S3-Guideline ”Helicobacter pylori and gastroduodenal ulcer disease” of the German Society for...

S3-Guideline “Helicobacter pylori and gastroduodenal ulcer disease” of the GermanSociety for Digestive and Metabolic Diseases (DGVS) in cooperation with the GermanSociety for Hygiene and Microbiology, Society for Pediatric Gastroenterology andNutrition e.V., German Society for Rheumatology, AWMF-Registration-no. 021/001

S3-Leitlinie „Helicobacter pylori und gastroduodenale Ulkuskrankheit” der Deutschen Gesellschaft fürVerdauungs- und Stoffwechselkrankheiten (DGVS) in Zusammenarbeit mit der Deutschen Gesellschaft fürHygiene und Mikrobiologie, Gesellschaft für Pädiatrische Gastroenterologie und Ernährung e. V. und derDeutschen Gesellschaft für Rheumatologie – AWMF-Register-Nr. 021 / 001

Authors W. Fischbach1, P. Malfertheiner2, J. C. Hoffmann3, W. Bolten4, J. Bornschein2, O. Götze5, W. Höhne6, M. Kist7,S. Koletzko8, J. Labenz9, P. Layer10, St. Miehlke11, A. Morgner11, U. Peitz12, J. Preiß6, C. Prinz13, U. Rosien10, W. Schmidt5,A. Schwarzer8, St. Suerbaum14, A. Timmer15, G. Treiber16, M. Vieth17

Affiliations The institutions are listed at the end of the document.

Schlüsselwörter!" Helicobacter pylori!" gastroduodenale Ulzera!" Ulkuskrankheit

Key words!" helicobacter pylori!" gastroduodenal ulcer!" ulcer disease

BibliographyDOI http://dx.doi.org/10.1055/s-0028-1109855Z Gastroenterol 2009; 47:1230–1263 © Georg ThiemeVerlag KG Stuttgart ! New York !ISSN 0044-2771

CorrespondenceProf. Dr. Wolfgang FischbachMedizinische Klinik II und Klinikfür Palliativmedizin, KlinikumAschaffenburg, Akad. Lehr-krankenhaus der UniversitätWürzburgAm HasenkopfD – 63739 AschaffenburgTel.: ++ 49/60 21/323010Fax: ++ 49/60 21/[email protected]

Introduction!

In 1983 Helicobacter pylori, which was calledstill Campylobacter pylori at the time, was re-discovered by the Australians Robin Warrenand Barry Marshall. It became a worldwidesuccess story highlighted by the Nobel Prizeaward to the Australian scientists. The interestin the first few years focused on the role ofHelicobacter pylori infection on gastroduode-nal ulcer disease. The complete consequencesof the infection became gradually evidentwhen an etiopathogenetic role of Helicobacterpylori for gastric cancer and gastric MALT-lym-phoma as well as an association with othergastric and extragastric diseases was discov-ered.

An update of the previous consensus recommen-dation of the German Association for Digestiveand Metabolic Diseases (“Deutsche Gesellschaftfür Verdauungs- und Stoffwechselkrankheiten”[DGVS]) that considers the knowledge and pro-gress of the last years seems justified. Further-more, it should take the special situation in Ger-many with respect to epidemiology, resistancesituation, diagnostics, and therapy into consid-eration. The new guideline was commissionedby the DGVS. It was prepared in cooperationwith the German Association for Hygiene andMicrobiology, the Society for Pediatric Gastroen-terology and Nutrition e.V., and the German As-sociation for Rheumatology. The guideline targetgroup is practicing physicians who work in pri-vate offices or clinics specifically general practi-

Zusammenfassung!

Die Leitlinie akualisiert eine frühere Konsen-susempfehlung der Deutschen Gesellschaft fürVerdauungs- und Stoffwechselkrankheiten(DGVS) aus dem Jahr 1996. Sie wurde interdis-ziplinär in Zusammenarbeit mit Vertretern derDeutschen Gesellschaft für Hygiene undMikrobiologie, der Gesellschaft für PädiatrischeGastroenterologie und Ernährung e. V. und derDeutschen Gesellschaft für Rheumatologie er-stellt. Die Leitlinie basiert auf den Empfehlungender Arbeitsgemeinschaft der WissenschaftlichenMedizinischen Fachgesellschaften (AWMF) füreine systematische evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S 3 und hat auchdie Bewertungskriterien der GRADE (Grading ofRecommendations Assessment, Developmentand Evaluation) implemetiert. Die Anwendbar-keit der Studienergebnisse und spezifische Gege-benheiten in Deutschland im Hinblick auf Epide-miologie, Resistenzlage, Diagnostik und Therapiewurden berücksichtigt.

Abstract!

This guideline updates a prior consensus recom-mendation of the German Society for Digestiveand Metabolic Diseases (DGVS) from 1996. Itwas developed by an interdisciplinary coopera-tion with representatives of the German Societyfor Hygiene and Microbiology, the Society forPediatric Gastroenterology and Nutrition (GPGE),and the German Society for Rheumatology. Theguideline is methodologically based on recom-mendations of the Association of the ScientificMedical Societies in Germany (AWMF) for pro-viding a systematic evidence-based S3 level con-sensus guideline and has also implementedgrading criteria according to the GRADE (Grad-ing of Recommendations Assessment, Develop-ment, and Evaluation) process. Clinical appli-cability of study results as well as specifics forGermany in terms of epidemiology, antibioticresistance status, diagnostics, and therapywere taken into account.

Fischbach W et al. S3-Guideline “Helicobacter pylori… Z Gastroenterol 2009; 47: 1230–1263

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tioners, internists, gastroenterologists, rheumatologists, pediatri-cians, and microbiologists.

Methodological procedure (guideline report)!

After being commissioned by the guideline committee of theDGVS, the expert groups were put together and the heads ofthe task forces were appointed by persons responsible for theorganization and implementation (W.Fischbach, P. Malferthei-ner, initially also W.F. Caspary: guideline heads/organizationcommittee). These were based on eight previously defined to-pic complexes (Attachment C). The temporal and organization-al course of the whole consensus process is shown in Attach-ment B. The guideline proposal was registered with the AWMF(AWMF-Register-Nr. 021/001) on August 1, 2008.

Topic complexes and structure of task forces!

The heads of the guideline committee initially defined eighttopic complexes (Attachment C). During the course of theguideline preparation it became clear that two of the topiccomplexes “Indications for therapy of neoplastic gastric disea-ses (gastric carcinoma, MALT-lymphoma)” and “Prevention ofHelicobacter pylori associated diseases” should be consolidatedto avoid unnecessary redundancies. This resulted in the topiccomplex IV “Prevention and therapy of neoplastic gastric dis-eases (MALT-type marginal-zone-B-cell-lymphoma, gastric car-cinoma)”. After determining the topic complexes, the organiza-tion committee appointed two task force heads each, who inagreement with the heads of the guideline committee put to-gether the individual task forces (Attachment C). It became ne-cessary to additionally appoint 1–2 young colleagues in thetask forces who systematically performed the literature search(Attachment C).

Organizational course of the consensus process!

The further methodical approach was standardized, because, atfirst, the compilation of search terms, the systematic review ofthe literature in the individual task forces, as well as the exter-nal biometric support were not practicable. This was donewith the help of the task force at the Charite (W. Höhne,J. Hoffmann, J. Preiß) that was originally formed as part ofthe competence net “Chronic inflammatory bowel diseases”. Ameeting took place in Frankfurt on January 30, 2007. The taskforce heads and the participants of the task forces who wereresponsible for the literature search were informed about theprocedure of choosing key words. The search was done inPubMed and Cochrane. It was limited to German and Englishoriginal publications from 2000 on. Computer support e.g.preparation of consented dictionaries was given by W. Höhne.Following the literature search based on key words and view-ing and supplementing of the literature, the heads of the taskforces drafted the questions. After they were answered in thetask forces, the final question catalogue was made available onthe internet. All task force members were asked by serialemail to answer these questions (Delphi technique). If neces-sary, they were reminded. Those who did not fulfill this taskwere excluded from the subsequent process. They also did

not take part in the final consensus conference. Based on theanswered question catalogue, the guideline recommendationsfor the individual topic complexes were completed by theheads of the task forces. The final consensus conference tookplace on Nov. 30./Dec. 1.2008 in Aschaffenburg. On the firstday, the suggestions for the consensus finding were drawn upin the individual task forces. On the second day, the state-ments were presented by the heads of the task forces, a dis-cussion was held, and if necessary, modifications of the con-sensus suggestions were made, and finally recommendationgrade and evidence level were voted on in the plenum usingTED. The participants of the consensus conference are listedin Attachment D. Two statements of the topic complex II (II.7.II.8.) were modified again after the consensus conference andwere posted on the internet for voting.

Classification of the recommendation grade, evidencelevel, and consensus size!

The level of evidence, the strength of recommendation, andconsensus size can be found in Attachment A (!" Table 1–3).The classifications are based on the methodological procedureof the DGVS-guideline on ulcerative colitis and the establishedguideline methodology as recently published1. In general, thelevel of evidence determines the strength of recommendation.In individual justified cases this was handled differently. Adowngrading or upgrading was done in the consensus confer-ence. The reasons for such deviations can be found in the cor-responding comment of each statement.

Guideline validity!

The validity of the guideline is estimated at 5 years. If changesthat are relevant for patient care become evident, the guide-line committee will decide whether the whole guideline or in-dividual topic complexes must be revised earlier.

Financing!

Costs for the guideline preparation were financed with fundsfrom the DGVS. This was handled by the office of the DGVS.No funds from industry were used. All participants have de-clared in writing possible financial conflicts of interest. Theyhave signed a statement of independence.

Acknowledgements, criticism and suggestions!

The guideline committee would like to thank everyone whoactively took part in the preparation of the guideline as atask force member, a participant responsible for the literaturesearch, a head of a task force, or a consensus conference parti-cipant. Special thanks go to W. Höhne and J. Hoffmann. Theysignificantly contributed to the realization of this project withtheir competence in the methodology of guideline preparationand their great dedication. This kind of help and support

1 Preiß JC, Timmer A, Zeitz M, Hoffmann JC. Neue Konzepte der Leitlinien-methodik. Z Gastroenterol 2007; 45: 1075–1081.


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cannot be expected for the preparation of future guidelines.Therefore, it is appreciated that specific competence and per-sonnel will be available in the future at the office of theDGVS. The behavior of individual representatives of Germangastroenterology and members of the DGVS must be criticized.They agreed in writing to participate in the preparation of theguideline, but did not make any contribution during its course(with the exception of few persons who were excused). A taskof the DGVS will be to create an “air of responsibility” and toset up rules on dealing with “deniers”.

