Helicobacter pylori - Université catholique de Louvain · Helicobacter pylori: From its discovery...
Transcript of Helicobacter pylori - Université catholique de Louvain · Helicobacter pylori: From its discovery...
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Helicobacter pyloriHelicobacter pylori: : From its discovery to a revolution in From its discovery to a revolution in
gastroenterologygastroenterology
Y. Glupczynski
Laboratoire de Microbiologie Cliniques Universitaires UCL de Mont-Godinne
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Peptic ulcer and Nobel prize…over more than a century
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H.pylori : Some key dates
Microscopic observation of spiral-shaped bacteria in stomach
1893 Bizzozero animal1906 Krienitz human1975 Steer human
Culture
1982 Marshall human
Nomenclature
1982 Marshall Campylobacter pyloridis1989 Goodwin Helicobacter pylori
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Evolution of Number of publications on H.pylori and gastroduodenal
diseases
0
400
800
1200
1600
2000
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
N = > 22,000 articles listed in PubMed
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The milestone publications…Organisms present in gastric biospies from:- 100% of duodenal ulcers- 80% of gastric ulcers- 90% of active chronic gastritis- 3% with no histological gastritis
H. Pylori on gastric epithelial cells
Warren JR, Marshall BJ; Lancet i: 1273-5; 1983Marshall B, Warren JR; Lancet i: 1313-5; 1984
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Fruitless attempts to culture the elusive organism until …
Culture of gastric mucosa biopsies from34 patients negative (after 48 h)
Royal Perth Hospital
5 days incubation
First cultures became positive onlyafter prolonged Easter week-end
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Resistance from the medicalestablishment…
Submission to the 1983 meeting of the AustralianGastroenterological Society was rejected….
…but was accepted to the 2nd International Microbiology Workshop on Campylobacterinfections in Brussels in 1983
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Attempts to fulfil Koch’spostulates (I)…
Marshall, Med J Aust 1985; 142: 436-9
- Day 5: halitosis, nausea, vomitingof acid free gastric juice
- Day 10: Endoscopy with biopsyAcute gastritis withmany H. pylori
- Day 14: Rx with Bismuth/tinidazoleresolution of symptoms
Self ingestion of a pure culture of H. pylori (109 organisms)
Marshall’scocktail
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Attempts to fulfil Koch’spostulates (II)…
Cimetidine vs Bismuth (CBS) (8 Wks)+ Placebo or tinidazole (10d)
Eradication of H. pylori :increases healing of duodenal ulcer92% (Hp -) vs 61% (Hp+)decreases relapse rates at 12
months21% (Hp-) vs 84% (Hp+)
Marshall BJ; Lancet 1988; 332;: 1437-42
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Hill causality criteria for association between H. pylori infection and
gastroduodenal ulcer
•Strong association
•Temporal relationship
•Major effects of therapeutic intervention on outcome
• Biologic plausibility• Biologic gradient ?
• But, no specificity of association
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H.pylori : Epidemiology
• Chronic infection• Prevalence increases with age
• incidence = 0.5-1% by person / year
• Infection acquired earlier in life and increased prevalence :
• developing countries • populations with low socio-economic status
• Inter-human transmission• oral-oral and/or faecal-oral
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Prevalence ageof H. pylori infection with
Developing countries Developed countries100
10-75%
64-96%
6-39%
7-54%
80%75
Prev
alen
ce(%
)
50
50%25
040-50 40-50<20 <20Age range (years)
Adapted with permission from Heatley-Helicobacter pylori and Gastrointestinal Disease;Oxford, UK: Blackwell Scientific Publications
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Divergent response to H. pylori infection
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Major pathogenic factors of H. pyloriVirulence factors Function Present in
all strains
Urease Acid resistance; Nitrogen metabolismEscape to immunologic responseCytotoxic effect
Y
Flagella Motility Y
BabA Adhesion to Lewisb antigens N
AlpA, AlpB Adhesins (receptors not identified) Y
CatalaseSuperoxide dismutase
detoxification (escape to immunologicresponse)
Y
LewisX,Y antigens(lipopolysaccharide)
Molecular mimicry (escape toimmunologic response), adherence
N
VacA Cytotoxicity N
CagA Immunodominant antigenunknown function
N
Cag pathogenicity island Secretion system (type IV) ?Induction of inflammation
N
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Cag pathogenicity island
ABCF E DIM GN L HQ P OR
TnpBTnpAST15 16 17 1813 1411 121097 86
Chromosome de H. pylori
cag II region
cag I region
II IS605 I
IS605
TnpBTnpA
IS605
Censini et al., PNAS 1996, 93: 14648-53Akopyants et al., Mol Microbiol 1998, 28: 37-53
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Role of cag pathogenicity islandand CagA protein
(Covacci et Rappuoli, 2000)
type IV secretionsystem
Gastric epithelial cell
CagA
CagAP
Polymerisationof actin filaments
nucleus
?
