24-h Esophageal pH Testing in Asthmatics^*

Materials and Methods

Subjects

All esophageal pH tests performed at the University of Alabama at Birmingham from July 1, 1989, through November 1, 1994 were reviewed. Subjects with self-reported asthma were further evaluated with a follow-up review of their medical records and/or a telephone interview with the patient and/or physician.

Asthmatics included in the analysis met the American Thoracic Society’s definition of asthma, including a 20% improvement in FEV₁ with bronchodilators or a 20% decrease in FEV₁ after methacholine challenge; the subjects were nonsmokers, had no symptoms consistent with chronic bronchitis, and had no other forms of chronic lung disease.^6,7 Asthmatics without reflux symptoms had indigestion or regurgitation less than twice a month, and had none of the following: dysphagia, history of esophageal or gastric surgery, scleroderma, or previous treatment with antireflux medications including H₂ antagonists, proton pump inhibitors, or prokinetic agents. GER was considered to be present if one or more esophageal acid exposure times were abnormal at either the proximal or the distal esophageal pH probe. Subjects were excluded from the analysis if esophageal pH monitoring was not done, if they were lost to follow-up, or if they did not meet entrance criteria.

Esophageal Manometry and pH Testing

Standardized methods of esophageal manometry and ambulatory 24-h esophageal pH testing were used throughout the study period, along with a standardized reflux and respiratory symptom questionnaire. After an overnight fast, esophageal manometry was performed in the supine position using a round polyvinyl catheter (4.5-mm diameter) (Arndorfer Specialties; Greendale, WI) continuously perfused with distilled water at a rate of 0.5 mL/min by a low-compliance pneumohydraulic capillary infusion system (Arndorfer). The location and mean resting pressure at midexpiration of the lower esophageal sphincter (LES) and upper esophageal sphincter (UES), mean esophageal contraction amplitude in the distal esophagus, and percentage of peristaltic contractions in response to 10 5-mL swallows of water were obtained and measured by previously described techniques.⁸

Immediately following esophageal manometry, a 2.5-mm diameter monocrystalline catheter with two antimony pH electrodes (Medtronic Upper Airway; Medtronic; Minneapolis, MN) was passed nasally and positioned with the distal electrode 5 cm above the cephalad border of the LES and the proximal electrode just below the UES. The electrodes were calibrated at pH 7 and 1, using a buffer solution (Fisher Scientific; Fairlawn, NJ) before and at the completion of each study. A reference electrode was placed on the anterior chest. Electrodes were connected to a data storage device (Digitrapper; Medtronic), which stored pH data every 4 s. Subjects went home with instructions to record meal times, time of assuming the supine position for sleep, and time of arising in the morning. Subjects were encouraged to perform normal daily activities and asked to avoid foods and beverages with a pH < 4. Subjects were instructed to report respiratory symptoms in a diary and to push the event button on the Digitrapper.

After at least 18 h of recording, data were downloaded into an IBM AT personal computer (IBM; Rochester, MN) and analyzed separately for the proximal and distal pH electrodes. Based on 110 healthy control subjects using 95th percentile data in our laboratory, abnormal amounts of acid reflux were present in the distal esophagus if the total percent of time that pH was < 4 exceeded 5.45% during the 24-h study period, upright acid exposure exceeded 8.05%, or supine acid exposure exceeded 2.98%.⁹ Based on studies of 20 healthy volunteers, abnormal amounts of proximal reflux occurred if the total percent of time that pH was < 4 exceeded 1.1%, upright acid exposure exceeded 1.7%, or supine acid exposure exceeded 0.6%.¹⁰ Subjects were considered to have abnormal pH tests if one or more pH parameters were outside the normal range.

Twenty-four–hour esophageal pH testing also allows correlation of respiratory symptoms with esophageal acid events. Respiratory symptom and esophageal acid correlation were assessed by reviewing patient diaries, Digitrapper event markers, and esophageal pH tracings. Respiratory symptoms monitored included wheezing, shortness of breath, and cough. Other symptoms monitored included chest pain, heartburn, regurgitation, and nausea. A respiratory or esophageal symptom was associated with a reflux event if the esophageal pH was < 4 simultaneously with the symptom or within 5 min before its onset. There are minimal data evaluating the symptom-reflux correlation on a temporal basis.¹¹ Investigators have used temporal relationships as long as 10 min and as restrictive as 2 min.^12,13 In our pH laboratory, 5 min has been used routinely for symptom correlation.¹⁴

