Increased Prevalence of Gastroesophageal Reflux in Patients with Idiopathic Pulmonary Fibrosis

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1 Increased Prevalence of Gastroesophageal Reflux in Patients with Idiopathic Pulmonary Fibrosis RICHARD W. TOBIN, CHARLES E. POPE II, CARLOS A. PELLEGRINI, MARY J. EMOND, JIM SILLERY, and GANESH RAGHU Department of Medicine, Division of Gastroenterology and Pulmonary/Critical Care, and Departments of Surgery and Biostatistics, University of Washington, Seattle, Washington Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) of unknown etiology. Introduction of acid into the respiratory tree can produce pulmonary fibrosis. Gastroesophageal reflux (GER) has previously been associated with several other respiratory conditions, including pneumonia, bronchitis, and asthma. To investigate prospectively the possible association of GER and IPF, 17 consecutive patients with biopsy-proven IPF and eight control patients with ILD other than IPF underwent dual-channel, ambulatory esophageal ph monitoring. Sixteen of 17 patients with IPF had abnormal distal and/or proximal esophageal acid exposure compared with four of eight control patients (p 0.02). In the patients with IPF, mean percent distal total (13.6 versus 3.34, p 0.006), distal upright (12.4 versus 5.1, p 0.04), distal supine (14.7 versus 0.88, p 0.02), and proximal supine (7.48 versus 0.24, p 0.04) esophageal acid exposure times were significantly greater than those in control patients. Only four patients with IPF (25%) with increased acid exposure had typical reflux symptoms such as heartburn or regurgitation. Patients with IPF have a high prevalence of increased esophageal acid exposure, usually without typical GER symptoms. GER in these patients tends to occur at night and extend into the proximal esophagus. Acid reflux may be a contributing factor in the pathogenesis of IPF. Tobin RW, Pope CE, II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. AM J RESPIR CRIT CARE MED 1998;158: Interstitial lung disease (ILD) is a heterogeneous group of acute and chronic, noninfectious, benign parenchymal lung diseases characterized by diffuse pulmonary infiltrates, exertional dyspnea, restrictive lung defects with decreased diffusing capacity of carbon monoxide (DL CO ), and histologic evidence of varying degrees of pulmonary inflammation and fibrosis (1). Although host susceptibility factors remain poorly understood, recent concepts in the pathogenesis of ILD have evolved with further understanding of parenchymal inflammation and fibrosis. Several proinflammatory and profibrotic cytokines, cellular and molecular mechanisms have been implicated as contributory factors (2). Progressive inflammation of the pulmonary parenchyma can lead to impairment of gas exchange, fibrosis, and pulmonary impairment. In many instances, the initiating inflammatory event is recognized such as exposure to toxic gases, dusts, certain medications, fibrogenic agents, or as part of a systemic autoimmune disease. However, many patients with interstitial lung disease have no identifiable initiating inflammatory event, and these patients are classified as having idiopathic pulmonary fibrosis (IPF). (Received in original form April 21, 1998 and in revised form July 13, 1998) Correspondence and requests for reprints should be addressed to Ganesh Raghu, M.D., Division of Pulmonary and Critical Care Medicine, Box , Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA Am J Respir Crit Care Med Vol 158. pp , 1998 Internet address: IPF is a specific clinical syndrome, which is considered by some as the prototype of ILD. IPF usually occurs in adults beyond the fifth decade of life, is progressive, and is uniformly fatal, with a mean survival of 4 to 5 yr. No cure is available, and current treatment strategies are ineffective (3). Proposed initiating inflammatory mechanisms for the progressive fibrosis seen in IPF have included unrecognized autoimmune disease (4), unrecognized viral infection (5), and gastroesophageal reflux (GER) (6). GER has been previously associated with several airway manifestations, including chronic bronchitis (7), recurrent pneumonia (8, 9), chronic cough (10), hoarseness (11), and asthma (7, 12). In both animal models (13, 14) and humans (15), pulmonary fibrosis can occur after aspiration of gastric contents. Thus, we set out to prospectively investigate the possible association of GER and IPF. METHODS Seventeen consecutive patients with newly diagnosed IPF and eight patients with ILD other than IPF were evaluated in the interstitial lung disease clinic at the University of Washington Medical Center and underwent dual-channel, ambulatory esophageal ph monitoring. All patients with IPF had an extensive evaluation, including: a thorough medical history with negative exposure history; no serologic evidence of autoimmune disease; chest radiograph with diffuse parenchymal, basilar-predominant infiltrates; pulmonary function tests with restrictive lung defect and decreased diffusing capacity of carbon monoxide corrected to hemoglobin (DL CO c); and histologic features of usual interstitial pneumonia on surgical lung biopsy. Eight consecu-

