Helicobacter Pylori 2

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Helicobacter Pylori

Eradication Therapy in Dyspeptic Disease

A Clinical Guideline

recommended for usedeveloped by a multi-professional expert group

sponsored by the

Clinical Audit and Resource Group (CRAG)and

recommended for usein

Scotlandby the

Scottish Intercollegiate

Guidelines Network

Pilot Edition

August 1996

Getting validated guidelines into local practice

SIGN PUB

LICAT

IONNUMBER

7

S I G N


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This guideline was issued inAugust 1996 and will be reviewed in 1998. Comments areinvited to assist the review process. All correspondence regarding the guideline shouldbe sent to:

Mrs Christina Pottinger, SIGN Administrative Support Group

Royal College of Physicians, 9 Queen Street, Edinburgh, EH2 1JQ

The definitions of the types of evidence and the grading of recommendations used inthis guideline originate from the USAgency for Health Care Policy and Research(1) andare set out in the following tables.

Level Type of Evidence

Ia Evidence obtained from meta-analysis of randomised controlledtrials.

Ib Evidence obtained from at least one randomised controlled trial.

IIa Evidence obtained from at least one well-designed controlled studywithout randomisation.

IIb Evidence obtained from at least one other type of well-designedquasi-experimental study.

III Evidence obtained from well-designed non-experimentaldescriptive studies, such ass comparative studies, correlation studiesand case control studies.

IV Evidence obtained from expert committee reports or opinionsand-or clinical experiences of respected authorities.

Grade Recommendation

A Required - at least one randomised controlled trial as part of the(Evidence body of literature of overall good quality and consistencyLevels Ia, Ib) addressing specific recommendation

B Required - availability of well conducted clinical studies but no(Evidence randomised clinical trials on the topic of recommendation.

Levels IIa,IIb, III)

C Required - evidence obtained from expert committee reports or (Evidence opinions and/or clinical experiences of respected authorities.

Indicates absence of directly applicable clinical studies of goodquality


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SIGN PUB

LICAT

IONNUMBER

7

S I G N

Helicobacter Pylori

Eradication Therapy in Dyspeptic Disease

A Clinical Guideline

recommended for usedeveloped by a multi-professional expert group

sponsored by the

Clinical Audit and Resource Group (CRAG)and

recommended for usein

Scotlandby the

Scottish Intercollegiate

Guidelines Network

Pilot Edition

August 1996

Getting validated guidelines into local practice


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Scottish Intercollegiate Guidelines Network

ISBN 1 899893 30 X

First published 1996

SIGN consents to the copying of this guideline forthe purpose of producing local protocols for use in Scotland

Published by the Scottish Intercollegiate Guidelines Network (SIGN)9 Queen Street, Edinburgh EH2 1JQ

Desktop published by Anne Farquharson, SIGN


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Contents Page

Foreword

Summary ... ... ... ... 1

1 Introduction ... ... ... 4

2 Background ... ... ... 52.1 Dyspepsia ... ... ... 5

Definition ... ... ... 5Prevalence ... ... ... 5Causes of Dyspepsia ... ... 5

2.2 H. pylori Infection ... ... ... 5

Microbiology ... ... ... 5Prevalence ... ... ... 6Acquisition and Natural History ... ... 6

3 The Role of H. pylori Infection in Dyspeptic DiseaseAssessment of Evidence ... ... ... 73.1 Introduction ... ... ... 73.2 Duodenal Ulcer (DU) ... ... ... 73.3 Benign Gastric Ulcer ... ... ... 73.4 Oesophagitis ... ... ... 8

3.5 Non-Ulcer Dyspepsia ... ... ... 83.6 Dyspepsia and Ulcer Disease Related to NSAIDs ... 83.7 Gastric Cancer ... ... ... 83.8 Summary and Conclusions ... ... 9

4 Which Patients Should Receive H. pylori Eradication Therapy?4.1 Duodenal Ulcer ... ... ... 104.2 Gastric Ulcer ... ... ... 104.3 Low Grade Gastric Lymphoma ... ... 10

5 H. pylori Eradication Therapy ... ... 125.1 Introduction ... ... ... 125.2 Efficacy of Eradication Therapy ... ... 125.3 Adverse Effects Associated with Eradication Therapy ... 135.4 The Problem of Antibiotic Resistance ... ... 135.5 Clinical Recommendations Concerning

Use of Anti-H. pylori Therapy ... ... 13Choice of Anti-H. pylori Therapy ... ... 13Mode of Prescribing of Anti-H. pylori Therapy ... 15


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6 Follow-Up After Eradication Therapy ... ... 166.1 Uncomplicated Duodenal Ulcer ... ... 166.2 Complicated Peptic Ulcer ... ... 166.3 Gastric Ulcer ... ... ... 166.4 Ulcers in Patients Requiring Continued NSAIDs ... 16

7 Can H. pylori Testing be used as a Substitute

for Endoscopy/Barium Meal in Determining

Management of Some Dyspeptic Patients? ... ... 177.1 Could Upper GI Investigations be Avoided

in H. pylori Negative Patients? ... ... 177.2 Could Upper GI Investigations be Avoided

in H. pylori Positive Patients? ... ... 177.3 Conclusion ... ... ... 17

8 Resource Implications ... ... ... 18

9 Research Needs ... ... ... 19

10 Implementation of the Guideline ... ... 2010.1 Development of Local Protocols ... ... 2010.2 Continuing Education ... ... ... 2010.3 Clinical Audit ... ... ... 20

Audit in General Practice ... ... 20Audit in Hospitals ... ... 2110.4 Information for Patients ... ... 21

11 Management of the National Guideline ... ... 2211.1 Statement of Intent ... ... ... 2211.2 Development of the Guideline ... ... 22

Responsible Bodies ... ... 22Professional Advisory Panel ... ... 23Funding ... ... ... 23Extended Reference Group ... ... 24Development Team ... ... 24Development Process ... ... 25Literature Searches ... ... 25Drafting Process ... ... ... 25Peer Review ... ... ... 25SIGN Editorial Board ... ... 26Economic Component ... ... 26


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11.3 Dissemination ... ... ... 2611.4 Review ... ... ... ... 26

References ... ... ... ... 27

Annexes

1 Staff Groups ... ... ... 302 Diagnostic Methods for H. pylori ... ... 313 Quick Reference Guide ... ... 35

Tables

1 Which Patients withH. pylori should

Receive Eradication Therapy ... ... 112 Recommended H. pylori Eradication Therapy ... 15


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Foreword

There is probably no other common disorder in which management has changedso dramatically in the last decade as peptic ulceration. The discovery ofHelicobacter pylori and the elucidation of its role in the aetiology of duodenaland gastric ulcers has revolutionised the management of these conditions. This iswhy the subject was chosen as the topic of the Clinical Resource andAudit Groups1995 clinical conference.

We are grateful to Professor KennethMcColl for chairing the guideline conference;to him and other members of the Guideline Development Team for the substantialwork involved in preparing this clinical guideline; and to Mrs Eileen Barnwellfor taking responsibility for the process. This will probably be the last clinicalguideline which CRAG will produce. Responsibility for guideline developmenthas now passed to the Scottish Intercollegiate Guidelines Network (SIGN). Thisguideline has been produced in accordance with SIGN criteria and is now acceptedformally by SIGN as the Scottish national guideline on which local practice shouldbe based.