I. Topic complex “Epidemiology”!

1. The prevalence of Helicobacter pylori infection varies de-pending on the geographic distribution (industrial nations anddeveloping countries), the ethnic affiliation, and the socioeco-nomic status. It shows an age-dependent increase (Recommen-dation grade A, evidence level 1c, no vote)Comment: The prevalence of H. pylori infections varies greatlybetween industrial nations and developing countries as well aswithin individual societies [1–4]. The variation between differentethnic groups is due to different exposure intensities to H. pylori(social, diet, and environmental factors) [5–7]. A genetically in-creased susceptibility to H. pylori has not been proven [8]. Thecountry of birth is a risk factor for H. pylori infection even after im-migration to an industrial nation. However, the risk inversely cor-relates with the duration of the stay in the country of immigration[9]. The infection prevalence is dependent on the socioeconomicstatus (occupation, income, living situation) especially duringchildhood when transmission is most frequent [10].The prevalence of H. pylori infection shows an age-dependentincrease within a population (about 1% per year of life in indus-trial nations). It is interpreted as an expression of the birth co-hort effect [11, 12]. The infection prevalence in the developingcountries is already high under the age of 20 years. It culminatesat an age between 20 and 30 years so that about 80% of this agegroup is infected [13].

2. The prevalence of Helicobacter pylori infection in Germanyis between 5% (children) and 24% (adults). It is significantlyhigher in immigrants (36–86%) (Recommendation grade A,evidence level 1c, no vote)Comment: The prevalence of H. pylori infection is 5–7% in Ger-man children at the age 5 to 7 years [14]. In women/men underthe age of 30 years it is 25%/30%, in 30–34 year-olds 19%/16%, andin over 35-year-olds 12%/24%, respectively [15, 16]. Also in Germa-ny a great H. pylori prevalence variation exists depending on na-tionality and country of birth. The prevalence for immigrants andtheir children is reported to be 36–44% at the age of 5 to 7 yearsand in adults between the age of 25 and 45 years 52–86% [14–16].

3. The frequency of Helicobacter pylori infection is decreasingin many countries (Recommendation grade A, evidence level1c, no vote).Comment: The improvement of the standard of living leads to adecline in the prevalence of H. pylori infection [12, 17–19].

4. The transmission of Helicobacter pylori occurs from personto person. The exact mode of transmission (oral-oral, gastric-oral, fecal-oral, or a combination) is not known (Recommenda-tion grade B, evidence level 2b, strong consensus).Comment: H. pylori can be cultivated from vomit, stool, or saliva[20, 21]. Vomit has an especially high bacterial density [21]. H. py-lori transmission to persons in contact with the patient was ob-served after breakouts of acute gastrointestinal infections [22].Close contact with H. pylori contaminated body secretions withinthe families explains the increased incidence of infections withinthe family (see I. 5.) There are no clear indications of zoonotictransmissions of H. pylori. However, the bacterium was also foundin primates and less frequently in other animals [23–25].

5. Close contact of children with Helicobacter pylori infectedfamily members is the most important mode of transfer (Re-commendation grade A, evidence level 1c, strong consensus).Comment: The intrafamilial transmission of H. pylori is well es-tablished [26–29]. There is a high molecular biological maternalconcordance of individually transmitted H. pylori strains withthose of the infected children [30, 31]. The number of family mem-bers and the size of the living quarters are reported to be additionalrisk factors [32]. Especially older infected siblings are a predictor ofH. pylori infection [26, 28, 33]. The incidence rate of H. pylori infec-tion is highest in children under 3 years of age and decreases signif-icantly from the age of 5 years [34].

6. Helicobacter pylori contaminated drinking water and foodhave been reported. The bacterial transmission through bodiesof water and sewage is disputed (Recommendation grade B,evidence level 2b, strong consensus).Comment: The role of bodies of water and sewage as a possiblesource of infection is disputed [10, 35–39]. Although H. pyloriDNA has been found in bodies of water and sewage, the proof ofcultured bacteria has only been seldom reported [38–40]. Due tothe limited metabolic and regulatory functions of H. pylori outsideof the stomach, a long-term extragastric survival of the bacteriumis almost impossible [41].

7. The rate of recurring infections in adults after successfuleradication therapy is low in industrial countries (Recommen-dation grade A, evidence level 1b, consensus).Comment: The rate of recurring infections in adults after suc-cessful H. pylori eradication therapy is about 1% per year in in-dustrial nations or about 13– 24% in developing countries [42].The recurring infection rate in children over 5 years of age is 2%per year [34, 43].

8. Established strategies to prevent Helicobacter pylori infec-tion do not exist. Currently an effective vaccination is notavailable (Recommendation grade D, evidence level 5, strongconsensus).Comment: Currently an effective vaccination is not available.After a 10 year vaccination program, an efficient vaccine is es-timated to cause a significant reduction of H. pylori prevalenceand associated diseases. It would still be cost effective with anefficacy of 55% [44–58].


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9. Gastroduodenal ulcer disease, distal gastric carcinoma, andprimary B-cell-lymphoma are diseases associated with Helicobac-ter pylori infection (Recommendation grade A, evidence level 1a,strong consensus).Comment: H. pylori infection induces chronic active gastritis.Possible complications or sequelae are gastroduodenal ulcer dis-ease, distal gastric adenocarcinoma, marginal zone B-cell-lym-phoma of MALT (mucosa-associated-lymphoid tissue)-type, anddiffuse large B-cell-lymphoma (DLBCL) of the stomach [59–63].An H. pylori infection increases the risk of developing distal gas-tric carcinoma by a factor of 2–3 (OR 1.92– 2.56) compared toindividuals who are not infected. The odds ratio (OR) for the oc-currence of non-cardia-carcinomas is 2.7– 3.8 depending on themeta-analysis. It is 0.99–1.23 (no risk) for the development ofcardia-carcinomas. The association of H. pylori infection withthe individual types of gastric carcinomas is similarly high: in-testinal type: OR2.49–4.45; diffuse type OR2.58– 3.39 [65–70].The relative risk is higher if the serum sample that was used forthe diagnosis of H. pylori infection was taken long before the cancerwas diagnosed (OR 5.9). This is because the relationship betweenH. pylori and gastric carcinoma may be strongly underestimateddue to a possible loss of the pathogen during the course of cancerand also depending on other seromarkers of the infection [70, 71].Among H. pylori infected persons seropositivity for cytotoxin asso-ciated gene A (CagA) increases the risk for gastric carcinoma ornon-cardia-carcinomas additionally by a factor of 1.64 or 2.01, re-spectively [69].The incidence of MALT-lymphomas correlates with the preva-lence of H. pylori. The relative risk of developing primary gastriclymphomas is increased by a factor of 6 for serologically provenH. pylori infection in large case-control-studies [72]. The role ofJHP 950 as a genetic marker for gastric MALT-lymphomas is beingdiscussed since it was found in a study that the risk of marginalzone B-cell-lymphoma of MALTwas increased by a factor of 3 [73].The mainly zoonotically occurring bacterium Helicobacter heil-mannii has a prevalence of about 0.5% in humans and is also asso-ciated with gastric MALT-lymphomas [74, 75].

10. An occupation associated risk exists for Helicobacter pyloriinfection (Recommendation grade A, evidence level 1c, consen-sus).Comment: Direct patient contact by doctors and nurses is a riskfactor for H. pylori infection [76–80]. It is not clear whether spe-cific medical tasks with a high exposure to oral, gastric, or fecal se-cretions (e.g. endoscopy, dental medicine) pose an additional risk.

II. Topic complex “Diagnostics, typing, resistancestatus, resistance testing”!

1. The following methods are available and have been evalu-ated to such an extent that they can be used for infection di-agnostics:" invasive methods i.e. using biopsies that have been taken dur-

ing esophagogastroduodenoscopy for:" rapid urease test" histology" bacterial culture" PCR or RealTime PCR to detect the pathogen" PCR or RealTime PCR to detect resistance-associated muta-

tions of the pathogen

non-invasive methods:" urea breath test (13C or 14C-labeled)" stool antigen test (based on monoclonal antibodies)" serological antibody test

(Recommendation grade A, evidence level 1a, strong consensus).Comment: The following reference data apply to sensitivity andspecificity of the tests provided disturbing factors are absent(see Comment under II. 3.) (!" Table 1).No test method by itself is absolutely accurate. With the excep-tion of the culture specificity, which is 100% according to defini-tion, diagnostic accuracy is limited to a greater or lesser extentfor each method. Therefore, in studies to validate new test meth-ods concordant results of several established test methods areused as references [81–83].For the invasive methods biopsies of the gastric antrum as wellas the gastric body have to be taken. The sensitivity increaseswith the number of biopsies, since H. pylori may show a patchydistribution [91]. The sites of the biopsy for histology should corre-spond to the updated Sydney-System [92], i.e. two biopsies from thegastric antrum (2 to 3 cm in front of the pylorus, one each at thelarge and small curvature); two biopsies from the gastric body(one at the small curvature about 4 cm above the angulus fold,one at the large curvature about 8 cm distal to the cardia). The re-commendations are aimed at detecting biopsy sites with higherbacterial density i.e. gastric antrum and large curvature, as wellas biopsy sites with higher prevalence of premalignant lesions(small curvature, gastric body). If specific problems of premalig-nant lesions are pending, a biopsy should be taken at the angulusfold [92, 93]. For the other methods biopsy sites with higher expec-ted bacterial density are of interest i.e. a biopsy each of the largecurvature in the gastric antrum and gastric body [94, 95]. Al-though the bacterial density is frequently greater in the gastric an-trum than in the gastric body, H. pylori can be detected in biopsiesthat have only been taken from the gastric body especially underhypoacidity [96–98].Although PCR-methods for the detection of H. pylori and resis-tance-associated mutations of the pathogen have been suffi-ciently validated [84, 85], so far they are hardly available.Currently antibody detection in urine or saliva [99] are not suffi-ciently validated as tests for an immune response to H. pylori. Thisis also the case for quick tests for the antibody detection in wholeblood [100, 101].Test kits to detect H. pylori-IgG-antibodies in serum should be va-lidated for their use in Europe. This is because H. pylori has alarge genetic variability, which becomes especially evident whenpersons from different continents are compared [89, 102, 103].

