High Prevalence of Proximal and Distal Gastroesophageal Reflux Disease in Advanced COPD*

Transcription

1 Original Research COPD High Prevalence of Proximal and Distal Gastroesophageal Reflux Disease in Advanced COPD* Robert R. Kempainen, MD; Kay Savik, MS; Timothy P. Whelan, MD; Jordan M. Dunitz, MD; Cynthia S. Herrington, MD; and Joanne L. Billings, MD, MPH Background: Gastroesophageal reflux disease (GERD) is common in a variety of chronic respiratory diseases, but little is known about GERD in the setting of COPD. The aims of this study were to determine the prevalence, presentation, and predictors of GERD based on proximal and distal esophageal ph monitoring in patients with severe COPD. Methods: Forty-one COPD patients with a mean FEV 1 of 24% of predicted underwent dual-probe 24-h esophageal ph monitoring, and 1 patient underwent esophagogastroduodenoscopy. Results: The prevalence of GERD was 57%. Elevated distal and proximal reflux were present in 41% and 46% of patients undergoing esophageal ph studies, respectively. Fifteen percent of these patients had abnormal proximal reflux despite having normal distal probe results. Most patients with GERD were not receiving acid blockers at the time of their referral, and only one third reported heartburn and/or acid regurgitation during the ph study. Only higher body mass index was predictive of reflux on regression analysis (odds ratio, 1.2; 95% confidence interval, 1.0 to 1.5; p 0.05). Conclusions: GERD is common in advanced COPD. Patients are often asymptomatic and have a relatively high prevalence of isolated abnormal proximal reflux. Dual-probe monitoring is therefore well suited for detecting GERD in patients with advanced COPD. (CHEST 2007; 131: ) Key words: acid blockers; aspiration; COPD; gastroesophageal reflux disease Abbreviations: BMI body mass index; CI confidence interval; Dlco diffusing capacity of the lung for carbon monoxide; EGD esophagogastroduodenoscopy; GERD gastroesophageal reflux disease; LES lower esophageal sphincter; OR odds ratio; TLC total lung capacity Patients with a variety of chronic respiratory diseases, including asthma, 1,2 cystic fibrosis, 3 and idiopathic pulmonary fibrosis, 2 have a higher prevalence of gastroesophageal reflux disease (GERD) when compared to the general population. Although the extent to which reflux plays a role in the pathogenesis of lung disease is not entirely clear, studies indicate treatment of GERD can improve the course *From the Division of Pulmonary, Allergy, and Critical Care (Drs. Kempainen, Whelan, Dunitz, and Billings), Department of Internal Medicine, School of Nursing (Ms. Savik), and Department of Surgery (Dr. Herrington), University of Minnesota School of Medicine, Minneapolis, MN. There was no external funding associated with this work. No financial or other potential conflicts of interest exist for any of the authors. of asthma, 4 6 idiopathic pulmonary fibrosis, 7,8 and chronic rejection following lung transplantation. 9 Patients with COPD may be particularly vulnerable to reflux. Exaggerated intrathoracic pressure shifts, increased frequency of cough, diaphragmatic flattening, and use of 2 -agonists exacerbate reflux Manuscript received September 12, 2006; revision accepted February 17, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Robert R. Kempainen, MD, Division of Pulmonary, Allergy, and Critical Care, University of Minnesota School of Medicine, MMC 276, 420 Delaware St SE, Minneapolis, MN 55455; kempa001@umn.edu DOI: /chest Original Research

2 and are common to most patients with COPD. 10 However, relatively little is known about the prevalence and role of GERD in COPD. Mokhlesi et al 11 found COPD patients had elevated scores on a reflux questionnaire, but studies 2,3,12,13 in other populations with respiratory disease indicate symptoms alone lack sufficient sensitivity and specificity to reliably diagnose or exclude GERD. The current gold standard for diagnosing GERD is 24-h esophageal ph monitoring, but to our knowledge there are only three reports of its use in the COPD population; these studies produced disparate results, with the reported prevalence of GERD ranging from 0 to 62%. In addition, the largest study, 13 which found the highest prevalence, was comprised exclusively of male subjects, and only one of the three studies 15 included proximal esophageal ph monitoring. The purpose of this study was to determine the prevalence, presentation, and predictors of GERD based on 24-h proximal and distal esophageal ph monitoring in a series of consecutive patients with severe COPD. Materials and Methods This study was approved by the