Analysis

Descriptive statistics were performed on demographic data, esophageal manometry data, and the pH values of all asthmatics with GER (as defined by an abnormal esophageal pH test). Asthma was characterized according to the National Asthma Education Program guidelines.¹⁵ χ² analysis or Fisher’s exact tests were performed on demographic variables in asthmatics with reflux symptoms and GER (+Sx GER) vs those without reflux symptoms and GER (−Sx GER). Esophageal acid contact times and manometry results from the two subject groups were compared using the Mann-Whitney rank-sum test. Asthmatics with reflux symptoms and GER taking theophylline were compared with those not taking theophylline. Data are expressed as mean ± SEM.

Results

From July 1, 1989, through November 1, 1994, 1,983 subjects were studied in the esophageal pH laboratory; 1,625 of them (82%) denied a history of asthma. Of the 358 subjects with self-reported asthma (18%), 159 (44%) did not meet entrance criteria. Subjects were excluded for the following reasons: they did not meet American Thoracic Society asthma criteria (n = 53), did not undergo pH testing (n = 46), were smokers (n = 38), had previous esophageal or pulmonary surgery (n = 14), were on antireflux medication (n = 1), or were lost to follow-up (n = 7). In the 199 asthmatics who met entrance criteria and qualified for analysis, esophageal manometry was incomplete in 1 subject, 17 subjects did not have a proximal esophageal pH probe placed, and 3 subjects had malfunctioning of the proximal esophageal pH probe. The data from these 21 subjects with minor data deficiencies were included in our analysis.

Fig 1 displays the entire group from which the study population was obtained, as well as the esophageal pH outcomes in all qualified asthmatics. Esophageal pH tests were abnormal in 118 of 164 +Sx GER asthmatics (72%) and in 10 of 35 −Sx GER asthmatics (29%).

Demographic variables of +Sx GER and −Sx GER asthmatics are displayed in Table 1 . Although χ² analysis may not be accurate because of the low frequency of occurrence of the demographic variables in the −Sx GER asthmatics, there were no apparent differences between asthmatics with GER with vs those without reflux symptoms, except that −Sx GER asthmatics had a higher frequency of being on a cromolyn inhaler.

Table 2 shows esophageal parameters in the two groups. There were no differences in esophageal manometry in +Sx GER asthmatics vs those categorized as −Sx GER. Fifty-five of 118 +Sx GER asthmatics (47%) had LES hypotension (defined as an LES pressure of ≤ 10 mm Hg), as did 5 of 10 −Sx GER asthmatics (50%). Esophageal pH tests demonstrated that +Sx GER asthmatics had higher total and upright esophageal acid contact times at the distal esophageal pH probe than did−Sx GER asthmatics, implying that −Sx GER asthmatics have less upright and total distal esophageal acid exposure compared with patients who have reflux symptoms. There was no significant difference in proximal esophageal acid exposure between the groups.

Respiratory symptoms were correlated with esophageal acid events in asthmatics with GER. In +Sx GER asthmatics, 35 of 55 wheezing or shortness of breath episodes (64%) were associated with esophageal acid, and 58 of 59 cough episodes (98%) were associated with esophageal acid (Table 3 ). When the results from both groups of asthmatics with GER are combined, it shows that 119 of the 151 respiratory symptoms (78.8%) were associated with esophageal acid. Further examination reveals that 43 of 67 wheezing episodes (64.2%) were associated with esophageal acid, as were 76 of 84 cough episodes (90.5%). In +Sx GER asthmatics, there was also excellent correlation of esophageal symptoms, including heartburn, regurgitation, and nausea, with esophageal acid.

Theophylline, a bronchodilator, has been shown to decrease LES pressure and worsen GER. To evaluate whether theophylline influenced LES pressure or esophageal acid contact times, reflux parameters were compared in +Sx GER asthmatics taking (n = 62) and not taking (n = 56) theophylline. There was no difference between these groups in terms of LES pressure (p = 0.60), total esophageal acid exposure at the distal probe (p = 0.77), supine esophageal acid exposure at the distal probe (p = 0.42), or upright esophageal acid exposure at the distal probe (p = 0.95).