H. pylori
Induction of IL-8secretion
rearrangements of cytoskeleton
Cellular proteinsP
Inflammation Of gastric mucosa
Apoptosis
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H. pylori genome(Tomb et al.1997, Alm et al. 1998)
Assign function to a putative genes
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H.pylori : from infection to gastric cancer
H.pylori
Chronic active gastritis
Interaction DNA/mutagene
Intestinal Metaplasia
Atrophic gastritis
Dysplasia
Gastric Cancer
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H. pylori and gastric pathology
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June 1994
• Working group WHO/IARC
« Establishment of a definite link betweenH. pylori infection and gastric cancer in
humans»
« H. pylori considered as Group 1 (definite) carcinogen »
IARC Monograph. - Evaluation of carcinogenic risks for humans- 1994, Lyon, France
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H.pylori and gastric cancer
• Epidemiologic data – Geographic and temporal concordance in
incidence
• Cross-sectional case-control studies– 50 -100 % of gastric cancers infected with Hp
• Prospective nested case-control studies– Hp infection --> Risk of developing gastric cancer
increased 2- to 9-fold• Causal relationship in animal model
– mongol gerbils
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The only good Helicobacter is a dead
Helicobacter !
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Evolution of the understandingtheories of gastroduodenal ulcers
No acid… No ulcer(K. Schwartz 1910)
H2-receptor antagonists(JW Black 1972)
Proton-pump inhibitors(G Sachs 1980)
50-60’sNo Helicobacter
…No ulcer(B Marshall, 1988)
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H. pylori infection:Therapeutic indications
• Peptic ulcer disease* – active or not• Gastric MALT lymphoma• Atrophic gastritis• Post-gastric cancer resection• First degree relatives of gastric cancer
patients• Patient’s wishes – after full consultation
with their physician
* Meta-analysis CRG, Ford, AJG 2004
Hp eradication Rx cost-effective*: > anti-H2 blockers for healing ulcers= to maintainance Rx for preventing
recurrences) (1-2 yrs)
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Characteristics of optimal drugsfor the treatment of H. pylori infection
• High in vitro antibacterial activity• High concentration in gastric
mucosa/mucus• Active by endoluminal and systemic
routes• Stable over wide range of pH (<2-7)• Good tolerance / few side effects• Low propensity for resistance• Inexpensive
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1 23 First choice antibioticsClarithromycin
– Most active single agent
– Good diffusion in gastric mucosa
– Synergy with acid-suppressive agents
– Increasing resistance
– Decreased efficacy in areas of high resistance (20%)
– High cost
Amoxicillin
– No resistance development
– Activity not affected by acidic pH
– Broad-spectrum
– Side effects (gastrointestinal, dermatologic)
Metronidazole
– Activity not influenced by pH
– Clinical efficacy little affected by resistance
– Inexpensive
– Side effects (gastrointestinal)
– High resistance rates in several areas (>40%)
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Second choice antibiotics
Tetracyclines
– Resistance rare– Synergy with bismuth salts– Clinical efficacy in
quadruple therapy– Inexpensive
– Side effects (gastrointestinal, rash)
1 23
Fluoroquinolones
– Potential interest for rescue therapy if previous treatment failures
– Well tolerated
– Wide usage of FQ in other indications
– Poorly active at acidic pH– Resistance increasing
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Proton-pump inhibitors
• Bacteriostatic activity against H. pylori
• Synergy with some antimicrobials (metro, clari, tetra)
• Effect of acid suppression (↑ gastric pH):– increases activity of several antibiotics (macrolides, quinolones)– Improved penetration of bismuth salts in gastric mucosa– Increased concentrations of metro, clari, tetra in the stomach
• Improve clinical efficacy of dual antimicrobial regimens
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Adjuvant effect of Omeprazole on H. pylori eradication by amoxicillin
Unge, Bordeaux 1988
87100 100
27
8580
13,5
38
0
50
100
0 15 40
ome 40% H. pylori +
days
amox 750 bd
ome + amox
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Therapeutic principles (1)
Rational choice of therapeutic agents
Based on clinical experience
Association regimens including :– amoxicillin– clarithromycin– 5-Nitroimidazoles– Tetracycline– Bismuth salts
• Other agents active in vitro have proven ineffective in vivo
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Hp : Therapeutic Principles (2)
15
60
85 88
0102030405060708090
100
Mono Bi Tri Quadri
Importance of drug associations
(2-4 wks) (2 wks) (1 wk) (1 wk)
% e
radi
catio
n (IT