University of Minnesota Institutional Review Board. Patients All lung transplant candidates referred to the University of Minnesota Medical Center-Fairview (Minneapolis, MN) with a diagnosis of COPD between July 2003 and November 2005 were considered for inclusion in the analysis. All patients had the diagnosis of COPD confirmed during their pretransplantation evaluation. All patients had a FEV 1 percentage of predicted 50%, FEV 1 /FVC ratio 0.7, and total lung capacity (TLC) 80% of predicted. Pulmonary function tests were performed within 4 weeks of esophageal ph monitoring. Sputum samples for routine culture and acid-fast bacilli smear and culture were obtained from all patients able to spontaneously produce a sputum sample. All patients had negative urine cotinine screen results, denied smoking in the previous 6 months, and had no recent history of alcohol abuse. All subjects were outpatients on their baseline medical regimen at the time the 24-h esophageal ph study. Esophageal Manometry and ph Monitoring All patients provided informed written consent to proceed with esophageal manometry and ph monitoring. Patients abstained from using histamine type-2 blockers, proton-pump inhibitors, prokinetic medications, and antacids for at least 7 days prior to their study. Patients also fasted for at least 4 h prior to insertion of the ph probe. A four-channel motility catheter (Medtronic; Minneapolis, MN) was introduced through the nose, and the distal catheter was positioned in the stomach based on pressure tracings. The location of the lower esophageal sphincter (LES) was identified by repeatedly withdrawing the catheter in 1-cm intervals while monitoring pressures. A resting LES pressure of 14.3 to 34.5 mm Hg was considered normal. The tip of the catheter was then left in the LES, and pressures were monitored while the subject swallowed 5 ml of water at 30-s intervals at least 10 times. Normal values for contraction amplitude and duration varied with distance from the LES. 16 At 3 cm above the LES, normal mean amplitude and duration were defined as 64 to 154 mm Hg and 2.9 to 5.1 s, respectively. At 18 cm above the LES, normal mean amplitude and duration were defined as 33 to 91 mm Hg and 2.0 to 3.6 s, respectively. Peristalsis was considered normal if 80% of swallows had normal amplitude and duration. A single-use, two-channel ph catheter with two monocrystalline antimony electrodes spaced 10-cm apart (Slimline; Medtronic) was calibrated at 37 C using ph 1.0 and 7.0 buffer solutions prior to insertion into the esophagus via the nose. The distal ph sensor was positioned 5 cm above the LES identified by manometry. Both sensors were connected to a portable digital recorder that stored ph data every 4 s for a minimum of 20 h. One patient underwent 48-h distal ph monitoring with a probe (Bravo; Medtronic; Shoreview, MN) probe placed endoscopically 6 cm above the squamocolumnar junction. During the study period, patients recorded meal times, time spent in upright and lying down positions, and times with heartburn and/or acid regurgitation. Patients were advised to maintain their normal daily activities and dietary habits but limit themselves to three meals per day. We diagnosed distal GERD if the distal esophageal ph was % of total study time, 8% of time in the upright position, or 3% of time in the supine position. 17 We diagnosed proximal GERD if the proximal ph was 4 for 1.2% of total study time; this cut-off is 2 SDs above the mean normal values determined for esophageal ph 15 cm above the LES. 18 One patient intolerant of ph probe placement underwent esophagogastroduodenoscopy (EGD), which revealed severe reflux esophagitis. This patient was not included in bivariate analysis. Statistical Analysis Patient demographics and medical history were abstracted from medical records. Descriptive data are reported as frequencies, means with SDs, or medians with ranges. Groups were compared using a 2 test of association, independent t tests, Mann-Whitney U test, or Fisher exact test depending on level of measurement and distribution of data. Variables included in bivariate analysis to assess association with GERD included age, gender, FEV 1, FVC, TLC, residual volume, diffusing capacity of the lung for carbon monoxide (Dlco), mean LES pressure, presence of decreased LES pressure, presence of decreased peristalsis, body mass index (BMI), prednisone use, theophylline use, proton-pump inhibitor use, histamine type-2 blocker use, symptoms of heartburn and/or acid regurgitation during the study, and diabetes status. Variables with a p value 0.1 on bivariate analysis were included in multivariate logistic regression analysis. Two models were generated, one with all candidate variables and one utilizing stepwise regression. The appropriateness of the models was assessed using Hosemer-Lemeshow goodness-of-fit test. There was no indication that the data did not fit the models. Analysis was performed using statistical software (SPSS v13.0; SPSS; Chicago, IL); p 0.05 was considered significant. Results A total of 51 COPD patients underwent screening for lung transplantation during the study period; of CHEST / 131 / 6/ JUNE,