This report summarises the evidence that Helicobacterpylori plays a key role inthe genesis of most peptic ulcers, and perhaps that of some gastric cancers as

well, and describes how infection with this organism is best identified anderadicated. It also contains the Quick Reference Guide derived from the guideline:this is also being published separately for ease of reference. Because the optimalmanagement of H. pylori infection is likely to change rapidly over the next yearor two as new evidence accumulates, the guideline will be kept under review, andupdated as necessary.

R E Kendell J C PetrieChairman, CRAG Chairman, SIGN

August 1996


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Summary

Dyspeptic Disease

Dyspepsia is one of the commonest chronic medical disorders. 40% of the UK population suffer from dyspeptic symptoms. 5% of all GP consultations and 30% of all gastroenterology referrals are for

dyspepsia.

50% of patients with dyspepsia who are investigated endoscopically havean underlying lesion. In order of prevalence, these are

oesophagitisduodenal ulcergastric ulcergastric-oesophageal cancer

H. pylori - Role in Dyspeptic Disease

50% of the adult population of Scotland is infected with H. pylori which has apathogenic role in various forms of dyspeptic disease. The evidence for this is asfollows:

there is strong evidence thatH. pylori plays an important role in causingduodenal ulcerswhere not associated with non-steroidal anti-inflammatorydrugs

(level of evidence Ia) there is also evidence of a role in benign gastric ulcer

(level of evidence Ib)

the evidence of a role in the causation of gastric carcinoma is limited(level of evidence IV) but for gastric lymphoma is level of evidence Ib

it is unclear whetherH. pylori has a role in non-ulcer dyspepsia H. pylori does not have a role in oesophagitis

(level of evidence III)

Which Patients should ReceiveH. pylori Eradication?YES, if the patient has:

a proven duodenalulcer (new cases and old cases with persisting symptoms).It is not necessary to check for the presence of infection.(Grade A recommendation)

a gastric ulcer, if positive for the infection, after endoscopy(Grade A recommendation)

low grade gastric lymphoma(Grade B recommendation)

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NO, if the patient has:

non-ulcer dyspepsia(Grade C recommendation)

oesophagitis(Grade C recommendation)

No recommendations can be made at present for:

patients with NSAID-related ulcers dyspepsia, with the infection, but not yet investigated

Eradication Treatment

eradication of over 90% has been achieved from triple therapy for sevendays with a proven regimen. Recommendations are made in the guidelinefor two preferred treatments.(SIGN Grade A).

recommended regimens will change rapidly with scientific advances andbecause of local patterns of resistant organisms. The guideline will be keptunder continuous review.

to minimise future resistance, patients should only be treated incircumstances where there is proven benefit.

side effects are common (30% of cases) and patients must be informed ofthese and the means of avoiding them. Patients should be informed of the

necessity to comply closely with the instructions for taking the medicineand warned that the efficacy of oral contraception may be impaired.

30% of patients experience persisting symptoms even after successfuleradication.

Which Patients should be Followed Up after Eradication Therapy?

in those with DU test, using a breath test, only if symptoms persist fourweeks post treatment. If still infected, use alternative treatment. If notinfected consider alternative diagnosis.

(SIGN Grade C) in those who have bled from an ulcer, keep on anti-secretory drug until

eradication is confirmed.(SIGN Grade C)

in those with gastric ulcer, repeat endoscopy in 4-8 weeks.(SIGN Grade C)

in those with NSAID-related ulcers, follow-up by endoscopy: H. pyloristatus may not be relevant.(SIGN Grade C)

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ImplementationGPs should identify all patients with newly diagnosed DU or patients withpreviously diagnosed DU and persistent or recurring symptoms and offereradication therapy.

GPs should identify all patients with diagnosed gastric ulcer and offer a test forH. pylori infection followed by eradication therapy, if positive.

The recommendations made in this guideline should be jointly reviewed and co-ordinated local policies agreed.

General Practices should establish audit tomonitor aspects of the use of eradicationtherapy.

The Royal College of Physicians of and Surgeons of Glasgow, on behalf of SIGN,will have continuing responsibility for the review and updating of this guideline.It will be reviewed formally every two years and amendments will be disseminatedat that time or at any other time when significant amendment becomes necessary.

The full report on the development of this guideline may be consulted at

the offices of the SIGN Secretariat and selected background papers may

be obtained fromMrs C Pottinger, SIGN Secretariat

Royal College of Physicians, 9 Queen Street, Edinburgh EH2 1JQ

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1 Introduction

This guideline deals specifically with eradication of H. pylori and not with themanagement of dyspepsia more generally.

The broad background to dyspepsia and to H. pylori infection is described insection 2. In section 3 the role ofH. pylori in the pathogenesis of various dyspepticdiseases and the evidence for the benefit of eradication of the infection in eachcase are considered. Section 4 synthesises the evidence and, on the basis of thatevidence, makes specific recommendations about eradication therapy. Scientificevidence is available on which to base firm recommendations only in relation toconfirmed duodenal ulcer, gastric ulcer and low grade gastric lymphoma.

The key references on which the guideline is based are set out in Annex 1 and theliterature searches performed are described in Annex 2.At Annex 3 are describedthe diagnostic methods forH. pylori infection and atAnnex 4 is a Quick ReferenceGuide to the guideline. The Quick Reference Guide is also published separately.

Three separate literature searches were performed by nominated members of theProfessionalAdvisory Panel (see paragraph 11.2.2) and several thousand abstractsreviewed. Selected articles were studied in full and the evidence was reviewed

and synthesised in discussion by all members of the Panel. The material wassubjected to review by an extended panel of expert reviewers in Scotland and atan open meeting held to debate the issues.

Successive drafts of the guideline were reviewed by members of the Panel and bythe Extended Reference Group (see paragraph 11.2.5). The final draft guidelinewas reviewed by two international experts selected by the Panel, by the SIGNEditorial Board, by four international experts nominated by SIGN and bymembersof CRAG.

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2 Background

2.1 Dyspepsia2.1.1 Definition

Dyspepsia is a medical term referring to a variety of symptoms related tothe upper gastrointestinal tract.An international working party has definedit as upper abdominal or retrosternal pain, discomfort, heartburn, nausea,vomiting or other symptoms considered to be referable to the proximalalimentary tract(2).

2.1.2 Prevalence

Dyspepsia is probably the most prevalent chronic disorder, with a recent

survey indicating that 40% of the general population of the UK suffer fromit(3) . About 5% of all general practice consultations and about 30% of allhospital gastroenterology referrals are for dyspepsia(4) .

2.1.3 Causes of Dyspepsia

Endoscopic examination of patients with dyspepsia reveals an underlyinglesion in about 50%. The findings in order of prevalence are: oesophagitis,duodenal ulcer, gastric ulcer and gastro-oesophageal cancer(5). The 50% ofsubjects with no identifiable underlying lesion to explain their symptomsare usually classified as having functional dyspepsia or non-ulcer

dyspepsia and may include patientswith gastro-oesophageal reflux disease,irritable bowel syndrome, ulcer disease healed at the time of endoscopy,bile reflux or stress-related disease.

2.2 H. Pylori Infection2.2.1 Microbiology

H. pylori is a bacterium found lying on the luminal surface of the humangastric mucosa. The infection is usually most intense in the distal antralregion of the stomach. The bacterium can also colonise islets of gastric

metaplasia sometimes present in the first part of the duodenum and elsewherein the gastrointestinal tract. The bacterium does not invade the underlyingmucosa but does stimulate infiltration of the mucosa with inflammatorycells, and evokes a systemic immune response.

