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S1070 Effect of Lansoprazole On Extraesophageal Manifestations of GERD in a Rat Chronic Acid Reflux Esophagitis Model
AGA Abstracts
1980 criteria; 7 diffuse and 17 limited SSc) using MII-pH monitoring. PPI therapy was discontinued >30 days prior the exam. We measured distal esophageal acid exposure (% time pH<4), number of reflux episodes (acid,nonacid) and proximal migration of the refluxate (15cm above LES). All patients underwent CT pulmonary scan to evaluate their degree of pulmonary fibrosis using a validated HRCT score (Warrick et al. J Rheumatol 1991) Results: Of 24 patients (21F,median age 53yrs;range 27-71), 10 (42%) had a positive pulmonary fibrosis score (HRCT score ≥7). Total number (median[25th-75th perc]) of reflux episodes in the distal esophagus was higher in patients with abnormal vs. normal HRCT (67.5[5396] vs 31[15-39];p<0.001). The same was true for reflux episodes reaching the proximal esophagus (46[43-66] vs 13.5[9-19];p<0.001). In addition there was a very good correlation between the degree of pulmonary fibrosis (HRCT score) and number of reflux episodes in the distal (r2=0.623,p<0.001) and proximal (r2=0.647,p<0.001) esophagus. Both patient groups had similar distal esophageal acid exposures (4.3[2.3-12.6] vs. 3.7[2.4-4.9]; p=ns). Conclusions: While confirming prior data on the role of GER in the pathogenesis of pulmonary fibrosis, the present study documents a correlation between severity of pulmonary findings and frequency of GER episodes. The study provides new targets in the treatment of reflux disease aimed at preventing progression of pulmonary fibrosis.
patients (25 SSLTx, 10 SLTx, 2 HLTx) to assess the predictive value of BAL 3 mo after LTx. Stable patients had no BOS and a followup > 36 mo after LTx, BOS patients had BOS grade ≥ 1. Compared to 14 non transplant controls, pepsin and bile acids were considered positive if > 25.4 ng/ml and if > 0.22 µM, respectively. Results: 16/18 stable LTx patients were positive for pepsin in BALF 3 mo and remained positive at 12 mo. 14/18 stable LTx had no bile acids in the BALF at 3 mo and 12 of these patients remained negative for bile acids 12 mo after LTx. In the case-control study, BAL was compared between 18 patients who developed BOS and 19 who did not. 33/37 tested positive for pepsin in the BALF (237,1072158 ng/ml), whereas 14/37 tested positive for bile acids (0.96, 0.26-2.39 µM). 10/14 (71%) patients with bile acids in the BALF developed BOS compared to 16/33 (48.5%) patients with positive pepsin levels. Bile acids had a higher specificity (78.9%), positive predictive value (71%) and negative predictive value (65%) for the development of BOS than pepsin. Conclusions: Presence of pepsin and bile acid in BALF is repeatable 3 months and 1 year after LTx. Presence of bile acids in BAL 3 mo after LTx is more specific and a better predictor for the development of BOS than the presence of pepsin.
S1066 Gastroesophageal Reflux and Aspiration of Gastric Contents in Adult Patients with Cystic Fibrosis Kathleen Blondeau, Lieven Dupont, Veerle Mertens, Geert M. Verleden, Anne Malfroot, Yvan Vandenplas, Bruno Hauser, Daniel Sifrim
S1069 New Approach to the Treatment of Laryngopharyngeal Reflux Symptoms Using Rikkunshito (Japanese Herbal Medicine TJ-43) in Patients Who Responded Poorly to Acid Suppression Therapy Nobuhiko Oridate, Hiroshi Takeda, Yasushi Mesuda, Noriko Nishizawa, Masahiro Asaka, Satoshi Fukuda
It is known that GER is increased in cystic fibrosis (CF), however, its prevalence, characteristics, association with gastric aspiration and respiratory impact are not well characterized. We investigated acid and weakly acidic (WA) reflux, gastric aspiration and respiratory symptoms/function in adult patients with CF. Methods: Thirty-three CF patients [19men; 29(18-55) years] underwent impedance-pH monitoring for detection of acid (pH<4) and WA GER (pH4-7). In 16 patients cough was objectively recorded with esophageal manometry. Saliva and Bronchoalveolair Lavage Fluid (BALF) were tested for the presence of bile acids (BA). Results: Twenty-eight patients had increased GER (21acid, 5WA and 2 acid+WA) and 10 patients had a +SAP for reflux-cough. GER was a primary event in CF. The sequence cough-reflux was uncommon. 16/38 patients had BA in saliva and 6/10 patients in BALF and this was almost exclusively observed in patients with genotype DF508/DF508. Only 12/28 with increased GER and 9/22 with BA in saliva/BALF had typical reflux symptoms. There was a positive correlation (r=0.53, p=0.03) between esophageal acid exposure and cough and patients with +SAP for reflux-cough had a lower lung function (FEV1%pred) than -SAP patients. Conclusion: Increased GER is prevalent and a primary phenomenon in CF. Acid GER is most common, but WA GER may also occur. Patients with CF have a high risk for gastric aspiration and reflux seems to be associated with more cough and poorer lung function. Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in the evolution of CF.
