- Email: [email protected]
Increased Prevalence of Gastroesophageal Reflux Symptoms in Patients With COPD
Increased Prevalence of Gastroesophageal Reflux Symptoms in Patients With COPD* Babak Mokhlesi, MD; Aaron L. Morris, RRT; Cheng-Fang Huang, MS; Anthony J. Curcio; Terrence A. Barrett, MD; and David W. Kamp, MD, FCCP
Study objectives: To determine the prevalence of gastroesophageal reflux (GER) symptoms in patients with COPD and the association of GER symptoms with the severity of airways obstruction as assessed by pulmonary function tests (PFTs). Design: Prospective questionnaire-based, cross-sectional analytic survey. Setting: Outpatient pulmonary and general medicine clinics at a Veterans Administration hospital. Patients: Patients with mild-to-severe COPD (n ⴝ 100) were defined based on American Thoracic Society criteria. The control group (n ⴝ 51) consisted of patients in the general medicine clinic without respiratory complaints or prior diagnosis of asthma or COPD. Intervention: Both groups completed a modified version of the Mayo Clinic GER questionnaire. Results: Compared to control subjects, a greater proportion of COPD patients had significant GER symptoms defined as heartburn and/or regurgitation once or more per week (19% vs 0%, respectively; p < 0.001), chronic cough (32% vs 16%; p ⴝ 0.03), and dysphagia (17% vs 4%; p ⴝ 0.02). Among patients with COPD and significant GER symptoms, 26% reported respiratory symptoms associated with reflux events, whereas control subjects denied an association. Significant GER symptoms were more prevalent in COPD patients with FEV1 < 50%, as compared with patients with FEV1 > 50% of predicted (23% vs 9%, respectively; p ⴝ 0.08). In contrast, PFT results were similar among COPD patients with and without GER symptoms. An increased number of patients with COPD utilized antireflux medications, compared to control subjects (50% vs 27%, respectively; p ⴝ 0.008). Conclusions: The questionnaire demonstrated a higher prevalence of weekly GER symptoms in patients with COPD, as compared to control subjects. There was a trend toward higher prevalence of GER symptoms in patients with severe COPD; however, this difference did not reach statistical significance. We speculate that although GER may not worsen pulmonary function, greater expiratory airflow limitation may worsen GER symptoms in patients with COPD. (CHEST 2001; 119:1043–1048) Key words: COPD; FEV1; gastroesophageal reflux disease; questionnaire Abbreviations: GER ⫽ gastroesophageal reflux; H2-RA ⫽ histamine 2-receptor antagonists; PFT ⫽ pulmonary function test; PPI ⫽ proton pump inhibitor
association between gastroesophageal reflux T he(GER) symptoms and respiratory symptoms is well recognized in the setting of asthma.1,2 In the US adult population, it has been estimated that GER *From the Division of Pulmonary and Critical Care (Drs. Mokhlesi and Kamp), Department of Preventive Medicine (Ms. Huang), and Division of Gastroenterology, Department of Medicine (Dr. Barrett), Northwestern University Medical School, Chicago, IL; the Division of Pulmonary and Critical Care (Drs. Mokhlesi, Kamp, and Mr. Morris), Veterans Administration Chicago Healthcare System, Lakeside Division, Chicago, IL; and TAP Pharmaceuticals (Mr. Curcio), Deerfield, IL. Drs. Barrett and Kamp are senior authors of this article. Manuscript received July 7, 2000; revision accepted October 27, 2000. Correspondence to: Babak Mokhlesi, MD, Division of Pulmonary and Critical Care, Louis A. Weiss Memorial Hospital/University of Chicago, 4640 North Marine Dr, Suite 5700, Chicago, IL; e-mail:[email protected]
symptoms occur at frequencies of 7% daily, 14 to 19% weekly, and 40% monthly.3–5 The prevalence of weekly GER symptoms in patients with asthma is much higher (39 to 70%).6 – 8 However, the mechanisms accounting for the strong relationship between GER symptoms and asthma are not well established. Two explanations have been proposed. One mechanism suggests that reflux induces microaspiration of gastric contents that irritate airways.9 Other studies9,10 suggest that asthma symptoms may be induced without direct exposure of the airways to refluxant material. Some studies9 –12 have demonstrated bronchoconstriction with distal esophageal acid perfusion (pH ⬍ 4) in patients with asthma. These results support the notion that acid reflux into the distal esophagus induces vagally mediated reflex bronchoCHEST / 119 / 4 / APRIL, 2001
1043
constriction.9,12 Based on these mechanisms, a recent review13 emphasized that patients with asthma be aggressively treated for GER. In contrast to asthma, the prevalence of GER symptoms is not well established in patients with COPD. Anderson and Jensen14,15 noted an increased prevalence of benign esophageal disease (eg, GER, insufficiency of the lower esophageal sphincter, esophageal dysmotility, hiatal hernia, esophagitis) in patients who self-reported COPD. El-Serag and Sonnenberg16 performed a retrospective review of a large group of veterans and demonstrated an increased risk of pulmonary diseases, including COPD, in patients with reflux esophagitis, as compared to control subjects. Unlike asthma patients, esophageal acid perfusion did not increase bronchoconstriction in patients with COPD.17,18 Thus, the relationship between GER symptoms and COPD is unclear. To further explore this association, we assessed the prevalence of GER symptoms in a large, veteranpatient population with COPD, as compared to a control group of internal medicine outpatients without COPD from the same medical center. Our findings suggest an association between GER symptoms and COPD.
developed by Locke and associates22 at the Mayo Clinic. This questionnaire is simple, understandable, and well accepted by patients. Our modified version contained 50 of the 80 original questions. The first 33 questions examined four symptoms in detail: heartburn, acid regurgitation, dysphagia, and chronic cough. The first question for each symptom served as a branch point, such that subjects who indicated “no” proceeded to the next symptom. The next two questions for each symptom addressed the frequency and severity of the symptom in the last year. Further questions assessed specific attributes of each symptom. Eight questions were added to assess the effect of heartburn and acid regurgitation on shortness of breath, cough, wheezing, and increased inhaler use. The remainder of the questions assessed patient’s demographic data, alcohol use, smoking history, use of over-the-counter antacids, and prescription antireflux medications. The terminology of the questionnaire was understandable at a fourth-grade reading level. In general, the questionnaires were completed in ⬍ 20 min. The study was approved by the Institutional Review Board of Northwestern University and the Veterans Administration Chicago Healthcare System, Lakeside Division. Statistical Analysis Statistical analysis consisted of t tests for comparing continuous variables between two groups. The associations between binary variables were tested using 2. These associations were verified by using Bonferroni’s multiple comparison adjustments.
