Prevalence of Gastroesophageal Reflux Disease in Patients With Nontuberculous Mycobacterial Lung Disease*

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1 Original Research MYCOBACTERIAL DISEASE Prevalence of Gastroesophageal Reflux Disease in Patients With Nontuberculous Mycobacterial Lung Disease* Won-Jung Koh, MD; Jun Haeng Lee, MD; Yong Soo Kwon, MD; Kyung Soo Lee, MD; Gee Young Suh, MD; Man Pyo Chung, MD; Hojoong Kim, MD, FCCP; and O. Jung Kwon, MD Background: Knowledge of the relationship between respiratory disorders and gastroesophageal reflux disease (GERD) is increasing. However, the association between GERD and pulmonary disease caused by nontuberculous mycobacteria (NTM) has not been studied in detail. We investigated the prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease. Methods: Fifty-eight patients with the nodular bronchiectatic form of NTM lung disease underwent ambulatory 24-h esophageal ph monitoring. Of the 58 patients, 27 patients were identified as having Mycobacterium avium complex infection (15 with Mycobacterium intracellulare and 12 with M avium), and 31 patients had Mycobacterium abscessus pulmonary infection. Results: The prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease was 26% (15 of 58 patients). Only 27% (4 of 15 patients) had typical GERD symptoms. No statistically significant differences were found between patients with GERD and those without GERD with regard to age, sex, body mass index, or pulmonary function test results. However, patients with GERD were more likely to have a sputum smear that was positive for acid-fast bacilli (12 of 15 patients, 80%), compared with patients without GERD (19 of 43 patients, 44%) [p 0.033]. In addition, bronchiectasis and bronchiolitis were observed in more lobes in patients with GERD than in patients without GERD (p and p 0.005, respectively). Conclusions: Patients with the nodular bronchiectatic form of NTM lung disease have a high prevalence of increased esophageal acid exposure, usually without typical GERD symptoms. (CHEST 2007; 131: ) Key words: atypical mycobacteria; gastroesophageal reflux; lung diseases; Mycobacterium avium complex Abbreviations: AFB acid-fast bacilli; GERD gastroesophageal reflux disease; HRCT high-resolution CT; NTM nontuberculous mycobacteria The incidence of pulmonary disease caused by nontuberculous mycobacteria (NTM) in HIVnegative patients has been increasing worldwide. 1 3 A substantial proportion of these patients have no predisposing risk factors such as preexisting lung disease or demonstrable immunodeficiency. 4,5 These patients are predominantly elderly women with no history of smoking. 1 3 Chest radiographs and highresolution CT (HRCT) reveal characteristic findings of multifocal bronchiectasis combined with multiple small nodules (nodular bronchiectasis) that are usually confined to or most severe in the right middle lobe and lingular segment of the left upper lobe NTM are ubiquitous environmental organisms with very weak virulence and rarely cause pulmonary disease in normal individuals. Since exposure to these organisms is universal and disease is rare, normal host defense mechanisms must be effective enough to prevent infection. Therefore, otherwise healthy individuals who acquire NTM lung disease likely have specific susceptibility factors that cause these infections CHEST / 131 / 6/ JUNE,

2 Gastroesophageal reflux disease (GERD) is reported to be associated with several respiratory diseases, including asthma, COPD, 15 chronic cough, 16 and idiopathic pulmonary fibrosis Aspiration into the tracheobronchial tree can be silent clinically and present as insidious-onset bronchiectasis, presumably via gastric acid-induced erosion triggering chronic airway inflammation. 20 However, many patients with GERD often lack typical symptoms such as heartburn or regurgitation. 13 Therefore, 24-h esophageal ph monitoring has become the most important tool for confirming the diagnosis of GERD, with a sensitivity and specificity of 90%. 