Background: According to the “The Montreal Definition”, chronic laryngitis is closely related to gastroesophageal reflux disease (GERD). GERD-related chronic laryngitis is often called laryngopharyngeal reflux (LPR). Patients having LPR complain of abnormal laryngopharyngeal sensation, chronic cough, throat clearing, and voice disorder. Although acid suppression using proton pump inhibitors (PPI) has been generally accepted as the first choice of treatment, this new definition makes it clear that medical and surgical treatment trials aimed at improving suspected LPR by treating GERD are associated with uncertain and inconsistent treatment effects. In fact, the effect of PPI is limited in some LPR patients. There is no systematic research on any supplementary treatments using gastrointestinal prokinetic agents in such patients. Therefore, we evaluated the effects of rikkunshito (TJ-43), a gastrointestinal prokinetic agent, on LPR symptoms in patients who showed a poor response to PPI treatment. Methods: The study subjects comprised patients who attended the Department of Otolaryngology at Hokkaido University Hospital (Japan) for their LPR symptoms, had shown a poor response to PPI treatment of at least 2 month's duration, and had requested additional therapy for the remaining symptoms. We saw 20 such patients (12 male and 8 female; mean age, 56.9 years) between October 2004 and September 2007. Their laryngopharyngeal (extraesophageal) and typical esophageal symptoms of GERD such as a heartburn and regurgitation were recorded using the LPR symptoms scoring system based on the Reflux Symptom Index proposed by Belafsky et al. We retrospectively evaluated the changes of these symptoms in each patient before and after of TJ-43 administration in comparison with pre-PPI treatment. Results: Before PPI treatment, the average scores for laryngopharyngeal and esophageal symptoms were 6.4 (full score: 12 points) and 2.0 (full score: 5 points), respectively. The mean scores for laryngopharyngeal and esophageal symptoms after the PPI treatment (median 7.0 months) were 4.2 and 0.9, respectively. The average symptom residual rates were then calculated as 78.5% and 47.8% of the pre-PPI treatment. Additional administration of TJ43 for a median 3.3 months decreased laryngopharyngeal and esophageal symptoms to 1.9 and 0.2 (symptom residual rates: 38.3% and 7.2% of the pre-PPI treatment), respectively. Improvement of LPR symptoms by addition of TJ-43 was observed in 16 of 20 patients. Conclusions: Supplementary administration of TJ-43 in addition to PPI was effective in patients who showed a poor response to acid suppression therapy alone.
S1067 Nocturnal Weakly Acidic Reflux Promotes Aspiration of Bile Acids in Lung Transplant Recipients Kathleen Blondeau, Veerle Mertens, Bart M. Vanaudenaerde, Robin Vos, Dirk E. Van Raemdonck, Geert M. Verleden, Lieven Dupont, Daniel Sifrim Background: Gastroesophageal reflux (GER) and bronchial aspiration of bile acids have been implicated as non-alloimmune risk factors for the development of Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation. The aim of our study was to investigate the association between GER and gastric aspiration of bile acids and to establish which reflux characteristics may promote aspiration of bile acids into the lungs and may feature as a potential diagnostic tool in identifying LTX patients at risk for bile acid aspiration Methods: Twenty-four stable LTx recipients were studied 1 year after transplantation. All patients underwent 24 hrs ambulatory impedance-pH recording for the detection of acid (pH <4) and weakly acidic (pH 4-7) reflux. On the same day, bronchoalveolar lavage fluid (BALF) was collected and was analyzed for the presence of bile acids (enzymatic assay, Bioquant). Results:Thirteen patients had increased GER, of which 9 patients had increased acid reflux and 4 patients had exclusively increased weakly acidic reflux. Sixteen patients had detectable bile acids in the BALF (0.6 (0.4-1.5) µmol/L). Five patients with bile acids in BALF did not have typical reflux symptoms. The 24 hr esophageal volume exposure was significantly increased in patients with bile acids compared to patients without bile acids in the BALF. Acid exposure and the number of reflux events (total, acid and weakly acidic) were unrelated to the presence of bile acids in the BALF. However, the nocturnal volume exposure and the number of nocturnal weakly acidic reflux events were significantly higher in patients with bile acids in the BALF. Conclusions: Weakly acidic reflux events especially during the night are associated with the aspiration of bile acids in LTX recipients and might therefore feature as a potential risk factor for the development of BOS.
S1070 Effect of Lansoprazole On Extraesophageal Manifestations of GERD in a Rat Chronic Acid Reflux Esophagitis Model Daisuke Asaoka, Akihito Nagahara, Yuko Izumi, Akihiko Kurosawa, Masato Kawabe, Mariko Hojo, Sumio Watanabe (Background and aim)There is uncertainty about the mechanisms for development of reflux esophagitis and extraesophageal manifestations of GERD. PPI is reported to have an effect on extraesophageal manifestations of GERD, however there is few histology examination about this syndrome. This study aimed to investigate whether the inflammation would occur near the laryngopharynx and PPI would have protective effect on esophageal mucosa including near the laryngopharynx using a newly developed rat chronic acid reflux esophagitis model. (Method)Chronic acid reflux esophagitis in rats was developed by modified Omura's method. Esophagitis group (n=9) was not taken any drugs after the operation. Lansoprazole group (n=8) was administered Lansoprazole (1mg/kg) from the day1 to day 7 after the operation. Control group (n=5) underwent sham operation. Seven days after the surgery, all rats were sacrificed and removed their esophagus. Esophageal epithelial thickness, leukocyte infiltration and IL-1beta labeling index in mucosa was investigated in (A) the upper (approx. 5 mm under crico-pharyngeus), (B) the middle (midpoint between crico-pharyngeus and esophago-columnar junction, EC junction) and (C) the lower (approx. 0.5 mm upper EC junction) areas. The number of IL-1beta-positive cells at mucosa was counted in high-power fields and defined as labeling index, and inflammatory activity was evaluated. And (1) survival rate, (2) ulcer occurrence ratio, (3) the size of ulcers, and (4) the number of ulcer was investigated in esophagitis and Lansoprazole groups. (Results)In esophagitis group, mucosal thickness in the lower and middle areas was significantly increased (p<0.03) compared with that of controls and leukocyte infiltration in each three areas was significantly higher (p<0.03) than that of controls. In Lansoprazole group, mucosal thickness in the lower
