1. Vincenzo Savarino, Prof., MD Head of the Department of Internal Medicine and Medical Specialties, University of Genoa, Italy Head of the Gastroenterology-Hepatology Unit, IRCCS Azienda Ospedaliera-Universitaria San Martino - IST, Genoa, Italy LE MANIFESTAZIONI EXTRASOFAGEE DELLA MRGE: REALI O IMMAGINARIE ?

2. GERD - New Montreal Definition GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms and / or complications Symptomatic Syndromes Typical reflux syndrome Reflux chest pain syndrome Syndromes with Esophageal Injury Reflux esophagitis Reflux stricture Barrett's esophagus Adenocarcinoma Esophageal Syndromes Established Association Reflux cough Reflux laryngitis Reflux asthma Reflux dental erosions Proposed Association Sinusitis Pulmonary fibrosis Pharyngitis Recurrent otitis media Extra-esophageal Syndromes Vakil et al., Am J Gastroenterol 2006

3. Abnormal 24-hour pH Monitoring in Patients With Suspected Reflux Laryngitis SourcenpH abnormality Havas et al, 19991553% Metz et al, 19971060% Little et al, 199622276% Chen et al, 199873550% Wiener et al, 19891580% Katz et al, 19901070% Ulualp et al, 19992075% McNally et al, 19891155% Shaker et al, 199512100% Ossakow et al, 19883868% Koufman et al, 19883275% Wilson et al, 19899718% Cumulative121754% Vaezi et al, 2003

4. Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32. Patients with abnormal acid reflux (%) Ducolone et al. (n=51) Nagel et al. (n=44) Giudicelli et al. (n=140) Sontag et al. (n=104) DeMeester et al. (n=77) Larrain et al. (n=105) Kiljander et al. (n=107) 100 80 60 40 20 0 55 33 61 82 70 90 53 Abnormal Acid Reflux Linked to Asthma

5. Prevalence of reflux-associated chronic cough by esophageal pH monitoring Vaezi MF, APT 2006

6. Dental erosions in GERD patients Ranjitkar S et al, J Gastroenterol Hepatol 2012

7. No. reflux episodes p<0.001 p<0.05 Savarino E et al, AJRCCM 2009 Boxplots showing the total number and the chemical composition of reflux episodes in the two subgroups of SSC patients with and without pulmonary fibrosis and healthy volunteers.

8. p<0.001 No. reflux episodes 15 cm above LES Savarino E et al, Am J Resp Crit Care Med 2009 Proximal migration of reflux episodes in scleroderma patients and in controls.

9. Correlation between proximal migration of refluxes and total number of reflux events and pulmonary fibrosis score r2=0.644,p<0.001r2=0.637,p<0.001 Savarino E et al, Am J Respir Crit Care Med 2009

10. Number and types of gastro-esophageal reflux in IPF (n=40) and non-IPF patients (n=40) and in healthy controls (n = 50). Bars indicate median values. IPF= idiopathic pulmonary fibrosis Boxplots showing the number of total, acid and non-acidic reflux in patients with IPF and non-IPF and in controls N° REFLUX EVENTS Savarino E et al, DDW 2012

11. Median number of reflux episodes reaching the proximal esophagus in IPF (n=40) and non-IPF patients (n=40) and in healthy controls (n = 50). Bars indicate median values. IPF= idiopathic pulmonary fibrosis N° PROXIMAL REFLUX EVENTS Savarino E et al, DDW 2012

12. Correlation between the grade of pulmonary fibrosis (HRCT score) and the number of total reflux episodes at both the distal (on the left) and proximal (on the right) esophagus r2=0.567,p<0.001r2=0.632,p<0.001 Savarino E et al, DDW 2012

13. Percentages of patients with presence of biliary acids and pepsin in IPF, non-IPF and controls SALIVABAL Biliary acids 61% IPF patients 36% non-IPF patients 0% controls Pepsin : 68% IPF patients 39% non-IPF patients 0% controls Biliary acids : 62% IPF patients 40% non-IPF patients 0% controls Pepsin : 67% IPF patients 40% non-IPF patients 0% controls P < 0.01 Savarino E et al, DDW 2012

14. PREVALENCE OF ATYPICAL SYMPTOMS Prevalence of atypical symptoms concerning upper airways: –Sporadic manifestations between 7% and 15% –Frequent manifestations : 5 % Locke GR Gastroenterology 1997; 112:1448-56. In more than 50% of patients with atypical symptoms, typical symptoms are lacking Koufmann JH. Laringoscope 1991

15. GERD and respiratory symptoms PATHOPHYSIOLOGY Microaspiration of gastric contents into the larynx or airways with consequent mucosal reaction Vagal reflex stimulated by refluxate in the distal esophagus with the production of cough and/or bronchospasm

16. DIAGNOSTIC STRATEGY (search for GERD in patients with extraesophageal symptoms) Clinical features Trial of aggressive acid suppression (PPI test) Endoscopy 24-h pH-metry [the choice of the diagnostic work-up should be based on test sensitivity, prevalence of the disease, cost-effectiveness, etc.]