Discussion

This is the first report correlating asthma symptoms with esophageal acid events in asthmatics with GER. The high correlation of respiratory events with esophageal acid in asthmatics with GER provides further evidence that esophageal reflux may be a potential trigger of asthma, even in asthmatics who deny reflux symptoms. Of a total of 151 respiratory events that occurred during 24-h esophageal pH monitoring in 128 asthmatics with GER, 119 of the respiratory symptoms (78.8%) were associated with esophageal acid; that is, an acid reflux episode in which pH was < 4.0 occurred coincident with, or not > 5 min before, a respiratory symptom. These findings are substantiated by Field et al,¹⁶ who found that in the week prior to completing the study questionnaire, 41% of asthmatics noted reflux-associated respiratory symptoms, and 28% used their inhalers while experiencing GER.

Esophageal symptoms, if present, also correlated with esophageal acid in 83% of heartburn episodes, 87% of regurgitation episodes, and 91% of nausea episodes. Esophageal acid was associated with 407 of 481 esophageal symptoms (84.6%).

This retrospective review also shows that asthma is a common indication for esophageal pH testing in subjects who are referred to a tertiary esophageal center. Of 1,983 subjects who had esophageal pH monitoring, 358 (18%) had self-reported symptoms of asthma. Additionally, −Sx GER asthmatics and +Sx GER asthmatics were similar with respect to asthma demographics and esophageal manometry variables. In the presence of abnormal esophageal pH tests, −Sx GER asthmatics had lower amounts of esophageal acid at the distal probe than +Sx GER asthmatics, especially in the upright position (p < 0.004).

Of the 164 asthmatics with reflux symptoms, 72% had at least one abnormal parameter consistent with GER. In asthmatics with reflux symptoms (heartburn and/or regurgitation), esophageal pH testing is not necessary and a therapeutic antireflux trial should be considered. This study does not address asthma outcomes with antireflux therapy. Larrain et al³ performed a placebo-controlled trial comparing placebo to cimetidine, 300 mg qid, or surgical therapy (Hill procedure) in 81 nonallergic asthmatics with GER. Asthma was considered improved in 36% of the control subjects, compared to 74% and 77% of patients who had medical and surgical therapy, respectively. More recently, Field and Sutherland¹⁷ critically reviewed all English-language studies evaluating the effects of medical antireflux therapy in asthmatics with GER, using the 1966 to 1996 MEDLINE database. Twelve studies with a total of 326 treated patients were analyzed. They concluded that (1) asthma symptoms improved in 69% of the subjects; (2) asthma medication use was reduced in 62% of the subjects; (3) evening peak expiratory flow rates improved in 26% of the subjects; and (4) spirometry did not improve in any of the placebo-controlled trials. A double-blind, placebo-controlled trial with documented acid suppression therapy for a prolonged period of time has not been performed.

Twenty-four–hour esophageal pH testing is required to detect GER in asthmatics without reflux symptoms. The 29% prevalence rate of GER in asthmatics without reflux symptoms is similar to the finding, by Irwin et al,¹⁸ that GER was “clinically silent” in 24% of difficult-to-control asthmatics. In both this study and the study by Irwin et al,¹⁸ the asthmatics were selected to receive a pH test. Furthermore, Irwin et al¹⁸ included only difficult-to-control asthmatics referred for further evaluation. Further research is needed to see whether antireflux therapy improves asthma outcome in asthmatics with clinically silent reflux.

Theophylline increases gastric acid secretion and decreases LES pressure, but there is debate about the clinical importance of this.^{5,19,20,21,22} Ekström and Tibbling²¹ found that therapeutic theophylline levels were associated with a 24% increase in acid exposure times and a 170% increase in reflux symptoms. Hubert et al²² found no difference in esophageal acid exposure or the number of reflux episodes in patients on oral theophylline compared with those on placebo. Our data agree with those of Hubert et al²² and Sontag et al⁵ in that subjects taking theophylline had LES pressures and esophageal acid contact times similar to those of subjects who were not taking theophylline preparations.

There are the expected limitations of this retrospective review. Subjects were referred to the esophageal laboratory by physicians who were concerned about the possibility of GER, thus introducing selection bias. This limits the generalizability of the results.

In conclusion, there is a high prevalence of GER in asthmatics. Asthmatics without reflux symptoms may require esophageal pH testing to detect GER. In asthmatics with GER, there is a high correlation of respiratory symptoms with esophageal acid, further supporting the hypothesis that GER may be a potential trigger of asthma.