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Another Extraesophageal Reflux Syndrome: Ventilator Associated Pneumoniaand Deteriorating Respiratory Function in ICU PatientsEge Altan, Özgür Harmanci, Ebru Ortaç, Arzu Topeli, Bülent Sivri

Background: Gastroesophageal reflux (GER) and microaspiration of gastric contents has beenproposed as an important mechanism in the pathogenesis of ventilator associated pneumonia(VAP) but properties of GER in patients receiving acid suppresive therapy in intensive careunit (ICU) and its effect on VAP and respiratory function in these patients is not elucidated.Aim: This study aims to assess the association between GER and VAP by defining thedifferences between VAP and non-VAP patients in ICU in terms of proximal extension andchemical properties of GER assessed by 24 hour combined esophageal intraluminal electricalimpedance/pH measurements. We also aimed to study the association of impedance/pHvalues with respiratory function (PaO2/FiO2 ratio) and gastropulmonary microaspirationassessed by pepsin measurements in deep tracheal aspirates(DTA). Methods: 20 intubatedpatients on acid suppressive medication for stress ulcer prophylaxis in a neurological andmedical ICU were included in this study. Patients who had pneumonia at the time ofintubation or who were diagnosed with pneumonia during the first 48 hours after intubationwere excluded. Pepsinmeasurements weremade onDTA samples on the third day. Afterwardsesophageal impedance/pHmetry catheters were placed and 24 hour recordings were analyzed.Patients were followed throughout their stay in ICU for VAP and daily PaO2/FiO2 ratioswere recorded for one week. Impedance/pH values and pepsin levels were compared betweenVAP and nonVAP patients. Results: 8 patients were diagnosed with VAP. VAP patientshad more proximal reflux compared to non-VAP patients (7(2-14) vs. 3,5(0-8))(p=0,003).Proximal weakly acidic reflux was again more common in VAP patients (4,5(2-9) vs 2(0-4)(p=0,006). Pepsin levels in DTA samples were correlated with the number of weakly acidicreflux episodes(r=0,615;p=0,004). Pepsin levels were also correlated with the number ofproximal reflux episodes, especially with proximal weakly acidic reflux(r=0,489;p=0,029 ;r=0,651,p=0,002 ). PaO2/FiO2 ratios were negatively correlated with both pepsin levels andproximal weakly acidic reflux (r=-0,585,p=0,007 ; r=-0,620;p=0,004). Conclusion: Proximalextension of GER, especially proximal weakly acidic reflux is associated with microaspiration,VAP and worsening of respiratory function in intubated ICU patients on acid suppressivetherapy.

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Presence of Bile Acids and Pepsin in Saliva and Broncho-Alveolar Lavage ofPatients With Idiopathic Pulmonary Fibrosis Is Associated to IncreasedSeverity of Lung DiseaseEdoardo Savarino, Patrizia Zentilin, Elisa Marabotto, Manuele Furnari, Luca Bruzzone,Luca M. Sconfienza, Nicola de Bortoli, Santino Marchi, Vincenzo Savarino

Introduction: Recent studies investigated the role of pepsin and bile acids (BAs) in salivaand bronchoalveolar lavage (BAL) of patients with respiratory diseases (i.e. asthma, cysticfibrosis) as specific and sensitive markers of gastro-oesophageal reflux-related pulmonaryaspiration. However, no data are available on the role of these markers in patients withidiopathic pulmonary fibrosis (IPF) who are characterized by increased gastroesophagealreflux (up to 85%) and potential aspiration of duodenogastric contents into the lungs. Aim:We aimed to assess aspiration in IPF patients by measuring pepsin and bile acids (BAs) insaliva and broncho-alveolar lavage (BAL) and to investigate whether their presence wascorrelated with disease severity and pulmonary function tests (PFTs). Methods: Saliva andBAL samples were collected in 38 and 21 IPF patients, 36 and 21 patients with interstitiallung disease other than IPF (non-IPF patients), and in 50 healthy volunteers (HVs) and 16patients undergoing bronchoscopy for other diseases (controls), respectively. All subjectsunderwent pulmonary high-resolution computed tomography (HRCT) scan and PFTs onthe day of saliva/BAL samples collection. BAs and pepsinweremeasured using two commercialavailable assays. The presence and severity of pulmonary fibrosis was defined using a previousvalidated HRCT-score (Best-score). Forced vital capacity (FVC), forced expiratory volume(FEV) and DLco curve were measured during PFTs. Results: Patients with IPF had moreBAs and pepsin (p,0.001) in BAL (62% and 67%) and saliva (61% and 68%) than non-IPF patients (40% and 40% in BAL, 33% and 36% in saliva) and controls (0% and 0% inBAL) or HVs (0% and 0% in saliva). The concentration of BAs in saliva and BAL was higher(p,0.001) in IPF [3.70 μmol/l and 0.90 μmol/l] than in non-IPF patients [1.5 μmol/l and0.50 μmol/l]. A good correlation (p,0.001) was found between HRCT score and presenceof pepsin and BAs in saliva (r2=0.5260 and r2=0.4269, respectively) and BAL (r2=0.6033and r2=0.4605, respectively). A significant correlation was observed between HRCT scoreand the concentration of BAs in saliva (r2=0.2591, p=0.013) and in BAL (r2=0.3843, p=0.024). We failed to find a significant association among HRCT score and lung functionparameters (p=ns). Conclusion: BAs and pepsin are present in saliva and BAL of more thanone-half of patients with IPF, suggesting aspiration of duodenogastric contents. Aspirationof pepsin and BAs is associated with increased severity of disease expressed by HRCT. Inpatients with aspiration, the levels of pepsin and BAs are associated with the degree oflung fibrosis.