S1068 Pepsin or Bile Acids: What Is the Best Marker of Gastric Aspiration in Lung Transplant Recipients? Veerle Mertens, Kathleen Blondeau, Bart M. Vanaudenaerde, Robin Vos, Dirk E. Van Raemdonck, Geert M. Verleden, Lieven Dupont, Daniel Sifrim Introduction: Increased gastroesophageal reflux (GER) and aspiration of gastric contents may favour the development of BOS. Markers of aspiration (pepsin and bile acids) in the BAL of LTx patients may feature as selection criteria for antireflux surgery. The aim was to compare the reproducibility and the predictive value for BOS development of pepsin and bile acids in BAL, obtained early after LTx. Methods: Repeatability of pepsin and bile acids levels was tested in 18 stable LTx patients (15 SSLTx, 3 SLTx) comparing BAL obtained at 3 mo and 12 mo after LTx. A retrospective case-control study was performed in 37 LTx
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to LAN in 2 identically-designed, double-blind, randomized, controlled trials in patients with EE (LA grades A-D) at global sites (188 US, 118 ex-US). 4092 H pylori-negative adult patients were to receive once-daily doses of TAK-390MR 60 or 90 mg, or LAN 30 mg. The primary efficacy endpoint was the overall healing rates by Week 8; analyses were conducted using both life-table and crude rate methods. A secondary variable was healing of EE with LA grades C or D by Week 8. RESULTS: For the primary endpoint, both TAK-390MR doses achieved the primary objective of non-inferiority to LAN in both studies. In study 1, healing rates using life table methods were 92.3% and 92.2% with TAK-390MR 60 mg (p= NS) and 90 mg (p=NS), respectively, and 86.1% with LAN. In study 2, healing rates were 93.1% and 94.9% with TAK-390MR 60 mg (p=NS) and 90 mg (p=NS), respectively, and 91.5% with LAN. In both studies, crude rates yielded similar treatment differences to lifetable methods for 8-week healing and demonstrated statistical superiority for TAK-390MR 90 mg over LAN. Results from the 2 trials were combined since they were identical in design with similar size and baseline demographics. Combined results demonstrated significantly higher overall healing rates for TAK-390MR 60 mg and 90 mg compared to LAN (Table); furthermore, TAK-390MR 90 mg was significantly superior to LAN in healing patients with LA grades C / D EE by Week 8. All treatments were generally well tolerated. Diarrhea was the most frequent treatment-related AE occurring in 3.1% of patients in the TAK-390MR groups and 2.1% on LAN. CONCLUSION: TAK-390MR (60 mg and 90 mg) was highly effective for the healing of all grades of EE. Combined results showed statistically significant superiority to LAN for both TAK-390MR doses and the 90 mg dose was significantly superior to LAN for healing moderate/severe EE. Both TAK-390MR doses demonstrated similar tolerability and safety profiles comparable to those of LAN.
S1071 Gastroesophageal Reflux in Idiopathic Pulmonary Fibrosis Patients Awaiting Lung Transplantation Yevgenia Pashinsky, Maria L. Padilla, Eric S. Goldstein, Barry W. Jaffin INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of the lung characterized by fibrosis of the lower respiratory tract. There is agreement that certain risk factors are associated with IPF including tobacco use, environmental exposures, medications, infectious respiratory pathogens and chronic aspiration. Among the current theories on the pathogenesis of IPF is the contribution of gastroesophageal reflux (GER). Recent data suggest that there may be an increase incidence in GER in patients who are status post lung transplantation. However, data on pre-lung transplantation patients without GER symptoms is lacking and the presence of manometric abnormalities in this subgroup has not been examined. AIM: To evaluate GER and esophageal manometry in patients with IPF awaiting lung transplantation. METHODS: We reviewed the 24 hour pH probe data (off proton pump medications) and esophageal manometry studies of 24 patients with IPF being evaluated for lung transplantation at the Mount Sinai Medical Center (New York, NY). Three patients were excluded from the analysis due to underlying scleroderma. RESULTS: For the 21 patients analyzed, the mean Johnson/DeMeester score was 28.3 with a median of 16.0. Forty three percent (9/21) of patients were found to have an abnormal Johnson/ DeMeester score (defined as >22). For these 9 patients, the mean Johnson/DeMeester score was 53.8 with a median of 41.6. The median upright reflux time for the 21 patients was 14.9% and median recumbent reflux time 10.6%. The manometry studies found the average LESP to be 18.9 mmHg and 15.5 mmHg among those with an abnormal Johnson/DeMeester scores. Incidentally, 5 out of 21 patients were noted to have an occult abnormal motility of the esophagus demonstrating <80% peristalsis. CONCLUSION: Our data demonstrate that GER and esophageal dysmotility are highly prevalent among IPF patients awaiting lung transplantation, thus supporting its role in the pathogenesis of the disease. More studies need to be done to evaluate the GER in both pre and post lung transplantation populations.