21 The association of GERD and NTM lung disease has not been studied carefully. Therefore, this study investigated the prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease, and determined the clinical and radiographic characteristics that were more likely to be associated with GERD in these patients. Patients Materials and Methods *From the Division of Pulmonary and Critical Care Medicine (Drs. Koh, Y.S. Kwon, Suh, Chung, Kim, and O.J. Kwon) and Gastroenterology (Dr. J.H. Lee), Department of Medicine (Dr. K.S. Lee), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Drs. Koh and J.H. Lee contributed equally to this work. The authors have no financial or other potential conflicts of interest to disclose. This work was supported by the Samsung Biomedical Research Institute grant SBRI C-A Manuscript received September 15, 2006; revision accepted February 7, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: O. Jung Kwon, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul , Republic of Korea; ojkwon@smc.samsung.co.kr DOI: /chest We screened consecutive patients with the nodular bronchiectatic form of NTM lung disease who were evaluated in the NTM lung disease clinic at the Samsung Medical Center (a 1,250-bed referral hospital in Seoul, Korea) during the 24-month period from January 2004 to December The diagnosis of NTM lung disease was made based on the diagnostic criteria published by the American Thoracic Society. 1 All patients had characteristic findings such as multifocal bronchiectasis combined with multiple small nodules and branching linear structures (tree-in-bud appearance) on chest radiographs and HRCT All of the patients tested negative for antibodies to HIV. The study was approved by the Institutional Review Board, and written informed consent was obtained from all participants. Ambulatory 24-h esophageal ph monitoring was performed on all patients participating in the study. Before the procedures, the patients completed a demographic questionnaire including questions about their pulmonary and gastric symptoms, which included the questions, Do you have heartburn at least once a week? and Do you have regurgitation at least once a week? Patients were considered to be free of typical GERD symptoms if they reported heartburn or regurgitation less than weekly. 22 Ambulatory 24-h Esophageal ph monitoring Ambulatory 24-h esophageal ph monitoring was performed using a 2.1-mm monocrystalline ph catheter equipped with two antimony electrodes (Synectics; Irving, TX). The ph catheters were calibrated at 37 C in standard buffer solutions of ph 1.0 and 7.0 (Fisher Scientific; Fairlawn, NJ) before and at the completion of each procedure. The ph catheter was passed into the esophagus transnasally, and the ph electrode was positioned 5 cm above the lower esophageal sphincter, which had already been determined manometrically. The ph electrode was connected to a portable digital data recorder (Mark III Gold; Synectics), which stored ph data every 4 s, for up to 24 h. The patients returned home with instructions to keep a diary that recording symptoms, meal times, time to bed, and waking time. The patients were encouraged to conduct normal daily activities with no dietary restrictions. The patients returned the next day (after 18 to 24 h) to have the probes removed and the diaries reviewed. Esophageal acid exposure values (percentage of time ph was 4) were calculated using a commercial software program (EsoPHogram, version 5.70C2; Gastrosoft; Milwaukee, WI). Pathologic acid exposure was defined as an intraesophageal ph of 4 for 4% of the recording time. 23,24 All the patients had been asked to stop possible histamine type-2 blocker or proton-pump inhibitor therapy for at least 1 week and possible antacid therapy for at least 3 days before ph monitoring. No patients were receiving theophylline at the time of the ph study. Although 7% (4 of 58 patients) had smoked cigarettes in the past, none had smoked within 6 months of the ph study. Imaging Evaluation The HRCT scans were reviewed retrospectively by an experienced chest radiologist (K.S.L.) who was unaware of the 24-h esophageal ph test results. Six lung lobes in each patient (the lingular segment was considered a separate lobe) were assessed for the presence of lung lesions. Each lobe was evaluated with regard to the presence or absence of bronchiectasis and bronchiolitis. Bronchiolitis was defined as the presence of well-defined small nodules (10 mm in diameter), and branching centrilobular nodules (ie, tree-in-bud pattern) on chest HRCT. The extent of involvement of bronchiectasis and bronchiolitis was estimated by counting the number of involved lobes. Statistical Analysis Data are presented as the median (interquartile range) for quantitative variables. The 2 test or Fisher exact test were used to compare differences in proportions, and the Mann-Whitney U test was used to compare differences in medians; p 0.05 was considered statistically significant. All statistical analyses were performed using statistical software (SPSS 11.0; SPSS; Chicago, IL). Results We screened 92 consecutive patients with the nodular bronchiectatic form of NTM lung disease. Five patients who were 75 years old were excluded from 1826 Original Research