Results Materials and Methods Patient Selection We consecutively enrolled 100 eligible patients with a diagnosis of COPD as defined by the American Thoracic Society,19 who were attending the outpatient pulmonary clinic at the Veterans Administration Chicago Health Care System, Lakeside Division. Inclusion criteria for COPD patients consisted of (1) age ⱖ 50 years, (2) ⱖ 30 pack-year smoking history, and (3) abnormal findings on pulmonary function tests (PFTs) demonstrating nonreversible airways obstruction based on American Thoracic Society criteria (⬍ 200 mL and 12% improvement in FEV1 or FVC after inhaling albuterol).20 To meet the criteria for COPD, the FEV1 and the FEV1/FVC had to be ⱕ 70% of predicted.21 Exclusion criteria included the following: (1) respiratory disorders other than COPD; (2) normal PFT results after bronchodilator therapy; (3) known esophageal disease such as cancer, achalasia, stricture; (4) active peptic ulcer disease; (5) ZollingerEllison syndrome; (6) mastocytosis; (7) scleroderma; or (8) current abuse of alcohol (more than three alcoholic drinks a day). Control Group The control group included patients attending general medicine clinics at the same institution who denied having respiratory symptoms such as dyspnea or chronic sputum production, or had a previous diagnosis of asthma or COPD or any respiratory illnesses.
The demographic data of the 100 consecutively eligible patients with COPD and the 51 control subjects are presented in Table 1. All control subjects and 99 of 100 COPD patients were men. COPD patients and control subjects were matched for body mass index and alcohol consumption. Patients in the COPD group were slightly older than control subjects (mean age [⫾ SD], 69.8 ⫾ 7.6 years vs 65.8 ⫾ 12.7 years, respectively; p ⫽ 0.04). As expected, the smoking pack-year exposures were greater in the COPD group (87 ⫾ 49 pack-years vs 50 ⫾ 43 pack-years; p ⬍ 0.001). The pack-year data were obtained by multiplying years of smoking by number of packs of cigarettes used per day. Coffee consumption was also greater in COPD patients, as
Table 1—Demographics of Control Subjects and Patients With COPD* Variables
COPD Patients (n ⫽ 100)
Control Subjects (n ⫽ 51)
p Value
69.8 ⫾ 7.6 28.4 ⫾ 7.7 87 ⫾ 49 2.3 ⫾ 2.3 0.21 ⫾ 0.06
65.8 ⫾ 12.7 27.9 ⫾ 5.3 50 ⫾ 43 1.4 ⫾ 1.5 0.22 ⫾ 0.10
0.04 0.61 ⬍ 0.001 0.01 0.96
Protocol
Age, yr BMI, kg/m2 Smoking, pack-yr Coffee, cups/d Alcohol, drinks/d†
Both COPD patients and control subjects completed a modified version of a previously validated, self-reported questionnaire
*Data are presented as mean ⫾ SD. †Score of 1 indicates none or less than one drink per day.
1044
Clinical Investigations
Table 2—PFT Results in the COPD Group* Spirometry and Lung Volumes FEV1, L FEV1, % of predicted FVC, L FVC, % of predicted FRC, % of predicted TLC, % of predicted RV, % of predicted
GER Disease Symptoms (n ⫽ 19)
No GER Disease Symptoms (n ⫽ 81)
p Value
1.2 ⫾ 0.34 41 ⫾ 11 2.30 ⫾ 0.51 62.0 ⫾ 9.8 137 ⫾ 36 (n ⫽ 13) 111 ⫾ 19 (n ⫽ 13) 176 ⫾ 53 (n ⫽ 13)
1.3 ⫾ 0.48 45 ⫾ 16 2.36 ⫾ 0.63 64.3 ⫾ 16.4 141 ⫾ 34 (n ⫽ 60) 111 ⫾ 18 (n ⫽ 60) 172 ⫾ 47 (n ⫽ 60)
0.36 0.26 0.73 0.41 0.71 0.94 0.75
*Data are presented as mean ⫾ SD. FRC ⫽ functional residual capacity; TLC ⫽ total lung capacity; RV ⫽ residual volume.
compared to control subjects (2.3 ⫾ 2.3 cups per day vs 1.4 ⫾ 1.5 cups per day; p ⫽ 0.01). The was no significant difference in the amount of smoking, coffee, and alcohol consumption between the 19 COPD patients with significant GER symptoms and the 81 COPD patients without GER symptoms. Figure 1 summarizes the data concerning the prevalence of significant heartburn and/or regurgitation (once or more per week), chronic cough, and dysphagia. The prevalence of infrequent heartburn (less than once per week) was similar among patients with COPD and control subjects (26% and 25%, respectively; p ⫽ 0.95). However, COPD patients had an increased prevalence of infrequent regurgitation as compared to control subjects (29% vs 10%; p ⫽ 0.01), significant heartburn and/or regurgitation (19% vs 0%; p ⬍ 0.001), dysphagia (17% vs 3%; p ⬍ 0.02), and chronic cough (32% vs 9%; p ⬍ 0.03). None of the patients with significant GER symptoms were current smokers. These results suggest that GER symptoms were more common in veterans with COPD, compared to a control-patient cohort attending internal medicine clinics.
Measures of spirometry and lung volume were similar among the 19 patients with COPD and significant GER symptoms and the 81 patients with COPD without significant GER symptoms, as shown in Table 2. By comparison, Table 3 and Figure 2 illustrate that significant GER symptoms were more prevalent in patients with FEV1 ⱕ 50%, compared to FEV1 ⬎ 50% without achieving statistical significance (24% vs 9%; p ⫽ 0.08). Thus, the results suggest that patients with more severe COPD may also have more frequent symptoms of GER. Reflux-Associated Respiratory Symptoms and Inhaler Use Among the 19 patients with significant GER symptoms, 5 patients (26%) reported increased respiratory symptoms (eg, cough, shortness of breath, or increased wheezing) associated with heartburn and/or acid regurgitation (Fig 3). Of the five patients with worse reflux-associated respiratory symptoms, four patients noted increased use of 2-agonist inhalers when they experienced reflux symptoms. Among control subjects, no association between respiratory symptoms and reflux events was detected. Thus, these results suggest a greater association between reflux events and the worsening of respiratory symptoms in COPD. Antacids and Antireflux Medication Use
Figure 1. Higher prevalence of significant GER symptoms in patients with COPD. The prevalence of significant GER symptoms (heartburn and/or regurgitation once or more per week), chronic cough, and dysphagia in patients with COPD (gray bars) are compared to control subjects (open bars). GER symptoms were assessed by a modified version of the Mayo Clinic GER questionnaire (see “Materials and Methods” section). *p ⬍ 0.05 COPD patients vs control subjects.
