H. pylori An endless source of lessons

Transcription

1 H. pylori An endless source of lessons Peter Malfertheiner Clinic of Gastroenterology, Hepatology and Infectious Diseases Otto von Guericke University Magdeburg

2 Helicobacter 1983 The show begins Inspired from René Magritte

3 The beginning was critical with more objections than support......most important a carrying team!!

4 The successful impact of interactive multisciplinarity and the foundation in 1987 of the European H.pylori study group Microbiologist Gastroenterologist Pathologist Epidemiologist Basic scientist

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6 H. pylori - a bestseller Publication number distribution per year,

7 Trends of articles and meeting abstracts on Helicobacter pylori from 1991 to 2008 Suk et al. European Journal of Gastroenterology & Hepatology 2011, Vol 23 No4

8 Comparison of the growth trends in subject categories containing over 1000 Helicobacter pylori-related articles Suk et al. European Journal of Gastroenterology & Hepatology 2011, Vol 23 No4

9 Publication trends of the top six countries and China Suk et al. European Journal of Gastroenterology & Hepatology 2011, Vol 23 No4

10 HOW TO LESSON 1 BREAK A DOGMA

11 Konietzny 1926,surgeon The inflamed gastric mucosa (Gastritis) is the essential condition for the development of peptic ulcer

12 Helicobacter pylori time was not mature! Dr. John Lykoudis: - General Practitioner - affected by gastric ulcer - Therapy with antibiotics combined with vitamines patients cured - no recognition by the University of Athens Dr.John Lykoudis ( )

13 C.pylori alias H.pylori In the remote 1983

14 inflammation = Basic condition for Peptic Ulcer development

15 R.Warren 1983 The change in paradigm Pathophysiology of H. pylori infection Mucus ph2 H + Urease (NH 3 NH 4 +) -Mucolytic enzymes - Cytotoxins ph6 Epithelial cells Submucosa T-Cells Cytokines Blood vessels Pain Inflammatory mediators Granulocytes, Macrophages

16 Topographical patterns of chronic gastritis Initial infection Multifocal atrophy accompanied by metaplasia Antrum predominant, Minimal corpus Involvement Auto immune Corpus-predominant with antrum normal

17 H. pylori-infection Chronic Gastritis no Symptoms Peptic Ulcer NEOPLASIA Extragastric diseases Predisposition for NSAIDs/Aspirin Lesions Dyspeptic Symptoms

18 HOW TO LESSON 1 CONTIN. CHANGE A DISEASE CONCEPT

19 H. pylori-infection Conceptual and therapeutic revolution in PUD ph + Hp

20 H.Pylori and the parietal cell K + H +

21 Helicobacter pylori a timeless source of lessons Destruction of a dogma with conservation of knowledge Multidisciplinary approach-example of modern research Role of big pharma in driving medical opinion Mistakes a chance to progress Guidelines ahead of the evidence Nobelpreis simpel and genial (... and never to late) H. pylori from cinderella to star Relentless to new horizons

22 Campylobacter pylori and recurrence of duodenal ulcers a 12 month follow up study J.G. Coghlan D. Gilligan H. Humphries D. McKenna C. Dooley E. Sweeney C. Keane C. O Morain The Lancet, November 14, 1987

23 Cure of duodenal ulcer associated with eradication of H. pylori E. Rauws, G. Tytgat Lancet 1990, 335:1233-5

24 Cure of peptic ulcer =concept of the repaired roof Acid inhibitors eradication (modif Goodwin et al. 1989)

25 THE SWITCH FROM ASSOCIATION TO CAUSALITY

26 Topographical patterns of chronic gastritis Initial infection Multifocal atrophy accompanied by metaplasia Antrum predominant, Minimal corpus Involvement Auto immune Corpus-predominant with antrum normal Duodenal ulcer

27 Acid secretion in antrum-predominant gastritis and gastric metaplasia Neural antral inhibitory complex + - Acid + Parietal cell - Somatostatin Gastrin r Malfertheiner