Table 1

sensitivity

(%)

specificity

(%)

invasivemethods

culture [81–83] 70 – 90 100histology [81–83] 80 – 98 90 – 98rapid urease test [81–83] 90 – 95 90 – 95PCR [84, 85] 90 – 95 90 – 95

non-invasivemethods

urea breath-test [86, 87] 85 – 95 85 – 95

stool-antigen-test basedon monoclonal anti-bodies [88]

85 – 95 85 – 95

IgG-antibody test inserum [83, 89, 90]

70 – 90 70 – 90


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2. To diagnose an existing Helicobacter pylori infection directtest methods that detect the bacterium as a whole (histology,pathogen culture), as a representative antigen (stool antigentest), or as a specific metabolic product (ammonia in the rapidurease test, carbon dioxide in the urea breath test) are espe-cially suited (Recommendation grade A, evidence level 1a, con-sensus).Comment: Aside from invasiveness the tests can be divided ac-cording to direct and indirect pathogen detection methods. Di-rect tests detect a current infection while indirect tests detectantibodies, which can indicate a current as well as a previousH. pylori infection. However, aside from epidemiologic studies,which may also be interested in previous infections [104], a posi-tive serum test due to a previous and not an acute infection wouldbe evaluated as false positive in the clinical situation [94, 95]. An-other reason for a false positive serum test could be cross-reactingantibodies. False negative serum tests are caused be the absence ofan immune response or antibody titer below the detection level.

3. The choice of the test that is applied depends on the prob-lem and especially on the individual situation (Recommenda-tion grade B, evidence level 2, consensus).Comment: Aside from invasiveness, the required diagnostic accu-racy is the most important factor when choosing a test. Thus, forepidemiologic studies non-invasive tests are usually used. How-ever, in the clinical situation an invasive method may be indi-cated because of the required H. pylori-diagnostics as well asthe endoscopy of the upper digestive tract e.g. to search for an or-ganic cause for dyspepsia or for a follow-up of gastric ulcer.Aside from the abovementioned sensitivity and specificity, infec-tion prevalence has an important affect on the predictive valueof a positive or negative test result. Thus, for example, a positivepredictive value of a positive test result is determined to be only50% even though its sensitivity is 90% because the prevalence isonly 10%.Important disturbing factors, which can lead to false negative orpositive results, should also be considered when choosing andevaluating a test. False negative results of direct tests may becaused by a low colonization density of the pathogen [94, 95,105]. The colonization density is strongly subject to interindividualvariability. However, additionally it is typically reduced by pre-vious therapy with proton pump inhibitors or H. pylori-effectiveantibiotics, by gastric atrophy [105–108], or by MALT-lymphoma[109].In general histology has the highest sensitivity. However, it toodoes not reach 100%, because colonization of H. pylori mayshow a patchy distribution and, thus, may be missed when tak-ing a biopsy. In addition, histology is dependent on the exami-ner. The sensitivity of the urea breath test is impaired after par-tial gastric resection. The reduced area of the gastric mucosa isa contributing factor [110]. The lower sensitivity of the rapid ureatest in case of acute upper gastrointestinal bleeding is an observa-tion for which the cause is not yet completely understood [111–115].False positive results of certain direct tests procedures can becaused by bacterial overgrowth in the stomach [116, 117]. How-ever, H. pylori culture including corresponding metabolic tests canbe viewed as 100% specific. A false positive histology result is veryrare for specialized pathologists. Thus, the specificity of histologiescan be assumed to be almost 100% [118]. Another advantage of his-tology is the possibility to detect the much more seldom infectionwith Helicobacter heilmannii [119]. However, for H. pylori tests

that assess urea activity i.e. rapid urease test and urea breath testthe overgrowth in the stomach with urease producing bacteria isan important cause for false positive test results [116, 117].

4. The following time intervals without H. pylori suppressivetherapy should at least be observed for reliable Helicobacterpylori diagnostics: 2 weeks after a proton-pump-inhibitor-ther-apy and 4 weeks after an eradication therapy or other antibio-tic therapies (Recommendation grade C, evidence level 3, con-sensus).Comment: The sensitivity of all direct tests is reduced by condi-tions that lead to a decrease in the bacterial density. A reduc-tion of the bacterial density is seen under proton-pump-inhibi-tor-therapy [120–126] or H. pylori-effective antibiotics. It isbeing debated whether H2-receptor-antagonists also reduce thesensitivity [120].The return to the original bacterial density takes several days orweeks after finishing such a therapy. This is of course also de-pendent on intensity and duration of the preceding treatment.In clinical practice this is an important problem, because dys-pepsia is often treated with proton-pump-inhibitors before H. py-lori-diagnostics or endoscopy is indicated. Therefore, this recom-mendation should be taken into consideration to avoid toomany false negative tests [43].

5. Two positive test results should exist for reliable Helicobac-ter pylori diagnostics. If there is a discrepancy in the results,an additional diagnostic test should be employed. A single po-sitive test result is sufficient for a therapy decision of manifestduodenal ulcers (Recommendation grade C, evidence level 3,strong consensus).Comment: This statement deviates partially from previous re-commendations and also from current recommendations ofother countries that consider a positive result of one suitabletest method as sufficient [47]. The current requirement for concor-dant positive results of at least two tests for the reliable diagnosis isdue to the low and decreasing prevalence of H. pylori infection inindustrialized countries. The positive predictive value also declineswith decreasing prevalence. An example is calculated in II. 3. Lowprevalence can be especially expected in young people.For patients for whom H. pylori diagnostics are indicated duringendoscopy a combination of a rapid urease test and histology issuitable to detect the pathogen. Culture of the pathogen is onlyindicated if resistance testing is necessary. A non-invasive testshould be done if the rapid urease test and histology are discre-pant. However, the histological combination of H. pylori detec-tion and typical H. pylori gastritis is usually considered as suffi-ciently specific if a specialized histopathology evaluation hasbeen done [41, 128].

6. Helicobacter pylori pathogenicity factors partially determinethe development of H. pylori gastritis sequelae such as gastriculcer or gastric carcinoma (Recommendation grade A, evi-dence level 1, strong consensusA routine testing of corresponding virulence factors should notbe done.Recommendation grade B, evidence level 2, strong consensus).Comment: Certain characteristics of the pathogen such as cyto-toxin-associated antigen CagA, specific alleles of the vacuolizedcytotoxin VacA, as well as the inflammation-associated surfaceproteins IceA, BabA, and OipA have been linked to different ex-tents with certain diseases such as ulcers or cancer [129–133].


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A common characteristic of these factors is that they are all associ-ated with a worsening of the inflammatory reaction of the mucosa.The proteins mentioned are either not present in all H. pylori-strains or as with VacA are present in different variants (alleles).They are usually detectable in H. pylori isolates using molecular ge-netic methods. The presence of CagA can also be determined indi-rectly using corresponding specific serum antibodies. Although itwas shown that virulence factors are significantly associated withcertain complications, the reverse conclusion that one has to expectthe corresponding complications in each individual case is not true.In addition, for almost all complications pathogen dependent andhost dependent causes have been described. There are also regionaldifferences especially between Asia and the rest of the world [134].Therefore, the knowledge of the pathogen’s pathogenicity and viru-lence factors currently has no significant implications on the clini-cal management of H. pylori infection. The routine testing of viru-lence factors is, thus, not indicated.

7. Resistance testing following therapy failure for the firsttime and a second line therapy based on sensitivity testingare suitable to minimize resistance development of reserve an-tibiotics. Therefore, they are always recommended after thefirst therapy failure when a new endoscopy is done (Recom-mendation grade B, evidence level 2, majority agreement[late electronic vote]).Comment: Every antibiotic therapy is associated with the devel-opment and selection of antimicrobial resistances of the patho-gen as well as the physiological flora. Therefore, an empirictherapy is only justified if due to the assumed resistance situa-tion of the pathogen excellent efficacy (> 90%) can be expected.Due to the positive primary resistance situation for H. pylori inGermany, this is usually the case for patients who have not beenpreviously treated. However, for example after a single therapyfailure more than 50% resistances to metronidazole and clari-thromycin are seen. For H. pylori unsuccessful pretreatmentsare also significant risk factors for the development and selec-tion of corresponding resistances. This was clearly demonstratedby the National Reference Center for Helicobacter pylori in aprospective, ongoing study of currently more than 1000 comple-tely evaluable patients (publication in preparation). If resistan-ces are to be expected, a specific therapy that is based on anantibiogram improves the success rate according to general ex-perience [135, 136]. In addition, the general use of second line anti-biotics is associated with the risk of developing resistances to them[137]. This can also be minimized with specific use. A microbiologi-cal test with pathogen culture and antibiogram makes specifictherapy possible if the resistance situation is unclear (e.g. after firsttherapy failure). Therefore, this procedure after the first therapyfailure has already been recommended in Germany since 2004[138].

8. If endoscopy was not done after the first therapy failure, anendoscopy with biopsies for culture and sensitivity testingshould be done routinely for repeated therapy failure (Recom-mendation grade B, evidence level 2b, consensus [late electro-nic vote]).Comment: After multiple therapy failures more than 80% ofH. pylori isolates that are cultured have resistances against themost important bacterially effective anti-infectives clarithromy-cin and metronidazole (ResiNet, ongoing study). In addition, in-creasing resistance quotas are seen especially against chinolonesand more seldom also against rifabutin and tetracycline (Resi-

Net, study). Therefore, the chances of successfully implementingother empiric therapy schemes are strongly restricted. Pathogenculture and sensitivity testing makes specific therapy possibleeven under difficult conditions.

9. The Etest should be used for sensitivity testing of Helicobac-ter pylori in routine diagnostics (Recommendation grade D,evidence level 5, consensus).Comment: The agar dilution test is considered the gold standardto determine antimicrobial sensitivity of slow growing bacteria.However, in routine diagnostics the agar dilution test is difficultto standardize because of the variable stability of the antibioticsused, the variance in culture media, and the inoculation effect.Different studies have shown that in practice the Etest can re-place the agar dilution test without significant loss of quality[95, 139–141].The individual molecular mechanisms of antimicrobial resistancedevelopment are known for the eradication relevant antibioticsclarithromycin, rifabutin, levofloxacin, tetracycline, and amoxi-cillin. In general, they are based on mutations of the correspond-ing microbial receptor molecules. Thus, in individual cases theyallow a molecular genetic confirmation of the phenotypic resis-tance [95]. No individual single molecular mechanism is known forthe resistance against metronidazole [95]. Therefore, phenotypictesting (Etest or agar dilution test) is currently the only possibilityto detect resistances of H. pylori against metronidazole.In addition, for the resistance based antimicrobial therapy ofH. pylori infection sensitivity testing of H. pylori gives informa-tion on in vitro resistance against a certain antibiotic. However,the actual clinical relevance of such an in vitro resistance mustbe confirmed in clinical trials due to the special pharmacokine-tic situation in acidic mucus. Antibiotics for eradication treat-ment should, therefore, not be based on antimicrobial sensitivitytesting, but should always also be combined with experiencefrom clinical studies.