Next, we assessed the prevalence of acid-suppressive medication use in these two groups. Data in Figure 4 indicate that the use of any antireflux medication was greater in COPD patients than in control subjects (50% vs 27%, respectively; p ⫽ 0.008). Among patients with COPD, 43% reported using over-the-counter antacids (excluding over-the-counter histamine 2-receptor antagonists [H2-RAs]) at least once a week, compared to 25% in control subjects (p ⬍ 0.05). Proton pump inhibitors (PPIs) and H2-RAs were used in 28 patients with COPD (6 patients and 22 patients, respectively). Of these 28 patients, only 12 patients were receiving CHEST / 119 / 4 / APRIL, 2001
1045
Table 3—Association of Symptoms With FEV1 in Patients With COPD Compared With Control Subjects* COPD Symptoms
Control Subjects (n ⫽ 51)
FEV1 ⱕ 50% (n ⫽ 67)
FEV1 ⬎ 50% (n ⫽ 33)
p Value
Any HB Any RG Significant HB and/or RG Chronic cough Dysphagia
13 (25) 5 (10) 0 8 (16) 2 (4)
22 (33) 22 (33) 16 (24) 22 (33) 14 (21)
4 (12) 7 (21) 3 (9) 10 (30) 3 (9)
0.08† 0.01† 0.001†‡ 0.1 0.02†
*Data are presented as No. (%). HB ⫽ heartburn; RG ⫽ regurgitation. †Control subject group was significantly different than FEV1 ⱕ 50% group. ‡Control subject group was significantly different than FEV1 ⬎ 50% group.
PPI and H2-RA medications for GER disease. The rest were either treated for inactive peptic ulcer disease or other reasons (eg, empiric therapy, gastritis). Only three of the control subjects (5.7%) were receiving H2-RA or PPI therapy, and none had significant GER symptoms. Taken together, these results indicate that the use of acid-suppressive medication was greater in COPD patients, compared to control subjects in outpatient clinics at a veterans’ hospital. This finding supports the increased prevalence of GER symptoms in patients with COPD.
the GER questionnaire. In both patients, GER symptoms and chronic cough resolved with no change in PFT results. Discussion
Nine patients who had significant respiratory and GER symptoms were receiving a medical regimen (five patients were receiving H2-RAs, and four patients were receiving PPIs) and were considered treatment failures. Two of nine patients agreed to receive high-dose PPI: lansoprazole, 30 mg bid for 1 month, followed by repeat PFTs and completion of
The goals of this study were to determine the prevalence of GER symptoms in patients with COPD and to address the relationship between severity of airways obstruction and GER symptoms. The most important finding of this study is that significant GER symptoms (heartburn and/or acid regurgitation once or more per week) are more prevalent in patients with COPD when compared with control subjects at the same institution. We utilized a GER symptoms questionnaire that accurately reflects the presence of GER disease.22 The utility of this questionnaire is supported by the finding that heartburn and acid regurgitation are specific symptoms of GER.23 We also noted a trend
Figure 2. Higher prevalence of significant GER symptoms in patients with severe COPD. Patients with severe COPD based on FEV1 ⱕ 50% of predicted (gray bars) had a higher prevalence of significant GER symptoms (heartburn and/or regurgitation once or more per week) compared with less severe COPD based on FEV1 ⬎ 50% (striped bars) and control subjects (open bars). *p ⬍ 0.05 FEV1 ⱕ 50% vs control subjects; **p ⬍ 0.05 FEV1 ⬎ 50% vs control subjects.
Figure 3. Proportion of COPD patients with significant GER symptoms who reported increased respiratory symptoms associated with reflux events. A total of 19 patients with COPD reported significant GER symptoms on the modified version of the Mayo Clinic GER questionnaire (see “Materials and Methods” section). Five of these patients (26%) reported increased respiratory symptoms, such as wheezing, shortness of breath, and/or cough associated with reflux events.
Intensive Therapy of GER Symptoms
1046
Clinical Investigations
Figure 4. Higher use of antireflux medications by COPD patients. The proportion of patients with COPD (gray bars) compared to control subjects (open bars) receiving over-thecounter antacids once or more per week, daily H2-RAs, or PPI therapy is indicated. Some patients were receiving multiple therapeutic regimens (eg, antacids and other prescription strength antireflux medications). *p ⬍ 0.05 COPD patients vs control subjects.
