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Dr. Field is Clinical Professor, Division of Respiratory Medicine, University of Calgary Medical School.
Correspondence to: Stephen K. Field, MD, CM, FCCP, Clinical Professor, University of Calgary Medical School, Foothills Hospital, 1403 29th St NW, Calgary, AB, Canada T2N 2T9
Despite the strong association between the two conditions, few topics in medicine are as controversial as the nature of the relationship between asthma and gastroesophageal reflux (GER).1 The reported prevalence of GER in asthma patients ranges from 34 to 89%, depending on the criteria used to define GER and the population studied.2 Even asthma patients without GER symptoms are shown to frequently have abnormal pH monitoring findings.3 Although the strong association between GER and asthma has been reported repeatedly, the relationship between them remains unclear. Data have been published4 that both support and contradict the hypotheses that GER causes asthma, asthma causes GER, and bronchodilator medications cause GER. Despite the conflicting data, interest in the association between the two conditions is increasing. A PubMed search combining the terms asthma and gastroesophageal reflux reveals > 500 citations in the medical literature: an average of two citations per year between 1966 and 1980, 20 per year between 1991 and 1995, and 79 citations in the year 2000 alone. The strong association between GER and asthma, as well as reports that GER causes respiratory symptoms in asthma patients, led most investigators to assume that the relationship was due to GER causing asthma.5 One study6 demonstrated a temporal association between esophageal pH monitoring-confirmed acid reflux and worsening respiratory symptoms in asthma patients with GER. Moreover, animal data7 8 9 10 suggest that GER or acid perfusion of the esophagus (APE) may increase bronchial tone by several mechanisms, including vagally mediated esophagobronchial or laryngobronchial reflexes, repeated microaspiration, or neurally mediated bronchial inflammation.
The studies of the effects of APE in asthma were designed to maximize the likelihood that the effects on pulmonary function would be identified. Approximately two thirds of these studies reported small changes in one or two of the more sensitive and less specific flow-volume loop or resistance parameters.5 Although these changes were statistically significant, they were probably not clinically significant. Moreover, the particular parameter that demonstrated a significant difference during APE varied between studies. Combining the results of these studies demonstrated that GER or APE had little, if any, effect on pulmonary function in asthma patients.5
The relationship between GER and asthma symptoms also led investigators to assume that antireflux therapy would improve asthma. The results of studies on the effects of antireflux therapy on asthma patients with GER are also conflicting. Some investigators11 12 reported that antireflux therapy was beneficial, whereas others were unable to identify its effect on asthma. Irwin et al13 identified GER to be the most common possible trigger in patients with difficult-to-control asthma and, in an uncontrolled trial, found that antireflux therapy improved asthma. Other uncontrolled studies of medical and surgical antireflux therapy reported beneficial effects in asthma patients with GER.11 The results of the controlled trials are more complex. Some have reported an improvement in peak flow rates, symptoms, and medication requirements but none have demonstrated an improvement in spirometry results.14 These studies suffer from a number of shortcomings, including small sample size, lack of objective confirmation of the presence of GER or that treatment controlled GER, short treatment duration, and the fact that some were not properly blinded.14 Clearly, there is a requirement for further properly powered statistically and controlled studies of antireflux therapy in asthma patients with GER. These studies should last a minimum of 3 months, but ideally would be 6 months long to allow adequate healing time for esophagitis and bronchial inflammation due to GER.15 Investigators should also document the presence of GER objectively, and objectively demonstrate that antireflux therapy controls it. One third of asthma patients with GER require more than the standard dose of omeprazole to adequately suppress GER, emphasizing the need to document that antireflux therapy controls GER.16
Rather than triggering asthma, GER may facilitate the triggering of asthma by other irritants. Several investigators have looked at the effects of APE on bronchial provocation testing. The reported effects have been minimal at best.5 Despite intense interest in the nature of their relationship, it is not clear that GER worsens asthma, and other hypotheses must be considered in order to explain the strong association between the two conditions. Cough and the increased respiratory effort accompanying asthma could facilitate GER by increasing the pressure gradient across the lower esophageal sphincter (LES).17 Hyperinflation may alter the relationship between the crural diaphragm and the gastroesophageal junction compromising LES function. This is probably not essential, since increased GER has been reported in conditions not associated with hyperinflation such as idiopathic pulmonary fibrosis.18 Moote et al17 found that bronchial provocation with methacholine increased GER in patients with mild asthma but not in subjects with normal pulmonary function. Ekstrom and Tibbling,19 however, were unable to show that histamine challenge testing increased GER in asthma patients. The differences between these two studies cannot be explained by the use of different bronchoconstricting agents, since methacholine increases LES tone.20
The strong association between the two conditions could also be due to asthma medication facilitating GER. IV infusion of isoproterenol has been shown to decrease LES pressure in animal models and in man.21 22 Inhaled ß-agonists, however, did not increase GER in normal subjects or asthma patients.23 24 25
The reported effects of theophylline are more complex.4 Theophylline has been shown to reduce LES tone in animal studies.21 It decreases LES pressure and increases gastric acid secretion in man, actions that facilitate GER.26 27 Some studies4 found that GER increased in asthma patients during theophylline therapy, whereas others did not. The differences between these studies are not explained by differences in theophylline dose or serum levels.4 In cross-sectional studies28 29 30 the prevalence of GER is not greater in asthma patients receiving theophylline. The apparent lack of effect of theophylline on GER prevalence may be due to patients with GER symptoms who discontinue medication.4 Unfortunately, many of the studies of the effects of theophylline on esophageal function have been flawed by small sample size, lack of controls, and lack of objective measurements of GER. An adequately powered and placebo-controlled study of the effects of theophylline on pulmonary function, esophageal manometric function, and pH monitoring in patients with stable asthma with rigidly controlled diets would help clarify its effects on GER.