III. Topic complex “Indications for therapy of Helico-bacter pylori infection in benign diseases”!

1. Peptic ulcer: Helicobacter pylori infection in peptic ulcer ofthe stomach or duodenum is an obligatory treatment indica-tion with the aim of bacterial eradication. It is also indicatedif the ulcer is resolved or anamnestic (Recommendation gradeA, evidence level 1a, strong consensus).Comment: Several concordant meta-analyses exist on this topic[142–148].

2. Dyspeptic symptom complex with negative endoscopy(“functional dyspepsia”): The eradication of Helicobacter pyloriinfection in patients with chronic dyspeptic symptoms andnegative endoscopy leads in a minority of patients (5–10%)to sustained symptom improvement (Recommendation gradeA, evidence level 1b, strong consensus).Comment: H. pylori infection in patients with long existing(!4 weeks2) dyspeptic symptoms is a facultative treatment indica-tion. The decision should be made on an individual basis. A subjec-

2 NB: The definition of functional dyspepsia in its actual sense requires ananamnesis of at least 6 months [162].


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tive feeling of suffering, therapeutic alternatives, previous thera-peutic failures, criteria of carcinoma prevention (see topic complexIV.), patient’s wish for appropriate information on chances andrisks etc. should be taken into consideration. On the one hand, theprobability of long-term symptomatic therapy success is 5–10%[149–157]. On the other hand, the chance of relevant gastrointest-inal side effects (especially antibiotic-associated diarrhea) is about10– 25% [158–161].

3. Unexamined dyspepsia: Helicobacter pylori monotesting(non-invasive) with subsequent eradication therapy (test &treat) is not recommended for patients with unexamined sus-tained dyspeptic symptoms (Recommendation grade D, evi-dence level 5, consensus).Comment: This recommendation was made despite the fact thatpublished studies (evidence level up to 1b) report results thatjustify a test & treat approach [151, 155, 157, 163]. These studieswere, however, performed in populations and under health eco-nomic conditions that are not comparable to the situation in Ger-many. Therefore, the test & treat concept has particularly beenshown to be economically useful for the following constellations:" high H. pylori infection rate and high probability of H. pylori-

associated lesions" high costs (especially for endoscopy)" limited endoscopy capacity and correspondingly long waiting

periodsFor the clinical use of the test & treat-procedure the data arecontroversial.In Germany other – partially fundamental – constellations exist:" low and decreasing H. pylori prevalence and, thus, low probabil-

ity of H. pylori-associated lesions in the potential test & treattarget population

" high availability and low cost of endoscopic diagnostics" only serology has been approved as a non-invasive procedure

for primary diagnostics (breath and stool tests are only allowedfor children, to evaluate therapy success, or when reinfection issuspected). For problems of serological diagnosis see II.2.

In addition, diagnostic clarification is obligatory for all patients> 55 years and if alarm symptoms (progressive symptoms, bleed-ing, anemia, quick satiation, unclear weight loss of > 10%, dys-phagia, odynophagia, continuous vomiting, and family historyor patient findings of gastrointestinal tumors, previous pepticulcers, lymph node enlargement, palpable resistances) are pres-ent [164].For all cases the test & treat-strategy demands careful patientselection with detailed anamnestic evaluation and physical ex-amination. Nonetheless, even with such a “correct” approach aconsiderable error rate of over 50% exists with false negativeclinical evaluation. This is due to the known low sensitivity ofthe abovementioned “alarm symptoms” during dyspeptic dis-comfort [165, 166].

4. Asymptomatic Helicobacter pylori gastritis: Asymptomaticchronic Helicobacter pylori associated gastritis may be treatedwith eradication therapy. This can be done for potential futureNSAID- or ASS-treatment or carcinoma prevention if at thesame time possible side effect rates are considered (Recom-mendation grade A, evidence level 1b, consensus).Comment: The reasons for this recommendation are given undertopic complexes IV and VII.

5. Reflux disease: Coexisting (or anamnestic) reflux disease hasno affect on the decision for or against Helicobacter pylori era-dication due to other indications (Recommendation grade A,evidence level 1b, strong consensus).Comment: H. pylori eradication does not cause reflux disease.However, it can make it visible and clinically manifest [167–169]. This is especially true for patients with corpus-dominant gas-tritis. For patients with antrum-dominant gastritis improvementof the clinical symptoms is more likely [170, 171]. As a whole thestudies available do not indicate that H. pylori eradication leads toworsening of GERD. On the contrary, it often leads to clinical im-provement [172–177]. Furthermore, an enhanced development ofatrophy under long-term PPI-therapy has not been proven forH. py-lori gastritis [178].

6. Other indications: Idiopathic thrombocytopenic purpura(ITP): Helicobacter pylori infection during ITP may be treatedwith eradication therapy (Recommendation grade B, evidencelevel 1b, consensus).Comment: A meta-analysis shows benefits of an eradicationtherapy. However, the data as a whole are sparse (small, hetero-geneous, mostly uncontrolled studies). Two randomized studieswith controversial results exist [179–184].Menetrier syndrome: Helicobacter pylori infection during Me-netrier’s disease may be treated with eradication therapy (Re-commendation grade C, evidence level 4, strong consensus).Comment: Only uncontrolled case descriptions exist on this topic[185–188].Lymphocytic gastritis: Helicobacter pylori infection during lym-phocytic gastritis may be treated with eradication therapy (Re-commendation grade C, evidence level 1b).Comment: This question was not voted on during the conference.The voting was done later in a circulating mail.A placebo controlled study shows a significant therapy effect ofH. pylori eradication [189].Iron deficiency anemia: In adults Helicobacter pylori eradica-tion therapy may be considered for unclear iron deficiency an-emia following adequate diagnostics (Recommendation gradeC, evidence level 2b, consensus).Comment: In adults the benefit of Helicobacter pylori eradica-tion therapy for ideopathic iron deficiency anemia followingadequate diagnostics is not sufficiently proven [190, 191]. Thedata are controversial (see also topic complex VI.).

IV. Topic complex “Prevention and therapy of neoplas-tic gastric diseases (marginal zone-B-cell-lymphoma(MZBCL) of MALT-type, gastric carcinoma)!

Preliminary remark: In the following the indications for Helico-bacter pylori infection therapy in patients with gastric marginalzone-B-cell-lymphoma (MZBCL) of MALT-type will be described.The criteria for diagnosing and the staging examinations, whichare considered necessary, will also be demonstrated. Further-more, the role of bacterial eradication for the prevention ofH. pylori-associated preneoplastic lesions and of gastric carcino-ma will be described.

1. Helicobacter pylori plays a key role in the development andprogression gastric marginal zone-B-cell-lymphoma (MZBCL) ofMALT (mucosa-associated-lymphoid tissue)-type (Recommen-dation grade B, evidence level 2b, strong consensus).


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Comment: The role of chronic H. pylori infection in the genesis ofgastric MZBCL of MALT-type has been scientifically acceptedworldwide. H. pylori gastritis is diagnosed in more than 95% ofall patients with gastric MZBCL of MALT-type [192–194]. In ad-dition, the incidence of the lymphoma correlates with H. pylori pre-valence. In Veneto (upper Italy) where the incidence of gastricMZBCL is exceptionally high (13.2/100000/year), the H. pylori pre-valence is 87% [195]. In comparison England, where the infectionprevalence is only 50–60%, has a much lower incidence of gastricMZBCL of MALT-type [195]. In the USA the incidence was estimatedat 1/30000 to 1/80000 of the H. pylori infected population [196].Furthermore, cell biological in vitro investigations indicate a di-rect connection between H. pylori infection and the developmentof gastric MALT-type MZBCL of MALT-type. Cultured lymphoma-cells from gastrectomy specimens of patients that had surgerywere activated by adding H. pylori. They expressed interleukin-2 (IL-2)-receptors (CD25) as a sign of activation [197]. This effectwas specific for each patient’s H. pylori strain and dependent on thepresence of normal T-cells in the culture. In addition, serologicaltests showed that chronic H. pylori infection increase the risk of la-ter development of gastric lymphoma by a factor of 4.0 [198].

2. The diagnosis of gastric MZBCL of MALT-type is done histo-morphologically according to the WHO classification. It shouldbe confirmed by one of the existing pathological reference in-stitutes (Recommendation grade C, evidence level 4, strongconsensus).Comment: A main characteristic of these lymphomas is a diffuseinfiltrate of small to medium-sized B-lymphocytes that are simi-lar to centrocytes (“centrocytoid”). These infiltrates lead to thetypical lymphoepithelial lesions with rarefication of the gastricglands [199–201]. Immunophenotypically these cells express pan-B-cell markers. They show no immunoreactivity for the “cluster ofdifferentiation” (CD) surface markers 5, 10, and 11c. However, theyare positive for CD20, 21, and 35. These lymphomas were definedas extranodal marginal zone B-cell lymphoma of MALT-type(MZBCL) in the revised European-American Classification of Lym-phatic Neoplasms (REAL) [202] and in the current WHO-classifica-tion of neoplastic diseases of hemopoetic and lymphatic tissue[203]. In the so-called “Lymphoma Classification Project” that eval-uated the clinical significance of the REAL-classification a relativeincidence of MZBCL of 7.6% was found referring to the about 1400patients with non-Hodgkin-lymphomas [204].

3. The basis for the histomorphologic diagnosis is a sufficientnumber of biopsies from macroscopically visible lesions andnormal appearing mucosa (“mapping”) (Recommendationgrade C, evidence level 5, strong consensus).Comment: The minimum number of biopsy samples that shouldbe taken from macroscopically visible lesions is ten. In addition,quadrant biopsies should be taken from macroscopically normalmucosa (n =4 each from antrum and corpus as well as n = 2from the fundus) and a rapid urease test should be done. In gen-eral, this will not have been done during the initial endoscopy.Therefore, after receiving the histologic (suspected) diagnosis ofMALT-lymphoma a second endoscopy will be necessary. An era-dication therapy should not be started until the results of the re-ference histology are available (see IV. 2.).

4. The staging of gastric MZBCL of MALT-type should be doneaccording to the Ann Arbor classification modified by Musshoffwith differentiation of stage EI according to Radaszkiewicz. Inaddition, staging can be done according to the Paris classifica-tion (corresponding to TNM), (!" Table 2) (Recommendationgrade C, evidence level 3, consensus).Comment: Over time the staging of extranodal lymphomas basedon the Ann Arbor classification has been modified many timesto make its application to lymphomas of the gastrointestinaltract possible. Musshoff introduced a first modification in 1977that differentiated between the infiltration of neighboring lymphnodes (II1) and distant lymph nodes (II2) in stage II lymphomas[205]. An additional differentiation of stage I followed: infiltrationof mucosa and submucosa (I1) and infiltration of the M. propria tothe serosa (I2) [206]. The TNM system for epithelial tumors had al-ready been considered as a new staging system for gastrointestinallymphomas [207, 208]. Therefore, for the specific diagnostic re-quirements of gastrointestinal lymphomas a modification of theexisting TNM system was implemented by the European GastroIn-testinal Lymphoma Study group (EGILS) [209, 210]. This Paris clas-sification (TNMB) safely, reproducibly, and adequately describesthe three most important characteristics of gastrointestinal lym-phomas: (i) depth of lymphoma infiltration, (ii) lymph node infil-tration, and (iii) lymphoma spread.