toward a direct relationship between the severity of airways obstruction as detected by FEV1 and GER symptoms. Previous survey studies3–5 have reported that 10 to 19% of the general population have weekly GER symptoms. This prevalence is similar to our patients with COPD. In fact, none of the 51 control subjects reported significant GER symptoms (once or more per week). The reason for this discrepancy is not clear. Results from Locke et al4 suggest that symptoms of GER disease decrease as patients age. Therefore, it is possible that either GER was more severe in patients with COPD or that the threshold for sensing reflux events was lower, compared to age-matched control subjects. In addition, patients with COPD consumed more coffee than control subjects (2.3 ⫾ 2.3 cups per day vs 1.4 ⫾ 1.5 cups per day; p ⫽ 0.01). One of the limitations of our study is the skewed population in which the results were obtained. Our study primarily involved elderly male veterans. It is difficult to rule out occult COPD in the control subjects because none of them underwent PFTs and many had significant smoking histories. However, all control subjects were asymptomatic without a known history of lung disease. The prevalence of GER symptoms in patients with COPD has not been well established previously. In this study, we demonstrated that significant GER symptoms occur in 19% of patients with COPD, considerably less than in previous reports6 – 8 in patients with asthma (39 to 70%). The significant difference in prevalence could in part be explained by differences in the questionnaires. The prevalence of dysphagia in our population was similar to the prevalence reported in asthmatics (17% vs 24%,
respectively).6 To our knowledge, this is the first study attempting to establish a relationship between the severity of COPD based on FEV1 with the severity of reflux symptoms. We observed a trend toward a higher prevalence of GER symptoms in patients with an FEV1 ⱕ 50% of predicted (severe COPD), as compared to those with an FEV1 ⬎ 50%. It is possible that a larger study may confirm this observation and reach statistical significance. There are several mechanisms by which GER can induce symptoms in patients with COPD and asthma. One mechanism suggests that reflux induces microaspiration, whereas other studies suggest that acid reflux induces reflex bronchoconstriction.9,10 Severe hyperinflation, vigorous cough, and bronchospasm may increase intra-abdominal pressure and change the relationship between the diaphragm and lower esophageal sphincter, possibly decreasing diaphragmatic contribution to sphincter tone and thereby promoting reflux of gastric contents.6,9,24 –26 Medications such as 2-agonists, anticholinergics, and theophylline may increase GER by lowering esophageal sphincter pressure.27,28 However, results of several studies29 –31 have questioned the association between reflux and these medications. Furthermore, several studies17,18 have demonstrated that esophageal acid perfusion does not induce bronchoconstriction in patients with COPD. It has been difficult to demonstrate if GER triggers bronchoconstriction.17,18,32,33 A recent critical review34 of the effects of both simulated or real GER on pulmonary function in adult asthmatic patients failed to demonstrate a direct relationship. However, asthmatics with GER do report reflux-associated dyspnea,6 and this phenomenon has been reported35 in nonasthmatics with normal PFT and methacholine challenge findings. It is possible that symptoms of dyspnea occur without significant worsening in PFT results. Reflux-associated dyspnea may increase minute ventilation, promoting air trapping and hyperinflation in patients with obstructive airways disease who have expiratory limitation to airflow. However, the mechanism whereby reflux causes dyspnea has not been fully elucidated. In summary, significant GER symptoms are more prevalent in patients with COPD, as compared to control subjects. There was a trend toward higher prevalence of GER symptoms in patients with more severe airways obstruction as detected by FEV1. However, the PFT results were similar in COPD patients with and without GER symptoms. Thus, the data suggest that COPD may increase GER symptoms in this study population. Although GER symptoms are commonly associated with asthma and COPD, an important causal relationship has not been fully elucidated. CHEST / 119 / 4 / APRIL, 2001
1047
References 1 Kennedy JH. Silent gastroesophageal reflux: an important but little known cause of pulmonary complications. Dis Chest 1962; 42:42– 45 2 Mays EE. Intrinsic asthma in adults: association with gastroesophageal reflux. JAMA 1976; 236:2626 –2628 3 Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953–956 4 Locke GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112:1448 –1456 5 Kahrilas PJ. Gastroesophageal reflux disease. JAMA 1996; 276:983–988 6 Field SK, Underwood M, Brant R, et al. Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996; 109:316 –322 7 Harding SM, Guzzo MR, Richter JE. 24-h esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest 1999; 115:654 – 659 8 Sontag SJ, Schnell TG, Miller TQ, et al. Prevalence of oesophagitis in asthmatics. Gut 1992; 33:872– 876 9 Boyle JT, Tuchman DN, Altschuler SM, et al. Mechanisms for the association of gastroesophageal reflux and bronchospasm. Am Rev Respir Dis 1985; 131:S916 –S920 10 Mansfield LE, Stein MR. Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978; 41:224 – 226 11 Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997; 111:1389 –1402 12 Mansfield LE. Gastroesophageal reflux and respiratory disorders: a review. Ann Allergy 1989; 62:158 –163 13 Richter JE. Gastroesophageal reflux disease and asthma: the two are directly related. Am J Med 2000; 108:153S–158S 14 Anderson LI, Jensen G. Prevalence of benign oesophageal disease in the Danish population with special reference to pulmonary disease. J Intern Med 1989; 225:393– 401 15 Anderson LI, Jensen G. Risk factors for benign oesophageal disease in a random population sample. J Intern Med 1991; 230:5–10 16 El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997; 113:755–760 17 Orr WC, Shamma-Othman Z, Allen M, et al. Esophageal function and gastroesophageal reflux during sleep and waking in patients with chronic obstructive pulmonary disease. Chest 1992; 101:1521–1525 18 Ducolone A, Vandevenne A, Jouin H, et al. Gastroesophageal reflux in patients with asthma and chronic bronchitis. Am Rev Respir Dis 1987; 135:327–332 19 Celli BR, Snider GL, Heffner J. American Thoracic Society statement: standards for the diagnosis and care of patients
1048
20
21
22
23
24
25
26
27
28
29
30 31
32 33 34 35
with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77–S120 American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 136:1286 –1296 Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123:659 – 664 Locke GR, Talley NJ, Weaver AL, et al. A new questionnaire for gastroesophageal reflux disease. Mayo Clin Proc 1994; 69:539 –547 Klauser AF, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990; 335:205– 208 Moote DW, Lloyd DA, McCourtie DR, et al. Increase in gastroesophageal reflux during methacholine-induced bronchospasm. J Allergy Clin Immunol 1986; 78:619 – 623 Welch RW, Gray JE. Influence of respiration on recordings of lower esophageal sphincter pressure in humans. Gastroenterology 1982; 83:590 –594 Boyle JT, Altschuler SM, Nixon, TE, et al. Role of the diaphragm in the genesis of lower esophageal sphincter pressure in cat. Gastroenterology 1985; 88:723–730 Stein MR, Towner TG, Weber RW, et al. The effect of theophylline on the lower esophageal sphincter pressure. Ann Allergy 1980; 45:238 –239 Berquist WE, Rachelefsky GS, Kadden M, et al. Effect of theophylline on gastroesophageal reflux in normal adults. J Allergy Clin Immunol 1981; 67:407– 411 Sontag S, O’Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613– 620 Hubert D, Gaudric M, Guerre J, et al. Effect of theophylline on gastroesophageal reflux in patients with asthma. J Allergy Clin Immunol 1988; 81:1168 –1174 Berquist WE, Rachelefsky GS, Rowshan N, et al. Quantitative gastroesophageal reflux and pulmonary function in asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy. J Allergy Clin Immunol 1984; 73:253–258 Tan WC, Martin RJ, Pandey R, et al. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis 1990; 141:1394 –1399 Ekstrom T, Tibbling L. Gastro-oesophageal reflux and triggering of bronchial asthma: a negative report. Eur J Respir Dis 1987; 71:177–180 Field SK. A critical review of the studies of the effects of simulated or real gastroesophageal reflux on pulmonary function in asthmatic adults. Chest 1999; 115:848 – 856 Pratter MR, Curley FJ, Dubois J, et al. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch Intern Med 1989; 149:2277–2282