3 these, 42 patients (82%) underwent testing for gastroesophageal reflux. GERD assessment included manometry and 24-h esophageal ph monitoring in 41 patients and EGD in 1 patient. Four patients did not undergo testing due to early identification of a contraindication to transplantation, and one patient did not tolerate placement of the ph probe; the reason for no evaluation in the remaining four patients was not documented. There was no significant difference (p 0.10) in age, gender, FEV 1, FVC, Dlco, BMI, prednisone, or use of acid blockers (proton-pump inhibitor or histamine type-2 blockers) between subjects completing and not completing the reflux evaluation. Demographics, medical history, and lung function of subjects are summarized in Table 1. A total of 24 patients (57%) met criteria for GERD, including 1 patient based on EGD. Table 2 summarizes the results of esophageal ph monitoring. Elevated distal and proximal acid reflux was present in 41% and 46% of patients undergoing esophageal ph studies, respectively. Six patients (15% of all patients) had elevated amounts of proximal reflux despite having normal distal probe results. Among the group with GERD, the median percentage of time the distal probe detected a ph Table 1 Characteristics of Patients With COPD (n 42)* Characteristics Data COPD subtype Tobacco related 33 (79) 1 deficiency 6 (14) Other 3 (7) Age, yr 55.5 (30 65) Female gender 24 (57) Diabetes 2 (5) BMI, kg/m Pulmonary function, % predicted FEV FVC TLC Residual volume Dlco Respiratory medications Inhaled bronchodilator 42 (100) Inhaled anticholinergic 40 (95) Inhaled steroid 36 (86) Prednisone 15 (36) Theophylline 5 (12) Acid-blocking medications Proton-pump inhibitor 12 (29) Histamine type-2 receptor antagonist 1 (2) Motility medications 0 *Data are presented as No. (%), median (range), or mean SD. Four of the six patients had a 20 pack-year smoking history. Based on Knutson standard. Corrected for hemoglobin. 4 was 6.4% (range, 3.2 to 19.7). A greater proportion of men than women had GERD (72% and 48%, respectively), but this difference was not statistically significant (p 0.12). Only 26% of patients with GERD reported heartburn and/or acid regurgitation during the 24-h ph study or at the time of the EGD compared to 11% in the non-gerd group (p 0.23). Thirty-five percent of patients with GERD were receiving a proton-pump inhibitor or histamine type-2 receptor antagonist at the time of referral for lung transplantation, compared to 17% in the non-gerd group (p 0.29). The results of manometry and their relation to ph study results are summarized in Table 3. LES pressure was normal in 57% of patients with available manometry results. Seventy-two percent of patients without GERD had normal LES pressure, compared to 46% of patients with GERD (p 0.12). Patients without GERD had higher mean LES pressure than those with GERD (15.6 mm Hg vs 14.1 mm Hg, respectively), but this difference was not statistically significant (p 0.08). Peristalsis was normal in 50% of patients and reduced in 35%. The predominant abnormalities observed in the remaining patients included simultaneous contractions (7.5%), increased peristalsis (5%), or dropped contractions (2.5%). Decreased peristalsis was present in 33% of patients without GERD, compared to 36% of patients with GERD (p 0.96). Of the six patients with isolated proximal reflux, three had normal peristalsis, two had decreased peristalsis, and one had increased frequency of simultaneous contractions. Of the 16 patients able to produce a sputum sample adequate for routine culture, 13 samples grew exclusively normal flora and/or Candida albicans. The sputum sample from two patients produced Pseudomonas aeruginosa, and Streptococcus pneumoniae grew in one case. None of the latter three patients had GERD based on their ph studies. A total of 28 patients produced sputum adequate for acid-fast bacilli smear and culture. Two patients grew atypical mycobacteria, including one with Mycobacterium avium intracellulare complex and one with Mycobacterium gordonae. Both patients had normal esophageal ph study findings. Candidate predictors of GERD (distal and/or proximal) on bivariate analysis were higher BMI, higher Dlco, and mean LES pressure. Multivariate stepwise logistic regression analysis including these variables identified higher BMI alone as a significant predictor of GERD (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0 to 1.6; 1668 Original Research