*P<0.05 vs LAN S1074 Tak-390MR, a Proton Pump Inhibitor with a Novel Dual Delayed Release Formulation, Maintains Healing and Controls Heartburn in GERD Patients with Healed Erosive Esophagitis David C. Metz, Colin W. Howden, Maria Claudia Perez, Lois M. Larsen, Janet M. O'Neil BACKGROUND: TAK-390MR is a delayed release formulation of an enantiomer of lansoprazole (LAN) with a dual-peaked pharmacokinetic profile. In phase 1 studies it increased mean intragastric pH and the % of time pH >4 over 24 hrs compared with LAN. The current trial assessed the efficacy and safety of TAK-390MR vs placebo (PBO) in maintaining healed erosive esophagitis (EE). METHODS: 445 adult patients with healed EE who completed 1 of 2 acute healing trials were enrolled in this randomized, double-blind trial at 94 centers (75 US; 19 ex-US). During the 6-month study, patients received TAK-390MR 30 or 60 mg or PBO once daily (QD) and had EGD at 1, 3, and 6 months. The primary efficacy variable was the % of patients who maintained healing over 6 months; analyses were conducted using life-table analysis and crude rates. Secondary variables were the % of 24-hour heartburnfree days and the % of nights without heartburn, based on patients' daily diaries. RESULTS: Both doses of TAK-390MR were statistically significantly superior to PBO for maintaining EE healing and for the % of 24-hour heartburn-free days and nights (Table). There were no significant differences between the 2 TAK-390MR treatment groups for these endpoints. The therapeutic gain in maintenance rates for TAK-390MR vs PBO was similar by life table (48%-55%) and crude rate analysis (52%). There was a therapeutic advantage (16% by crude rate, 22% by life table) for TAK-390MR 60 mg over the 30 mg dose in patients with moderate to severe EE at baseline. Both TAK-390MR doses showed highly effective control of heartburn with medians of 91%-96% for 24-hour heartburn-free days, and 96%-99% for heartburn-free nights. The more commonly reported AEs for TAK-390MR with higher frequency than PBO were upper respiratory tract infections, diarrhea, musculoskeletal/ connective tissue and joint-related signs & symptoms. CONCLUSION: TAK-390MR 30 and 60 mg QD were highly effective and statistically significantly superior to PBO at maintaining EE healing over 6 months and relieving heartburn. Most patients receiving TAK390MR were heartburn-free for over 90% of treatment days. TAK-390MR was well tolerated.
S1072 Reflux Characteristics in Asthmatic Patients Refractory to Acid Suppression As Defined By Impedance Testing Jeremy M. Alvord, Kristen Thomas, Wayne Samuelson, John C. Fang, Kathryn A. Peterson Background:The association between asthma and gastroesophageal reflux (GER) has been the subject of intensive research. GER occurs commonly in asthmatics; however, not all asthmatics improve with acid suppression. It is unclear whether incomplete response is related to non-acid reflux, acid breakthrough, microaspiration or whether incomplete response is due to the lack of any causality between reflux and bronchial reactivity. We hypothesized that the use of esophageal manometry and 24 hour impedance in asthmatics refractory to acid suppression would further define the association of reflux with asthma. Aim: To describe manometric and impedance characteristics within a cohort of asthmatic patients who have not substantially improved their pulmonary symptoms with acid suppression. Methods: Retrospective chart review was performed on all patients referred for impedance testing from 2005-2007. Patients were included if they were referred from the asthma clinic at the University Hospital with an indication of refractory “asthma”. All patients had a prior diagnosis of asthma and were currently on proton pump inhibitor (PPI) therapy. Data abstracted included age, gender, esophageal manometric findings, 24 hour impedance results, dose/frequency of PPI, symptoms of heartburn, reflux, regurgitation, night choking, and cough. Results: A total of 36 patients were identified. 6/36 (17%) were males. The average age was 46 years (std 15.9). 29/36 (81%) complained of ongoing reflux. 20/32 (63%) had regurgitation. 23/34 (68%) described night choking while 31/35 (89%) complained of cough. Manometric data revealed a high prevalence of hypotensive lower esophageal sphincter (LES) pressures (17/36, 47%). 22/36 (61%) demonstrated abnormal 24 hour impedance testing. Impedance testing revealed that 9/36 (25%) of the patients had breakthrough pathologic acid reflux while on medication - this held true for even BID therapy (3/12, 25%). Night choking was significantly associated with abnormal amounts of supine reflux (p<0.02). Conclusions: Patients with asthma refractory to acid suppression will benefit from further diagnostic testing with 24 hour impedance. Many patients on high dose PPI suffer from acid breakthrough possibly contributing to bronchial reactivity. Continued nocturnal symptoms despite PPI therapy is likely related to acid/nonacid reflux. Fundoplication may improve symptoms in such patients; however, future studies are needed.
*P<0.0025 vs PBO using Hochberg's method of multiple comparisons.@ Crude rate considers subjects who prematurely terminate with last endoscopy showing no relapse as relapsed.
S1073 Tak-390MR, a Proton Pump Inhibitor (PPI) with a Novel Dual Delayed Release (DDR) Formulation, Is Highly Effective in the Healing of Erosive Esophagitis (EE): Data from Two Randomized Controlled Trials Prateek Sharma, Nicholas J. Shaheen, Maria Claudia Perez, Betsy Pilmer, Misun Lee, David A. Peura BACKGROUND: TAK-390MR employs a DDR delivery system that extends drug exposure and prolongs pH control compared with lansoprazole (LAN) and can be administered without regard to food or the timing of food. METHODS: Efficacy of TAK-390MR was compared
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and middle areas was significantly decreased (p<0.03) compared with that of esophagitis group, and leukocyte infiltration and the IL-1beta labeling index in each three areas was significantly decreased (p<0.05) compared with that of esophagitis group. The ulcer occurrence ratio (p<0.03), the size of ulcers(p<0.03), and the number of ulcer(p<0.03) were lower in Lansoprazole group compared with that of esophagitis group. (Conclusions)This study revealed that intra-mucosal inflammation was observed in the upper part of the esophagus located near the laryngopharynx which showed macroscopically normal mucosa. Lansoprazole attenuated the intra-mucosal inflammation not only lower part but also middle and upper part of esophagus near the laryngopharynx.