28 Pathogenesis of Helicobacter pyloripositive duodenal ulcer Somatostatin H. pylori infection Gastrin H. pylori gastritis Acid secretion antrum predomiant Induce Defect: Bicarbonate secretion Clearance of bulbar acidity Gastric metaplasia in duodenum H. Pylori infects H. Pylori Infection Virulence factors CagA VacA Other: IceA, OiPA, BabA Fakultative factors (stress, smoking) Duodenitis Duodenal ulcer Mucosal barrier breakdown Malfertheiner et al, Lancet 2009; 374:

29 Helicobacter pylori Barry Marshall Robin Warren Nobelprice for medicine 2005 Eradication cures peptic ulcer disease

30 LESSON 3 HOW TO OVERCOME HURDLES IN THE SCIENTIFIC COMMUNITY AND AGAINST BLOCK BUSTERS

31 LEARN TO LESSON 4 DEAL WITH GRAY NOT ALL IS BLACK AND WHITE

32 H.pylori Infection: Devil or Butterfly? GASTRIC CANCER Gastric lymphoma Protection from GERD Barrett and - adenocarcinoma?? Peptic Ulcer Dyspeptic Symptoms Increased vulnerability to ASPIRIN -NSAID

33 H. pylori and GERD

34 Incidence of Reflux Esophagitis in DU with Cured Hp Infection versus DU with Ongoing Infection : cured Hp infection : ongoing infection 25. 8% p< % The clinical evidence for H. pylori as esophageal protector Months Labenz J, et al. Gastroenterology 1997;112:

35 Frequency of the symptom heartburn in patients with duodenal ulcer (n=136) or gastric ulcer (n=133) 60% 51% Baseline 4 weeks 6 months 51% 40% 31% 41% 20% 0% DU H. pylori negative DU H. pylori positive GU H. pylori negative GU H. pylori positive Malfertheiner et al, APT 2002

36 Prevalence of H. pylori also a matter of geographical area Pandolfino et al, Am J Gastroenterol 2004, Editorial

37 Do the Benefits of H. pylori Treatment Outweigh the Theoretic Risk of GERD-Associated Complications? Hypothetical Comparison of 10,000 H. pylori Positive & Negative Persons 10,000 H. pylori negative 20% develop GERD 2000 patients 10% develop Barrett s 200 patients 5% die from esoph. CA 10 deaths 100 patients 10,000 H. pylori positive 10% develop PUD 1000 patients 10% complicated PUD 5% die 5 deaths 50 deaths 0,5% die from gastric cancer 55 deaths After Anand, B.S., Graham, D.Y. Endoscopy 1999;31 (1):

38 Helicobacter pylori and his multiple faces

39 Ghrelin, Leptin and Helicobacter Ghrelin in H.p. infected decreased Leptin increased hormonal control of satiety H.pylori and obesity?????? Konturek P.C. J Physiol Pharmacol 2006

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41 Treg cells - clinical outcome Atherton & Blaser J Clin. Invest. 2009

42 A BUG AND THE LESSON 5 SEQUENCE FROM CHRONIC INFECTION TO CANCER

43 Global burden of cancer 7.9 million (= 13% of all deaths) worldwide in % of all cancer deaths in 2007 occurred in low- and middle-income countries Gastrointestinal- represent highest contingent Gastric cancer ranks sadly second concerning death rate WHO Fact sheet N 297, July 2008

44 H. pylori and gastric cancer Population based control study gastric cancer controls n = 279 n = 238 H. pylori (IgG Ab) 72 % 55 % OR 2,2 [1,4-3,6] Immunoblot (CagA+) 91 % 56 % OR 21 [8,3-53,4] 71 % of non cardia adenocarcinoma attributable to H. pylori Ekstrom et al., Gastroenterology 2001

45 Microbes and cancer in the GI tract Localisation Oesophageal cancer Microbial pathogen Evidence HPV (++) JCV (+) Comment frequent detection of HPV-16,-18, but lack of invivo data detection of T-Ag in cancer tissues, but so far only one report EBV (-) low or no detection of EBV Gastric cancer H. pylori (+++) EBV (++) JCV (+) Colon cancer JCV (++) Anal cancer HPV (+++) confirmed evidence for a subset of gastric cancer, strong evidence for a subset of gastric cancer, but no expression of several EBV oncogenes detection of T-Ag in cancer tissues with high viral copy numbers, but so far only two reports T-Ag expression in about 50 % of colon cancer specimens HPV DNA in % of anal cancer; mainly HPV-16,-18 (-) no evidence; (+) weak evidence); (++) strong evidence; (+++) confirmed evidence