17. Katz et al, Am J Med 2000; 108(suppl 4a): 170S-177S. SymptomMedication and doseDuration Chest painPPI b.i.d.1-8 weeks AsthmaPPI b.i.d.≤3 month CoughPPI b.i.d.1-3 months Upper airwayPPI b.i.d.1-3 months Suggested Regimens for Extra- esophageal Manifestations of GERD

18. Cough scores dramatically decrease after the introduction of omeprazole 40 mg bid and the patient remains free of cough 1 yr after PPI withdrawal Ours T et al, Am J Gastroenterol 1999

19. Usefulness of PPI test in GERD N° Studies mg/die om/lan/eso duration days Sens % Spec % Typical symptoms 840-605-1427-896-73 NCCP340-807-3069-8075-90 Cough Laryngitis 340-807-9063-8155-90  Gold standard: pH-metry and/or endoscopy De Vault et al, 2000

20. Endoscopy

21. It’s not simple to establish a cause- effect relationship between GERD and extraesophageal manifestations ! Regurgitation or pyrosis : 20%-75% Erosive Esophagitis : < 30% Irvin,1993; Ours,1999 GERD and extraesophageal manifestations GERD and extraesophageal manifestations

22. Ear, nose and throat (ENT) signs in normal volunteers (n = 105) Ear, nose and throat (ENT) signs in normal volunteers (n = 105) Hicks DM et al, 2002

23. pH- Asthma is not GORD-related Asthma improved Begin maintenance anti-GORD therapy, which may include: l PPIs l H 2 RAs l Prokinetic agents l Surgery in selected patients pH+ Increase anti-GORD therapy or refer to gastroenterologist Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32. Adult asthma patients Asthma not improved Perform 24-hour oesophageal pH test while on anti-GORD regimen Monitor baseline asthma symptom, PEF, asthma medication use and spirometry 3-month trial with omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily, or rabeprazole 20 mg twice daily Continue monitoring as above Therapeutic trial of anti-GORD therapy for asthma patients PEF = Peak Expiratory Flow

24. 24-hour ambulatory pH-impedance

25. Episode of acid gastroesophageal reflux

26. Episode of weakly acidic GER

27. Criteria for selection of patients with chronic cough in whom GERD should be investigated Galmiche JP et al, APT 2008

28. Nonacid reflux episode associated with cough Nonacid reflux episode associated with cough Rosen and Nurko, 2004

29. Relevance of acid and/or weakly acidic reflux in chronic cough Weakly Acidic Reflux in Patients with Chronic Unexplained Cough During 24 Hour Pressure, pH and Impedance Monitoring; D. Sifrim et al; GUT; 2005; 54;449-454 3 Non acid Associated2 Acid & Non acid Associated 5 Acid Associated 10 SAP + Reflux-Cough 22 Patients

30. Identification of three subgroups with chronic cough Blondeau et al, APT 2007

31. NEG Proposal of a diagnostic work-up in patients with suspected atypical GERD Quigley et al, 2008

32. Therapeutic results in patients with atypical symptoms of GERD

33. Medical Treatment of Patients with Chronic Cough from Suspected GERD 35 PPI ( Ome 40 mg bid ) Double-blind, placebo-controlled 17 Ours et al, ‘99 100 H2RAs or PPIsUncontrolled 11 Vaezi et al, ‘97 97 H2RAs  prokinetics Uncontrolled 20 Smyrnios et al, ‘95 80 H2RAs, PPIsUncontrolled 25 Waring et al, ‘95 70 Antacids, Cimetidine, Metoclopramide Uncontrolled 20 Fitzgerald et al, ‘89 100 Metoclopramide and/or H2RAs Uncontrolled 28 Irwin et al, ‘90 100 Metoclopramide and/or H2RAs Uncontrolled 9 Irwin et al, ‘89 Asymtomatic patients (%) TherapyStudy designn