Clinical Investigations
Study objectives: To determine the prevalence of gastroesophageal reflux (GER) symptoms in patients with COPD and the association of GER symptoms with the severity of airways obstruction as assessed by pulmonary function tests (PFTs). Design: Prospective questionnaire-based, cross-sectional analytic survey. Setting: Outpatient pulmonary and general medicine clinics at a Veterans Administration hospital. Patients: Patients with mild-to-severe COPD (n ⴝ 100) were defined based on American Thoracic Society criteria. The control group (n ⴝ 51) consisted of patients in the general medicine clinic without respiratory complaints or prior diagnosis of asthma or COPD. Intervention: Both groups completed a modified version of the Mayo Clinic GER questionnaire. Results: Compared to control subjects, a greater proportion of COPD patients had significant GER symptoms defined as heartburn and/or regurgitation once or more per week (19% vs 0%, respectively; p < 0.001), chronic cough (32% vs 16%; p ⴝ 0.03), and dysphagia (17% vs 4%; p ⴝ 0.02). Among patients with COPD and significant GER symptoms, 26% reported respiratory symptoms associated with reflux events, whereas control subjects denied an association. Significant GER symptoms were more prevalent in COPD patients with FEV1 < 50%, as compared with patients with FEV1 > 50% of predicted (23% vs 9%, respectively; p ⴝ 0.08). In contrast, PFT results were similar among COPD patients with and without GER symptoms. An increased number of patients with COPD utilized antireflux medications, compared to control subjects (50% vs 27%, respectively; p ⴝ 0.008). Conclusions: The questionnaire demonstrated a higher prevalence of weekly GER symptoms in patients with COPD, as compared to control subjects. There was a trend toward higher prevalence of GER symptoms in patients with severe COPD; however, this difference did not reach statistical significance. We speculate that although GER may not worsen pulmonary function, greater expiratory airflow limitation may worsen GER symptoms in patients with COPD. (CHEST 2001; 119:1043–1048) Key words: COPD; FEV1; gastroesophageal reflux disease; questionnaire Abbreviations: GER ⫽ gastroesophageal reflux; H2-RA ⫽ histamine 2-receptor antagonists; PFT ⫽ pulmonary function test; PPI ⫽ proton pump inhibitor
association between gastroesophageal reflux T he(GER) symptoms and respiratory symptoms is well recognized in the setting of asthma.1,2 In the US adult population, it has been estimated that GER *From the Division of Pulmonary and Critical Care (Drs. Mokhlesi and Kamp), Department of Preventive Medicine (Ms. Huang), and Division of Gastroenterology, Department of Medicine (Dr. Barrett), Northwestern University Medical School, Chicago, IL; the Division of Pulmonary and Critical Care (Drs. Mokhlesi, Kamp, and Mr. Morris), Veterans Administration Chicago Healthcare System, Lakeside Division, Chicago, IL; and TAP Pharmaceuticals (Mr. Curcio), Deerfield, IL. Drs. Barrett and Kamp are senior authors of this article. Manuscript received July 7, 2000; revision accepted October 27, 2000. Correspondence to: Babak Mokhlesi, MD, Division of Pulmonary and Critical Care, Louis A. Weiss Memorial Hospital/University of Chicago, 4640 North Marine Dr, Suite 5700, Chicago, IL; e-mail:[email protected]
symptoms occur at frequencies of 7% daily, 14 to 19% weekly, and 40% monthly.3–5 The prevalence of weekly GER symptoms in patients with asthma is much higher (39 to 70%).6 – 8 However, the mechanisms accounting for the strong relationship between GER symptoms and asthma are not well established. Two explanations have been proposed. One mechanism suggests that reflux induces microaspiration of gastric contents that irritate airways.9 Other studies9,10 suggest that asthma symptoms may be induced without direct exposure of the airways to refluxant material. Some studies9 –12 have demonstrated bronchoconstriction with distal esophageal acid perfusion (pH ⬍ 4) in patients with asthma. These results support the notion that acid reflux into the distal esophagus induces vagally mediated reflex bronchoCHEST / 119 / 4 / APRIL, 2001
1043
constriction.9,12 Based on these mechanisms, a recent review13 emphasized that patients with asthma be aggressively treated for GER. In contrast to asthma, the prevalence of GER symptoms is not well established in patients with COPD. Anderson and Jensen14,15 noted an increased prevalence of benign esophageal disease (eg, GER, insufficiency of the lower esophageal sphincter, esophageal dysmotility, hiatal hernia, esophagitis) in patients who self-reported COPD. El-Serag and Sonnenberg16 performed a retrospective review of a large group of veterans and demonstrated an increased risk of pulmonary diseases, including COPD, in patients with reflux esophagitis, as compared to control subjects. Unlike asthma patients, esophageal acid perfusion did not increase bronchoconstriction in patients with COPD.17,18 Thus, the relationship between GER symptoms and COPD is unclear. To further explore this association, we assessed the prevalence of GER symptoms in a large, veteranpatient population with COPD, as compared to a control group of internal medicine outpatients without COPD from the same medical center. Our findings suggest an association between GER symptoms and COPD.
developed by Locke and associates22 at the Mayo Clinic. This questionnaire is simple, understandable, and well accepted by patients. Our modified version contained 50 of the 80 original questions. The first 33 questions examined four symptoms in detail: heartburn, acid regurgitation, dysphagia, and chronic cough. The first question for each symptom served as a branch point, such that subjects who indicated “no” proceeded to the next symptom. The next two questions for each symptom addressed the frequency and severity of the symptom in the last year. Further questions assessed specific attributes of each symptom. Eight questions were added to assess the effect of heartburn and acid regurgitation on shortness of breath, cough, wheezing, and increased inhaler use. The remainder of the questions assessed patient’s demographic data, alcohol use, smoking history, use of over-the-counter antacids, and prescription antireflux medications. The terminology of the questionnaire was understandable at a fourth-grade reading level. In general, the questionnaires were completed in ⬍ 20 min. The study was approved by the Institutional Review Board of Northwestern University and the Veterans Administration Chicago Healthcare System, Lakeside Division. Statistical Analysis Statistical analysis consisted of t tests for comparing continuous variables between two groups. The associations between binary variables were tested using 2. These associations were verified by using Bonferroni’s multiple comparison adjustments.