3 this study. Twenty patients refused to participate in the study. Of the 67 patients who agreed to participate, 9 patients were excluded due to problems in placing the ph catheter, such as increased cough or dyspnea. Ultimately, we analyzed the data from 58 patients who completed the 24-h esophageal ph monitoring. The only difference between the study patients and those refusing or not completing esophageal ph monitoring was that the nonparticipants were more likely to have had Mycobacterium avium complex infection (20 of 29 patients, 60%), compared with the participants (27 of 58 patients, 47%) [p 0.048]. Fifty-eight patients ranged in age from 24 to 73 years (median, 56.5 years). The majority of patients were female (n 50, 86%). Of the 58 patients, 27 patients were identified as having M avium complex infection (15 with Mycobacterium intracellulare and 12 with M avium), and 31 patients had Mycobacterium abscessus pulmonary infection (Table 1). Pathologic acid reflux was documented in 15 patients (26%), although 11 of these patients (73%) lacked typical GERD symptoms. The proportion of the patients with typical GERD symptoms was not significantly different between patients with GERD and those without GERD (27% vs 19%, p 0.487). The results of the 24-h esophageal ph monitoring are reported in Table 2. Patients with and without GERD are compared in Table 3. No statistically significant differences were found between patients with GERD and those without GERD with regard to age (p 0.320), sex (p 1.000), body mass index (p 0.316), or pulmonary function test results (p 0.05). Patients with M abscessus infection were more likely to have GERD (10 of 31 patients, 32%), compared with patients with M avium complex infection (5 of 27 patients, 19%), although the difference was not significant (p 0.368). Table 1 Demographic Data for the 58 Patients With the Nodular Bronchiectatic Form of NTM Lung Disease* Variables Data Age, yr 56.5 (47 64) Body mass index, kg/m ( ) Male/female gender 8 (14)/50 (86) Smoking status Nonsmoker 54 (93) Ex-smoker 4 (7) Etiology M avium complex 27 (47) M intracellulare, No 15 M avium, No. 12 M abscessus 31 (53) *Data are presented as the median (interquartile range) or No. (%) unless otherwise indicated. Patients with GERD were more likely to have a positive sputum smear for acid-fast bacilli (AFB) [12 of 15 patients, 80%] than the patients without GERD (19 of 43 patients, 44%) [p 0.033]. In addition, the involvement of bronchiectasis and bronchiolitis on HRCT was more extensive in patients with GERD. Bronchiectasis and bronchiolitis were observed in more lobes in patients with GERD than in patients without GERD (p and p 0.009, respectively) [Fig 1]. The prevalence of GERD did not differ significantly according to age (p 0.577). Among the patients 50 years old, those with M abscessus infection were more likely to have GERD (3 of 11 patients, 27%) than those with M avium complex infection (0 of 8 patients), although the difference was not significant (p 0.228). Discussion In this study using ambulatory esophageal ph monitoring, we made some important findings. First, there was a high prevalence of GERD in patients with NTM lung disease. Second, GERD can be present in patients with NTM lung disease without typical reflux symptoms such as heartburn or acid regurgitation. Third, the presence of GERD was associated with sputum AFB-positive smear results in patients with NTM lung disease. In addition, the involvement of bronchiectasis and bronchiolitis on HRCT was more extensive in patients with GERD. An association between NTM lung disease and gastroesophageal disorders has been suggested in previous reports Hadjiliadis et al 26 reported 20 patients with NTM lung disease-associated esophageal disorders. Most patients had achalasia and pulmonary infection by rapid growers, such as Mycobacterium fortuitum or M abscessus. Griffith et al 27 reported that 6% (10 of 154 patients) with NTM lung disease caused by rapid growers such as M abscessus or M fortuitum had gastroesophageal disorder with chronic vomiting. Based on these reports, many authorities 2,28,29 have stated that GERD is one of the important predisposing factors for NTM lung disease and have recommended that patients with pulmonary disease caused by NTM, especially rapid growers, be questioned carefully about symptoms suggesting recurrent aspiration. However, rapid growers are relatively uncommon causes of NTM lung disease, whereas M avium complex is the most common cause in many countries. 