46 Duodenal ulcer Hyperplasiogenic Polyp Maltlymphoma Gastric cancer Clinical Folgen consequences der H. pylori of H.pylori GastritisInfection

47 Virchow Inflammation is at the origin of cancer Many common gastrointestinal cancers develop as a consequence of chronic inflammation and microbial pathogens

48 Carcinoma-Sequence Chronic Hp-Gastritis Multifocal Atrophy Intestinal Metaplasia IEN,high grade Adapted from Correa Cancer Cancer Res 48: , 1988

49 RISK GASTRITIS Cancer related Multifocal atrophic gastritis with intestinal metaplasia Auto immune Corpus-predominant with antrum normal

50 Abnormalities at Base Line Grade of atrophy Histology All HP+ Patients (n=1246) HP+ Patients with Gastric Ca (n=36) None or mild (0.8) 1.0 Relative Risk (95% CI)* Moderate (2.7) 1.7 ( ) Severe (7.2) 4.9 ( ) Distribution of gastritis Antrum predominant (0.3) 1.0 Pangastritis (4.2) 15.6 ( ) Corpus predominant (9.5) 34.5 ( ) Follow up period 7-8 yrs N Uemura. N Engl J Med 2001; 345:794-9

51 Atropphy and Intestinal Metaplasia Narrow band imaging

52 Biological effects H. pylori and gastric cancer VacA S1m1 CagA Gastrin Somatostatin Gastric glandular atrophy Mucosal proliferation Ascorbic acid ROM Mutation Nitroso compounds Acid secretion Gastric cancer

53 Contribution of host genetic, bacterial and environmental factors to pathogenesis of.h. pylori-induced gastric cancer Bacterial virulence factors caga PAI Vac A s1/m1 Environmental factors smoking Dietary factors Host genetic factors IL-1B-511*T IL-1_RN*2*2 IL-10 ATA haplotype TNF-A-308*A IL-8-251*A TLR4+896*G MBL2 HYD haplotype Gastric cancer phenotype Corpus-predominant gastritis Multi-focal atrophic gastritis High gastrin + Hypochlorhydria Low pepsinogen I and pepsinogen I/II ratio Bacterial overgrowth

54 Cancer preventable by H.pylori eradication! NNT 227 Gastric Cancer in patients without pre-cancerous lesion 1,4 1,2 Log-Rank P= ,8 0,6 0,4 0, Placebo Active Treatment 80 No. at Risk Active Treatment Placebo Follow-up, months JAMA 2004;291:

55 The potential and the mission to prevent gastric cancer

56 GUIDELINES LESSON 6 CONSENSUS: A STEP FORWARDS

57 Maastricht and managment of H.pylori infection...an exercise from 1996 to 2010 to-...?

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59 Urticaria Chronic Urticaria (CU) with 4 subtypes -autoreactive-cu Infectious-CU Intolerance-CU CU of other cause Possible cause of infection driven urticaria Infection with H.pylori. (Eradication an attempt) other bact. Infections (Sinusitis, Tonsillitis) dental

60 THE ONGOING CHALLENGE FOR EFFECTIVE TREATMENT

61 H. pylori infection Drug choices Acid suppressants PPI: Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazole Antiinfectious agents Clarithromycin Amoxicillin Metronidazole or Tinid. Tetracycline Rifabutin Furazolidone Levofloxacin Bismuth salts

62 PPI based triple standard since 1996 H. pylori eradication rate % ITT analysis The pioneers Bazzoli, OMC Italian Triple 1993 Lamouliatte,OAC French Triple MACH1 MACH2 DU-MACH GU-MACH OAC Lind et al 1996; Lind et al 1999; Veldhuyzen van Zanten et al 1999; Malfertheiner et al 1999;