It is also possible that the relationship between the GER and asthma is different in different patients or at different times. One condition may exacerbate the other in some but not all patients. The reported studies have not been large enough to determine whether this was the case, nor have they determined which features of either condition predict which patients will develop the other.31
Is the association between GER and asthma worthy of investigation if GER does not compromise pulmonary function? Awareness of the association is important to help identify and treat asthma patients with symptomatic GER promptly and appropriately.21 Treating symptomatic GER improves the quality of life in affected patients. Even if GER does not adversely affect pulmonary function, it causes cough and other respiratory symptoms in asthma patients who may benefit from antireflux therapy.28 32 One study33 reported that treating GER can improve quality-of-life measures in asthma patients with GER. Symptomatic GER can also cause upper airway disease and esophagitis. It is also associated with an increased risk of esophageal cancer.34
In the February 2002 issue of CHEST, Lazenby et al35 reported that oral corticosteroids (prednisone) increase both distal and proximal GER in asthma patients. This observation adds a new dimension to the relationship between GER and asthma and possibly to the relationship between GER and other respiratory diseases. Previous studies13 36 37 have found a high prevalence of both symptomatic and pH monitoring-confirmed GER in steroid-dependent asthmatics, but there are no controlled studies to determine whether the prevalence of GER is greater in asthma patients receiving corticosteroids. Lazenby et al35 found that prednisone increased esophageal acid contact times at both the upper and lower esophagus, but the mechanism for these observations was not established. There were no significant changes in weight, spirometry, asthma, or GER symptoms in the patients during prednisone treatment. They found no differences in esophageal and respiratory manometric parameters, including LES pressure, upper esophageal sphincter pressure, peristaltic contractions, transdiaphragmatic gradient, or diaphragmatic pinch pressure. Neither basal nor stimulated gastric acid secretion increased during prednisone therapy. Lazenby et al35 point out that neither transient LES relaxations nor delayed gastric emptying were measured.
This study of the effects of 7 days of treatment with prednisone, 60 mg/d, on patients with stable asthma with relatively mild GER symptoms raises important questions. Studies in asthma patients with more severe GER symptoms need to be undertaken. Manometric findings and GER symptoms may be different when asthma is not as well controlled. Eighteen of the 20 participants were female with a mean weight of 100 kg and a mean body mass index > 35 kg/m2.36 Obesity is an important risk factor for GER, and further observations are needed to determine whether the findings are applicable to asthma patients who are not obese. The subjects were instructed to eat normally, although diet content and volume were not controlled during the study. Corticosteroids stimulate appetite, and food intake increases in volunteers not maintained on a controlled dietary regimen.38 Although the increase in weight over 7 days was not statistically significant (p = 0.08), it suggests that food intake increased during the prednisone treatment period. Increased food intake and greater gastric distension may have contributed to the observed increase in GER during prednisone therapy. Although the findings are novel and add an important piece to the puzzle of the relationship between GER and asthma, further investigations are needed to elucidate the mechanism of increased GER during prednisone therapy and to determine whether the observations are applicable over a wider range of asthma patients.
References
This article has been cited by other articles:
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  D. J. Prezant, M. Weiden, G. I. Banauch, G. McGuinness, W. N. Rom, T. K. Aldrich, and K. J. Kelly Cough and Bronchial Responsiveness in Firefighters at the World Trade Center Site N. Engl. J. Med., September 12, 2002; 347(11): 806 - 815. [Abstract] [Full Text] [PDF]
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