2 Tobin, Pope, Pellegrini, et al.: Gastroesophageal Reflux in Idiopathic Pulmonary Fibrosis 1805 tive patients with ILD other than IPF served as control patients. These control patients had symptoms, chest radiographs, and pulmonary function test results similar to those of the patients with IPF. However, they were found to have identifiable syndromes known to be associated with the development of pulmonary fibrosis. These syndromes included sarcoidosis (four patients), systemic lupus erythematosus (one patient), mixed connective tissue disease (one patient), bronchiolitis obliterans organizing pneumonia (one patient), and Langerhans cell granulomatosis (one patient). Patients with sarcoidosis, bronchiolitis obliterans organizing pneumonia, and Langerhans cell granulomatosis had characteristic histopathologic findings on surgical lung biopsy. Patients with systemic lupus erythematosus and mixed connective tissue disease had appropriate autoimmune markers and clinical presentations consistent with these diseases (16, 17). All patients signed an informed consent approved by the human subjects committee at the University of Washington. Pulmonary function testing, including DL CO c was performed within 2 mo of entrance to the study. At the time of ambulatory ph monitoring, a second investigator completed a structured interview with the patient. This interview included obtaining a careful history of pulmonary symptoms, gastroesophageal reflux symptoms, medications, ethanol intake, and tobacco use. Height and weight were also recorded. Ambulatory esophageal ph monitoring was carried out using a 2.1-mm ph catheter with two monocrystalline antimony electrodes (Medtronic Synectics, Shoreline, MN). The ph electrodes were calibrated at 37 C in ph 7.0 and 1.0 buffer solutions (Medtronic Synectics), before and after each study was completed. After calibration, the catheter was placed transnasally into the esophagus. The catheter was positioned so that the distal ph sensor was 5 cm and the proximal ph sensor 15 cm proximal to the lower esophageal sphincter using the ph step-up method (18) or by manometry. Manometric placement was used in eight of the 25 patients (five of 17 patients with IPF and three of eight of the control patients). The ph electrodes were connected to a portable digital data recorder (Mark III Gold; Medtronic Synectics), which stored ph data every 4 s for as long as 24 h. Patients returned home with careful instructions to record in a diary the exact time of all symptoms such as heartburn, regurgitation, chest pain, cough, or nausea as well as their meal times, time of lying down for sleep, and time of rising in the morning. Patients were encouraged to carry out their normal daily activities, including their usual eating and sleeping habits. Patients returned the next day after 20 to 24 h of recording. Their catheters were removed, and their diaries were reviewed by two different investigators. Portable digital data recorders were downloaded into a computer and analyzed using Esophagram software (Medtronic Synectics). Abnormal distal esophageal acid exposure was identified when the ph was less than 4 for greater than or equal to 4.5% of the total time in the distal esophagus (19). Abnormal proximal esophageal acid exposure was noted if the ph was less than 4 for greater than or equal to 1% of the total time (19). Symptoms were said to correlate with reflux episodes in the distal esophagus, proximal esophagus, or both if the ph dropped to less than 4 in the appropriate channel in the 2 min preceding the symptom (20). All symptom analysis was confirmed by visual analysis of the expanded ph tracing by the same investigator. Baseline characteristics of the two groups were compared using a two sample t test or Fisher s exact test as appropriate. To test for differences in esophageal acid exposure between groups, Welch s t test was used after log transformation of the percent acid exposure time to create normally distributed data (21). Multiple linear regression models of the log-transformed percent acid exposure times were used to adjust for potential confounding by age, sex, body mass index (BMI), percent DL CO c, prednisone use, and -agonist inhaler use. These variables were entered singly and jointly into the models along with the presence or absence of IPF to test for confounding. TABLE 1 CHARACTERISTICS OF PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS (IPF) AND INTERSTITIAL LUNG DISEASE (ILD) OTHER THAN IPF Variable IPF ILD Other than IPF p Value Patients, n 17 8 Mean age, yr 57.9 (39 80)* 49.8 (42 56)* 0.06 Female