T)
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Hp : Therapeutic principles (3)
0102030405060708090
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
MTZ resistant MTZ susceptible
%
Treatment duration: eradication rates withbismuth based triple therapies
days
% e
radi
catio
n (P
P)
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Hp : Therapeutic principles (4)
96%
72%
0
20
40
60
80
100
19%
88%
0
20
40
60
80
100
Rx with Metro Rx with Clari
Importance of resistance on Hp eradication
S SR R
% e
radi
catio
n (P
P)
Mégraud, Gut 2004
Metro-R-25%
Clari-R-70%
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Importance of patients compliance for eradication of H. pylori
97 91
75
33
0
20
40
60
80
100
Duodenal ulcer Gastric Ulcer
Compliance >60% Compliance <60%
Graham, Gastroenterol 1992
%
% e
radi
catio
n (P
P)
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Factors of importance for predicting outcome of therapy in Hp infection
PROVEN• Choice of agents• Choice of associations• Compliance• Antimicrobial resistance• Dosage• Duration of therapy
POSSIBLE• Drug formulation • Number of daily
administration• Drug intake in relation to
meal• Polymorphism of CYP2C19
in metabolism of PPIs
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First line therapyEUROPEAN
HELICOBACTER STUDY GROUP
Maastricht 2005-3 consensus report
PPI standard dose bid (omeprazole, lanso, panto) + Clarithromycin 500 mg bid (C) Amoxicillin 1000 mg bid (A)
+ or
Metronidazole 500 mg bid (M)
CA preferred in area with Metro-R > 40%
≥ 80% cure rates on ITT to basis
1 23
1 week, Triple therapy, 2x/daily(PPI + 2 ABs)
Malfertheiner, APT 2002
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Primary resistance rates of H. pylori in Belgium
30,6
13,618,1
1,3 0,70
10
20
30
40
Metro Clari Cipro Amoxi Tetra
% resistance(N=151, 10 centres)
Belgian Helicobacter Study Group, 2004
I seeresistance
coming
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Antimicrobial resistanceof H. pylori in Europe
% résistance
Clari Metro Amox05
1015202530354045
9.9
33.1
0.8
(0-27.2)
(18.9-61.6)
Risk factors for resistanceMetro-RBorn outside Europe (OR: 2.7)Living in East. Europe (OR: 1.9)Female (OR: 2.3)Clari-RLiving in South. Europe (OR: 2.3)Age < 12 yrs (OR: 1.8)
N=1274 (N° d’isolats/Centre = 64, valeurs extrêmes: 21-115)22 centres, 17 pays
Glupczynski , EJCMID 2001
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Consumption of macrolides in 17 European countries in 1998
DDD/1000 inh.per day
www.ua.ac.be/ESAC
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Secondary resistance of H. pylori after eradication failure
1
64
53
37
010203040506070
Amox Clari Métro Clari + Métro
% resistance First Rx: PPI-AC (90% cases)(N=225)
Mégraud et al. Gut 2001
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Second line therapyBismuth quadruple therapy, 10-14 d
(failure, allergy, intolerance, high level of resistance to clari)
Maastricht 2005-3 consensus report
EUROPEAN HELICOBACTER STUDY
GROUP
PPI standard dose bid (omeprazole, lanso, panto) + Bismuth salt (CBS) 120 mg qid + Metronidazole 500 mg tid Tetracycline 500 mg qid
+ or
Amoxicillin 500 mg tid
Unaffected by Clari-R; little influenced by Metro-R Cost < to PPI-triple therapy
≥ 85% cure rates on ITT to basis Fishbach, APT 2004
1 23
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Rescue therapy
Treatment adjusted on the basis of culture and susceptibility results (antibiogramme)
Should be handled on « Case-by-case » basis
Avoid re-using same agents (clari, metro)
Proposed triple therapies (under evaluation): PPI + Amox + fluoroquinolones (Levoflo, Moxiflo)
rifamycins (rifaximin, rifabutin)
after failure of two courses of different therapies
EUROPEAN HELICOBACTER STUDY
GROUP
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Evolution of H. pylori resistance
6,1
16,616,9
1,32,6
18,9
0
5
10
15
20
1989-1994 1995-2000
Clari
Metro
Clari +Metro
%re
sist
ance
ns
Period
P < 0.001
N=555 Hp isolates; 1989-2000
Bontems et al., PIJD 2001
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Evolution of prevalence ofH.pylori infection in Europe
40 40 38 33 2822
0
50
100
1925 1935 1945 1955 1965 1975
Year of birth
% H. pylori +
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Perspectives
• H. pylori infection becoming more rare
• Consequences of infection in terms of burden of associated diseases (ulcer, cancer) is going to be with us for a while
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The H. pylori saga endingin a Nobel Prize ….
• …Being at the right place at the right time, and seeing what other people had seen but thinking what nobody else thought…
• The role of chance…
• … »Challenging established dogmas withpassion, tenacity and prepared mind …
• Possibility of making important discoveries as clinicians in the course of daily practice…