1 Interestingly, M avium complex and M abscessus account for most of the pathogens in NTM lung disease in Korea. 3,30 The prevalence of 24-h esophageal ph probeproven GERD in our patients with NTM lung CHEST / 131 / 6/ JUNE,

4 Table 2 Results of the Questionnaire and 24-h Esophageal ph Monitoring in 58 Patients With the Nodular Bronchiectatic Form of NTM Lung Disease* Variables GERD Positive (n 15) GERD Negative (n 43) GERD symptoms 4 (27) 8 (19) Heartburn 3 (20) 5 (12) Regurgitation 4 (27) 5 (12) Reflux episodes 120 (50 178) 19.5 (7 34) 5-min reflux episodes 8 (5 10) 0 (0 1) Longest reflux episode, min 25 (16 39) 2 (1 5) Time of ph 4, % 9.6 ( ) 0.6 ( ) *Data are presented as No. (%) or median (interquartile range). Results were considered abnormal if the total time of ph 4 in the distal esophagus was 4%. disease was 26% (15 of 58 patients). The prevalence of GERD in the general population is very different from that in the study population. GERD is a common condition, and approximately 20% of the adult population have reflux symptoms at least once a week in the Western world, including the United States and the United Kingdom However, the prevalence of GERD in Asia is much lower than that in Western countries. The reported population prevalence of GERD in eastern Asia was 5% for at least weekly symptoms of heartburn or acid regurgitation In our cohort, 12 of 58 patients (21%) had at least weekly symptoms of GERD, fourfold that expected in the general population in our region. Unfortunately, the rate of ph probe-proven GERD in the general population in our region is unknown, making it impossible to estimate the differential frequency of ph probe-proven GERD in people with and without NTM lung disease. Most of our GERD patients were asymptomatic. This has been described in patients with other respiratory disorders. Harding et al 13 observed a prevalence of 16 of 26 abnormal 24-h esophageal ph tests results (62%) in asthma patients without reflux symptoms. Tobin et al 17 reported that only 4 patients (25%) had typical reflux symptoms among 16 patients with idiopathic pulmonary fibrosis with GERD. However, the necessity of using esophageal ph monitoring to detect clinically silent GERD in all patients with the nodular bronchiectatic form of NTM lung disease is unclear. An important finding of our study is that the involvement of bronchiectasis and bronchiolitis on HRCT was more extensive in patients with GERD. Table 3 Demographic Characteristics of GERD-Positive and GERD-Negative Patients With the Nodular Bronchiectatic Form of NTM Lung Disease* Characteristics GERD Positive (n 15) GERD Negative (n 43) p Value Age, yr 56 ( ) 57 ( ) Female gender 13 (87) 37 (86) Body mass index, kg/m ( ) 20.6 ( ) Smoking status Non-smoker 14 (93) 40 (93) Ex-smoker 1 (7) 3 (7) Etiology M avium complex 5 (33) 22 (51) M abscessus 10 (67) 21 (49) AFB smear positive 12 (80) 19 (44) Involved lobes on HRCT, No. Bronchiectasis 4 (3 4) 2 (2 3) Bronchiolitis 4 (3 5) 2 (2 4) Pulmonary function tests FVC, % of predicted 93.0 ( ) 87.0 ( ) FEV 1, % of predicted 92.5 ( ) 88.0 ( ) FEV 1 /FVC, ratio 76.0 ( ) 74.0 ( ) Peak expiratory flow, % of predicted 92.0 ( ) 96.0 ( ) *Data are presented as the median (interquartile range) or No. (%). Bronchiolitis was defined as the presence of small centrilobular nodules ( 10 mm in diameter) or branching nodular structures (tree-in-bud pattern) on HRCT Original Research