Results Materials and Methods Patient Selection We consecutively enrolled 100 eligible patients with a diagnosis of COPD as defined by the American Thoracic Society,19 who were attending the outpatient pulmonary clinic at the Veterans Administration Chicago Health Care System, Lakeside Division. Inclusion criteria for COPD patients consisted of (1) age ⱖ 50 years, (2) ⱖ 30 pack-year smoking history, and (3) abnormal findings on pulmonary function tests (PFTs) demonstrating nonreversible airways obstruction based on American Thoracic Society criteria (⬍ 200 mL and 12% improvement in FEV1 or FVC after inhaling albuterol).20 To meet the criteria for COPD, the FEV1 and the FEV1/FVC had to be ⱕ 70% of predicted.21 Exclusion criteria included the following: (1) respiratory disorders other than COPD; (2) normal PFT results after bronchodilator therapy; (3) known esophageal disease such as cancer, achalasia, stricture; (4) active peptic ulcer disease; (5) ZollingerEllison syndrome; (6) mastocytosis; (7) scleroderma; or (8) current abuse of alcohol (more than three alcoholic drinks a day). Control Group The control group included patients attending general medicine clinics at the same institution who denied having respiratory symptoms such as dyspnea or chronic sputum production, or had a previous diagnosis of asthma or COPD or any respiratory illnesses.
The demographic data of the 100 consecutively eligible patients with COPD and the 51 control subjects are presented in Table 1. All control subjects and 99 of 100 COPD patients were men. COPD patients and control subjects were matched for body mass index and alcohol consumption. Patients in the COPD group were slightly older than control subjects (mean age [⫾ SD], 69.8 ⫾ 7.6 years vs 65.8 ⫾ 12.7 years, respectively; p ⫽ 0.04). As expected, the smoking pack-year exposures were greater in the COPD group (87 ⫾ 49 pack-years vs 50 ⫾ 43 pack-years; p ⬍ 0.001). The pack-year data were obtained by multiplying years of smoking by number of packs of cigarettes used per day. Coffee consumption was also greater in COPD patients, as
Table 1—Demographics of Control Subjects and Patients With COPD* Variables
COPD Patients (n ⫽ 100)
Control Subjects (n ⫽ 51)
p Value
69.8 ⫾ 7.6 28.4 ⫾ 7.7 87 ⫾ 49 2.3 ⫾ 2.3 0.21 ⫾ 0.06
65.8 ⫾ 12.7 27.9 ⫾ 5.3 50 ⫾ 43 1.4 ⫾ 1.5 0.22 ⫾ 0.10
0.04 0.61 ⬍ 0.001 0.01 0.96
Protocol
Age, yr BMI, kg/m2 Smoking, pack-yr Coffee, cups/d Alcohol, drinks/d†
Both COPD patients and control subjects completed a modified version of a previously validated, self-reported questionnaire
*Data are presented as mean ⫾ SD. †Score of 1 indicates none or less than one drink per day.
1044
Clinical Investigations
Table 2—PFT Results in the COPD Group* Spirometry and Lung Volumes FEV1, L FEV1, % of predicted FVC, L FVC, % of predicted FRC, % of predicted TLC, % of predicted RV, % of predicted
GER Disease Symptoms (n ⫽ 19)
No GER Disease Symptoms (n ⫽ 81)
p Value
1.2 ⫾ 0.34 41 ⫾ 11 2.30 ⫾ 0.51 62.0 ⫾ 9.8 137 ⫾ 36 (n ⫽ 13) 111 ⫾ 19 (n ⫽ 13) 176 ⫾ 53 (n ⫽ 13)
1.3 ⫾ 0.48 45 ⫾ 16 2.36 ⫾ 0.63 64.3 ⫾ 16.4 141 ⫾ 34 (n ⫽ 60) 111 ⫾ 18 (n ⫽ 60) 172 ⫾ 47 (n ⫽ 60)
0.36 0.26 0.73 0.41 0.71 0.94 0.75
*Data are presented as mean ⫾ SD. FRC ⫽ functional residual capacity; TLC ⫽ total lung capacity; RV ⫽ residual volume.
compared to control subjects (2.3 ⫾ 2.3 cups per day vs 1.4 ⫾ 1.5 cups per day; p ⫽ 0.01). The was no significant difference in the amount of smoking, coffee, and alcohol consumption between the 19 COPD patients with significant GER symptoms and the 81 COPD patients without GER symptoms. Figure 1 summarizes the data concerning the prevalence of significant heartburn and/or regurgitation (once or more per week), chronic cough, and dysphagia. The prevalence of infrequent heartburn (less than once per week) was similar among patients with COPD and control subjects (26% and 25%, respectively; p ⫽ 0.95). However, COPD patients had an increased prevalence of infrequent regurgitation as compared to control subjects (29% vs 10%; p ⫽ 0.01), significant heartburn and/or regurgitation (19% vs 0%; p ⬍ 0.001), dysphagia (17% vs 3%; p ⬍ 0.02), and chronic cough (32% vs 9%; p ⬍ 0.03). None of the patients with significant GER symptoms were current smokers. These results suggest that GER symptoms were more common in veterans with COPD, compared to a control-patient cohort attending internal medicine clinics.
Measures of spirometry and lung volume were similar among the 19 patients with COPD and significant GER symptoms and the 81 patients with COPD without significant GER symptoms, as shown in Table 2. By comparison, Table 3 and Figure 2 illustrate that significant GER symptoms were more prevalent in patients with FEV1 ⱕ 50%, compared to FEV1 ⬎ 50% without achieving statistical significance (24% vs 9%; p ⫽ 0.08). Thus, the results suggest that patients with more severe COPD may also have more frequent symptoms of GER. Reflux-Associated Respiratory Symptoms and Inhaler Use Among the 19 patients with significant GER symptoms, 5 patients (26%) reported increased respiratory symptoms (eg, cough, shortness of breath, or increased wheezing) associated with heartburn and/or acid regurgitation (Fig 3). Of the five patients with worse reflux-associated respiratory symptoms, four patients noted increased use of 2-agonist inhalers when they experienced reflux symptoms. Among control subjects, no association between respiratory symptoms and reflux events was detected. Thus, these results suggest a greater association between reflux events and the worsening of respiratory symptoms in COPD. Antacids and Antireflux Medication Use
Figure 1. Higher prevalence of significant GER symptoms in patients with COPD. The prevalence of significant GER symptoms (heartburn and/or regurgitation once or more per week), chronic cough, and dysphagia in patients with COPD (gray bars) are compared to control subjects (open bars). GER symptoms were assessed by a modified version of the Mayo Clinic GER questionnaire (see “Materials and Methods” section). *p ⬍ 0.05 COPD patients vs control subjects.