The organism is remarkable for its high urease enzyme activity whichconverts urea in the gastric juice to ammonia and carbon dioxide. Ammoniais alkaline and its production by the bacterium facilitates the organismssurvival in the acidic gastric milieu.

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2.2.2 Prevalence

H. pylori is probably the commonest chronic bacterial infection found inhumans and is present in about 50% of the worlds population(6). In theWestern world its prevalence rises with age and the percentage of any age

group infected approximately equates to the age of the group. The infectionis more common in developing countries and in poor socio-economicconditions.

2.2.3 Acquisition and Natural History

The mode of acquisition of infection is incompletely understood. Currentdata indicate that most subjects acquire it in early childhood probably byfaecal-oral or oral-oral spread. Once contracted the infection usually persistsindefinitely unless treated. The rising prevalence of H. pylori with age is

thought to be due to older subjects having had a higher rate of contractingthe infection due to their poorer childhood living conditions. However,some people may contract the infection in later life.

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3 The Role of H. pylori Infection in Dyspeptic

Disease - Assessment of Evidence

3.1 IntroductionDyspepsia may be due to a variety of underlying diseases of the upper gastrointestinal tract. The evidence for a role forH. pylori infection in the variousdyspeptic diseases has been reviewed. Full details of the literature search areincluded in Annex 2. Diagnostic methods forH. pylori are set out in Annex 3.

3.2 Duodenal Ulcer (DU)Definition: This refers to ulceration of the duodenum confirmed by endoscopy

and/or barium meal examination and not associated with non-steroidal anti-inflammatory therapy (NSAIDs).

There is now strong evidence thatH. pylori infection is an important co-factor inthe pathogenesis of the great majority of duodenal ulcers. Ninety five percent ofDU patients have the infection. Eradicating it reduces the ulcer relapse rate, asassessed by endoscopy, to less than 10% per year compared with 80% in thosewith persisting infection(7). Eradicating H. pylori has also been shown to reducethe risk of bleeding from DU, and to do this more effectively than maintenance

anti-secretory therapy(8)

.

Duodenal ulcer can occur in patients on NSAIDs in the absence of H. pyloriinfection. The value of eradicating the infection in patients with DU induced byNSAIDs is not known.

Level of evidence for H. pylori infection playing an important role in the

pathogenesis of DU (not associated with NSAIDs) is level Ia.

3.3 Benign Gastric UlcerDefinition: This refers to ulcers of the stomach (including the pre-pyloric region),not associated with NSAIDs, which have been demonstrated by endoscopy orbariummeal and inwhich underlyingmalignancy has been excluded by endoscopicbiopsies.

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H. pylori infection is present in about 75% of patients with gastric ulcers andcontrolled studies have demonstrated that eradicating the infection reduces theulcer relapse rate to about 10% per year compared with 50% in those who remainuntreated(9). The value of eradicating H. pylori infection in patients with gastriculcers associated with NSAIDs is not known.

Level of evidence for H. pylori infection playing an important role in the

pathogenesis of benign gastric ulcer (not associated with NSAIDs) is level Ib.

3.4 OesophagitisDefinition: This refers to patients with endoscopic evidence of inflammationand/or ulceration of the distal oesophagus which is usually secondary to gastro-oesophageal reflux.

The prevalence ofH. pylori infection in patients with oesophagitis is the same asthat in the healthy population(10).

Available evidence thus indicates that the infection does not play a role in thepathogenesis of oesophagitis (level of evidence III).

3.5 Non-Ulcer DyspepsiaDefinition: This refers to patients who have symptoms which are thought to berelated to the upper GI tract but in whom endoscopic examination shows no

evidence of macroscopic disease.

Studies indicate that the prevalence of H. pylori in patients with non-ulcerdyspepsia is the same as or slightly higher than that of asymptomatic controls(11,12).It is unclear, therefore, whetherH. pylori infection plays a role in the pathogenesisof non-ulcer dyspepsia. At present there are no published results of double blindplacebo controlled studies assessing the value of eradicating H. pylori in non-ulcer dyspepsia.

3.6 Dyspepsia and Ulcer Disease Related to NSAIDsNSAIDs are associated with dyspeptic symptoms and peptic ulceration even inthe absence ofH. pylori infection(13). The value of eradicatingH. pylori in patientswith dyspeptic disease induced by NSAIDs has not been studied.

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3.7 Gastric CancerEpidemiological studies have shown an association betweenH. pylori infectionand the subsequent development of gastric carcinoma and lymphoma. There areseveral reports of regression of low grade gastric lymphoma following eradicationof H. pylori. The World Health Organisation InternationalAgency for Research

on Cancer has recently concluded that there is sufficient evidence for thecarcinogenicity of infection with H. pylori in humans(14). However, it is notknown whether eradicatingH. pylori will remove or reduce the risk of developinggastric cancer.

Level of evidence for H. pylori playing a role in the pathogenesis of gastric

carcinoma is level IV and in gastric lymphoma is level IIb.

3.8 Summary and Conclusions

At present there is evidence that H. pylori infection is implicated in thepathogenesis of duodenal and gastric ulcer disease. There is some evidence for arole for the infection in the pathogenesis of some forms of gastric cancer.

For recommendations regarding eradication therapy, see Table 2 and

Section 4

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4 Which Patients Should Receive H. Pylori

Eradication Therapy?

In the light of the evidence reviewed above it is recommended that H. pyloriinfection is eradicated in patients confirmed to have the following disorders:

4.1 Duodenal UlcerPatients with duodenal ulcer confirmed by barium meal or endoscopy shouldreceive eradication therapy. This includes both newly diagnosed cases and patientspreviously confirmed to have duodenal ulcer who have persistent or recurrentulcer symptoms and/or requirement for ulcer therapy. Because >95% of DU

patients have H. pylori infection it is unnecessary routinely to check for thepresence of the infection before prescribing anti-H. pylori treatment to suchpatients. The prevalence of infection is lower in complicated DU disease or DUassociated with NSAID therapy and it may be appropriate to test for H. pyloriprior to treatment in these subgroups.

This is a Grade A recommendation based on level Ia evidence.

4.2 Gastric Ulcer

Patients with endoscopically confirmed, benign gastric ulcers who are positivefor H. pylori should receive eradication therapy. It is recommended that thepresence of infection is checked before commencing eradication therapy as only75% will be positive.

This is a Grade A recommendation based on level Ib evidence.

4.3 Low Grade Gastric LymphomaPatients with low grade gastric lymphoma should have H. pylori eradicated.

This is a Grade B recommendation based on level IIb evidence.

Table 1 summarises the conclusions reached in Sections 3 and 4.

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Table 1: Which Patients with H. pylori should Receive Eradication Therapy?

Eradicate?

Duodenal ulcer Yes A Ia

Gastric ulcer Yes A Ib

Gastric Lymphoma Yes B IIb

NSAID -related ulcers Unclear -

H.pylori + veDyspeptics who have Controversial No recommendation -not been further possibleinvestigated

Non-Ulcer Dyspepsia No C IV

Oesophagitis No C IV

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No recommendationpossible

Grade of

Recommendation

Level of

Evidence


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5 H. Pylori Eradication Therapy

5.1 IntroductionEradication therapy should be effective, safe and easy to take. Although manydifferent combinations of drugs have been shown to be effective, each treatmenthas potential side-effects. Improvements in treatment are being made at a rapidrate and any recommendation will require regular updating. Details of the literaturereview for this section are given in Annex 2.