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Predictors of Response in Patients With Chronic Cough Referred for GERDEvaluationRobert T. Kavitt, James C. Slaughter, C. Gaelyn Garrett, Michael F. Vaezi

Introduction: Patients with chronic cough are often referred to gastroenterologists forevaluation and treatment of GERD as a potential contributing etiology. Many are commonlytested extensively for GERD and are often treated with aggressive acid suppression. However,the clinical outcome of such testing and therapy is currently unknown. The aims of thiscohort study in patients with chronic cough were: 1) to determine the prevalence of baselineesophageal parameters (EGD, pH, and impedance monitoring) and 2) to examine the treat-ment outcomes and assess predictors for identifying GERD-related chronic cough. Methods:Patients with chronic cough (defined as cough duration . 8 weeks) who were referred for

S-51 AGA Abstracts

evaluation and treatment of GERD as a potential etiology underwent both impedancemonitor-ing on BID PPI as well as EGD and 48-hr wireless pH monitoring off acid suppressivetherapy for one week. Patients were subsequently treated with aggressive acid suppressivetherapy (BID PPI) for 4 months with a subset undergoing surgical fundoplication. Treatmentresponse was defined by . 50% improvement in chronic cough post therapy. Baselinephysiologic and demographic characteristics were then used to determine response to therapy.% time pH , 4 (total, upright, and supine), number of reflux episodes, and SI and SAPwere determined. Abnormal reflux off therapy was defined as % time pH , 4, total . 5.5%,upright . 8.2%, and supine . 3.0%. Abnormal reflux on therapy was defined as totalnumber of events . 48. Results: 140 patients with chronic cough [72% female, median(IQR) age 55 yrs (53-56), BMI 30 (29-31)] were studied. Esophagitis was present in only20% of patients (95% grade A or B) and hiatal hernia was present in 36% (63% less than3 cm). While 80% of patients had abnormal pH monitoring off therapy (14% supine only,30% upright only, 36% upright and supine), only 20% of patients had moderate to severereflux (% time pH , 4 greater than 10%). 38% had abnormal impedance monitoring ontherapy. A median (IQR) of 90% (81%-98%) of the impedance events occurred in theupright state. 61% of patients were symptomatically improved post-therapy (49% after PPItherapy and 72% after fundoplication). Acid exposure (% time pH , 4) greater than 12%and concomitant presence of heartburn, regurgitation, and hiatal hernia greater than 4 cmwere independent predictors of symptom response [OR 10.5, 95% CI (2-58)]. Neitherbaseline impedance parameters nor SI or SAP on or off PPI therapy predicted response totherapy. Conclusions: In patients with chronic cough referred for GERD evaluation: 1)Endoscopic signs for GERD are uncommon, 2) Most patients have a mild degree of acidreflux at best, and 3) Symptomatic response to reflux therapy is likely in those with moderateto severe reflux based on traditional parameters and not impedance monitoring.