Next, we assessed the prevalence of acid-suppressive medication use in these two groups. Data in Figure 4 indicate that the use of any antireflux medication was greater in COPD patients than in control subjects (50% vs 27%, respectively; p ⫽ 0.008). Among patients with COPD, 43% reported using over-the-counter antacids (excluding over-the-counter histamine 2-receptor antagonists [H2-RAs]) at least once a week, compared to 25% in control subjects (p ⬍ 0.05). Proton pump inhibitors (PPIs) and H2-RAs were used in 28 patients with COPD (6 patients and 22 patients, respectively). Of these 28 patients, only 12 patients were receiving CHEST / 119 / 4 / APRIL, 2001
1045
Table 3—Association of Symptoms With FEV1 in Patients With COPD Compared With Control Subjects* COPD Symptoms
Control Subjects (n ⫽ 51)
FEV1 ⱕ 50% (n ⫽ 67)
FEV1 ⬎ 50% (n ⫽ 33)
p Value
Any HB Any RG Significant HB and/or RG Chronic cough Dysphagia
13 (25) 5 (10) 0 8 (16) 2 (4)
22 (33) 22 (33) 16 (24) 22 (33) 14 (21)
4 (12) 7 (21) 3 (9) 10 (30) 3 (9)
0.08† 0.01† 0.001†‡ 0.1 0.02†
*Data are presented as No. (%). HB ⫽ heartburn; RG ⫽ regurgitation. †Control subject group was significantly different than FEV1 ⱕ 50% group. ‡Control subject group was significantly different than FEV1 ⬎ 50% group.
PPI and H2-RA medications for GER disease. The rest were either treated for inactive peptic ulcer disease or other reasons (eg, empiric therapy, gastritis). Only three of the control subjects (5.7%) were receiving H2-RA or PPI therapy, and none had significant GER symptoms. Taken together, these results indicate that the use of acid-suppressive medication was greater in COPD patients, compared to control subjects in outpatient clinics at a veterans’ hospital. This finding supports the increased prevalence of GER symptoms in patients with COPD.
the GER questionnaire. In both patients, GER symptoms and chronic cough resolved with no change in PFT results. Discussion
Nine patients who had significant respiratory and GER symptoms were receiving a medical regimen (five patients were receiving H2-RAs, and four patients were receiving PPIs) and were considered treatment failures. Two of nine patients agreed to receive high-dose PPI: lansoprazole, 30 mg bid for 1 month, followed by repeat PFTs and completion of
The goals of this study were to determine the prevalence of GER symptoms in patients with COPD and to address the relationship between severity of airways obstruction and GER symptoms. The most important finding of this study is that significant GER symptoms (heartburn and/or acid regurgitation once or more per week) are more prevalent in patients with COPD when compared with control subjects at the same institution. We utilized a GER symptoms questionnaire that accurately reflects the presence of GER disease.22 The utility of this questionnaire is supported by the finding that heartburn and acid regurgitation are specific symptoms of GER.23 We also noted a trend
Figure 2. Higher prevalence of significant GER symptoms in patients with severe COPD. Patients with severe COPD based on FEV1 ⱕ 50% of predicted (gray bars) had a higher prevalence of significant GER symptoms (heartburn and/or regurgitation once or more per week) compared with less severe COPD based on FEV1 ⬎ 50% (striped bars) and control subjects (open bars). *p ⬍ 0.05 FEV1 ⱕ 50% vs control subjects; **p ⬍ 0.05 FEV1 ⬎ 50% vs control subjects.
Figure 3. Proportion of COPD patients with significant GER symptoms who reported increased respiratory symptoms associated with reflux events. A total of 19 patients with COPD reported significant GER symptoms on the modified version of the Mayo Clinic GER questionnaire (see “Materials and Methods” section). Five of these patients (26%) reported increased respiratory symptoms, such as wheezing, shortness of breath, and/or cough associated with reflux events.
Intensive Therapy of GER Symptoms
1046
Clinical Investigations
Figure 4. Higher use of antireflux medications by COPD patients. The proportion of patients with COPD (gray bars) compared to control subjects (open bars) receiving over-thecounter antacids once or more per week, daily H2-RAs, or PPI therapy is indicated. Some patients were receiving multiple therapeutic regimens (eg, antacids and other prescription strength antireflux medications). *p ⬍ 0.05 COPD patients vs control subjects.