5.2 Efficacy Of Eradication TherapyThe only treatments which have consistently achieved eradication rates above

90% have been those using three drugs i.e. the triple therapies. The first tripletherapy consisted of tripotassium dicitratobismuthate (DeNol) combined withmetronidazole and amoxycillin and this had to be taken for two to three weeks(15).More recent studies have demonstrated that one week of triple therapy consistingof omeprazole plus two specified antibiotics can achieve equivalent or superioreradication rates to the original 2-3 week bismuth triple therapy(16,17). The regimenswhich have been most thoroughly evaluated are:

omeprazole, metronidazole and amoxycillin;omeprazole, clarithromycin and amoxycillin;omeprazole, metronidazole and clarithromycin.

Very recent studies indicate that using the proton pump inhibitor lansoprazole inplace of omeprazole may produce similar eradication rates(18,19).

Reinfection following successful eradication is fortunately rare being in the orderof 1% per year(20).

Eradication rates vary from country to country and relatively little information isavailable concerning the rates achieved in the Scottish population. Eradicationrates are also likely to fall with time owing to emergence of resistant strains ofthe organism.


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5.3 Adverse Effects Associated with Eradication TherapyAdverse effects are commonly experienced by patients takingH. pylori eradicationtherapy and are reported by about 30% of patients taking triple therapy. Thecommonest side-effect is gastrointestinal upset including diarrhoea, nausea orvomiting. Headache and allergic reactions may also occur. An antabuse reaction

is likely to occur if patients take alcohol during metronidazole treatment. Theefficacy of oral contraception may also be impaired by treatment. The occasionalpatientwilldevelop severe and possibly life threatening diarrhoeadue to antibiotic-induced pseudomembranous colitis but this has been reported in less than 1% ofpatients treated.

5.4 The Problem of Antibiotic ResistanceIn the UK resistance to metronidazole is found in 11-68% of H. pylori isolatesprior to treatment and to clarithromycin in 3 - 10%.(21) The resistance rates are

higher in countries where the drugs are more widely used and in individuals whohave previously received such drugs. Metronidazole resistance is a factor indetermining the eradication rate achieved when this drug is part of the treatmentregimen. However, sensitivity testing is of limited value in routine clinical practiceas in vitro resistance to either clarithromycin or metronidazole does not precludesuccessful eradication when these antibiotics are used as part of a triple therapy.H.pylori strains have not yet been shown to be resistant to amoxycillin.

It should be emphasised that little information is available concerning H. pyloriresistance rates in the Scottish population. This requires to be assessed and

monitored. The rate of emergence of strains of H. pylori resistant to currentantibiotics is likely to increase with the increased use of eradication therapy. It istherefore important that the treatment is only used for patients in whom

eradicating the infection is of proven benefit.

5.5 Clinical Recommendations Concerning Use Of Anti-H. Pylori

Therapy5.5.1 Choice of Anti-H. pylori Therapy

It is not possible to make a dogmatic recommendation concerning which of

the numerous eradication treatments should be employed. However, it isrecommended that patients are treated initially with either 7 days ofomeprazole, metronidazole and amoxycillin or with 7 days of omeprazole,clarithromycin and amoxycillin(17,22). (See Table 2). If the infection is noteradicated following the first treatment then the alternative treatment shouldbe administered. In patients who are allergic to amoxycillin, treatmentwithomeprazole,metronidazole plusclarithromycin is recommended. The reasonfor not employing this combination generally is that there is no second-linetreatment if it fails. Though omeprazole is the proton pump inhibitor selected

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for current use in one week eradication therapy, recent studies indicate thatother proton pump inhibitor drugs e.g. lansoprazole, may be equallyeffective(18,19).

These are Grade A recommendations based on level 1a evidence.

In patients with active ulcers it may be appropriate to continue the protonpump inhibitor on its own for a further 1 week (DU) or 3 weeks (GU) toensure adequate healing.

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Table 2: Recommended H. pylori Eradication Therapy:

5.5.2 Mode of Prescribing of Anti-H. pylori Therapy

The efficacy of anti-H. pylori therapy depends upon the compliance of thepatientwith the timing and dosage of drug therapy. The relative complexityof the current anti-H. pylori regimens means that time has to be spent

explaining the treatment carefully to the patient along with the importanceof complying with these instructions.

Present anti-H. pylori regimens have a high incidence of side-effects.Patients should be fullywarned about side-effects and potential interactionswith alcohol. For the above reasons it may be helpful to provide patientswith a leaflet explaining how to take the therapy and the side-effects theymay experience.

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FOR EXAMPLE

Seven days of Seven days of

omeprazole 20 mg b.d. omeprazole 20 mg b.d.

metronidazole 400 mg t.d.s. OR clarithromycin 250 mg t.d.s.

amoxycillin 500 mg t.d.s. amoxycillin 500 mg t.d.s.

IFALLERGIC TO AMOXYCILLINSeven days of

omeprazole 20 mg b.d.

metronidazole 400 mg b.d.

clarithromycin 250 mg b.d.

One week triple therapy with a proton pump inhibitor plus 2 antibiotics.

NB: a) Other proton pump inhibitors (e.g. lansoprazole, 30 mg b.d.) maybe used in place of omeprazole.

b) Little information is available concerning the choice of eradicationtherapy in children and such treatment should be undertaken byspecialists.


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6 Follow Up After Eradication Therapy

The follow-up required after a course ofH. pylori eradication therapywill depend

upon the nature of the underlying gastrointestinal disease.

The following are Grade C recommendations based on level IV evidence.

6.1 Uncomplicated Duodenal UlcerAnti-H. pylori therapy is successful in eradicating the infection in about 80-90%of those treated. Complete resolution of dyspeptic symptoms usually indicatessuccessful eradication of the infection(23). However, persistence of symptoms is apoor predictor of persistenceof the infection(23). It is therefore recommended thatpatients with persisting symptoms after eradication therapy should have theirH.pylori status rechecked. This should be performed no sooner than four weeksafter discontinuation of the antibiotic and proton pump inhibitor therapy. If thebreath test is performedearlier it may givea false negativeresult due to suppressionrather than eradication of the infection. If the infection persists patients shouldbe given the alternative course of H. pylori eradication therapy. If symptomspersist, despite successful eradication ofH. pylori , patients may have persistingulceration or, more commonly, another cause of dyspepsia such as gastro-oesophageal reflux disease or non-ulcer dyspepsia.

6.2 Complicated Peptic UlcerPatients who have had a previous gastrointestinal bleed from an ulcer should bemaintained on anti-secretory therapy until it is confirmed by breath test or repeatendoscopy that H. pylori has been eradicated(24). H

2 receptor antagonists would

be the most appropriate maintenance therapy after completion of the eradicationregimen as continuing the proton pump inhibitor may result in a false negativeH.pylori test.

6.3 Gastric Ulcer

Patients should have a further endoscopy 4-8 weeks after completing eradicationtherapy in order to confirm successful eradication and healing of the ulcer, and toexclude malignancy.