5. Obligatory investigations for the determination of the lym-phoma stage include findings of a physical examination, rou-tine laboratory results, lymph node sonography, abdominalCT-scan, and endoscopic ultrasound. Optional are: ileocolono-scopy, imaging of small intestine, x-ray/thorax-CT, abdomen

Table 2 Stage classification ofgastric lymphomas.

Ann Arbor system TNM classification spreading of lymphoma

Musshoff [205] Paris [207–210]

Radaszkiewicz [206]

EI 1 T1 N0M0 mucosa, submucosaE I 2 T2 N0M0 muscularis propria, subserosaE I 2 T3 N0M0 serosa penetrationE I 2 T4 N0M0 per continuitatem infiltration of neighboring organsE II 1 T1 – 4 N1M0 infiltration of regional lymph nodes

(compartment I + II)E II 2 T1 – 4 N2M0 infiltration of distant lymph nodes

(compartment III inclusive retroperitoneal, mesenteric and para-aortal lymph nodes)

E III T1 – 4 N3M0 infiltration of lymph nodes on both sides of the diaphragmE IV T1 – 4 N0 – 3M1 diffuse or disseminated infiltration of extragastrointestinal organs


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sonography, and bone marrow biopsy (Recommendation gradeB, evidence level 2a, strong consensus).Comment: The physical examination should always evaluategeneral health and nutritional status and pay special attentionto peripheral lymph node status. Routine laboratory resultsshould include blood count and LDH. Lymph node sonographyshould include the following lymph node sites: cervical, supra-clavicular, axillar, and inguinal. An abdomen sonography seemsnot mandatory with the existence of an abdominal CT. Severalwell planned controlled studies analyzed the extent of the initialstaging examination that is necessary. In more than 87% ofcases gastric MZBCL of MALT-type presents as stage I or II. Inabout 6% of patients they are located multifocally in the gastro-intestinal tract [211–217]. Systematic data on the involvement ofthe small intestine hardly exist [218]. Therefore, a general recom-mendation on small intestine diagnostics cannot be given. Restric-ted staging (obligate and facultative examination) is not valid forgastric diffuse large cell B-cell-lymphomas or MALT-type MZBCLwith blasts.

6. Bacterial eradication must be done in Helicobacter pyloripositive gastric MZBCL of MALT-type (Recommendation gradeA, evidence level 1a, strong consensus).Comment: As already described experimental data and epide-miologic studies have shown a connection between gastricMZBCL of MALT-type and H. pylori infection. The perceptionthat lymphoma proliferation in vitro is modified by H. pylori de-pendent factors and that eradication of the infection leads tolymphoma remission, was established in 1992 [194, 195, 197].Eradication therapy should be done according to the general re-commendations for choosing treatment regimens (see V.). Consis-tent and long-term follow-ups are necessary after antibiotic treat-ment of the lymphoma. If eradication is not done with curativeintent, it can nevertheless serve as a relapse prophylaxis in allstages following radiation or chemotherapy [219–222].

7. The first choice therapy for gastric MZBCL of MALT-type stageI is Helicobacter pylori eradication with curative intent (Recom-mendation grade A, evidence level 1a, strong consensus).Comment: Many clinical studies have shown that H. pylori era-dication in H. pylori positive patients with gastric MZBCL stage Ileads to complete lymphoma remission in about 80% of the cases[223–236]. These remissions are also stable on a long-term basis;the relapse rate is about 3% [234, 235]. These data suggest that atleast some of the patients can be healed with antibiotic monother-apy. Therefore today, eradication therapy for this indication mustbe seen as first choice curative treatment. Its importance for moreadvanced stages is controversial. The rate of complete remissions instage II1 is significantly lower at a maximum of 40% [230, 235].However, if the established response probability is based on endo-sonography, the rate for lymphomas with nodal lymph node infil-tration is almost 0% [231, 237]. Nonetheless in patients with dif-fuse large cell B-cell-lymphomas (DLBCL) with and without MALT-components complete remission was observed after successfulH. pylori eradication [219–221].

8. A watch-and-wait strategy is the procedure of choice for his-tological minimal residues (hMR =histological minimal residualsor MRD=minimal residual disease) of MZBCL after successful He-licobacter pylori eradication (Recommendation grade C, evidencelevel 3, consensus).

Comment: About 20% of patients with H. pylori positive MZBCLof MALT-type stage I do not reveal complete lymphoma remis-sion even months after successful eradication therapy. Detectionof histological minimal residual infiltrates and persistent B-cellmonoclonality and inconspicuous endoscopy define the terms“histological minimal residuals” (hMR) or “minimal residual dis-ease” (MRD) [238, 239]. Fischbach et al. recently reported on a pa-tient collective with minimal histological residues that had no fur-ther treatment. However, they were regularly examined byendoscopy and biopsies. 94% demonstrated a positive diseasecourse. Only 6% of these patients had a relapse or developed highlymalignant lymphomas during the 34-month-follow-up (range:22– 44) [240]. The so-called watch-and-wait strategy is a good op-tion for hMR / MRD because of these positive data and the indolentnature of these lymphomas. Close follow-ups and a good patientcompliance are prerequisites for such a procedure.

9. The detection of translocation t(11;18)(q21;q21) is not man-datory outside of studies (Recommendation grade C, evidencelevel 3, strong consensus).Comment: The translocation t(11;18)(q21;21) is the most fre-quent cytogenetic aberration of MZBCL of MALT-type [241]. It isdetectable in 20–60% of the cases [242–245]. Its clinical signifi-cance became clear in a first analysis of 18 patients who had re-sponded to eradication therapy in stage I with complete lymphomaremission. In these patients translocation t(11;18) was not detect-able [246]. However, the majority of patients who did not reactwith CR to eradication therapy were positive for t(11;18) [244,247]. The translocation t(11;18) is a predictive marker for non-re-sponders to H. pylori eradication therapy, a higher lymphomastage, and an increased relapse rate [245, 248, 249]. The test oftranslocation outside of studies is, however, not mandatory, be-cause t(11;18) positive patients should also initially undergo aneradication therapy.

10. Radiation therapy with curative intent should be done forHelicobacter pylori negative gastric MZBCL of MALT-type or forfailure of eradication therapy in stage I and II (no completelymphoma remission except hMR/MRD – see V. 8.) (Recom-mendation grade B, evidence level 2a, consensus).Comment: About 5 to 10% of gastric MZBCL of MALT-type areH. pylori negative and also demonstrate no serologic antibodies.The role of eradication therapy for these H. pylori negative lym-phomas is currently controversial. Two large studies that analyzedpredictive factors for the response to eradication therapy showedthat H. pylori negativity is a negative predictor [227, 230]. A smallsingle center case series reported recently on 5 complete remissionsafter eradication therapy in 6 patients who were proven H. pylorinegative (also serologically) [250]. A general recommendation can-not be given because of the controversy and at the same timesparse data. However, in individual cases eradication therapy forH. pylori negative gastric MZBCL of MALT-type may be performed.In general, gastric MZBCL of MALT-type is sensitive to radiation.Radiation therapy should be done with curative intent in stages Iand II at a dose of 30–35Gy (involved-field) [214–216, 251–254]. Despite frequent therapy related nausea it is well toleratedand significant complications such as ulcers or bleeding are veryrare [255]. In addition, the risk of developing a secondary malig-nant tumor due to the radiation is very low [256, 257]. Thus, radia-tion therapy, alone or also in a multimodal therapy approach, is avery good curative option for gastric MZBCL of MALT-type in stagesI and II.


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11. Surgical therapy for gastric MZBCL of MALT-type should belimited to treating complications (Recommendation grade B, evi-dence level 2a, strong consensus).Comment: Despite excellent data on the overall survival for lym-phoma stage I surgical therapy is associated with high morbidity[258–260]. Several large multicenter studies clearly show that aconservative, organ-preserving treatment approach is not inferiorto surgical therapy [214, 215, 261, 262]. This explains why despitemissing prospective randomized studies surgical treatment in pri-mary disease management are not taken into consideration innewer therapy algorithms. They merely emphasize the importanceof surgery for the treatment of complications (e. g. perforation orendoscopic uncontrollable bleeding).

12. Chemotherapy should be done for gastric MZBCL of MALT-type stage > II2 (Recommendation grade B, evidence level 2a,consensus).Comment: To date no chemotherapy standard has been estab-lished for gastric MZBCL of MALT-type and data on curativetherapies are rare. Oral monotherapy using cyclophosphamide orchlorambucil shows complete remission rates of 82% to 100% andfor stage IV still 50% to 57% [263, 264]. Translocation t(11;18) is anegative predictor for therapy response [265]. Patients with a CRrate of 84% responded very well to cladribine or 2-chlorodeoxyade-nosine [2-CdA] in a phase-II study [266]. The t(11;18) status did nothave an affect on these therapy results [267]. The efficacy of oxali-platin was also evaluated. It showed an objective response rate(ORR) of 94% and a CR rate of 54% for gastric MZBCL of MALT-typeat different sites [268]. A translocation t(11;18) also had no effecton the therapy result. The efficacy data of rituximab for gastricMZBCL of MALT-type is controversial. The first phase-II study[269] as well as another retrospective trial [270] demonstratedan ORR of 64% and 50% with a CR of 29% and 33%, respectively. Ac-cording to the authors, the low rate of complete remissions was dueto the poor mucosa penetration of the antibodies. The results wereslightly better in a less heterogeneous cohort i.e. H. pylori negativegastric MZBCL of MALT-type : the ORR was 70% with a CR rate ofalmost 45% [271, 272]. The reported efficacy of rituximab therapywas independent of the translocation status t(11;18) [271, 273].

13. Gastric diffuse large B-cell-lymphoma (DLBCL) with andwithout MALT components should initially be treated withstandard (R)-CHOP plus/minus radiation (Recommendationgrade B, evidence level 2a, consensus).Comment: H. pylori infection is found in 35% of all gastricDLBCLs [274, 275]. The role of an eradication therapy as a curativeoption is controversial. Some retrospective studies and smaller caseseries show complete remission rates between 50 and 63% in theearly stage of disease [219–222]. The established standard therapyis polychemotherapy containing antracyclines preferably in combi-nation with the anti-CD20 antibody rituximab ((R)-CHOP proto-col) [215, 276, 277]. For confirmed H. pylori infection treatmentshould be accompanied by eradication therapy.

