GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications

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2 GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications Esophageal Syndromes Extra - esophageal Syndromes Symptomatic Syndromes Typical reflux syndrome Reflux chest pain syndrome Syndromes with Esophageal injury Reflux esophagitis Reflux stricture Barrett s esophagus Adenocarcinoma Established Association Reflux cough Reflux laryngitis Reflux asthma Reflux dental erosions Proposed Association Sinusitis Pulmonary fibrosis Pharyngitis Recurrent otitis media Swiss Med Wkly. 2012;142:w13544

3 The Montreal definition of constituent syndromes of extraesophageal reflux Extraesophageal syndromes Estabilished associations Proposed associations Reflux cough syndrome Reflux laryngitis syndrome Reflux asthma syndrome Reflux dental erosion syndrome Pharyngitis Sinusitis Idiopathic pulmonary fibrosis Recurrent otitis media Gastroenterology & Hepatology Volume 8, (9);2012 :590-9.

4 Laryngopharyngeal reflux (LPR) Definition : symptoms associate with the reflux of gastric contents (acid and enzymes such as pepsin) into the laryngopharynx. - hoarseness of voice - globus - chronic cough

5 Pathophysiology of LPR Refluxate in esophagus Direct Refluxate pass through UES into pharynx and larynx cause hoarseness of voice and laryngitis In direct Refluxate evokes laryngeal reflexes via vagus nerve cause chronic caugh

6 Belafsky, P, Postma, G, Amin, M, Koufman, J. Ear Nose Throat J 2002; 81(9 Suppl 2):10 1)Subglottis edema 3) Vocal fold edema 2) Ventricular obliteration 4) Posterior commissural hypertrophy

7 Common causes of Chronic cough PNDS Asthma GERD Chronic bronchitis *Exclude drug induced Bronchiectasis Misc. PNDS + asthma +GERD Gastroenterology & Hepatology Volume 8, (9);2012 :590-9.

8 Testing for Laryngopharyngeal Reflux Reflux symptom Index :Within the last MONTH, how did the following problems affect you? 0 = no problem, 5 = severe problem 1. Hoarseness or a problem with your voice Clearing your throat Excess throat mucous or postnasal drip Difficulty swallowing food, liquids, or pills Coughing after you ate or after lying down Breathing difficulties or choking episodes Troublesome or annoying cough Sensations of something sticking in your throat or a lump in your throat Heartburn, chest pain, indigestion, or stomach acid coming up Total

9 Advantages and Disadvantages of Various Methods for Detection of Laryngopharyngeal Reflux Method Advantages Disadvantages Endoscopy Laryngoscopy Easy visualization of mucosal damage and erosions No sedation required Direct visualization of the larynx and laryngeal pathology Poor sensitivity, specificity, and positive predictive value Sedation required High cost No specific laryngeal signs for reflux Overdiagnosis of gastroesophageal reflux disease ph monitoring Easy to perform Relatively noninvasive Prolonged monitoring Ambulatory Catheter - based method False negative rate of up to 30% No ph predictors of treatment response in patients with laryngopharyngeal reflux Impedance monitoring ph measurement system Lateral flow device for pepsin detection Easy to perform Relatively noninvasive Prolonged monitoring Ambulatory Measurement of acidic and nonacidic gas and liquid reflux (combined with ph) Faster detection rate and time to equilibrium ph than traditional ph catheters Fast and easy detection of salivary pepsin Acceptable sensitivity and specificity Catheter - based method Unknown false negative rate (but likely similar to that of catheter based ph monitoring) Unknown clinical relevance when abnormal results are found in patients taking proton pump inhibitors Unknown importance in patients with laryngopharyngeal reflux Unknown clinical usefulness in patients with laryngopharyngeal reflux Has only been examined in limited outcome studies so far Gastroenterology & Hepatology Volume 8, (9);2012 :590-9.

10 45 patients with unexplained chronic persistent caugh Analysis of concordance between 24 h ph-metry and PPI test 24 h ph-metry Positive Negative Total PPI test positive PPI test negative Total Youden s index = K (measure of reliability) = (no reliability) *PPI test+ defined as symptoms response after 4 weeks of lansoprazole 30 mg twice/day Baldi F et al. World J Gastroenterol 2006;12(1):82-8.