5 Bronchiectasis Bronchiolitis P = P = No. of invloved lobes GERD-negative GERD-positive 0 GERD-negative GERD-positive Figure 1. Box-and-whiskers graph of the quantitative imaging analysis showing the number of involved lobes with bronchiectasis and bronchiolitis. Bronchiolitis is defined as the presence of centrilobular small nodules ( 10 mm in diameter) or branching nodular structures (tree-in-bud pattern) on HRCT. The ends of the boxes indicate the 25th and 75th percentiles, and the lines in the bars indicate the median value. The 10th and 90th percentiles are indicated with whiskers. In the patients without GERD, the median numbers of involved lobes with bronchiectasis and bronchiolitis are both 2. In the patients with GERD, the median numbers of involved lobes with bronchiectasis and bronchilitis are both 4. Bronchiectasis and bronchiolitis were observed in more lobes in pateints with GERD than in patients without GERD (p and p 0.009, respectively). In addition, patients with GERD were more likely to have AFB-positive sputum smear results in comparison with patients without GERD. These findings suggest that further studies to investigate the nature of the association between GERD and NTM lung disease are needed. If GERD is causative, its treatment may be critical. If GERD is secondary to more advanced lung disease, its treatment may be less important in managing the lung disease. Our study had some limitations. First, this study did not include a control group. However, our principal goal was to investigate the prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease, and ours is the only study to use 24-h ph monitoring to determine this. Second, a significant proportion (34 of 92 patients, 37%) of screened patients did not perform 24-h esophageal ph monitoring. Then, the study group did not accurately reflect total population of patients with NTM lung disease. In particular, the study group had a significantly higher proportion of patients with M abscessus infection than the total group. This is very significant because it has been shown that patients with M abscessus infection have a higher rate of gastroesophageal abnormalities. Third, we used accepted criteria used by gastroenterologists for the diagnosis of GERD, but these may not apply for a person to be susceptible to NTM infection by possible aspiration. For example, it is not known if someone has to have a ph 4 for 4% of the study time to place NTM in his or her lungs. Also, the patients were only studied for 24 h, which does not exclude that aspiration may have occurred at other times not studied. Although we showed that GERD is prevalent in patients with NTM lung disease, the nature of this relationship remains uncertain. Our study was not designed to investigate a possible causal association between GERD and NTM lung disease. Our data are consistent with GERD causing or contributing to the development or progression of NTM lung disease via recurrent exposure of the pulmonary parenchyma to the acidity of the refluxed gastric contents. Alternatively, GERD might be a secondary phenomenon. Patients with NTM lung disease might be at increased risk for abnormal reflux because of the increased pressure gradient across the diaphragm during frequent coughing and changes in pulmonary mechanics. In addition, non-acid reflux as well as acid reflux may be present in patients with NTM lung disease. The measurement of acid reflux using esophageal ph monitoring is just a marker for possible aspiration but may not be related to the pathogenesis of NTM infection. In fact, it is possible that the increased use of acid suppressants with a resultant aspiration of relative alkaline ph into the esophagus may actually make the environment more favorable to NTM infection and the relative alkaline ph exacerbate further aspiration. In conclusion, our study showed that patients with the nodular bronchiectatic form of NTM lung disease have a high prevalence of GERD. However, most patients with NTM lung disease and GERD lacked the typical symptoms of heartburn and regur- CHEST / 131 / 6/ JUNE,

6 gitation. Patients with GERD were more likely to have AFB-positive sputum smear results. In addition, the involvement of bronchiectasis and bronchiolitis on HRCT was more extensive in patients with GERD that in those without GERD. Further studies are needed to clarify if there is a causal association between GERD and NTM lung disease. References 1 American Thoracic Society. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997; 156:S Field SK, Cowie RL. Lung disease due to the more common nontuberculous mycobacteria. Chest 2006; 129: Koh WJ, Kwon OJ, Lee KS. Diagnosis and treatment of nontuberculous mycobacterial pulmonary diseases: a Korean perspective. J Korean Med Sci 2005; 20: Guide SV, Holland SM. Host susceptibility factors in mycobacterial infection: genetics and body morphotype. Infect Dis Clin North Am 2002; 16: Hwang JH, Koh WJ, Kim EJ, et al. 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