14. Helicobacter pylori is a significant risk factor for distal(non-cardia) gastric carcinoma (Recommendation grade A, evi-dence level 1a, strong consensus).Comment: The association between H. pylori gastric infectionand the risk of developing gastric carcinoma was demonstratedin animal experiments [278]. The risk is comparable for the intest-inal and diffuse type [279]. H. pylori was already classified as aclass 1 carcinogen by theWHO in 1994 [280]. The risk of carcinoma

development is also dependent on host [281], environmental [282],and bacterial virulence factors [283]. The dietary habits also con-tribute to the risk of developing cancer [284, 285]. H. pylori eradi-cation prevents progression and development of pre/paracancerouschanges such as intestinal metaplasia and atrophy [286]. Proximalgastric carcinoma has a different etiology than distal gastric carci-noma [287–289].

15. Helicobacter pylori eradication with the goal of gastric car-cinoma prevention is suitable for high risk patients (Recom-mendation grade C, evidence level 4, strong consensus).Comment: The frequency of pan-gastritis and/or corpus-domi-nant H. pylori gastritis in a population correlates with the gas-tric cancer risk [290]and a high risk population status [291]. Pa-tients with pan-gastritis or corpus-dominant H. pylori gastritishave a higher risk of developing gastric carcinoma than thosewith intestinal metaplasia or atrophy [292]. Corpus-dominantH. pylori gastritis is found significantly more often in gastric carci-noma patients [293], in 1st degree relatives of patients with gastriccarcinoma [294], and in patients with adenomas [295]and hyper-plastic polyps [296]. In general, eradication of H. pylori has the po-tential to prevent the development of gastric cancer [297]. The timeof treatment is crucial for the efficacy of H. pylori eradication toprevent gastric carcinomas [298]. It is especially effective if nopre/paraneoplastic changes such as atrophy or intestinal metapla-sia are present. Mass screening is probably not cost effective in Ger-many, because of the comparably low prevalence of H. pylori infec-tion and low incidence of gastric cancer [299]. The cost efficiency ofprophylactic H. pylori eradication increases if concomitantly H. py-lori-associated diseases are considered (stomach/duodenal ulcer,MALT-lymphoma).

16. Focal atrophy and intestinal metaplasia do not have to beendoscopically monitored (Recommendation grade B, evidencelevel 2a, consensus).Comment: Focal atrophy and intestinal metaplasia are histologi-cal diagnoses. They do not have to be endoscopically monitored,because the risk of cancer development is only slightly increasedcompared to pan-gastritis and/or corpus-dominant H. pylorigastritis [300].

V. Topic complex “Therapy of Helicobacter pyloriinfection”!

1. Before Helicobacter pylori infection therapy is started theremust be a generally accepted indication as well as a confirmedinfection (Recommendation grade D, evidence level 5, consensus).Comment: There is no gastroduodenal disease that is associatedto such a high percentage with H. pylori that infection confir-mation is not necessary. Meanwhile, this is also the case forduodenal ulcers [62, 63]. An exception to this recommendation isthe H. pylori negative early stage gastric MALT-lymphoma, becausein individual cases eradication can lead to lymphoma regressioneven if all H. pylori tests are negative (see IV. 10.).

2. If duodenal ulcer is detected endoscopically, a clearly posi-tive rapid urease test is sufficient to initiate eradication ther-apy (Recommendation grade D, evidence level 5, consensus).Comment: Since H. pylori infection is common in ulcer patientsthe urease test has a high predictive value and a corresponding-ly low probability of false positive results. However, in case of


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functional dyspepsia the infection should be confirmed by a val-idated complementary method, because otherwise unacceptablyhigh false positive results must be anticipated. This is due tothe low prevalence of H. pylori especially in young patients.

3. The sole serological detection of antibodies against Helico-bacter pylori or its virulence factors do not give enough infor-mation for a therapy decision (Recommendation grade D, evi-dence level 5, consensus).Comment: In individual cases it should be taken into considera-tion that if the probability of a H. pylori infection is low a priori(e.g. in Germany in children and young adults), a high rate offalse positive results must be anticipated (see II. 1.–5.). The ser-ology is often not validated and does not allow a statement asto whether an active infection is present or not.

4. The pretherapeutic resistance status of Helicobacter pylori isof great therapeutic relevance (Recommendation grade A, evi-dence level 1a, consensus).Comment: Accordingly pretreatments with antibiotics – also forother indications – should be taken into consideration whenchoosing a therapy regimen. Resistance to metronidazole signifi-cantly reduces the chance of a successful metronidazole basedtriple therapy. Based on a meta-analysis, the Italian triple-ther-apy (PPI, clarithromycin, imidazol) still remains effective in morethan 70% of treated patients. However, clarithromycin-resistanceis almost always associated with a complete effect loss of theItalian and French (PPI, amoxicillin, clarithromycin) triple-ther-apy. Pretherapeutic resistance against amoxicillin is extremelyrare. An efficacy loss must be anticipated if resistances againstso-called reserve antibiotics arise (levofloxacin, moxifloxacin,tetracycline, rifabutin) [300–304].

5. Efficacy factors of a Helicobacter pylori therapy that can beinfluenced are compliance, smoking, and the extent of acidsuppression (Recommendation grade B, evidence level 2b,strong consensus).Comment: This statement is based on explorative analyses ofclinical studies. Correct prescriptions, motivation to complywith treatment that is as easy to follow as possible, and givingup smoking are all measures that improve the success of treat-ment. Acid suppression must be chosen at a high enough level.The extent of acid suppression is crucial for the efficacy ofamoxicillin and clarithromycin. However, combination therapywith clarithromycin and metronidazole is less acid sensitive.Other factors that cannot be influenced are e.g. indication forH. pylori therapy or the patient’s age [305–319].Compliance can be positively influenced by giving detailed infor-mation on indications, treatment performance, and potentialside effects. The extent of acid suppression is determined bychoice, dose, and frequency of intake of proton pump inhibitors(PPI). In addition, it is determined by the genetic polymorphismof cytochrome-P450 2C19 (this is especially true for racemicomeprazol and lansoprazol; partially also for other PPIs). Kidneyand liver functions change with increasing age. Thus, individualsignificantly higher drug levels at equal doses can result (in-creased eradication success).

6. Helicobacter pylori testing should only be done if a positivetest result would also have therapeutic consequences (Recom-mendation grade D, evidence level 5, strong consensus).Comment: Positive test results without subsequent H. pyloritherapy is difficult to communicate in a doctor-patient-discus-sion. In addition, diagnostics without therapeutic consequencesare not economical. Prophylactic testing of the H. pylori statusfor indications (e.g. before starting ASS or NSAR therapy) thatmay become evident at a later time is not recommended, be-cause H. pylori infection should be detected shortly before start-ing treatment of this pathogen.

7. Absolute contraindications for Helicobacter pylori therapyare unknown (Recommendation grade D, evidence level 5, con-sensus).Comment: A relative contraindication for therapy always existsif the risk-benefit-ratio is not adequate. This is the case e.g. forconfirmed or suspected drug intolerance or allergy with a corre-spondingly increased therapy risk. Resolved pseudo-membranouscolitis is not a contraindication.However, the repetition of an already correctly performed ther-apy regimen that failed is contraindicated. A discrepancy withrespect to indications exists between the medical recommenda-tions in guidelines and the official approval status of drugs thatare used in eradication therapies (e. g. PPI is approved only forH. pylori eradication for ulcers) [314, 320].

8. Therapy regimens should be used that have reached an era-dication rate of at least 80% using intention-to-treat (ITT) ana-lyses in randomized, controlled therapy studies (Recommenda-tion grade D, evidence level 5, strong consensus).Comment: In certain clinical situations (e.g. multiple allergies,special resistance situations) deviation from this recommenda-tion is possible. Economic aspects with regard to therapy costsper day are only relevant if the therapy regimens are compar-ably effective. Otherwise, efficacy (eradication rate) has thehighest priority for the choice of the regimens, because the con-sequential costs (diagnostics, repeated therapy) are usuallymuch higher.This recommendation was first given in the Maastricht-recom-mendation. The 80% limit is artificial. Some licensing authorities(e.g. FDA) use other criteria. Recently, medical scientists havedemanded that only regimens with eradication rates of > 90%(ITT) should be prescribed. This goal is preferable, but currentlynot realistic, because of the drugs available, the approval statusof the authorities, and the poor compliance often seen in prac-tice [314, 319–321].

9. The rate of severe regimen side effects should be under 5%(Recommendation grade D, evidence level 5, consensus).Comment: For most infected patients H. pylori infection is a be-nign disease which can be treated with well tolerated regimensand few side-effects. In justified individual cases eradicationtherapy alternatives such as PPI-continuous therapy for ulcersexist. Thus, when considering the risk-benefit-ratio the morbidityrisk of H. pylori treatment must not be high.


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10. For initial treatment of H. pylori infection triple therapy con-sisting of PPI and clarithromycin plus metronidazole or amoxi-cillin should be administered for at least one week (!" Table 3)(Recommendation grade A, evidence level 1a, strong consensus).Comment: A reduction of therapy time under 7 days is not re-commended. The clinical benefit of a longer duration of therapyhas not been conclusively confirmed in Europe [302, 305, 316,319, 322–329].

11. For reasons of efficacy and tolerance therapy with clari-thromycin and metronidazole may be preferred (Recommenda-tion grade A, evidence level 1a, majority agreement).Comment: This recommendation is valid as long as the probabil-ity of metronidazole resistance of H. pylori is under 40%. If theresistance rate is higher, clarithromycin combined with amoxi-cillin is more effective.Therapy consisting of PPI, clarithromycin, and metronidazole(Italian therapy) is better tolerated than the French regimen(PPI, clarithromycin, amoxicillin). The primary resistance rate ofH. pylori to metronidazole in Germany is under 30% (data ofGerman Resinet-program). Thus, the Italian regimen should bepreferred. Earlier reservations against the Italian therapy as aprimary option are due to the high risk of inducing double resis-tances against clarithromycin and metronidazole if treatmentfails (in general under metronidazole mutation rates are highduring the course of therapy). This argument is still valid. How-ever, it has to be put into perspective because of the option of asecond line therapy based on sensitivity testing and effective re-serve therapy regimens. Exceptions to this recommendation arepatients who have definitely or probably had pretreatmentwith imidazol derivatives for other indications (see also V.4.)[314, 316, 327, 330–334].