6.4 Ulcers in Patients Requiring Continued NSAIDsAt present the effectiveness of eradicating H. pylori in patients with NSAIDassociated ulcer is not clear. Consequently, ulcer patients requiring continuationofNSAIDs should undergo endoscopicmonitoring despite eradication ofH. pylori.NSAID-associated ulcers may be asymptomatic.

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7 Can Non-Invasive H. Pylori Testing be Used

as a Substitute for Endoscopy/Barium Meal

in Determining Management of SomeDyspeptic Patients?

The question has been raised as to whether non-invasive H. pylori testing bycarbon urea breath test or serology might replace investigation by endoscopy orbarium meal in young dyspeptic patients who have no sinister symptoms andwho are not taking NSAIDs. It has been proposed that this might occur in eitheror both of the following ways.

7.1 Could Upper GI Investigations be Avoided inH. pylori

Negative Patients?Studies indicate that upper GI investigations are very unlikely to reveal positivefindings other than oesophagitis in youngH.pylori negative patients with simpledyspepsia not associated with NSAID usage(25). It has been suggested that suchpatients with a negativeH.pylori screening test could be treated symptomaticallyand only proceed to formal GI investigations if further management provesproblematic. However, this approach does not take account of the evidence that

a negative endoscopy is reassuring to patients and may reduce subsequentmorbidity(26).

7.2 Could Eradication Therapy be Prescribed for H. pylori Positive

Dyspeptic Patients Without Further Investigations?It has also been suggested that young patients presenting with simple dyspepsiaand found to be H. pylori positive by non-invasive tests could be treated witheradication therapy and proceed to upper GI investigations only if symptoms

persist. However, this approach would mean that a considerable proportion ofpatients who receive eradication therapy will not directly benefit. The risk/benefitof this approach is unknown.

7.3 ConclusionThere are no controlled studies comparing the strategies described above withthe more conventional approach of investigating the cause of the dyspepsia byendoscopy/barium meal prior to treatment. Consequently no recommendationcan be made. Research into this important question is required.

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8 Resource Implications

The largest group of patients for whomH. pylori eradication therapy is currentlyindicated comprises patients already diagnosed to have DU and who are onmaintenance or intermittent acid inhibitory therapy. Such patients with confirmedDU disease not associated with NSAIDs could receive eradication therapy fromtheir general practitioner without further investigation. Patients with previouslyconfirmed benign gastric ulcers or ulcers associated with NSAIDs should bechecked forH. pylori before being prescribed eradication therapy. This could beperformed either by endoscopy or by carbon urea breath test.

Patients with persisting following symptoms and those with previous ulcer

complications should have a urea breath test to confirm eradication followingtherapy.

It should be noted that about 30% of ulcer patients have persisting symptomsfollowing eradication ofH. pylori(23).

At present, therefore, it is important to provide adequate facilities for confirmingH. pylori status. This would be performed most appropriately by the urea breathtest. Provision of the facility to general practitioners would reduce referrals to GI

clinics and reduce the inappropriate use of eradication therapy. The approximatecost of a urea breath test is 30 which compares favourably with the cost of anendoscopy or clinic assessment. In addition, most patients would prefer to undergoa non-invasive breath test than be subjected to a further endoscopy to check thesuccess of eradication therapy.

If future research supports non-invasiveH. pylori testing as ameans of determiningthe initial management of simple dyspepsia, increased provision of breath testingand/or serological testing would be required.

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9 Research Needs

The possibility of using H. pylori screening tests as a means of reducingendoscopic workload needs to be investigated. This will require arandomised trial assessing outcome in terms of economic cost and patientsatisfaction.

More research is required to investigate the role ofH. pylori in gastric cancer.

Research to find better H. pylori eradication therapies is required, thoughthis will probably be undertaken by the pharmaceutical companies.

Information should be obtained concerning eradication rates achieved withanti-H. pylori therapies within the Scottish population.

Monitoring should be undertaken to detect any rise in prevalence of resistantstrains of H. pylori and any fall in efficacy of anti-H. pylori therapyassociated with increased prescribing of the antibiotics.

Research is required to establish the prevalence of the infection in Scotland,

and to determine the age at acquisition and mode of transmission. Thiswould facilitate the planning of intervention programmes to reduceprevalence in the community.

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10 Implementation of the Guideline

10.1 Development of Local Protocols

This guideline is one of a group of clinical guidelines in clinical conditions agreedto be priorities for attention under the common core work programme for theNHS in Scotland. These will be drawn to the attention of the service by theManagement Executive and related advice will be provided to purchasers throughthe Scottish Health Purchasing Information Centre.

All relevant professional organisations at local level should be involved jointly inreviewing this guideline and agreeing co-ordinated protocols for implementationin primary and secondary care. The staff groups who require to be involved in

development of, and familiar with, protocols derived from this national guidelineare set out in Annex 1.

10.2 Continuing EducationThe agreed protocol should be available to all relevant staff including communitypharmacists along with information about access to the full national guidelineand to supporting background material. The national guideline and, as appropriate,the local protocols derived from it, should form part of continuing education forall professional staff groups. This will also be included in education and skills

training developed centrally for the support of clinical guideline developmentand implementation.

10.3 Clinical AuditThe desired clinical outcome is eradication ofH. pylori in all patients in all groupsinwhich eradication is of proven benefit,with associated elimination or significantreduction in symptoms.

10.3.1 Audit in General Practice

The proportion of patients in general practice who have confirmed peptic

ulcer disease and receive eradication therapy should be audited.Comparisons over time will be desirable.

Individual practices should make arrangements to identify all patients inthe relevant groups, to offer eradication therapy and to monitor results.

Levels of uptake of offers of therapy may usefully be monitored.Surveys of patients views about therapy and their subsequent quality oflife will be relevant.

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A system ofpatient specific reminders should be developed for flaggingup individual patients with chronic or recurrent dyspeptic symptoms forreview at agreed points in time. This might be related, for example, torepeat prescribing intervals. Full investigation, including establishing adiagnosis and consideration of eradication therapy, might be appropriate

when long-term maintenance therapy is being contemplated.

10.3.2 Audit in Hospitals

Audit in the hospital services should include

eradication rates achieved; the emergence and prevalence of resistant strains of bacteria

should be monitored;(This might most appropriately be undertaken by two or threedesignated units).

10.4 Information for PatientsPatients should receive general information about their condition and informationabout any specific investigations or treatment proposed. This should includeinformation about the arrangements agreed under local protocols between primaryand secondary care. Patients should be made aware of the necessity to complyfullywith instructions for taking the medicine and warned of possible side effectsand ways of avoiding or coping with these. Information given by the GP shouldbe reinforced by the community pharmacist when the patient receives the drugs.

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11 Management of the National Guideline

11.1 Statement of IntentThis report is not intended to be construed or to serve as a standard of medicalcare. Standards of medical care are determined on the basis of all clinical dataavailable for an individual case and are subject to change as scientific knowledgeand technology advance and patterns evolve.

These parameters of practice should be considered guidelines only.Adherence to them will not ensure a successful outcome in every case, norshould they be construed as including all proper methods of care or excluding

other acceptable methods of care aimed at the same results.

The ultimate judgement regarding a particular clinical procedure or treatmentplan must be made by the doctor in light of the clinical data presented bythe patient and the diagnostic and treatment options available.