1980 criteria; 7 diffuse and 17 limited SSc) using MII-pH monitoring. PPI therapy was discontinued >30 days prior the exam. We measured distal esophageal acid exposure (% time pH<4), number of reflux episodes (acid,nonacid) and proximal migration of the refluxate (15cm above LES). All patients underwent CT pulmonary scan to evaluate their degree of pulmonary fibrosis using a validated HRCT score (Warrick et al. J Rheumatol 1991) Results: Of 24 patients (21F,median age 53yrs;range 27-71), 10 (42%) had a positive pulmonary fibrosis score (HRCT score ≥7). Total number (median[25th-75th perc]) of reflux episodes in the distal esophagus was higher in patients with abnormal vs. normal HRCT (67.5[5396] vs 31[15-39];p<0.001). The same was true for reflux episodes reaching the proximal esophagus (46[43-66] vs 13.5[9-19];p<0.001). In addition there was a very good correlation between the degree of pulmonary fibrosis (HRCT score) and number of reflux episodes in the distal (r2=0.623,p<0.001) and proximal (r2=0.647,p<0.001) esophagus. Both patient groups had similar distal esophageal acid exposures (4.3[2.3-12.6] vs. 3.7[2.4-4.9]; p=ns). Conclusions: While confirming prior data on the role of GER in the pathogenesis of pulmonary fibrosis, the present study documents a correlation between severity of pulmonary findings and frequency of GER episodes. The study provides new targets in the treatment of reflux disease aimed at preventing progression of pulmonary fibrosis.
patients (25 SSLTx, 10 SLTx, 2 HLTx) to assess the predictive value of BAL 3 mo after LTx. Stable patients had no BOS and a followup > 36 mo after LTx, BOS patients had BOS grade ≥ 1. Compared to 14 non transplant controls, pepsin and bile acids were considered positive if > 25.4 ng/ml and if > 0.22 µM, respectively. Results: 16/18 stable LTx patients were positive for pepsin in BALF 3 mo and remained positive at 12 mo. 14/18 stable LTx had no bile acids in the BALF at 3 mo and 12 of these patients remained negative for bile acids 12 mo after LTx. In the case-control study, BAL was compared between 18 patients who developed BOS and 19 who did not. 33/37 tested positive for pepsin in the BALF (237,1072158 ng/ml), whereas 14/37 tested positive for bile acids (0.96, 0.26-2.39 µM). 10/14 (71%) patients with bile acids in the BALF developed BOS compared to 16/33 (48.5%) patients with positive pepsin levels. Bile acids had a higher specificity (78.9%), positive predictive value (71%) and negative predictive value (65%) for the development of BOS than pepsin. Conclusions: Presence of pepsin and bile acid in BALF is repeatable 3 months and 1 year after LTx. Presence of bile acids in BAL 3 mo after LTx is more specific and a better predictor for the development of BOS than the presence of pepsin.
S1066 Gastroesophageal Reflux and Aspiration of Gastric Contents in Adult Patients with Cystic Fibrosis Kathleen Blondeau, Lieven Dupont, Veerle Mertens, Geert M. Verleden, Anne Malfroot, Yvan Vandenplas, Bruno Hauser, Daniel Sifrim
S1069 New Approach to the Treatment of Laryngopharyngeal Reflux Symptoms Using Rikkunshito (Japanese Herbal Medicine TJ-43) in Patients Who Responded Poorly to Acid Suppression Therapy Nobuhiko Oridate, Hiroshi Takeda, Yasushi Mesuda, Noriko Nishizawa, Masahiro Asaka, Satoshi Fukuda
It is known that GER is increased in cystic fibrosis (CF), however, its prevalence, characteristics, association with gastric aspiration and respiratory impact are not well characterized. We investigated acid and weakly acidic (WA) reflux, gastric aspiration and respiratory symptoms/function in adult patients with CF. Methods: Thirty-three CF patients [19men; 29(18-55) years] underwent impedance-pH monitoring for detection of acid (pH<4) and WA GER (pH4-7). In 16 patients cough was objectively recorded with esophageal manometry. Saliva and Bronchoalveolair Lavage Fluid (BALF) were tested for the presence of bile acids (BA). Results: Twenty-eight patients had increased GER (21acid, 5WA and 2 acid+WA) and 10 patients had a +SAP for reflux-cough. GER was a primary event in CF. The sequence cough-reflux was uncommon. 16/38 patients had BA in saliva and 6/10 patients in BALF and this was almost exclusively observed in patients with genotype DF508/DF508. Only 12/28 with increased GER and 9/22 with BA in saliva/BALF had typical reflux symptoms. There was a positive correlation (r=0.53, p=0.03) between esophageal acid exposure and cough and patients with +SAP for reflux-cough had a lower lung function (FEV1%pred) than -SAP patients. Conclusion: Increased GER is prevalent and a primary phenomenon in CF. Acid GER is most common, but WA GER may also occur. Patients with CF have a high risk for gastric aspiration and reflux seems to be associated with more cough and poorer lung function. Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in the evolution of CF.