11 Characteristics of the patients entering the randomized double-blind phase of the study Lansoprazole (30 mg/d) (n = 17) Lansoprazole (60 mg/d) (n = 18) Age (mean±sd) Gender, male (% ) Upper endoscopy positive ph-metry positive (%) PPI test positive (%) 57.5 ± (17.6) 4 (23.5) 13 (76.5) 11 (64.7) 52.4 ± (11.1) 3 (16.7) 10 (55.5) 11 (64.7) No statistical differences between the groups in any of the parameters Baldi F et al. World J Gastroenterol 2006;12(1):82-8.

12 Visual analog scale(vas) 0-10, Score system: overall frequency 0-3,daily frequency 0-3,severity 0-3 Visit 1(baseline) Visit 2(after PPI Test) Visit 3(end of 12 wk) VAS Score VAS Score VAS Score Lansoprazole (30 mg/d) (n = 17) 8 ( ) 9 (8-9) 2 ( ) b 4 (3-7) a 1 (0-4.5) b 3 (0-6.5) b Lansoprazole (60 mg/d) (n = 18) 9 (8-9) 8 (7-9) 2 (1-6.5) b 3.5 (3-7) a 1 (0-5) b 3 (0-6.25) b Data expressed as median (25%-75% quartiles) b P < vs visit 1; a P < vs visit 1. Baldi F et al. World J Gastroenterol 2006;12(1):82-8.

13 Percentage of patients showing symptomatic response at the end of 12-wk treatment with 30 mg/d (n = 17) or 60 mg/d (n = 18) lansoprazole 100 Lanso 30 mg/d Lanso 60 mg/d Complete response (21 pts) Patial response (5 pts) No response (9 pts) Baldi F et al. World J Gastroenterol 2006;12(1):82-8.

14 Percentage % Percentage of patients showing symptomatic response at the end of 12-wk treatment with 30 or 60 mg/d lansoprazole (n = 35), subdivided according to the outcome of PPI test. P<0.05 vs negative PPI test resolution Partial resolution Complete resolution PPI test positive (22 pts) PPI test negative (13 pts) Baldi F et al. World J Gastroenterol 2006;12(1):82-8.

15 A Forest plot depicting the risk ratios of studies assessing the efficacy of proton pump inhibitors (PPIs) in patients with reflux laryngitis Gastroenterology & Hepatology Volume 8, (9);2012 :590-9.

16 Surgical treatment outcomes in GER-related cough Investigators study design Number of patients response rate Irwin et al. Prospective 8 Cough improvement in 100% of patients at 1 year follow-up (medical nonresponders) Pellegrini et al. Prospective 5 5 Cough resolution in 100% of patients (highly selective patients who were thought to be aspirators) DeMeester et al. Prospective 17 Cough resolution in 100% of patients with normal esophageal manometry Giudicelli et al. Prospective 13 Cough resolution in 85% of patients (highly selected) Johnson et al. Prospective 50 Cough resolution in 76% at 3 years Allen et al. Prospective 354 Cough improvement based on cough score in 81% of patients at 6 months So et al. Prospective 16 Cough resolution or improvement at 1 year in 56% (medical responders might have been included) Novitsky et al. Prospective 21 Cough improvement in 86% and complete resolution in 62% of patients at 1 year (medical non-responders) Allen et al. Prospective 528 Cough improvement in 83% at 6 months, 74% at 2 years and 71% of patients at 5 years GASTROENTEROLOGY & HEPATOLOGY 2007;4(11):

17 Algorithm for Assessment and Management of LPR Initial Assessment Patient with possible LPR Reflux symptom index (history, symptoms) > 13 and Reflux finding score (Laryngoscopy) > 7 Empirical therapeutic trial Lifestyle, Diet PPI therapy 3 mo Follow-up assessment Symptoms Resolved Titrate PPI therapy Symptoms improved Increase dose of PPI Continue lifestyle and diet modifications Symptoms unchanged or worse 6 mo Follow-up assessment Symptoms Resolved Titrate PPI therapy Charles N. Ford.JAMA. 2005;294(12): Symptoms not resolved Definitive assessment (Perform 1 or more studies) Multichannel impedance and ph monitoring (Demonstrate reflux) EG D (Document pathology) Manometry (Assess etiology)