Significant departures from the national guideline as expressed in the localprotocol should be fully documented and the reasons for the differencesexplained.

Significant departures from the local protocol should be fully documentedin the patients case notes at the time the relevant decision is taken.

11.2 Development Of The Guideline11.2.1 Responsible Bodies

This guideline was developed by a Professional Advisory Panel set up bythe Clinical Resource and Audit Group (CRAG) using the methodology setout by SIGN for the development of national clinical guidelines for use in

Scotland. The guideline has been appraised by the SIGN Editorial Boardand endorsed by SIGN as the national guideline for Scotland from whichlocal protocols should be developed.

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Name Location Discipline

K E L McColl Greater Glasgow Gastroenterology(Chairman)E Barnwell CRAG Administration

Patients interests

J E Forrester Greater Glasgow Medical Prescribing Adviser B M Goudie Tayside General PracticeI Heron Lothian Community PharmacyA Humphrey Highland General PracticeA McKinlay Grampian GastroenterologyF MacRae Tayside, (until July 1995) Pharmaceutical Adviser R Simmons SODof H Medical Services

(General Practice)D Sykes Lothian PharmacyA Timoney Tayside, (from July 1995) Pharmaceutical Adviser A Walker Greater Glasgow Health Economics

I Wallace Greater Glasgow General PracticeL Weaver Greater Glasgow Child HealthC Williams Argyll & Clyde Microbiology

Declarations of personal and non-personal specific and non-specificinterests of each number of the Group are held by the SIGNSecretariat.

11.2.2 ProfessionalAdvisory Panel

The Chairman of the Panel was Professor Kenneth McColl, Department ofMedicine and Therapeutics at the University of Glasgow. He was chosenafter consultation with leading clinicians in Scotland. The Panel memberswere identified in discussion with Professor McColl and membership was

representative of all relevant specialties and professions and of mostgeographical areas in Scotland. Themembers of the Panel are listed below:

11.2.3 Funding

Incidental expenses ofmembers of the Panel carrying out literature searcheswere met by CRAG. GP members of the Panel received the customarysessional payments plus travel for participating in approved activity relatedto clinical audit at national level.


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11.2.4 Extended Reference Group

The Panel identified an extended group of experts in selected specialtiesand professional groups in Scotland for peer review of background materialand the synthesis of evidence, and for participation in the guidelinesdevelopment conference. Members of the Group are shown below.

11.2.5 Development Team

The team was led by Professor McColl. The members were as for theProfessional Advisory Panel.

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Name Location Discipline

R C Brown Argyll & Clyde General MedicineGastroenterology

L M Campbell Greater Glasgow Postgraduate EducationA Clubb Lothian Practice NursingO E Eade Borders General Practice

M J Ford Lothian General MedicineG Fullarton Greater Glasgow General SurgeryG R Gray Greater Glasgow General Surgery

GastroenterologyH Highley Lothian Practice ManagementT Hiditch Greater Glasgow Nuclear MedicineA D Irvine Tayside General SurgeryM Kelly Forth Valley Trust ManagementG Lindsay Lothian Hospital PharmacyC Mackie Greater Glasgow Community PharmacyJ McCabe Greater Glasgow Drug Information service

G Murray Tayside General MedicineK Palmer Lothian GastroenterologyK Park Grampian General SurgeryC Penney Greater Glasgow GastroenterologyI Watt Argyll & Clyde General SurgeryP L Zentler-Munro Highland General Medicine

Gastroenterology


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11.2.6 Development Process

The Professional Advisory Panel met on three occasions in spring 1995and in October 1995. A conference, attended by 90 people, was held on14 June 1995 when scientific papers were presented by members of thePanel. Key issues regarding possible recommendations for clinical care

and preferred prescribing were debated in workshop groups and in plenarysessions. Working groups were chaired by members of the Panel and threeof the four groups had general practitioners as rapporteurs.A plenary sessionconsidered implementation strategies and the Chairman of SIGN set outthe criteria for appraising guidelines for national use in Scotland.

11.2.7 Literature Searches

Literature searcheswere the responsibility of Professor McColl, Dr Forresterand Mrs McCabe (prescribing) and Dr McKinlay (diagnostic methods).

11.2.8 Drafting Process

A draft guideline was prepared by the Chairman of the Panel drawing onthe review and synthesis of scientific evidence about clinical applications,eradication therapy and diagnostic tests; on reports back from delegates tothe development conference and from its working groups; on correspondencewith members of the Panel and with the Extended Reference Group; and ondiscussion in the Panel.

11.2.9 Peer Review

The guideline was submitted in draft to; Professor Colm OMorain, Department of Gastroenterology,

Charlemont Clinic, Dublin, Eire;

toDrG D Bell, Consultant Gastroenterologist, Ipswich HospitalNHS Trust; and

to the Health Economics Research Unit,University ofAberdeen.

The final draft was submitted to;

the SIGN Editorial Board; Professor A Ferguson, University of Edinburgh; Professor M J S Langman, University of Birmingham; Dr R Logan, University of Nottingham; and Professor PW Brunt, University of Aberdeen. The last four

named were nominated by the SIGN Board.The guideline was also considered bymembers of CRAG at its meetingon 27th June 1996.

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11.2.10 SIGN Editorial board

The guideline was reviewed and prepared for publication by the SIGNEditorial Board.

J C Petrie Royal College of Physicians, EdinburghChairman of SIGN

P Donald Royal College of General PractitionersG C W Howard Royal College of Radiologists

Vice Chairman of SIGND R Harper Royal College of Surgeons of EdinburghA Findlay The Scottish Office Department of HealthJ M Grimshaw Health Services Research Unit,

University of Aberdeen

11.2.11 Economic Component

A health economist was a member of the Professional Advisory Panel andthe Health Economics Research Unit of the University of Aberdeencommented on the final text.

11.3 DisseminationFull details of the development process are set out in the guidelines report whichmay be consulted at the SIGN offices in the Royal College of Physicians ofEdinburgh

The guideline will be sent to

named practitioners in each of the relevant staff groups (seeAnnex 1) throughout Scotland.

Chief Executives and Clinical Directors in Trusts Board General Managers and Directors of Public Health and other

chief professional officers in each Health Board

Chairmen of Area Clinical Audit Committees and of Area Medicaland other professional Advisory Committees

Local Medical Committees

relevant education and training bodies; selected others.

11.4 ReviewThe Royal College of Physicians and Surgeons of Glasgow acting on behalf ofSIGN will have continuing responsibility for the review and updating of theguideline. The guideline will be reviewed formally in June 1998. Amendmentswill be disseminated as required at that time or at any other time when significantamendment becomes necessary.

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References

1 US Department of Health and Human Services. Public Health Service. Agency

for Health Care Policy and Research. Acute Pain Management: Operative orMedical Procedures and Trauma. (AHCPR Pub 92-0038). Rockville: TheAgency,1992.

2 Colin-Jones DG, Bloom B, Bodenar G, et al. Management of dyspepsia: Reportof a working party.Lancet, 1988; I: 576-579.

3 Jones RH, Lydeard SE, Hobbs FD, et al. Dyspepsia in England and Scotland.Gut, 1990; 31: 401-405.

4 Knill-Jones R. Geographical differences in the prevalence of dyspepsia. Scand. JGastroenterol., 1991; 26: (Suppl. 182): 17-

5 Richter JE. Dyspepsia: Organic Causes and Differential Characteristics fromFunctional Dyspepsia. Scand J Gastroenterol, 1991; 26: (Suppl. 182): 11-16.