63 H. pylori Eradication Therapy The current global standard acid suppressant (PPI) 2 antibiotics (Clari,Amoxi or Metron) duration of therapy 7 to 14 days PPI based triple therapy

64 Percentage of intention-to-treat treatment succes for `legacy triple therapy`in populations in southern Europe and other geographic areas Graham et al. GUT 2010, 59:

65 H. pylori antibiotic resistance in Europe ( ) Adults (N:1894) ATB No. of Resistant % Resistant Clarithromycin Amoxicillin Levofloxacin Tetracycline Rifabutin Metronidazole Mégraud F et al unpublished

66 H. Pylori eradication therapy Sequential therapy > PPI triple Efficacy 15 % > 7 days 13 % > 10 days effective also in clarithromycin-resistant strains (?) Gatta et al., Am J Gastroenterol 2009; 104:

67 Eradication Rates Primary End Point (Per-protocol Population) OBMT OBMT PPI triple OAC Patients (%) % (166/178) 69.6% (112/161) Treatment difference, 23.7% ± 8.6%; P < Eradication Rates Malfertheiner,Bazzoli Megraud Lancet 2011

68 Don`t forget testing breath blood stool breath Non invasive methods for diagnosis

69 THE FUTURE WILL A VACCINE WORK?

70 H. pylori Infection In Childhood Leads to Gastritis,later it my be complicated by Ulcers, and Cancer Lifetime Risk ~10% ~1% Exposure Acute Gastritis (usually no sx) Chronic Lifelong Gastritis (usually no sx) Primary Prophylaxis Treatment Secondary Prophylaxis Intervention Opportunities 1st 2nd 3rd 4th 5th 6th 7th 8th 9th Decades of Life

71 Per vedere questa immagine occorre QuickTime e un decompressore GIF. Approach to Vaccine Development antigens crucial in the pathogenesis of H. pylori infection VacA (cell vacuolation) CagA (immunodominant, associated with induction of severe disease and cancer) NAP (neutrophil, monocyte and mast cell recruitment and activation)

72 Immunogenicity Results In Healthy Adults: Antibody Titers Anti-CagA antibody titers Monthly 0, 1, Monthly 0, 1, Weekly Low dose (10 g) High dose (25 g) Immunization Anti-NAP antibody titers > Anti-VacA antibody titers Months post-1st immunization > Months post-1st immunization Months post-1st immunization

73 H. pylori Vaccine In Healthy Adults: Cellular Immune Response Proliferative Response Interferon Response Low dose High dose Placebo (alum alone) A CagA-driven prolierative response (stimulation index) Monthly 0, 1, Monthly 0, 1, Weekly B CagA-driven IFN- production (ng/ml) Monthly 0, 1, Monthly 0, 1, Weekly NAP-driven proliferative response (stimulation index) NAP-driven IFN- production (ng/ml) VacA-driven proliferative response (stimulation index) VacA-driven IFN- production (ng/ml) Months post-1st immunization Months post-1st immunization Malfertheiner et al Gastroenterology 2008

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75 CREATION OF A HUMAN INFECTION MODEL

76 H. pylori vaccine Antigen candidates UREASE CAG A VAC A NAP Bab A, Sab A, Hpa A, Alp A, flagellin

77 Vaccine and challenge Visit 4 Hp oral challenge ) Hp ELISA FAT Serum sample Famotidine (40mg PM prior + 20 mg AM of challenge) Visit 10 Visit 5 1WPC* UBT FAT Visit 6 2 WPC* UBT FAT Serum sample Visit 7 3 WPC* UBT FAT Visit 8 4 WPC* UBT FAT Serum sample Visit 9 8 WPC* UBT FAT 12 WPC* Hp ELISA (Enzygnost) UBT FAT UGE (path, culture, RUT) Serum sample Eradication Phase If Hp infected at 12WPC: treat 14 days WPC = weeks post challenge UBT = urea breath test FAT = fecal Ag test Visit wks after therapy UGE (path, culture, RUT) UBT FAT

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80 We need a vaccine

81 Vaccine is possible (still a prophecy), but we need move on search for antigen combinations routes of application Human models better understanding of immune response field trials sponsors

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