18 Summary Up to 75% of patients with GER-related cough have no esophageal GER symptoms, but it is still possible to predict the presence of GER-related cough. An empiric trial of conservative measures plus twice-daily PPIs for 3 months can successfully identify and treat GER-related cough in approximately 80% of patients; GER- related cough can take more than 3 months to improve even with aggressive medical GER therapy. Esophageal diagnostic testing is recommended if an empiric therapy trial fails and should include esophageal manometry, ph monitoring and impedance monitoring and pepsin detection, if available, while maintaining GER therapy. Surgical fundoplication can be considered in selected patients who desire surgical therapy and who respond to medical therapy after a comprehensive evaluation, or in patients with documented nonacid reflux who do not respond to medical therapy

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20 Mechanisms of esophageal acid-induced bronchoconstriction Esophagus Tracheobronchial tree Airway inflammation edema mucus Smooth muscle contraction

21 % Asthma Control Heartburn Regurgitation Heartburn + Regurgitation Aras et al. Multidisciplinary Respiratory Medicine 2012, 7:53

22 Lower esophageal sphincter pressure Reflux parameters, number of episodes per hour esophageal ph was below 4.0 Compared to controls, asthmatics had significantly decreased lower esophageal sphincter pressure, more frequent reflux episodes, and higher esophageal acid contact times Aras et al. Multidisciplinary Respiratory Medicine 2012, 7:53

23 Peak expiratory flow rate during esophageal acid infusion Aras et al. Multidisciplinary Respiratory Medicine 2012, 7:53

24 Analysis 1.1 C omparison 1 Medical Therapy of GOR vs Placebo, Outcome 1 Morning Peak Expiratory Flow. Review: Gastro-oesophageal reflux treatment for asthma in adults and children Comparison: 1 Medical Therapy of GOR vs Placebo Outcome: 1 Morning Peak Expiratory Flow Study or subgroup Medical Therapy Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 H2 Antagonist Ekstrom (104) (111) % 6.00 [ , ] Subtotal (95% CI) % 6.00 [ , ] Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.78) 2 Proton Pump Inhibitor Boeree (109) (98) 27.3 % [ , ] Ford (86) (86) 28.3 % 7.00 [ , ] Teichtahl (99) (95) 44.4 % [ , ] Subtotal (95% CI) % 4.65 [ , ] Heterogeneity: Chi 2 = 0.30, df = 2 (P = 0.86); I 2 =0.0% Test for overall effect: Z = 0.23 (P = 0.82) 3 H2 Antagonist or Proton Pump Inhibitor Boeree (109) (98) 14.6 % [ , ] Ekstrom (104) (111) 46.5 % 6.00 [ , ] Ford (86) (86) 15.1 % 7.00 [ , ] Teichtahl (99) (95) 23.8 % [ , ] Subtotal (95% CI) % 5.28 [-24.05, ] Heterogeneity: Chi 2 = 0.30, df = 3 (P = 0.99); I 2 =0.0% Test for overall effect: Z = 0.35 (P = 0.72) Test for subgroup differences: Chi 2 = 0.00, df = 2 (P = 1.00), I 2 =0.0% Placebo better Therapy better Peter G Gibson, Richard Henry and Jennifer JL Coughlan The Cochrane Library Published Online: 21 JAN 2009

25 Analysis 1.2. Comparison 1 Medical Therapy of GOR vs Placebo, Outcome 2 Evening Peak Expiratory Flow. Review: Gastro-oesophageal reflux treatment for asthma in adults and children Comparison: 1 Medical Therapy of GOR vs Placebo Outcome: 2 Evening Peak Expiratory Flow Study or subgroup Medical Therapy Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 H2 Antagonist Ekstrom (104) (104) % 8.00 [ , ] Subtotal (95% CI) % 8.00 [ , ] Heterogeneity: not applicable Test for overall effect: Z = 0.38 (P = 0.71) 2 Proton Pump Inhibitor Ford (81) (78) 65.6 % 3.00 [ , ] Teichtahl (124) (155) 34.4 % [ , ] Subtotal (95% CI) % 541 [ , 59.22] Heterogeneity: Chi 2 = 0.01, df = 1 (P = 0.90); I 2 =0.0% Test for overall effect: Z = 0.20 (P = 0.84) 3 H2 Antagonist or Proton Pump Inhibitor Ekstrom (104) (104) 62.2 % 8.00 [ , ] Ford (81) (78) 24.5 % 3.00 [ , ] Teichtahl (124) (155) 12.9 % [ , ] Subtotal (95% CI) % 7.03 [ , 39395] Heterogeneity: Chi 2 = 0.02, df = 2 (P = 0.99); I 2 =0.0% Test for overall effect: Z = 0.42 (P = 0.68) Test for subgroup differences: Chi 2 = 0.01, df = 2 (P = 1.00), I 2 =0.0% Placebo better Therapy better Peter G Gibson, Richard Henry and Jennifer JL CoughlanThe Cochrane Library Published Online: 21 JAN 2009