6 The Eurogast Study Group. An international association between Helicobacterpylori infection and gastric cancer.Lancet, 1993; 341: 1359-1362.

7 Velduyzen van Zanten SJO, Sherman PM. Indications for treatment of Helicobacter pylori infection: a systematic overview. Can Med Assoc J, 1994;150: 189-198.

8 McColl KEL. The role ofH pylori eradication in the management of acute bleedingpeptic ulcer. Eur J Gastroenterol Hepatol, 1995; 7(8): 753-755.

9 Sung JJ, Chung SC, Ling TK, Yung MY, Leung VK, Ng EKW et al. Antibacterialtreatment of gastric ulcers associated with Helicobacter pylori. N Engl J Med,1995; 332: 139-142.

10 OConnor HJ, Cunane K. Helicobacter pylori and gastro-oesophageal refluxdisease - a prospective study.IJMS, 1994; 163(8): 369-373.

11 Schlemper RJ, van derWerf SDJ, Vanderbroucke JP, Biemond I, Lamers CBHW.Non-ulcer dyspepsia in a Dutch-working population and Helicobacter pylori.Ulcer history as an explanation of an apparent association. Arch Intern Med,1995; 155: 82-87.

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12 Talbey NJ. A relationship betweenHelicobacter pylori and non-ulcer dyspepsia:is there enough data to know?Eur J Gastroenterol Hepatol, 1994; 6: 567-570.

13 McColl KEL, El-NujumiAM, Chittajallu RS, Dahill SW, Dorrian CA, El-OmarE et al. A study of the pathogenesis of Helicobacter pylori negative chronic

duodenal ulceration. Gut, 1993; 34: 762-768.

14 Schistosomes, liver flukes andHelicobacter pylori. IARCWorking Group on theEvaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARCMonogr Eval Carcinog Risks Hum. 1994; 61: 1-241.

15 Chiba N, Rao BV, Rademaker JW, Hunt R. Meta-analysis of the efficacy ofantibiotic therapy in eradicating Helicobacter pylori.Am J Gastroenterol, 1992;87(12): 1716-1727.

16 Tytgat GNJ. Review article: treatments that impact favourably upon the eradicationof Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther, 1994; 8:359-368.

17 Lind T, Velhuyzen van Zanten SJO, Unge P et al. The Mach 1 Study: Optimalone-week treatment for H. pylori defined?Gut, 1995; 37 Suppl 1: A4.

18 Moayyedi P,TompkinsDS, Shanaghan K, Langworthy H, AxonATR. Comparison

of one and two weeks of lansoprazole, amoxycillin and clarithromycin ineradicating Helicobacter pylori. Gut, 1995; 37 Suppl 2: A7.

19 Lamouliatte H, Cayla R, Zerbib F, Talbi P,Mgraud F. Triple therapy using protonpumpinhibitor amoxycillinand clarithromycin forHelicobacterpylori eradication.Gut, 1995; 37 Suppl 1: A91.

20 Bell GD, Powell KU, Burridge SM,Harrison G,RamehB, Weil J et al. Reinfectionor recrudescence after apparently successful eradication of Helicobacter pyloriinfection: implications for treatment of patientswith duodenal ulcer disease. QJM,1993; 86: 375-382.

21 Karim QN, Logan RPH. The epidemiology of Helicobacter pylori (H. pylori)antimicrobial resistance - preliminary funding of a national survey.Gut, 1995; 37Suppl 2: A6.

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22 Bell G D, Powell K U, Burridge S M, Bowden A F, Atoyebi W, Bolton G H et al.Rapid eradication of Helicobacter pylori infection.Aliment Pharmacol Ther, 1995;9: 41-46.

23 Phull PS, Halliday D, Price AB, Jacyna MR. Is absence of dyspeptic symptoms a

useful test to assessH. pylori eradication.Gut, 1995; 36. suppl. 1: A12.

24 Deltenre M, Glupczyski Y, De Prez C, Nyst JF, Burette A, Labb M et al. Thereliability of urease tests, histology and culture in the diagnosis ofCampylobacterpylori infection (Review). Scand J Gastroenterol Suppl, 1989; 160: 19-24.

25 Patel D, Khulusi S, Mendall MA, Lloyd R, Jazrawi R, Maxwell JD et al.Prospective screening of dyspeptic patients by Helicobacter pylori serology.Lancet, 1995; 346: 1315-1318.

26 Jones R. What happens to patients with non-ulcer dyspepsia after endoscopy?Practitioner, 1988; 232: 75-78.

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Annex 1

Staff groups who require to be involved in development and implementation oflocal protocols derived from this national guideline.

Hospital and primary care medical staff Nursing staff The Association of Practice Nurses Pharmacy staff Medical Prescribing Advisers Pharmacy PA or Facilitator - check with PD Gastroenterology staff

Management Area audit committees Deans and Postgraduate Deans of University Faculties of medicine

in Scotland and other relevant professional bodies.

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Annex 2 - Diagnostic Methods for H. Pylori

Aims and MethodsH. pylori infection can be diagnosed by (1) analysis of gastric mucosal biopsiesobtained at endoscopy; (2) by carbon urea breath test; or (3) by serological tests.This section reviews the published literature on each of thesemethods for detectingthe infection.

Endoscopic TestsH. pylori can be diagnosed by (a) histological examination, (b) culture or (c)measurement of the urease activity of endoscopic mucosal biopsies.

Histological Examination

One biopsy should be taken from the antrum and one from the body of thestomach because the infection may affect either or both of these regions. Avariety of histological stains can be used to identify the organism but noneis specific. However, in practice only two other organisms have been shownto colonise the normal stomach, and both are uncommon. Review ofavailable studies indicates that in trained hands histology has a sensitivityof approximately 98%(1).

Culture

Culture of mucosal biopsy specimens is the only method that can identifythe organism with complete certainty. It is, therefore, 100% specific but itssensitivity varies greatly between published studies. In expert hands itssensitivity can be between 90 and 94%, but it has never been shown to bemore sensitive than histology(2). Some studies, however, have found cultureto have a much lower sensitivity, of around 70%(3). Culture is a less robustdiagnostic method than histology because, to achieve accuracy, specimenshave to be transported rapidly to the laboratory. It has no advantage overhistology for routine diagnosis but it can provide unique informationconcerning antimicrobial sensitivity(4).

Biopsy Urease Test (e.g. CLO Test)

The biopsy urease test makes use of the large quantities of urease producedbyH. pylori. Themucosal biopsy specimen is placed directly into a mediumcontaining urea and a pH sensitive dye indicator. The presence of theorganism is shown by a colour change which is usually apparent within onehour. Biopsy urease tests have been widely compared with histology andculture. The majority of studies suggest a sensitivity between 80 and 95%and a specificity between 85 and 100%(5). The test is simple, reliable and

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cheap and can provide a diagnosis very soon after endoscopy.

Endoscopic Tests for Routine Clinical Diagnosis

The ProfessionalAdvisory Panel concluded that for routine clinical diagnosisofH. pylori at endoscopy mucosal biopsies should be taken from the gastric

antrum and body for urease test and, when appropriate, also for histology.

This is a Grade B recommendation based on level IIa evidence.