patients, n Mean body mass index 28.7 ( )* 30.6 ( )* 0.60 Mean corrected DL CO, % pred 35.9 (9 62)* 55.3 (23 96)* 0.09 Patients receiving prednisone, n Patients receiving inhaled -agonists * Values in parentheses are ranges. t test. Fisher s exact test. The body mass index was defined as the weight in kilograms divided by the square of the height in meters. Corrected to blood hemoglobin concentration. differences were statistically significant. Although some of the patients with IPF and some of the control patients had smoked cigarettes in the past, none had smoked within 6 mo of the ph study. All patients with IPF and control patients denied having more than two alcoholic drinks per day at the time of the ph study. Only two of 17 patients with IPF and one of eight patients with ILD other than IPF were receiving inhaled beta-agonists at the time of the ph study (p 1.00). Eight of 17 patients with IPF and three of eight control patients were receiving prednisone at the time of their ph study (p 1.00). Two patients were receiving an investigational antifibrotic agent (perfenidone) at the time of their ph study in an ongoing Phase 2 clinical trial. No patients were receiving theophylline at the time of their ph study. RESULTS Nine men and eight women with IPF, and seven women and one man with pulmonary fibrosis other than IPF were studied. Patients with IPF were older, more likely to be male, and had poorer pulmonary function (as measured by DL CO c) than patients with ILD other than IPF (Table 1), but none of these Figure 1. Percent of total time ph is less than four in patients with idiopathic pulmonary fibrosis (IPF) and control patients with interstitial lung disease (ILD) other than IPF. Each closed circle represents one patient with IPF or one control patient with ILD other than IPF. Horizontal bars represent the mean value for each column.

3 1806 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL The percent of the total time during which the ph was less than 4 in the distal and proximal esophagus for patients with IPF and control patients with ILD other than IPF is shown in Figure 1. Sixteen of 17 (94%) patients with IPF had abnormal acid exposure in the distal and/or proximal esophagus. Eleven patients with IPF had abnormal distal and proximal acid exposure, four had abnormal distal acid exposure only, and one had only abnormal proximal acid exposure times. In the eight control patients with pulmonary fibrosis other than IPF, four (50%) had abnormal distal and/or proximal acid exposure (p 0.02 compared with the IPF group, Fisher s exact test). Three of these patients had abnormal distal and proximal values, and one had abnormal proximal exposure only. Examining acid exposure times in the supine position only, patients with IPF had more supine reflux than did the control patients (Figure 2). Comparing the mean percent acid exposure times between the IPF and control groups in the distal esophagus, there were significant differences for total (13.6 versus 3.34, p 0.006), upright (12.4 versus 5.1, p 0.04), and supine reflux (14.7 versus 0.88, p 0.02) (Table 2). In the proximal esophagus, there was a significant difference between the IPF and the control group in the mean percent acid exposure time in the supine position (7.5 versus 0.2, p 0.04) (Table 2). Mean percent total time and acid exposure time in the proximal esophagus and mean percent acid exposure time in the proximal esophagus while in the upright position were not significantly different between the patients with IPF and those with ILD other than the IPF group using the t test. Results were materially unchanged after controlling for potential confounders (sex, age, lung function as measured by percent DL CO c, BMI, prednisone use, or -agonist use), although prednisone use was itself significantly associated with greater percent total time ph less than 4 in the distal esophagus (p 0.04). There was no association between lung function (as measured by DL CO c) and acid exposure times in this study (p 0.4 for all acid exposure times). Of particular note, 12 of the 16 patients (75%) with IPF and abnormal reflux did not have the typical GER symptoms TABLE 2 MEAN PERCENT TIME ph IS LESS THAN FOUR IN THE DISTAL AND PROXIMAL ESOPHAGUS IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS (IPF) AND CONTROL PATIENTS WITH INTERSTITIAL LUNG DISEASE (ILD) OTHER THAN IPF Variable of heartburn or regurgitation. No control patients with abnormal reflux had symptoms of heartburn or regurgitation. Not surprisingly, the most prominent symptom in both groups was cough. Cough occurred in all patients during the monitoring period. Patients with IPF experienced an average of 17.5 coughs per recording session versus 23.1 coughs per recording session for control patients. Patients with IPF and abnormal reflux averaged 17.6 coughs per recording session. Cough correlated with acid