26 Analysis 1.3. Comparison 1 Medical Therapy of GOR vs Placebo, Outcome 3 Nocturnal Symptoms Score Review: Gastro-oesophageal reflux treatment for asthma in adults and children Comparison: 1 Medical Therapy of GOR vs Placebo Outcome: 3 Nocturnal Symptoms Score Study or subgroup Medical Therapy Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 H2 Antagonist Ekstrom (0.55) (0.62) 56.7% [ ] Gustafsson (0.43) (0.43) 43.3 % [ -0.78, 0.14 ] Subtotal (95% CI) % [ -0.52, 0.09 ] Heterogeneity: Chi 2 = 0.36, df = I (P = 0.55); I 2 =0.0% Test for overall effect: Z = 0.3 (P = 0.71) 2 Proton Pump Inhibitor Boeree (0.51) (0.64) 57.6 % 0.05 [ -0.67, 0.77 ] Ford (0.6) 11 1 (0.7) 42.4 % 0.0 [ -0.84, 0.84 ] Subtotal (95% CI) % 0.03[ -0.52, 0.57 ] Heterogeneity: Chi 2 = 0.01, df = 1 (P = 0.93); I 2 =0.0% Test for overall effect: Z = 0.11 (P = 0.92) 3 H2 Antagonist or Proton Pump Inhibitor Boeree (0.51) (0.64) 13.5 % 0.05 [ -0.67, 0.77 ] Ekstrom (0.55) (0.62) 43.4% [ ] Ford (0.6) 11 1 (0.7) 100% 00 [ ] Gustafsson (0.43) (0.43) 33.1 % [ -0.78, 0.14 ] Subtotal (95% CI) % -0.16[ -0.42, 0.11 ] Heterogeneity: Chi 2 = 0.97, df = 3 (P = 0.81); I 2 =0.0% Test for overall effect: Z = 1.18(P = 0.24) Test for subgroup differences: Chi 2 = 0.60, df = 2 (P = 0.71), I 2 =0.0% Peter G Gibson, Richard Henry and Jennifer JL CoughlanThe Cochrane Library Published Online: 21 JAN 2009

27 Analysis 1.4. Comparison 1 Medical Therapy of GOR vs Placebo, Outcome 4 B2 Use Puffs per Day. Review: Gastro-oesophageal reflux treatment for asthma in adults and children Comparison: 1 Medical Therapy of GOR vs Placebo Outcome: 4 B2 Use Puffs per Day Study or subgroup Medical Therapy Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 H2 Antagonist Ekstrom (0.88) (4.16) 100.0% [ ] Subtotal (95% CI) % 0.60[ -2.21, 1.01] Heterogeneity: not applicable Test for overall effect: Z = 0.73 (P = 0.46) 2 Proton Pump Inhibitor Ford (2.8) 11 6 (4) 37.1 % [ -4.19, 1.59 ] Teichtahl (3.39) (3.39) 62.9 % 0.10 [ -2.11, 2.31 ] Subtotal (95% CI) % -0.42[ -2.18, 1.34] Heterogeneity: Chi 2 = 0.57, df = 1 (P = 0.45); I 2 =0.0% Test for overall effect: Z = 0.47 (P = 0.64) 3 H2 Antagonist or Proton Pump Inhibitor Ekstrom (3.88) (4.16) 54.4 % [ -2.21, 1.01 ] Ford (2.8 ) 11 6 (4) 16.9 % [ -4.19, 1.59 ] Teichtahl (3.39) (3.39) 28.7 % 0.10 [ -2.11, 2.31 ] Subtotal (95% CI) % -0.52[ -1.70, 0.67] Heterogeneity: Chi 2 = 0.59, df = 2 (P = 0.74); I 2 =0.0% Test for overall effect: Z = 0.85(P = 0.39) Test for subgroup differences: Chi 2 = 0.02, df = 2 (P = 0.99), I 2 =0.0% Placebo better Therapy better Peter G Gibson, Richard Henry and Jennifer JL CoughlanThe Cochrane Library Published Online: 21 JAN 2009