34. Results of Seven Randomized, Controlled Trials of PPIs in Subjects with GERD-related Asthma AuthorsYearPts no.RXResponse Ford et al199410Ome 20, 4 wks- sympts, - PEF Meier et al199415Ome 40, 6 wks- FEV1 Teichtahl et al199620Ome 40, 4 wks- sympts, - FEV1, + PEF Levin et al19989Ome 20, 8 wks+ sympts, + PEF, - FEV1 Boeree et al199830Ome 80, 12 wks-day + night sympts, - FEV1, - PEF Kiljander et al199952Ome 40, 8 wks-Day + night symptoms, - FEV1, - PEF Jiang et al200330Ome 20, Domperidone 10 TID, 6 wks + FEV1, + PEF Shaheen N, DDW 2004

35. Medical treatment trials for GERD-related asthma Medical treatment trials for GERD-related asthma Richter et al, 2005

36. Treatment difference (95% CI) in change in morning and evening PEF rate (L/min), classified according to GERD and nocturnal symptoms in asthmatic subjects receiving esomeprazole 40 mg twice daily or placebo Kiljander et al, AJRCCM 2006

37. Questionnaire scores and lung function measures at 24 weeks of follow up Holbrook J et al, JAMA 2012

38. Results of Uncontrolled Studies in the Treatment of Patients With Suspected Reflux Laryngitis SourcenTherapyDuration (mo) SymptomsLarynx Koufman et al, 1991 33H2RAs685% Metz et al, 199710PPI (80 mg)*160% Hanson et al, 1995 182H2RA/PPI1-398% Kamel et al, 199416PPI (40 mg)*1-692%56% Shaw et al, 199768PPI (40 mg)*360% Wo et al, 199721PPI (40 mg)*267%50% Vaezi et al, 200145PPI*± H2RA467%62% Cumulative3753.683%85% Response (*PPIs were given generally twice daily, before breakfast and dinner) Vaezi et al, 2003

39. Medical antireflux treatment of reflux laryngitis: placebo- controlled studies Medical antireflux treatment of reflux laryngitis: placebo- controlled studies Richter et al, 2005

40. Estimates of relative risk for improvement or resolution of laryngeal symptoms in patients treated with PPIs Gatta et al, APT 2007

41. Summary of proton pump inhibitor efficacy for potential manifestations of GORD as assessed in randomised controlled trials. Kahrilas and Boeckxstaens, Gut 2012

42. Surgical therapy of chronic cough due to GORD 60 FundoplicatioProspectic, controlled 7 Leeder ‘02 56 FundoplicatioProspectic, uncontrolled 16 So ‘98 51%(asintom) 31%(migliorat i FundoplicatioProspectic, uncontrolled 20 Allen, Anvari ‘98 76 FundoplicatioProspectic, uncontrolled 40 Johnson ‘96 85% FundoplicatioProspectic, uncontrolled 13 Giudicelli ‘90 100 FundoplicatioProspectic, uncontrolled 17 DeMeester ‘90 100 FundoplicatioProspectic, uncontrolled 5 Pellegrini ‘79 Asymptomatic (%) TreatmentStudy designno. pts.

43. Preoperative and postoperative voice frequency (CFx) and amplitude (CFa) are compared in patients with documented irregularity in their preoperative electroglottography (n = 6). p < 0.0012 and p < 0.0415 Ayazi S et al, J Clin Gastroenterol 2012

44. Shortcomings Shared by Studies on Extra-esophageal Reflux Disease Most studies feature small number of subjects Case definition is variable (also 24-hour pH data are of limited utility) In patients with abnormal pH data, a simple association instead of causation between reflux and laryngeal-respiratory symptoms may be present In a subgroup of patients with chronic cough acid and/or weakly acidic gastroesophageal reflux can be present Study outcome measures are not standardized and may vary considerably across studies Treatment amount and duration may be inadequate

45. Atypical GERD: key messages GERD can manifest with atypical symptoms Their prevalence ranges between 5% and 20% There is no diagnostic method of adequate reliability It is mandatory to distinguish simple association from causality between GERD and extra-esophageal disorders It is recommended to treat these patients with higher-than- standard doses of PPIs and for longer-than-usual time periods However, both medical and surgical therapies are frequently disappointing in controlled studies Our future efforts should be addressed to identify the subgroup of patients who can respond to anti-reflux treatment

46. The End