reflux in the esophagus in only 83 of 297 (28%) of the episodes in patients with IPF, and in 38 of 185 (21%) of the episodes in patients with pulmonary fibrosis other than IPF. In patients with IPF and abnormal reflux, coughs correlated in 83 of 282 episodes (29%). In the four patients with IPF and symptoms of heartburn, a total of nine episodes of heartburn were recorded. All of these heartburn episodes correlated with acid reflux into the esophagus. DISCUSSION Patients with IPF* Patients with ILD Other than IPF* p Value Distal, total percent time 13.6 ( ) 3.34 ( ) Distal, upright percent time 12.4 ( ) 5.1 (0 15.9) 0.04 Distal, supine percent time 14.7 (0 70.6) 0.88 ( ) 0.02 Proximal, total percent time 5.52 ( ) 2.01 ( ) 0.16 Proximal, upright percent time 3.86 ( ) 3.23 (0 11.2) 0.35 Proximal, supine percent time 7.48 (0 43.4) 0.24 (0 1.0) 0.04 * Values in parentheses are ranges. Welch s t test of log-transformed percentages. IPF is a chronic debilitating disease of unknown etiology characterized by progressive pulmonary fibrosis and impairment of gas exchange with eventual secondary pulmonary hypertension, cor pulmonale, and death. Gastroesophageal reflux may be one of the initiating factors of IPF or it may be a secondary phenomenon. Using ambulatory esophageal ph monitoring, we found that IPF is highly associated with abnormal acid exposure in the esophagus. Furthermore, patients with IPF have significantly more esophageal acid reflux than do patients with ILD other than IPF. However, most patients with IPF and abnormal esophageal acid exposure do not have typical symptoms of GER such as heartburn or regurgitation. Particularly intriguing is our finding of increased proximal acid exposure in TABLE 3 PROXIMAL ESOPHAGEAL REFLUX IN HEALTHY CONTROL PATIENTS Reference Patients (n) Distance Above Lower Esophageal Sphincter Percent Total Time ph Is Less than 4 Percent Supine Time ph Is Less than 4 Figure 2. Percent time ph is less than four in the supine position in patients with idiopathic pulmonary fibrosis (IPF) and control patients with interstitial lung disease (ILD) other than IPF. Each closed circle represents one patient with IPF or one control patient with ILD other than IPF. Horizontal bars represent the mean value for each column. Singh, et al. (22) (0 11)* 0.4 (0 24.7)* Gastal, et al. (23) (0 0.5)* Weusten, et al. (24) (0.16) 0.04 (0.03) Patti, et al. (25) (0.8) Dobhan, et al. (19) (0.9) 0.0 (0.0) * Median (range). Mean (standard deviation). Median (95th percentile).

4 Tobin, Pope, Pellegrini, et al.: Gastroesophageal Reflux in Idiopathic Pulmonary Fibrosis 1807 the supine (nocturnal) position in patients with IPF. Proximal supine reflux is very unusual in healthy patients (Table 3). Similar to that in our patients with IPF, proximal nocturnal acid exposure is increased in patients with reflux laryngitis (26). Given the additional evidence that resting upper esophageal sphincter pressure is greatly reduced during sleep (27), protective cough reflexes are suppressed during sleep, and nocturnal aspiration is common even in healthy control subjects (28), a possible pathophysiologic mechanism for IPF is strongly suggested. Other pulmonary manifestations associated with gastroesophageal reflux have previously been noted. In fact, as much as up to 80% of patients with adult-onset asthma (29), 75% of patients with chronic hoarseness (11), and 20% of patients with chronic cough have evidence for abnormal GER (10). In a small number of selected asthmatics, a drop in proximal esophageal and tracheal ph has been shown to be correlated with decreased peak airway flow measurements (30). Survivors of massive acute aspiration of gastric contents can develop pulmonary fibrosis (15) and experimental installation of acid into animal lungs can also cause pulmonary fibrosis (13, 14). Using barium radiography (a relatively insensitive measure of reflux), Mays and colleagues (31) demonstrated an increased prevalence of hiatal hernia and gastroesophageal reflux in patients with IPF when compared with control patients and patients with other types of ILD. Identifying patients with GER-associated pulmonary manifestations can be difficult as these patients often do not have typical GER symptoms such as heartburn or regurgitation (11, 32). Proving a causal relationship between GER and pulmonary disease is problematic because some patients may also have both conditions without a causal relationship. In addition, patients with pulmonary disease may be at increased risk for abnormal reflux because of increased pressure gradients across the diaphragm, changes in pulmonary mechanics, or possibly secondary to medication effects. In fact, four of the eight patients in this study with pulmonary fibrosis other than IPF did have evidence of abnormal esophageal acid reflux, although the mean acid exposure time was less in the proximal esophagus and