28 Analysis 1.6. Comparison 1 Medical Therapy of GOR vs Placebo, Outcome 6 Improvement in wheezing Review: Gastro-oesophageal reflux treatment for asthma in adults and children Comparison: 1 Medical Therapy of GOR vs Placebo Outcome: 6 Improvement in wheezing Study or subgroup Medical Therapy Placebo Risk Ratio Weight Risk Ratio n/n n/n M-H,Fixed,95% CI M-H,Fixed,95% CI 1 H2 Antagonist Larrain /27 10/ % 2.07 [ 1.20, 3.58 ] Subtotal (95% CI) % 2.7 [1.20, 3.58] Total events: 20 (Medical Therapy), 10 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 2.62 (P = ) 2 Proton Pump Inhibitor Subtotal (95% CI) % 0.0 [0.0, 0.0] Total events: 0 (Medical Therapy), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: not applicable 3 Surgery Larrain /26 10/ % 2.15 [ 1.26, 3.69 ] Subtotal (95% CI) % 2.15 [1.26, 3.69] Total events: 20 (Medical Therapy), 10 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 2.79 (P = ) 4 Conservative Therapy Kjellen /29 5/ % 2.99 [ 1.23, 7.26 ] Subtotal (95% CI) % 2.99 [1.23, 7.26] Total events: 14 (Medical Therapy), 5 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 2.42 (P = 0.015) Placebo better Therapy better Peter G Gibson, Richard Henry and Jennifer JL CoughlanThe Cochrane Library Published Online: 21 JAN 2009

29 Summary Treatment asthmatic patients with H2R or PPI did not seem to improve the pulmonary function test nor decrease the use of inhaler therapy. The wheezing seem to become improve.

30 Symptoms of gastroesophageal reflux in patients with asthma Esophageal symptoms Heartburn Regurgitation Water brash Dysphagia Extraesophageal symptoms Sore throat Choking Hoarseness Dental erosions Chest pain Cervical pain Worsened asthma symptoms with Eating Alcohol Reflux symptoms Supine position Theophylline Systemic beta-adrenergic agonists

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32 Epitherial hypothesis : proposed mechanisms of alveolar epitherial injury and fibrosis in IPF Aspiration of gastric refluxate Cigarette smoke Autoimmunity Alveolar epithelial cell Inflammation Unknown insult (s) Proapoptotic stimuli Epitherial injury Impaired tissue repair Fibroblast proliferation and activation Collagen deposition Pulmonary fibrosis Fahim A, et alpulmonary Medicine 2011:1-7.

33 Prominent clinical studies evaluating gastroesophageal reflux in IPF Study Methodology Number of subjects Prevalence of GERD Other outcomes Tobin, et al (35) Raghu et al (36) Raghu et al (19) Prospective with non-ipf ILD control Prospective, control group without ILD Retrospective case review 17 IPF 8 controls 65 IPF 133 asthmatics Salvioli et al.2006 (37) Prospective 18 IPF 10 secondary pulmonary fibrosis 94% IPF 50% Controls 87% IPF 68% Asthma 4 IPF 100% as one of the inclusion criteria 67% of IPF patients had abnormal distal reflux 25% of IPF patients had typical reflux symptoms 47% of IPF patients had heartburn and regurgitation. No significant difference in proximal reflux in IPF and asthma, 63% versus 61%, respectively 2-6 year follow up with stable FVC and TLCO with proton pump inhibitors 57% of total patients had heartburn and regurgitation Bandiera et al.2009(38) Prospective 28 IPF 35.7% Participants divided into GERD + and GERD - groups Fahim A, et alpulmonary Medicine 2011:1-7.

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