12. As alternative first line protocols sequential therapies (PPIplus amoxicillin day 1–5 followed by PPI plus clarithromycinplus imidazol derivatives day 6–10) as well as quadruple-therapies without sequence build up may be considered (Re-commendation grade A, evidence level 1a, majority agree-ment).Comment: Present data which have mainly been collected in Ita-ly and to a small extent in Spain show about a 10% increase ofefficacy (ITT) of sequential therapy compared to standard tripletherapy using PPI, clarithromycin, and amoxicillin. This improve-

ment mainly affects patients who are infected with clarithromy-cin resistant H. pylori. Since this resistance is (still) rare in Ger-many compared to e.g. southern Europe, the superiority underlocal conditions must be proven before a general recommendationcan be made. So far, there is no meaningful randomized compara-tive study on the new sequential therapy compared to the Italiantriple therapy. Thus, the data are not yet sufficient to recommendthis form of therapy as standard for primary treatment. The impor-tance of this new option compared to the established triple therapyas first line therapy must be reevaluated during the course withfurther data.International recommendations or guidelines state quadruple-therapy consisting of PPI, bismuth salt, metronidazole, and tetra-cycline as another option. These forms of therapy are effective.However, they often have side effects and the implementationis complicated because of the large number of tablets that haveto be taken 4 times a day. In addition, scientifically establishedbismuth preparations are no longer commercially available inGermany. This therapy form still has certain validity as a re-serve option if there are no therapy alternatives [314, 335–339].

13. The medication should be taken before meals (Recommen-dation grade B, evidence level 2b, consensus).Comment: Formal endpoint studies (eradication success) on thisproblem do not exist for the recommended therapy schemes. Therecommendation is based, on the one hand, on the improved ef-ficacy of PPI if they are taken before meals and, on the otherhand, on the reduced demand on compliance if drugs (PPI andantibiotics) are taken together and not separately (e.g. PPI be-fore and antibiotics after meals) [340]. Furthermore, pharmaco-kinetic studies show a partially improved antibiotic resorption ifthey are taken on an empty stomach.

14. Acid suppressive pretreatment with PPI does not jeopar-dize therapy success (Recommendation grade A, evidence level1b, strong consensus).Comment: A previous explorative study on dual therapy consist-ing of omeprazol and amoxicillin demonstrated that pretreat-ment with omeprazol over 1 week has a poor eradication rate.A metaanalysis of randomized controlled study excluded PPI-pre-treatment as a significant negative influencing factor [340–342].

Table 3 Suitable therapy regi-mens for first line therapy of H. py-lori infection.

name day scheme dose

Italian TT 1 – 7 PPI3 1 – 0 – 11 – 7 Clarithromycin 250 – 500mg 1 – 0 – 11 – 7 Metronidazole 400 – 500mg 1 – 0 – 1

French TT 1 – 7 PPI1 1 – 0 – 11 – 7 Clarithromycin 500mg 1 – 0 – 11 – 7 Amoxicillin 1 000mg 1 – 0 – 1

Sequential therapy 1 – 5 PPI1 1 – 0 – 11 – 5 Amoxicillin 1 000mg 1 – 0 – 16 – 10 PPI1 1 – 0 – 16 – 10 Clarithromycin 500mg 1 – 0 – 16 – 10 Metronidazole 500mg 1 – 0 – 1

Quadruple-therapy 1 – 7 PPI1 1 – 0 – 11 – 7 Clarithromycin 250 – 500mg 1 – 0 – 11 – 7 Metronidazole 400mg 1 – 0 – 11 – 7 Amoxicillin 1 000mg 1 – 0 – 1

1 Esomeprazole 20mg, lansoprazole 30mg, omeprazole 20mg, pantoprazole 40mg, rabeprazole 20mg.


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The total extent of the acid secretion inhibition significantly andclinically relevantly affects the efficacy of H. pylori treatment.

15. Probiotics alone do not lead to Helicobacter pylori eradica-tion. Probiotic administration is not necessary in addition toan effective Helicobacter pylori therapy (Recommendationgrade A, evidence level 1a, consensus).Comment: Aside from a reduction of H. pylori colonization therate of side effects of the eradication therapy can be reducedwith probiotics. An increase of the eradication rate is possible.Probiotics can improve the efficacy of repeated therapy especial-ly in patients where previous eradication therapy has failed[343–345].

16. In adults in case of uncomplicated Helicobacter pylori posi-tive ulcer eradication therapy should be started immediatelyafter the diagnosis has been made (Recommendation gradeA, evidence level 1a, strong consensus).Comment: Studies in patients with acute H. pylori associatedduodenal or stomach ulcers are regularly performed accordingto the recommendations [346, 347]. Comparative data on the re-verse procedure – ulcer healing therapy first then H. pylori eradica-tion – do not exist. Another fact that argues for immediate initia-tion of treatment is that often several doctors are involved. WithPPI monotherapy during the course of ulcer healing eradicationtherapy is forgotten. This is because the information on the H. py-lori status is often lost when the treating physician changes.It is known that H. pylori increase the pH-raising effect of PPI.Thus, it is possible that in the presence of H. pylori PPI leads tofaster ulcer healing. This hypothesis is supported by the observa-tion that NSAR and H. pylori associated ulcers heal slightly bet-ter with PPI alone than after eradication therapy followed byPPI-monotherapy.If a genuine H. pylori ulcer is present i.e. intake of ASS and NSARcan reliably be excluded, especially uncomplicated small duodenalulcers heal after 1 week of triple-monotherapy i.e. PPI-monother-apy after the end of eradication therapy is not necessary. The dataon this topic are much sparser for stomach ulcers. Thus, a generallyvalid therapy recommendation – i.e. no PPI after finishing eradica-tion therapy – cannot be made.

17. For complicated Helicobacter pylori positive ulcers (e.g.bleeding) eradication therapy should be initiated after the pa-tient has started to eat again. An intravenous eradication ther-apy is not necessary (Recommendation grade D, evidence level5, strong consensus).Comment: Individual small studies indicate that H. pylori ther-apy can also be administered intravenously (omeprazol, amoxi-cillin, metronidazole). However, there is no medical necessity.The main therapy component for complicated ulcers is asidefrom necessary endoscopic therapies profound acid suppression.This does not significantly reduce the therapy success of oraleradication therapies. Thus, it can be resumed when the patientstarts eating again if the acute complications are under control[348].

18. In adults a second line therapy can be done without pre-ceding resistance testing if the first line therapy is taken intoconsideration (Recommendation grade A, evidence level 1a,majority agreement).Comment: In individual cases resistance testing before secondline therapy can be helpful. It can be an alternative to the

abovementioned procedure (see also II.7. and II.8.). Basic knowl-edge on the probability of inducing resistances after therapyfailure as well as the alternative antibiotics that are availablein modern H. pylori therapy often make resistance testing unne-cessary after the first therapy attempt. It must also be consid-ered that there is not always a close correlation between in vi-tro resistance and in vivo efficacy. For example, the Italiantriple-therapy is often still effective even if in vitro a resistanceto metronidazole exists. In these cases, it is still more effectivethan a sole dual therapy with PPI and clarithromycin [349].

19. The choice of the eradication protocol for second line ther-apy must take the antibiotics that were used for first line ther-apy into consideration including the probability of resistanceinduction and individual intolerances of the patient (!" Table 4)(Recommendation grade B, evidence level 2b, strong consensus).Comment: The therapy regimens that are available today do nothave to include bismuth preparations, which are no longer avail-able in Germany anyway.Amoxicillin almost never induces resistances. Therefore, it can berepeatedly used. The probability of inducing clarithromycin re-sistances after failure of a macrolide containing regimen is> 50%. Thus, resistance testing must be done before repeateduse. The probability of resistances against imidazols (metronida-zole, tinidazol) after unsuccessful pretreatment is extraordinarilyhigh. Therefore, these drugs are only very rarely considered forrepeated use.Reserve antibiotics that can also be combined with amoxicillinand clarithromycin or with one another are modern chinolones(levofloxacin, moxifloxacin) and rifabutin. Even if there are noformal studies on this topic, it is recommended to extend the

Table 4 Recommended second line therapy (empirical without resistanceassessment).

first line

therapy

day scheme dose

Italian TT/sequentialtherapy

1 – 10 PPI1 1 – 0–1

1 – 10 Amoxicillin 1 000mg 1 – 0–11 – 10 Levofloxacin 500mg 1 – 0–0

(Penicillin allergy: rifabutineinstead of amoxicillin)

1 – 10 PPI1 1 – 0–11 – 10 Amoxicillin 1 000mg 1 – 0–11 – 10 Rifabutin 150mg 1 – 0–1

French TT 1 – 10 PPI1 1 – 0–11 – 10 Amoxicillin 1 000mg 1 – 0–11 – 10 Levofloxacin 500mg 1 – 0–0

(Penicillin allergy: rifabutin in-stead of amoxicillin)

1 – 10 PPI1 1 – 0–11 – 10 Amoxicillin 1 000mg 1 – 0–11 – 10 Rifabutin 150mg 1 – 0–11 – 10 PPI1 1 – 0–11 – 10 Amoxicillin 750 – 1 000mg 1 – 1–11 – 10 Metronidazole 400 – 500mg 1 – 1–1

all schemes 1 – 14 PPI2 40mg 1 – 1–11 – 14 Amoxicillin 750 – 1 000mg 1 – 1–1

1 Esomeprazol 20mg, lansoprazol 30mg, omeprazol 20mg, pantoprazol40mg, rabeprazol 20mg.

2 Only studies on esomeprazole and omeprazole exist.


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duration of therapy to 10 days during second line therapy. Allprocedures on therapy optimization should be used such as com-pliance, no smoking, optimal acid blocking, and antibiotic dosesat the upper limit that is allowed.Other reserve options are PPI, amoxicillin, and metronidazoleafter failure of the French triple therapy, high dose dual therapy(PPI 3!40mg+amoxicillin 3!750–1000mg) over a period of14 days, as well as bismuth containing quadruple-therapy (PPI+ bismuth subcitrate or –subsalicylate + metronidazole + tetra-cycline) over a period of 7–10 days. Aside from the two testedbismuth preparations, ranitidin-bismuth citrate and furazolidonplay some role internationally in the therapy of H. pylori [350–353]. However, they have not been approved in Germany.

20. After the second Helicobacter pylori therapy failure, thepatient must be presented to a specialist for further individu-alized therapy (Recommendation grade D, evidence level 5,majority agreement).Comment: The specialist can be an internist or gastroenterologistwho has sufficient experience with H. pylori therapy indications,therapy implementation including the control of complications,sample collection for resistance testing including interpretation ofthe results, and the differential choice of reserve regimens. It is re-commended that specialists monitor and in certain intervals, forexample once a year, evaluate the quality and the results of theresistance testing in cooperation with the microbiology laboratorythat they work with.