4 Table 2 Results of Ambulatory 24-h Dual Esophageal ph Monitoring in 41 COPD Patients* ph Study Interpretation Variables Normal Distal Positive; Proximal Unknown Distal Positive; Proximal Positive Distal Positive; Proximal Negative Distal Negative; Proximal Positive Patients, No. (%) 17 (41) 1 (2) 13 (32) 4 (10) 6 (15) Distal probe results Total time ph 4.0, % Median Range NA Supine time ph 4.0, % Median Range NA Upright time ph 4.0, % Median Range NA Reflux episodes, median (range) Total 52 (0 116) (68 562) 157 ( ) 86 (65 144) Preprandial 18 (0 49) (8 515) 89.5 (20 129) 28.5 (7 79) Postprandial 22 (0 68) (19 76) 72.5 (15 96) 36 (20 68) Proximal probe results Total time ph 4.0, % Median 0.5 NA Range NA Supine time ph 4.0 Median 0 NA Range NA Upright time ph 4.0, % Median 0.8 NA Range NA Reflux episodes, median (range) Total 25 (0 55) NA 82 (25 550) 32 (13 35) 55 (27 79) Preprandial 6 (0 31) NA 38 (11 513) 13 (3 21) 19.5 (4 251) Postprandial 10 (0 20) NA 25 (1 64) 9 (2 16) 22 (4 30) With symptoms, % Receiving acid blocker, % *NA not applicable. Includes one patient with 6.2% and 0% supine time with ph 4.0 at proximal and distal probes, respectively. Gastric patch in proximal esophagus is suspected. Symptoms include heartburn and acid regurgitation. Includes patients receiving proton-pump inhibitors and histamine type-2 receptor antagonists at the time of initial evaluation at our center. Acid blockers were discontinued prior to esophageal ph studies. p 0.05). Limiting the analysis to patients whose emphysema was attributed exclusively to tobacco smoking also identified higher BMI as the lone predictor of GERD. Bivariate predictors of proximal reflux (isolated or associated with distal GERD) again included higher BMI, higher Dlco, and mean LES pressure; but on multivariate stepwise logistic regression, Dlco (OR, 1.07; 95% CI, to 1.1; p 0.03) and LES pressure (OR, 0.77; 95% CI, 0.62 to 0.97; p 0.03) were predictive of GERD rather than BMI. Discussion This series of patients with advanced COPD found a prevalence of GERD approximately five times that of the general population. 19 A strikingly high proportion of patients had proximal reflux disease, often in the absence of pathologic amounts of distal reflux. The lack of association between reflux symptoms and the diagnosis of GERD, along with the small proportion of patients with GERD receiving acid blockers at the time of their referral, suggests there is a large burden of clinically silent disease in this population. This is consistent with previous studies that found a high prevalence of asymptomatic reflux in patients both with 2,3,12,13 and without 20,21 respiratory disease. We hypothesized that patients with GERD would have a greater burden of Gram-negative organisms in their sputum, but we did not observe this. This study did not identify any predictors of reflux that are likely to be useful in screening patients for GERD. To our knowledge, D Ovidio et al 15 are the only CHEST / 131 / 6/ JUNE,

5 Table 3 Relationship Between Manometry and Ambulatory 24-h Dual Esophageal ph Monitoring in 40 COPD Patients* LES Pressure and Peristalsis All Patients Normal ph Study Results (n 18) Any GERD on ph Study (n 23) Proximal GERD Only on ph Study (n 6) LES pressure, mm Hg 14.8 ( ) 15.6 ( ) 14.1 ( ) 15.2 ( ) Decreased LES 17 (43) 5 (28) 12 (55) 1 (17) Swallows with normal peristalsis 79 (0 100) 60 (0 100) 83.5 (10 100) 75 (40 100) Decreased peristalsis 14 (35) 6 (33) 8 (36) 2 (33) *Data are presented as median (range) or No. (%). previous investigators to report dual 24-h ph monitoring in the COPD population; based on DeMeester scores, they found a 19% prevalence of GERD among 21 patients. However, 29% of their patients had elevated amounts of proximal reflux while in the supine position. The current study found not only a large proportion of patients with proximal reflux (46%) but also a relatively high prevalence of isolated proximal reflux. Specifically, 15% of all patients had normal amounts of reflux at the distal probe that extended proximally to an abnormal degree. These findings are a noteworthy departure from the 5 to 6% prevalence of isolated proximal reflux disease found in previous studies 22,23 of symptomatic members of the general population. D Ovidio and colleagues 15 hypothesized that stretching of the esophagus may account for the higher prevalence of proximal reflux in COPD patients. 