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Lung Transplantation and Proton Pump Inhibition: Acid May Not Be the OnlyIssueCristina Almansa, Augustine Lee, Kenneth R. DeVault, Cesar A. Keller, Lesley A.Houghton

Gastroesophageal reflux disease (GERD) is implicated in bronchiolitis obliterans syndrome(BOS) and consequently long-term survival after lung transplantation. Acid suppressiontherapy is therefore routinely administered, despite limited evidence of therapeutic benefit.Aim: To investigate the relationship between GERD as measured by impedance/pH and lungtransplant outcomes. Methods: This was a retrospective study of 84 patients (mean age 61,range 43-74 yrs; 53 males) who had undergone either single (n=35) or double (n=49) lungtransplantation and also received pH/impedance testing at the Mayo Clinic, Jacksonvillefrom March 2003 to March 2010. All patients were taking proton pump inhibitor (PPI)therapy. We chose the primary combined outcome to be death or the need for re-transplanta-tion, as re-transplantation is only reconsidered in a terminal state, and secondarily, analyzedfor BOS. Group differences were assessed by Fisher's exact test at a significance level of0.05. Results: Of the 84 patients reviewed, 80 had complete data and had been followedup for an average of 33.2 months (range, 3-116 months). Twenty five (31%) of these hadan abnormally increased number of distal reflux events on impedance (defined as .47 onPPI) and 20 (25%) had abnormal distal acid reflux on pH (defined as percentage of timepH ≥ 1.3% on PPI). Those patients with increased numbers of total reflux events (both acidand non-acid) had a greater incidence of BOS [9/25 (36%) vs 3/55 (5%); p=0.001], needfor re-transplantation [6/25 (24%) vs 3/55 (5%); p=0.023], and death due to transplant-related complications [7/25 (28%) vs 3/52 (6%); p=0.011] as compared to those with normallevels of reflux. Consequently, for the combined primary outcome, the risk of death or re-transplantation was also significantly increased in those with abnormal numbers of refluxevents with an odds ratio 9.4 (95% confidence interval: 2.6 to 34). In contrast, those withabnormal distal acid reflux despite PPI therapy did not show an increased risk for BOS [4/22 (18%) vs 9/62 (15%); p=0.74], re-transplantation [2/22 (9%) vs 7/62 (11%); p=1.00]or death [3/22 (14%) vs 8/59 (14%); p=1.00]. Conclusion: While the total number of refluxepisodes was found to be associated with a greater risk for BOS, re-transplantation ordeath, breakthrough esophageal acid exposure in PPI treated patients was not. This studyunderscores that reflux evaluation should include impedance testing and not be limited topH only, and that anti-reflux therapies besides acid suppression should be considered.

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Cell-Autonomous ADAM10 Signaling Is Required for Adenoma Initiation AfterAPC MutationYu-Hwai Tsai, Ying Feng, Sabita Rakshit, Eric Fearon, Peter J. Dempsey

INTRODUCTION: ADAM10 is a cell surface sheddase that regulates various signaling eventsincluding Notch activation. We have previously shown that ADAM10 is required for mainte-nance of intestinal stem cells (ISCs) including Lgr5+ cells. In this study, we tested therequirement for ADAM10 in APC-mediated adenoma initiation in genetically-defined Cdx2+intestinal epithelial cells (IECs) and Lgr5+ ISCs, respectively. METHODS: To study the roleof ADAM10 in adenoma formation, conditional ADAM10flox/flox mice were bred withconditional APCflox/flox mice. Two tamoxifen (TX)-inducible CreER lines were used thatallowed maximal ADAM10 loss in IECs without affecting survival. CDX2P-CreER line pro-duced mosaic recombination within Cdx2+ IECs of the distal intestine whereas Lgr5-EGFP-ires-CreER line produced recombination in Lgr5+ ISCs throughout the intestine. Notchrescue experiments were performed with CreER;ADAM10KO;APCKO;Rosa26NICD mice.Adenoma formation was assessed by whole mount counting and histological analysis (H&E and beta-catenin staining). ADAM10, Lgr5 (EGFP) and BrdU labeling were analyzedby immunohistochemistry. RESULTS: Adult Cdx2P-CreER;APCKO and compound Cdx2P-CreER;ADAM10KO;APCKO mice were given a single TX dose (100mg/kg, i.p.) and followedfor 28 days. All Cdx2P-CreER;APCKO mice became moribund and did not survive beyond16 days post-TX treatment. Adenomas were detected throughout the distal intestine especiallythe cecum. By contrast, Cdx2P-CreER;ADAM10KO;APCKO mice were healthy and adenomaformation was markedly reduced in these mice. Importantly, all the tumors found in thesemice had retained ADAM10 expression and no ADAM10-deficient tumors were detected.

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