It should be emphasised that antibiotics for intercurrent illness and protonpump inhibitors may suppressH. pylori and render all the endoscopic testsnegative. The infection is likely to reappear following discontinuation ofthese drugs.

Urea Breath TestsThe carbon isotope urea breath test is very useful for assessing the carriage ofH.pylori because it is minimally invasive.

Both the 13C and 14C tests have been shown to be reliable. The 14Cmethod uses aradioisotope and therefore may not be appropriate during pregnancy. TheAdministration of Radioactive SubstancesAdvisory Committee states in its currentguidelines that Only such investigations (involving radioactivity) as areimperative should be conducted during pregnancy. However, in these

considerations it should be noted that the radiation dose associated with the14

C-urea breath test is very low. The effective dose equivalent for a 0.3MBq of 14C-urea has been estimated to be 10-55 micro Sv which is equivalent to no more than10 days exposure to natural background radiation (6,7). The 13C test is non-radioactive. It is difficult to compare costs, but the 14C test is probably cheaperbecause most hospitals have facilities to measure 14C, while few have a massspectrometer which is required to measure 13C. The majority of studies show asensitivity of greater than 94% and a specificity of greater than 90%(8). It may beunreliable in patients with previous gastric surgery. In addition, patients receiving

antibiotics for intercurrent illnesses or on proton pump inhibitor therapy mayshow a false negative result.

The carbon isotope urea breath test is the most suitable test for assessing theeffect of eradication therapy.

This is a Grade B recommendation based on level IIa evidence.

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Serological TestsSerological tests are minimally invasive, relatively inexpensive and may have aparticular role in screening forH. pylori. However, anti-H. pylori IgG titres fallslowly and unpredictably following eradication therapy and thus serological testsare not reliable for assessing success of eradication therapy.

Several different methods have been described, but most commercial tests arebased on an ELISA. Comparison of the current commercial assays indicate thattheir sensitivity lies between 70 and 96% withmost achieving a sensitivity greaterthan 80%(9). The specificity of the tests shows a similar variability.An importantreason for variations in the predictive value of serological tests is that the cut-off point quoted by themanufacturer may not be appropriate for every population.Serological tests should be validated within the local populations before use

as a clinical diagnostic tool.

Tests are becoming available which measure anti-H. pylori IgA in samples ofsaliva. Little information is available regarding their sensitivity and specificityor accuracy in clinical practice.

Summary and ConclusionsH. pylori can be reliably diagnosed at endoscopy. Biopsies should be taken fromboth the antrum and body for histology and/or urease test.

The carbon isotope urea breath tests have been extensively validated and representsensitive and specificmethods of diagnosis. Their particular value lies in assessingthe success of eradication therapy.

Endoscopic biopsy tests and carbon isotope urea breath tests may give falsenegative results if patients are taking antimicrobial agents or proton pump inhibitortherapy.

Further information is required on the effects of proton pump inhibitory therapy

on the reliability of these tests, with specific reference to the duration of theireffect.

Serology may be a useful screening test for determiningH. pylori status. However,serological tests are not reliable for determining the success of eradication therapy.The current commercial tests have widely varying sensitivities and specificities.It is recommended that serological tests for H. pylori are validated within thetarget population before they are used for clinical diagnosis.

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References

1 Wyatt J, Gray S. Detection of Helicobacter pylori by histology.In: Rathbone B,Heatley R, eds.Helicobacter pylori and gastroduodenal disease.Oxford:BlackwellScientific, 1992; 51-57.

2 Deltenre M, Glupczyski Y, De Prez C, Nyst JF, Burette A, Labb M et al. Thereliability of urease tests, histology and culture in the diagnosis ofCampylobacterpylori infection (Review). Scand J Gastroenterol Suppl, 1989; 160: 19-24.

3 Weiss J, Mecca J, da Silva E, GassnerD. Comparison of PCR and other diagnostictechniques for detection ofHelicobacter pylori infection in dyspeptic patients.J Clin Microbiol, 1994; 32: 1663-1668.

4 Goodwin C, Marshall B, Blincow E, Wilson D, Blackbourn S, Phillips M.Prevention of nitroimidazole resistance in Campylobacter pylori by co-administration of colloidal bismuth subcitrate: clinical and in vitro studies. J ClinPathol, 1988; 41: 207-210.

5 McNulty C. Detection of Helicobacter pylori by the biopsy urease test. In:Rathbone B, Heatley R. eds: Helicobacter pylori and gastroduodenal disease.Oxford: Blackwell Scientific, 1992; 58-63.

6 Marshall BJ, Surveyor I. 14C-urea breath test for the diagnosis ofCampylobacterpylori associated gastritis.J.Nucl.Med, 1988; 29: 11-16

7 Rauws EAJ, Royen EA, Langenberg W, Woensel JV, Vrij AA, Tytgat GN et al.14C-urea breath test in C.pylori gastritis. Gut, 1989; 30: 798-803

8 Marshall BJ, Plankey MW, Hoffman SR, Boyd CL, Dye KR, Frierson HF jr et al.A 20 minute breath test for Helicobacter pylori. Am J Gastroenterol, 1991; 86:

438-445.

9 Newell D, StaceyA. The serology ofHelicobacter pylori infections.In: RathboneB, Heatley R, eds. Helicobacter pylori and gastroduodenal disease. Oxford:Blackwell Scientific, 1992; 64-73.

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Annex 3 - Quick Reference Guide

- 36-

Which patients with H. pylori

should receive eradication

therapy?

FOR EXAMPLE

omeprazole 20 mg b.d. omeprazole 20 mg b.d.

metronidazole 400 mg t.d.s. OR clarithromycin 250 mg t.d.s.

amoxycillin 500 mg t.d.s. amoxycillin 500 mg t.d.s.

IFALLERGIC TO AMOXYCILLIN

omeprazole 20 mg b.d.

metronidazole 400 mg b.d.clarithromycin 250 mg b.d.

ARecommended Therapy

One week triple therapy with a proton pump inhibitor plus 2 antibiotics

Patients with:Duodenal ulcerBenign Gastric UlcerGastric Lymphoma

A

A

B

Note: 1 The value of eradicating H. pylori in NSAIDs related ulcers is unclear. 2 Other proton pump inhibitors (e.g. lansoprazole, 30 mg b.d.) may be used

in place of omeprazole. 3 In patients with active ulcers continue the acid inhibitor alone for one

week (DU) or 3 weeks (GU), after triple therapy.

A B C refers to grade of recommendation based on definitions of levels of evidence used by theUS Agency for Health Care Policy and Research (for details see National Guideline)


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Follow up after Eradication TherapyThese are grade C recommendations based on level IV evidence

Complicated Peptic Ulcer

If previous ulcer complication confirm eradication in all patients by breathtest or endoscopy.

Gastric Ulcer

Undertake endoscopy to confirm eradication and healing of ulcer.

Consider othercause(s) of symptoms

Symptoms persist 4weeks post-treatment

Consider othercause(s) of symptoms

Treat with 2nd choicetherapy

+ve -ve

Breath test

Symptoms persist 4weeks post-treatment

No follow up necessary

Resolution of symptoms 4weeks post-treatment

TREAT WITH FIRST CHOICE THERAPY

Resolution of symptoms 4weeks post-treatment

No follow up necessary

Uncomplicated DU

Follow flow chart below


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Documents

Helicobacter Pylori 2