15 Sleep is associated with increased proximal reflux independent of supine position, 24 and it is possible that abnormal sleep patterns in the study population contributed to our findings. Many centers do not routinely test for proximal reflux, and the newer wireless ph monitoring option does not offer proximal ph monitoring. 25 This may have important implications for accurate diagnosis and treatment. For instance, a previous study 4 found a greater response to treatment of reflux-associated asthma in patients with proximal reflux. Davis et al 9 found the use of Nissan fundoplication in lung transplant recipients with distal GERD reduced the risk of chronic graft rejection. Screening for isolated proximal reflux with dual-probe ph monitoring may identify an additional group of transplant recipients suitable for this intervention. There are important differences in methodology and study populations in previous studies of GERD in COPD. For instance, the largest previous series of COPD patients undergoing 24-h ph monitoring, by Casanova et al, 13 was comprised of 42 male subjects. Despite not including proximal ph monitoring, these investigators diagnosed GERD in 62% of their patients. The lower prevalence of GERD among female subjects in our study, as well as in a previous study 26 of healthy adults, suggests selection bias may have contributed to the high prevalence observed by Casanova et al. 13 Variability in the ph criteria used to define GERD may also contribute to the differences in study results. 13,15 Two studies 27,28 published in the 1980s found a prevalence of GERD among COPD patients in the 40 to 60% range, but both limited esophageal ph monitoring to a single 3-h postprandial period. Orr et al 14 found no GERD among COPD patients undergoing 24-h ph monitoring, but the majority of the 12 patients had a significant bronchodilator response and may have had asthma instead of, or in addition to, COPD. Our results are consistent with the majority of previous studies among COPD patients showing a GERD prevalence of roughly 50%. Although obesity is a known risk factor for GERD, 19 the fact that a higher BMI was predictive of GERD in this study was unexpected given only five patients met criteria for obesity (BMI 30 kg/m 2 ). One possibility is that lesser degrees of being overweight, when combined with GERD risk factors associated with severe obstructive lung disease, are sufficient to significantly increase the prevalence of GERD. The observed association between LES pressure and GERD is intuitive, but the relationship between higher Dlco and GERD is less clear. Our study has limitations. All study patients had advanced COPD, and the findings may not be applicable to individuals with milder disease. The study did not include a control group. However, normal values for the general population have been established for 24-h esophageal ph monitoring. A number of previous studies 3,15,22,23 utilizing dual-probe monitoring placed the proximal probe 20 cm above the LES instead of the 15 cm used in the current study. This difference is unlikely to account for the high prevalence of proximal reflux disease in the study population. The threshold used for diagnosing reflux was 2 SDs above normal values for 15 cm above the LES ( 1.2% of total time with ph 4.0), 18 which is higher than the commonly used threshold for 20 cm above the LES ( 0.9% total time with ph 4.0). 17 Shorter spacing between the distal and proximal probes also reduces the likelihood 1670 Original Research

6 the proximal probe was positioned above the upper esophageal sphincter, which can occur with proximal probe placement 20 cm above the LES. 29 Last, a more in-depth assessment of reflux symptoms and greater sample size may have identified additional predictors of GERD. In summary, GERD is common in advanced COPD. Patients are often asymptomatic and have a relatively high prevalence of isolated abnormal proximal reflux. Thus, dual-probe esophageal ph monitoring is well suited for detecting GERD in this population. However, further study is needed to determine whether treatment of reflux impacts the clinical course of COPD, and whether fundoplication for isolated proximal reflux reduces the risk of chronic rejection in lung transplantation recipients. Until that information becomes available, routine use of dual-probe monitoring in patients with advanced COPD is not recommended. References 1 Sontag SJ, O Connell S, Khandelwal S, et al. 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