Background: According to the “The Montreal Definition”, chronic laryngitis is closely related to gastroesophageal reflux disease (GERD). GERD-related chronic laryngitis is often called laryngopharyngeal reflux (LPR). Patients having LPR complain of abnormal laryngopharyngeal sensation, chronic cough, throat clearing, and voice disorder. Although acid suppression using proton pump inhibitors (PPI) has been generally accepted as the first choice of treatment, this new definition makes it clear that medical and surgical treatment trials aimed at improving suspected LPR by treating GERD are associated with uncertain and inconsistent treatment effects. In fact, the effect of PPI is limited in some LPR patients. There is no systematic research on any supplementary treatments using gastrointestinal prokinetic agents in such patients. Therefore, we evaluated the effects of rikkunshito (TJ-43), a gastrointestinal prokinetic agent, on LPR symptoms in patients who showed a poor response to PPI treatment. Methods: The study subjects comprised patients who attended the Department of Otolaryngology at Hokkaido University Hospital (Japan) for their LPR symptoms, had shown a poor response to PPI treatment of at least 2 month's duration, and had requested additional therapy for the remaining symptoms. We saw 20 such patients (12 male and 8 female; mean age, 56.9 years) between October 2004 and September 2007. Their laryngopharyngeal (extraesophageal) and typical esophageal symptoms of GERD such as a heartburn and regurgitation were recorded using the LPR symptoms scoring system based on the Reflux Symptom Index proposed by Belafsky et al. We retrospectively evaluated the changes of these symptoms in each patient before and after of TJ-43 administration in comparison with pre-PPI treatment. Results: Before PPI treatment, the average scores for laryngopharyngeal and esophageal symptoms were 6.4 (full score: 12 points) and 2.0 (full score: 5 points), respectively. The mean scores for laryngopharyngeal and esophageal symptoms after the PPI treatment (median 7.0 months) were 4.2 and 0.9, respectively. The average symptom residual rates were then calculated as 78.5% and 47.8% of the pre-PPI treatment. Additional administration of TJ43 for a median 3.3 months decreased laryngopharyngeal and esophageal symptoms to 1.9 and 0.2 (symptom residual rates: 38.3% and 7.2% of the pre-PPI treatment), respectively. Improvement of LPR symptoms by addition of TJ-43 was observed in 16 of 20 patients. Conclusions: Supplementary administration of TJ-43 in addition to PPI was effective in patients who showed a poor response to acid suppression therapy alone.
S1067 Nocturnal Weakly Acidic Reflux Promotes Aspiration of Bile Acids in Lung Transplant Recipients Kathleen Blondeau, Veerle Mertens, Bart M. Vanaudenaerde, Robin Vos, Dirk E. Van Raemdonck, Geert M. Verleden, Lieven Dupont, Daniel Sifrim Background: Gastroesophageal reflux (GER) and bronchial aspiration of bile acids have been implicated as non-alloimmune risk factors for the development of Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation. The aim of our study was to investigate the association between GER and gastric aspiration of bile acids and to establish which reflux characteristics may promote aspiration of bile acids into the lungs and may feature as a potential diagnostic tool in identifying LTX patients at risk for bile acid aspiration Methods: Twenty-four stable LTx recipients were studied 1 year after transplantation. All patients underwent 24 hrs ambulatory impedance-pH recording for the detection of acid (pH <4) and weakly acidic (pH 4-7) reflux. On the same day, bronchoalveolar lavage fluid (BALF) was collected and was analyzed for the presence of bile acids (enzymatic assay, Bioquant). Results:Thirteen patients had increased GER, of which 9 patients had increased acid reflux and 4 patients had exclusively increased weakly acidic reflux. Sixteen patients had detectable bile acids in the BALF (0.6 (0.4-1.5) µmol/L). Five patients with bile acids in BALF did not have typical reflux symptoms. The 24 hr esophageal volume exposure was significantly increased in patients with bile acids compared to patients without bile acids in the BALF. Acid exposure and the number of reflux events (total, acid and weakly acidic) were unrelated to the presence of bile acids in the BALF. However, the nocturnal volume exposure and the number of nocturnal weakly acidic reflux events were significantly higher in patients with bile acids in the BALF. Conclusions: Weakly acidic reflux events especially during the night are associated with the aspiration of bile acids in LTX recipients and might therefore feature as a potential risk factor for the development of BOS.
S1070 Effect of Lansoprazole On Extraesophageal Manifestations of GERD in a Rat Chronic Acid Reflux Esophagitis Model Daisuke Asaoka, Akihito Nagahara, Yuko Izumi, Akihiko Kurosawa, Masato Kawabe, Mariko Hojo, Sumio Watanabe (Background and aim)There is uncertainty about the mechanisms for development of reflux esophagitis and extraesophageal manifestations of GERD. PPI is reported to have an effect on extraesophageal manifestations of GERD, however there is few histology examination about this syndrome. This study aimed to investigate whether the inflammation would occur near the laryngopharynx and PPI would have protective effect on esophageal mucosa including near the laryngopharynx using a newly developed rat chronic acid reflux esophagitis model. (Method)Chronic acid reflux esophagitis in rats was developed by modified Omura's method. Esophagitis group (n=9) was not taken any drugs after the operation. Lansoprazole group (n=8) was administered Lansoprazole (1mg/kg) from the day1 to day 7 after the operation. Control group (n=5) underwent sham operation. Seven days after the surgery, all rats were sacrificed and removed their esophagus. Esophageal epithelial thickness, leukocyte infiltration and IL-1beta labeling index in mucosa was investigated in (A) the upper (approx. 5 mm under crico-pharyngeus), (B) the middle (midpoint between crico-pharyngeus and esophago-columnar junction, EC junction) and (C) the lower (approx. 0.5 mm upper EC junction) areas. The number of IL-1beta-positive cells at mucosa was counted in high-power fields and defined as labeling index, and inflammatory activity was evaluated. And (1) survival rate, (2) ulcer occurrence ratio, (3) the size of ulcers, and (4) the number of ulcer was investigated in esophagitis and Lansoprazole groups. (Results)In esophagitis group, mucosal thickness in the lower and middle areas was significantly increased (p<0.03) compared with that of controls and leukocyte infiltration in each three areas was significantly higher (p<0.03) than that of controls. In Lansoprazole group, mucosal thickness in the lower