significantly less in the distal esophagus compared with patients with IPF. There was no association between lung function (as measured by DL CO c) and acid exposure times in this study. Furthermore, significant differences in acid exposure times between the patients with IPF and the control patients remained after controlling for DL CO c. These results suggest that differences in lung function do not explain the differences in acid exposure between the two groups in this study. Similarly, the use of beta-agonists or prednisone did not change the results of this study. The best available method to demonstrate that GER may be contributing to pulmonary disease is to treat the GER and observe if the pulmonary disease improves. In a recent review, 42 of 54 patients with chronic cough or asthma suspected to be due to reflux had abnormal acid reflux documented by dualchannel, ambulatory ph monitoring. Seventy-one percent of these documented reflux patients had good to excellent response in their pulmonary symptoms when treated with antireflux therapy, whereas none of the patients without abnormal reflux on ambulatory ph monitoring had improvement of their pulmonary symptoms with antireflux therapy (33). A prospective cohort study of 36 selected asthmatics revealed that 73% had improvement in asthma symptoms or peak expiratory flow rates after a 3-mo course of acid-suppressive therapy with omeprazole (34). In a randomized, placebo-controlled study of selected asthmatics in Chile, patients treated with cimetidine or surgery had significant improvement in asthma symptoms and medication scores after 6 mo compared with those given placebo (35). Perhaps a more impressive result in this same study is the finding that 11 of 22 patients treated with antireflux surgery versus only 1 of 20 patients treated with placebo were free of respiratory symptoms at the 6-yr follow-up. Given that IPF is often a slowly progressive disease that does not have a clearly reversible component, as does asthma, prospective treatment trials are difficult to undertake. However, prospective, long-term treatment trials may be the only way to clearly document whether gastroesophageal reflux is a cause of IPF. In our study, several factors could have influenced the results. A referral bias could have occurred because all of our patients were referred to a well-established ILD clinic. However, IPF is an unusual and serious disease, and thus we believe that most symptomatic patients with this disease process will be seen at a tertiary center. Although several other patients with IPF referred to our ILD clinic had abnormal ambulatory esophageal ph monitoring tests, these tests were performed outside of the University of Washington Swallowing Center. These patients were excluded from this study because we could not verify the reasons for performing the test or the methods used to perform it. No patients referred specifically for GER symptoms were included in this study. We further attempted to avoid selection bias by offering entrance into the study to all other consecutive patients with IPF presenting to the ILD clinic. Patients were not selected because of presence or absence of reflux symptoms and, in fact, only four of 17 patients with IPF had any symptoms of heartburn or regurgitation on detailed questioning. Accurate placement of the ph sensors is critical to ambulatory esophageal ph monitoring. Placement of the ph catheter too proximal in the esophagus (hypopharyngeal placement) can lead to drying of the proximal ph sensor and falsely elevated proximal acid exposure times. Similarly, if the probe is placed too distal, the distal ph sensor will be closer to or within the stomach, and distal acid exposure times will be falsely elevated. Optimal placement can be accomplished using manometry; however, the ph step-up method has been validated (18) and was used in most patients in this study. Two investigators independently reviewed each ph tracing in this study for evidence of gastric placement of the distal esophageal sensor or hypopharyngeal placement of the proximal ph sensor. The frequent finding of abnormal acid exposure in both the proximal and the distal esophageal ph electrodes in the same patient also suggests that ph catheter placement was not a major factor in the outcome of this study. In conclusion, our study has shown that patients with IPF have a high prevalence of abnormal esophageal acid exposure. GER in these patients tends to occur at night and often extends into the proximal esophagus. Most patients with IPF and GER do not have the typical symptoms of heartburn or regurgitation. GER may be an etiologic factor in patients with IPF. Further studies are needed to see if aggressive, chronic treatment of GER in these patients might be able to improve or halt further progression of their pulmonary disease. 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