthma is a heterogenous disorder characterized by increased airway reactivity with evidence of airflow obstruction exacerbated by multiple triggers . Trigger avoidance can reduce the number of exacerbations and improve the quality of life in asthmatics. One common, overlooked trigger is gastroesophageal reflux disease (GERD) [2-6]. The prevelence of GERD in adult asthmatics has been reported to range between 34% and 89% [5, 6] Antireflux therapy can potentially improve symptoms and pulmonary function. However, previous medical trials using antacids, histamine-receptor antagonists and proton pump inhibitors reported only mixed results [7-13]. In contrast, the combined results of surgical trials found that of 110 asthmatics with GERD, 34% were free of asthma symptoms post-operatively, 42% were improved, and 24% were unchanged [3, 14, 16-18]. Recently, Larrain et al. reported the only randomized placebo controlled trial of medical (cimetidine 300 mgs BID) versus surgical (Hill anti-reflux) therapy in 81 non allergic asthmatics with GERD . After six months of therapy, pulmonary symptoms were no longer present in 9 (35%) of 26 surgically treated patients, 13 (48%) of 27 cimetidine treated patients, and only 1 (4%) of 28 placebo treated patients . lnconsistencies among studies to date may be attributed to poorly defined patient populations, inadequate documentation of asthma response, and the duration of therapy may have been too short.
We performed a prospective cohort study in asthmatics with reflux symptoms and GERD defined by 24-hour esophageal pH testing and asked whether documented acid suppression improves asthma symptoms and/or pulmonary function including peak expiratory flow rates (PEF).
Thirty non-smoking adult asthmatics with GERD (asthma defined by American Thoracic Society criteria and reflux defined by symptoms and abnormal 24-hour esophageal pH testing) were recruited from the out-patient clinics of a 900 bed University Hospital [20-24]. Subjects underwent baseline studies including a demographic questionnaire, esophageal manometry, and dual probe 24-hour esophageal pH test, barium esophagram, and pulmonary function tests including spirometry. During the 4 week pre-therapy phase, patients recorded reflux and asthma symptom scores. Reflux symptoms included heartburn, regurgitation, indigestion, and belching. Asthma symptoms included coughing, wheezing, shortness of breath, sputum production, and decreased exercise capacity. Each individual symptom was scored on a scale of 0 to 3: 0 = no symptoms, 1 = mild symptoms or limitation of daily activity, 2 = moderate symptoms or limitation of daily activity, and
3 = severe symptoms or limitation of daily activity. Symptom scores were totaled weekly with the following possible range of values: reflux symptoms, 0 to 84; asthma symptoms, 0 to 105. Monthly scores were computed using averaged 4-week data. Subjects recorded PEFs in the morning upon awakening, 1 hour after the evening meal and at bedtime. Subjects recorded the best of three efforts at each time point.
After a month long pretherapy phase, all subjects began 20 mg per day of omeprazole. After 4 weeks of omeprazole therapy, 24-hour esophageal pH testing was repeated to ensure adequate acid suppression. If acid reflux was not controlled, the omeprazole dose was increased monthly by 20 mg increments until normalisation of acid reflux parameters was achieved or the omeprazole dose exceeded 60 mg, at which time the subject exited the study (acid titration phase).
Subjects remained on acid suppressive doses of omeprazole for three months. Subjects continued to record reflux and asthma symptoms and PEFs throughout the study. After 3 months of acid suppressive therapy, the symptom and PEF diaries were collected and pulmonary function tests were repeated.
Asthma response was defined by a priori definitions:
1) asthma symptom score reduction by > 20%,
2) PEF improvement by > 20%.
The efficacy of omeprazole was assessed by performing a series of paired Student's t-tests in which mean pre-therapy symptom scores and PEFs for the entire group were compared with those obtained during the final 4 weeks of acid suppression. The outcomes produced by omeprazole within the responder and non-responder subgroups were also assessed by paired Student's t-test comparisons of the same dependent variable. Two-tail probabilities were used with an alpha level of 0.05.
Baseline demographic characteristics of the 30 patients are shown in Table I. Eight (27%) subjects required more than 20 mg per day of omeprazole to suppress esophageal acid contact time into the normal range. Six subjects required 40 mg per day and 2 subjects required 60 mg per day. The mean acid suppressive dose of omeprazole required was
27 ± 2.2 mg per day.
Across the entire group, there was significant improvement in GERD and asthma symptoms scores: the GERD symptom score (range 0-84) decreased from a baseline of
21.5 ± 3.3 to 3.7 ± 1.0 (p < 0.0001); and the asthma symptom score (range 0-105) decreased from a baseline mean of 32.2 ± 3.7 to 1 9.0 ± 2.7 (p < 0.001).
Twenty-two (73%) subjects met at least one a priori definition of asthma response with twenty (67%) asthma symptom responders and 6 (20%) PEF responders. Table II displays GERD and asthma symptoms and PEFs at baseline and after 3 months of acid suppression in the asthma symptom and/or PEF responder group. The responders had significant improvement in GERD symptom score (p < 0.001), asthma symptom score (p < 0.001), PEFs in the morning (p > 0.005), one hour after dinner (p < 0.012), and at bedtime
(p < 0.005). GERD symptom scores were reduced by 84%, asthma symptom scores were reduced by 57%, and morning and night PEF improved by 8% to 9% with acid suppressive therapy. Figure 1 shows the asthma symptom scores at baseline and at omeprazole treatment months 1, 2 and 3. The asthma and/or PEF responder group had progressive improvement in asthma symptom score throughout the treatment period: after 1 month of acid suppressive therapy, there was a 30% reduction in asthma symptoms; at 2 months, there was a 43% reduction, and by 3 months, there was a 57% reduction in asthma symptoms compared to baseline.
There was also objective improvement in pulmonary function tests in the asthma symptom and/or PEF responder group with 3 months of acid suppressive therapy (Table III). There was significant improvement in measurements of obstructive airflow obstruction including FEV1, FEF(25-75%) and PEF.
Figure 1. Asthma symptom score at baseline and at omeprazole treatment month 1 (Tx1), treatment month 2 (Tx2), and treatment month 3 (Tx3) in 22 asthma symptom and/or peak expiratory flow rate responders and 8 non responders. Means ± standard error are shown. There is a significant difference between groups only at baseline (p < 0.004).
GERD is a trigger of asthma and documented acid suppressive therapy can improve asthma symptoms and/or PEF in up to 73% of asthmatics. In the asthma symptom and/or PEF responders, there was a 57% reduction in asthma symptoms after three months of acid suppressive therapy. Also, peak expiratory flow rates improved 8% over baseline with acid suppressive therapy. There was also an improvement in pulmonary function tests including FEV1, FEF(25-75%) and PEF after three months of acid suppressive therapy. Many asthmatics with GERD (27%) required more than 20 mg per day of omeprazole to suppress esophageal acid. The time course for maximum asthma symptom improvement is at least 3 months. Although our study is not a placebo controlled trial, our response rate of 73% is much higher than previously reported placebo [3, 14, 15, 18, 26] responses and similar to successful reports of antireflux surgery.
Although a well designed placebo controlled trial will further delineate the importance of aggressive esophageal acid suppression in asthmatics with GERD, patients with asthma and GERD should be identified and treated.
This study has been published in The American Journal of Medicine 1996;100:395-405.
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