S1068 Pepsin or Bile Acids: What Is the Best Marker of Gastric Aspiration in Lung Transplant Recipients? Veerle Mertens, Kathleen Blondeau, Bart M. Vanaudenaerde, Robin Vos, Dirk E. Van Raemdonck, Geert M. Verleden, Lieven Dupont, Daniel Sifrim Introduction: Increased gastroesophageal reflux (GER) and aspiration of gastric contents may favour the development of BOS. Markers of aspiration (pepsin and bile acids) in the BAL of LTx patients may feature as selection criteria for antireflux surgery. The aim was to compare the reproducibility and the predictive value for BOS development of pepsin and bile acids in BAL, obtained early after LTx. Methods: Repeatability of pepsin and bile acids levels was tested in 18 stable LTx patients (15 SSLTx, 3 SLTx) comparing BAL obtained at 3 mo and 12 mo after LTx. A retrospective case-control study was performed in 37 LTx
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to LAN in 2 identically-designed, double-blind, randomized, controlled trials in patients with EE (LA grades A-D) at global sites (188 US, 118 ex-US). 4092 H pylori-negative adult patients were to receive once-daily doses of TAK-390MR 60 or 90 mg, or LAN 30 mg. The primary efficacy endpoint was the overall healing rates by Week 8; analyses were conducted using both life-table and crude rate methods. A secondary variable was healing of EE with LA grades C or D by Week 8. RESULTS: For the primary endpoint, both TAK-390MR doses achieved the primary objective of non-inferiority to LAN in both studies. In study 1, healing rates using life table methods were 92.3% and 92.2% with TAK-390MR 60 mg (p= NS) and 90 mg (p=NS), respectively, and 86.1% with LAN. In study 2, healing rates were 93.1% and 94.9% with TAK-390MR 60 mg (p=NS) and 90 mg (p=NS), respectively, and 91.5% with LAN. In both studies, crude rates yielded similar treatment differences to lifetable methods for 8-week healing and demonstrated statistical superiority for TAK-390MR 90 mg over LAN. Results from the 2 trials were combined since they were identical in design with similar size and baseline demographics. Combined results demonstrated significantly higher overall healing rates for TAK-390MR 60 mg and 90 mg compared to LAN (Table); furthermore, TAK-390MR 90 mg was significantly superior to LAN in healing patients with LA grades C / D EE by Week 8. All treatments were generally well tolerated. Diarrhea was the most frequent treatment-related AE occurring in 3.1% of patients in the TAK-390MR groups and 2.1% on LAN. CONCLUSION: TAK-390MR (60 mg and 90 mg) was highly effective for the healing of all grades of EE. Combined results showed statistically significant superiority to LAN for both TAK-390MR doses and the 90 mg dose was significantly superior to LAN for healing moderate/severe EE. Both TAK-390MR doses demonstrated similar tolerability and safety profiles comparable to those of LAN.
S1071 Gastroesophageal Reflux in Idiopathic Pulmonary Fibrosis Patients Awaiting Lung Transplantation Yevgenia Pashinsky, Maria L. Padilla, Eric S. Goldstein, Barry W. Jaffin INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of the lung characterized by fibrosis of the lower respiratory tract. There is agreement that certain risk factors are associated with IPF including tobacco use, environmental exposures, medications, infectious respiratory pathogens and chronic aspiration. Among the current theories on the pathogenesis of IPF is the contribution of gastroesophageal reflux (GER). Recent data suggest that there may be an increase incidence in GER in patients who are status post lung transplantation. However, data on pre-lung transplantation patients without GER symptoms is lacking and the presence of manometric abnormalities in this subgroup has not been examined. AIM: To evaluate GER and esophageal manometry in patients with IPF awaiting lung transplantation. METHODS: We reviewed the 24 hour pH probe data (off proton pump medications) and esophageal manometry studies of 24 patients with IPF being evaluated for lung transplantation at the Mount Sinai Medical Center (New York, NY). Three patients were excluded from the analysis due to underlying scleroderma. RESULTS: For the 21 patients analyzed, the mean Johnson/DeMeester score was 28.3 with a median of 16.0. Forty three percent (9/21) of patients were found to have an abnormal Johnson/ DeMeester score (defined as >22). For these 9 patients, the mean Johnson/DeMeester score was 53.8 with a median of 41.6. The median upright reflux time for the 21 patients was 14.9% and median recumbent reflux time 10.6%. The manometry studies found the average LESP to be 18.9 mmHg and 15.5 mmHg among those with an abnormal Johnson/DeMeester scores. Incidentally, 5 out of 21 patients were noted to have an occult abnormal motility of the esophagus demonstrating <80% peristalsis. CONCLUSION: Our data demonstrate that GER and esophageal dysmotility are highly prevalent among IPF patients awaiting lung transplantation, thus supporting its role in the pathogenesis of the disease. More studies need to be done to evaluate the GER in both pre and post lung transplantation populations.