toward a direct relationship between the severity of airways obstruction as detected by FEV1 and GER symptoms. Previous survey studies3–5 have reported that 10 to 19% of the general population have weekly GER symptoms. This prevalence is similar to our patients with COPD. In fact, none of the 51 control subjects reported significant GER symptoms (once or more per week). The reason for this discrepancy is not clear. Results from Locke et al4 suggest that symptoms of GER disease decrease as patients age. Therefore, it is possible that either GER was more severe in patients with COPD or that the threshold for sensing reflux events was lower, compared to age-matched control subjects. In addition, patients with COPD consumed more coffee than control subjects (2.3 ⫾ 2.3 cups per day vs 1.4 ⫾ 1.5 cups per day; p ⫽ 0.01). One of the limitations of our study is the skewed population in which the results were obtained. Our study primarily involved elderly male veterans. It is difficult to rule out occult COPD in the control subjects because none of them underwent PFTs and many had significant smoking histories. However, all control subjects were asymptomatic without a known history of lung disease. The prevalence of GER symptoms in patients with COPD has not been well established previously. In this study, we demonstrated that significant GER symptoms occur in 19% of patients with COPD, considerably less than in previous reports6 – 8 in patients with asthma (39 to 70%). The significant difference in prevalence could in part be explained by differences in the questionnaires. The prevalence of dysphagia in our population was similar to the prevalence reported in asthmatics (17% vs 24%,
respectively).6 To our knowledge, this is the first study attempting to establish a relationship between the severity of COPD based on FEV1 with the severity of reflux symptoms. We observed a trend toward a higher prevalence of GER symptoms in patients with an FEV1 ⱕ 50% of predicted (severe COPD), as compared to those with an FEV1 ⬎ 50%. It is possible that a larger study may confirm this observation and reach statistical significance. There are several mechanisms by which GER can induce symptoms in patients with COPD and asthma. One mechanism suggests that reflux induces microaspiration, whereas other studies suggest that acid reflux induces reflex bronchoconstriction.9,10 Severe hyperinflation, vigorous cough, and bronchospasm may increase intra-abdominal pressure and change the relationship between the diaphragm and lower esophageal sphincter, possibly decreasing diaphragmatic contribution to sphincter tone and thereby promoting reflux of gastric contents.6,9,24 –26 Medications such as 2-agonists, anticholinergics, and theophylline may increase GER by lowering esophageal sphincter pressure.27,28 However, results of several studies29 –31 have questioned the association between reflux and these medications. Furthermore, several studies17,18 have demonstrated that esophageal acid perfusion does not induce bronchoconstriction in patients with COPD. It has been difficult to demonstrate if GER triggers bronchoconstriction.17,18,32,33 A recent critical review34 of the effects of both simulated or real GER on pulmonary function in adult asthmatic patients failed to demonstrate a direct relationship. However, asthmatics with GER do report reflux-associated dyspnea,6 and this phenomenon has been reported35 in nonasthmatics with normal PFT and methacholine challenge findings. It is possible that symptoms of dyspnea occur without significant worsening in PFT results. Reflux-associated dyspnea may increase minute ventilation, promoting air trapping and hyperinflation in patients with obstructive airways disease who have expiratory limitation to airflow. However, the mechanism whereby reflux causes dyspnea has not been fully elucidated. In summary, significant GER symptoms are more prevalent in patients with COPD, as compared to control subjects. There was a trend toward higher prevalence of GER symptoms in patients with more severe airways obstruction as detected by FEV1. However, the PFT results were similar in COPD patients with and without GER symptoms. Thus, the data suggest that COPD may increase GER symptoms in this study population. Although GER symptoms are commonly associated with asthma and COPD, an important causal relationship has not been fully elucidated. CHEST / 119 / 4 / APRIL, 2001
1047
References 1 Kennedy JH. Silent gastroesophageal reflux: an important but little known cause of pulmonary complications. Dis Chest 1962; 42:42– 45 2 Mays EE. Intrinsic asthma in adults: association with gastroesophageal reflux. JAMA 1976; 236:2626 –2628 3 Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953–956 4 Locke GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112:1448 –1456 5 Kahrilas PJ. Gastroesophageal reflux disease. JAMA 1996; 276:983–988 6 Field SK, Underwood M, Brant R, et al. Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996; 109:316 –322 7 Harding SM, Guzzo MR, Richter JE. 24-h esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest 1999; 115:654 – 659 8 Sontag SJ, Schnell TG, Miller TQ, et al. Prevalence of oesophagitis in asthmatics. Gut 1992; 33:872– 876 9 Boyle JT, Tuchman DN, Altschuler SM, et al. Mechanisms for the association of gastroesophageal reflux and bronchospasm. Am Rev Respir Dis 1985; 131:S916 –S920 10 Mansfield LE, Stein MR. Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978; 41:224 – 226 11 Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997; 111:1389 –1402 12 Mansfield LE. Gastroesophageal reflux and respiratory disorders: a review. Ann Allergy 1989; 62:158 –163 13 Richter JE. Gastroesophageal reflux disease and asthma: the two are directly related. Am J Med 2000; 108:153S–158S 14 Anderson LI, Jensen G. Prevalence of benign oesophageal disease in the Danish population with special reference to pulmonary disease. J Intern Med 1989; 225:393– 401 15 Anderson LI, Jensen G. Risk factors for benign oesophageal disease in a random population sample. J Intern Med 1991; 230:5–10 16 El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997; 113:755–760 17 Orr WC, Shamma-Othman Z, Allen M, et al. Esophageal function and gastroesophageal reflux during sleep and waking in patients with chronic obstructive pulmonary disease. Chest 1992; 101:1521–1525 18 Ducolone A, Vandevenne A, Jouin H, et al. Gastroesophageal reflux in patients with asthma and chronic bronchitis. Am Rev Respir Dis 1987; 135:327–332 19 Celli BR, Snider GL, Heffner J. American Thoracic Society statement: standards for the diagnosis and care of patients
1048
20
21
22
23
24
25
26
27
28
29
30 31
32 33 34 35
with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77–S120 American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 136:1286 –1296 Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123:659 – 664 Locke GR, Talley NJ, Weaver AL, et al. A new questionnaire for gastroesophageal reflux disease. Mayo Clin Proc 1994; 69:539 –547 Klauser AF, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990; 335:205– 208 Moote DW, Lloyd DA, McCourtie DR, et al. Increase in gastroesophageal reflux during methacholine-induced bronchospasm. J Allergy Clin Immunol 1986; 78:619 – 623 Welch RW, Gray JE. Influence of respiration on recordings of lower esophageal sphincter pressure in humans. Gastroenterology 1982; 83:590 –594 Boyle JT, Altschuler SM, Nixon, TE, et al. Role of the diaphragm in the genesis of lower esophageal sphincter pressure in cat. Gastroenterology 1985; 88:723–730 Stein MR, Towner TG, Weber RW, et al. The effect of theophylline on the lower esophageal sphincter pressure. Ann Allergy 1980; 45:238 –239 Berquist WE, Rachelefsky GS, Kadden M, et al. Effect of theophylline on gastroesophageal reflux in normal adults. J Allergy Clin Immunol 1981; 67:407– 411 Sontag S, O’Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613– 620 Hubert D, Gaudric M, Guerre J, et al. Effect of theophylline on gastroesophageal reflux in patients with asthma. J Allergy Clin Immunol 1988; 81:1168 –1174 Berquist WE, Rachelefsky GS, Rowshan N, et al. Quantitative gastroesophageal reflux and pulmonary function in asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy. J Allergy Clin Immunol 1984; 73:253–258 Tan WC, Martin RJ, Pandey R, et al. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis 1990; 141:1394 –1399 Ekstrom T, Tibbling L. Gastro-oesophageal reflux and triggering of bronchial asthma: a negative report. Eur J Respir Dis 1987; 71:177–180 Field SK. A critical review of the studies of the effects of simulated or real gastroesophageal reflux on pulmonary function in asthmatic adults. Chest 1999; 115:848 – 856 Pratter MR, Curley FJ, Dubois J, et al. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch Intern Med 1989; 149:2277–2282
Clinical Investigations