*P<0.05 vs LAN S1074 Tak-390MR, a Proton Pump Inhibitor with a Novel Dual Delayed Release Formulation, Maintains Healing and Controls Heartburn in GERD Patients with Healed Erosive Esophagitis David C. Metz, Colin W. Howden, Maria Claudia Perez, Lois M. Larsen, Janet M. O'Neil BACKGROUND: TAK-390MR is a delayed release formulation of an enantiomer of lansoprazole (LAN) with a dual-peaked pharmacokinetic profile. In phase 1 studies it increased mean intragastric pH and the % of time pH >4 over 24 hrs compared with LAN. The current trial assessed the efficacy and safety of TAK-390MR vs placebo (PBO) in maintaining healed erosive esophagitis (EE). METHODS: 445 adult patients with healed EE who completed 1 of 2 acute healing trials were enrolled in this randomized, double-blind trial at 94 centers (75 US; 19 ex-US). During the 6-month study, patients received TAK-390MR 30 or 60 mg or PBO once daily (QD) and had EGD at 1, 3, and 6 months. The primary efficacy variable was the % of patients who maintained healing over 6 months; analyses were conducted using life-table analysis and crude rates. Secondary variables were the % of 24-hour heartburnfree days and the % of nights without heartburn, based on patients' daily diaries. RESULTS: Both doses of TAK-390MR were statistically significantly superior to PBO for maintaining EE healing and for the % of 24-hour heartburn-free days and nights (Table). There were no significant differences between the 2 TAK-390MR treatment groups for these endpoints. The therapeutic gain in maintenance rates for TAK-390MR vs PBO was similar by life table (48%-55%) and crude rate analysis (52%). There was a therapeutic advantage (16% by crude rate, 22% by life table) for TAK-390MR 60 mg over the 30 mg dose in patients with moderate to severe EE at baseline. Both TAK-390MR doses showed highly effective control of heartburn with medians of 91%-96% for 24-hour heartburn-free days, and 96%-99% for heartburn-free nights. The more commonly reported AEs for TAK-390MR with higher frequency than PBO were upper respiratory tract infections, diarrhea, musculoskeletal/ connective tissue and joint-related signs & symptoms. CONCLUSION: TAK-390MR 30 and 60 mg QD were highly effective and statistically significantly superior to PBO at maintaining EE healing over 6 months and relieving heartburn. Most patients receiving TAK390MR were heartburn-free for over 90% of treatment days. TAK-390MR was well tolerated.
S1072 Reflux Characteristics in Asthmatic Patients Refractory to Acid Suppression As Defined By Impedance Testing Jeremy M. Alvord, Kristen Thomas, Wayne Samuelson, John C. Fang, Kathryn A. Peterson Background:The association between asthma and gastroesophageal reflux (GER) has been the subject of intensive research. GER occurs commonly in asthmatics; however, not all asthmatics improve with acid suppression. It is unclear whether incomplete response is related to non-acid reflux, acid breakthrough, microaspiration or whether incomplete response is due to the lack of any causality between reflux and bronchial reactivity. We hypothesized that the use of esophageal manometry and 24 hour impedance in asthmatics refractory to acid suppression would further define the association of reflux with asthma. Aim: To describe manometric and impedance characteristics within a cohort of asthmatic patients who have not substantially improved their pulmonary symptoms with acid suppression. Methods: Retrospective chart review was performed on all patients referred for impedance testing from 2005-2007. Patients were included if they were referred from the asthma clinic at the University Hospital with an indication of refractory “asthma”. All patients had a prior diagnosis of asthma and were currently on proton pump inhibitor (PPI) therapy. Data abstracted included age, gender, esophageal manometric findings, 24 hour impedance results, dose/frequency of PPI, symptoms of heartburn, reflux, regurgitation, night choking, and cough. Results: A total of 36 patients were identified. 6/36 (17%) were males. The average age was 46 years (std 15.9). 29/36 (81%) complained of ongoing reflux. 20/32 (63%) had regurgitation. 23/34 (68%) described night choking while 31/35 (89%) complained of cough. Manometric data revealed a high prevalence of hypotensive lower esophageal sphincter (LES) pressures (17/36, 47%). 22/36 (61%) demonstrated abnormal 24 hour impedance testing. Impedance testing revealed that 9/36 (25%) of the patients had breakthrough pathologic acid reflux while on medication - this held true for even BID therapy (3/12, 25%). Night choking was significantly associated with abnormal amounts of supine reflux (p<0.02). Conclusions: Patients with asthma refractory to acid suppression will benefit from further diagnostic testing with 24 hour impedance. Many patients on high dose PPI suffer from acid breakthrough possibly contributing to bronchial reactivity. Continued nocturnal symptoms despite PPI therapy is likely related to acid/nonacid reflux. Fundoplication may improve symptoms in such patients; however, future studies are needed.
*P<0.0025 vs PBO using Hochberg's method of multiple comparisons.@ Crude rate considers subjects who prematurely terminate with last endoscopy showing no relapse as relapsed.
S1073 Tak-390MR, a Proton Pump Inhibitor (PPI) with a Novel Dual Delayed Release (DDR) Formulation, Is Highly Effective in the Healing of Erosive Esophagitis (EE): Data from Two Randomized Controlled Trials Prateek Sharma, Nicholas J. Shaheen, Maria Claudia Perez, Betsy Pilmer, Misun Lee, David A. Peura BACKGROUND: TAK-390MR employs a DDR delivery system that extends drug exposure and prolongs pH control compared with lansoprazole (LAN) and can be administered without regard to food or the timing of food. METHODS: Efficacy of TAK-390MR was compared
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and middle areas was significantly decreased (p<0.03) compared with that of esophagitis group, and leukocyte infiltration and the IL-1beta labeling index in each three areas was significantly decreased (p<0.05) compared with that of esophagitis group. The ulcer occurrence ratio (p<0.03), the size of ulcers(p<0.03), and the number of ulcer(p<0.03) were lower in Lansoprazole group compared with that of esophagitis group. (Conclusions)This study revealed that intra-mucosal inflammation was observed in the upper part of the esophagus located near the laryngopharynx which showed macroscopically normal mucosa. Lansoprazole attenuated the intra-mucosal inflammation not only lower part but also middle and upper part of esophagus near the laryngopharynx.