21. The therapy success must be checked in case of an ulcer orMALT-lymphoma. Eradication success should also be checkedfor other therapy indications (Recommendation grade A/B, evi-dence level 1a/2a, strong consensus).Comment: Ulcer disease can lead to life threatening complica-tions that can often be avoided by eradication therapy. There-fore, it is necessary to check the success of the H. pylori therapyusing suitable methods. For uncomplicated duodenal ulcers theycan be a non-invasive breath or stool test. For complicated duo-denal and stomach ulcers a control endoscopy is always neces-sary. It should be timed so that the success of the eradicationtherapy and the healing of the ulcer can be checked at thesame time.For MALT-lymphoma eradication check using invasive test meth-ods (during obligatory endoscopy, which has to be done any-way) is mandatory, because if eradication is not successful, pro-gression of lymphoma is possible. Therapy alternatives areavailable.It is recommended to also check the success for other therapyindications, because persistent H. pylori infection has prognosticrelevance, patient compliance will likely be increased by sys-tematic planning of controls, and the physicians will keep anoverview of the efficacy of the implemented eradication therapy(quality aspect).

22. The period between the end of the antibiotic therapy andthe assessment of treatment eradication success must be atleast 4 weeks (Recommendation grade B, evidence level 2a,strong consensus).Comment: If the period between the end of the antibiotic ther-apy and the assessment of the treatment success is less than 4weeks, “negative bacterial results” cannot be sufficiently inter-preted. This is because it may be a mere suppression of the bac-teria under the detection level and not a permanent elimination

( = eradication). In this case false conclusions for the further dis-ease course would result (see II. 4.).

23. The period between the end of PPI-treatment and reliableassessment of eradication success must be at least 2 weeks(Recommendation grade B, evidence level 2a, consensus).Comment: If the interval is shorter, PPI can cause up to 80%false negative results, because they lead to a suppression ofH. pylori. H2-receptor antagonists taken once a day or antacidsgenerally do not lead to false negative results (see II. 4.).

24. Patients with MALT-lymphoma, duodenal ulcers with com-plications, and stomach ulcers must have a control endoscopy.In this case therapy control should be a combination of aurease test and histologies of antrum and corpus biopsies (Re-commendation grade B, evidence level 2a, consensus).Comment: If an endoscopy has to be done anyway, a combina-tion of a urease-test (1 biopsy from the antrum and corpuseach) and the histology of 2 antrum and 2 corpus biopsies (ifnecessary including specific staining) is recommended for clini-cal routine. If locally available and with corresponding micro-biologic expertise, bacterial culture diagnostics are also an alter-native.

25. If a control endoscopy is not necessary, eradication controlmay be done using a 13C-urea breath test or a monoclonal an-tigen stool test (Recommendation grade B, evidence level 2a,strong consensus).Comment: If there is no indication for another endoscopy, a 13Curea breath test or a monoclonal antigen stool test would be acomparable option. Serologic results would only be useful ifcompared to pretherapeutic tests with an identical kit a signifi-cant titer reduction (by more than 50%) is detected. It can takeup to one year until such a decline is measurable. In some pa-tients it is never detectable despite successful eradication ther-apy. Therefore, serology as a clinical follow-up control is not re-commended (see II. 1. to II. 3.).

26. A routine search for Helicobacter pylori reinfection shouldnot be done if the primary eradication control was done cor-rectly (Recommendation grade B, evidence level 2a, strongconsensus).Comment: Data from developed countries indicate a small rein-fection probability (< 1% per year) if “eradication” was doneusing recommended treatments (see above), the success of eradi-cation was checked using reliable methods at least 4 weeks aftercompletion of antibiotic therapy, and factors influencing e.g.bacterial suppression by PPI at the time of diagnostic testing wereexcluded (see I. 2. and I. 7.). If these procedures are done, a routinecontrol is not recommended. In case of “vital” indications (e.g. sta-tus following ulcer bleeding, MALT-lymphoma) reassessment of the“permanent eradication” e.g. after one year is definitely useful.

VI. Topic complex “Characteristics of Helicobacterpylori infection in children and adolescents ”!

Preliminary remark: Differences in H. pylori infection betweenchildren and adults are prevalence, complication rate, absenceof malignant tumors due to infection in the first two decadesof life, special problems with diagnostic tests, and therapywith a higher primary resistance rate against macrolides and


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almost no reserve antibiotics because of restricted approval orcontraindications [354]. Differential diagnoses based on ab-dominal symptoms are different in children than adults. In ad-dition, children up to the age of 8–12 years often cannot giveprecise information on location and character of the pain. Theevidence is frequently poorer for children and adolescentsthan for adults. Randomized placebo-controlled studies onlyexist for few problems and only for small case numbers[355]. Some diseases in adults that are associated with H. py-lori infections such as idiopathic thrombocytopenia purpuraare not related to H. pylori status in children and probablyhave a different pathogenesis. These and other differences ex-plain why recommendations for children and adolescents withH. pylori infection deviate in some points from those for adults[355, 356].

Which children or adolescents should be examined forHelicobacter pylori infection?1. Invasive or non-invasive diagnostic tests for Helicobacter py-lori infection should only be done in children and adolescentsif in case of a positive result therapy is planned (Recommenda-tion grade C, evidence level 4, strong consensus).Comment: In Germany non-invasive tests are easily availableand their costs are covered by health insurance. Therefore, thethreshold to use these tests also for unspecific symptoms suchas periumbilical abdominal pain or asymptomatic children andsiblings of infected persons is very low. A positive test result im-plies that the parents and patients must be informed of the re-sults. The potential risk and costs of such further diagnostics (in-cluding upper endoscopy) and therapy are only justifiable if thechild directly benefits from such measures. This risk-benefit-ratiomust be evaluated differently in children and adolescents thanin adults.Complications of H. pylori infection especially ulcers are muchless frequent in children than adults. This may be due to theduration of infection, but more likely to the absence of other ul-cer risk factors such as alcohol, smoking, and use of non-steroi-dal antiphlogistics. A large European multicenter study in 1180H. pylori infected children who had upper endoscopies becauseof abdominal symptoms showed that only 80 (6.8%) had duode-nal or stomach ulcers [357]. MALT-lymphomas due to H. pylori in-fection or gastric carcinoma are extremely rare in the first two dec-ades of life if other primary diseases such as immune deficienciesare absent [358]. However, complications of eradication therapyin the form of gastrointestinal symptoms especially antibiotic-as-sociated diarrhea are common [359]. “Blind” therapy which is notbased on an antibiogram has a high risk of failing and at the sametime of inducing resistances to antibiotics. Since there are hardlyany reserve antibiotics available indications for anti-H. pylori ther-apy and, thus, also initial diagnostic testing should be stringent.

2. Asymptomatic children and adolescents should not havenon-invasive diagnostic tests for Helicobacter pylori infectionsmerely because persons living in their household have orhave had a Helicobacter pylori infection (Recommendationgrade C, evidence level 4, strong consensus).Comment: The individual benefit of non-invasive tests with sub-sequent eradication therapy if the result is positive is limited inasymptomatic children or adolescent to risk reduction of possi-ble later complications. As described under VI.1. infection com-plications in children and adolescents are rare. The reassuringeffect of a negative test result may be another potential benefit.

However, a positive result bears the risk of inducing anxiety inthe child and parents. Since the indication for upper endoscopyin asymptomatic children is not ethical only a “blind” tripletherapy can be considered. Eradication rates of “blind” tripletherapies of 70– 80% on average even under study conditionsin children are unacceptably low [360]. Outside of studies theywere even lower [361].The benefit of treating infected members of a household with thegoal to keep the risk of reinfection for an index patient low iscontroversial. Altogether, the reinfection rate in children andadolescents in Germany of 2.3% per year is low [362]. An Irishstudy confirmed the low reinfection rate of only 2% per year eventhough 81% of the children had at least one parent who was infec-ted and 2/3 had an infected sibling [363].

3. Relapsing abdominal pain in children and adolescents aloneare not an indication for a non-invasive test for Helicobacterpylori infection (Recommendation grade B, evidence level 2b,consensus).Comment: Relapsing abdominal pain in children and adolescentsare frequent. The exact prevalence is not known. Its causes aremanifold and are usually functional symptoms [364]. The defini-tions of abdominal pain in children in various studies are very dif-ferent [365]. Children under 8 years or even under 12 years of ageare often not capable of giving exact information on severity, char-acter, and localization of pain [366]. In an American study 13% ofthe 12– 13-year-old and even 17% of the 16-year-old students re-ported that they had weekly abdominal pain [367]. Relapsing ab-dominal pain defined according to Apley [368] including restric-tion of daily routine was found in 13% of unselected Swedishschool children age 10 to 12 years [369].The importance of H. pylori positive gastritis as the cause forabdominal pain in children is still controversial. In case-con-trol-studies unvalidated diagnostic tests were partially used forH. pylori diagnostics, an ulcer was not endoscopically excluded,in some studies the case numbers were very small, and possibleinfluencing factors were not taken into consideration and/orwere not adjusted for [370–372]. In Germany H. pylori infectionis mainly found in children of immigrants, who perceive and reportabdominal pain differently. This is due to language problems and adifferent cultural context. In addition, other causes of relapsing ab-dominal pain such as adult forms of hypolactasia are more com-mon in children from Southern Europe, Asia, or Africa.In studies with an influence factor-adjusted analysis on 945German [373] and 695 Swedish children [369] a positive associa-tion was no longer found between relapsing abdominal pain andH. pylori status. In some of the studies unspecific abdominal painwas also significantly less frequently found in H. pylori positivechildren [369]. In a study of 1221 children living in Germany Bodeet al. showed that relapsing abdominal pain was associated withsingle parents, positive family history for dyspeptic symptoms, butnot with H. pylori infections in these children [372]. In a meta-ana-lysis of 45 studies there was no association between H. pylori infec-tion and relapsing abdominal pain [374]. In addition, no specificsymptom pattern was found in H. pylori infected children com-pared to H. pylori negative children with abdominal pain [375,376].Uncontrolled intervention studies showed an improvement ofsymptoms after eradication therapy [377–379]. However, the re-sponse rate of children with abdominal pain to placebo was veryhigh and the success of the bacterial eradication was not examinedin some studies [377, 380, 381]. The improvement of symptoms


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was similar in children with treatment failure and in children withsuccessful eradication therapy [379]. The only randomized place-bo-controlled study in 20 symptomatic children with H. pylori in-fection and endoscopically excluded ulcers demonstrated no differ-ence between placebo and verum group with regard to symptomimprovement during the 12-month follow-up. In the verum groupimprovement was independent of whether bacterial eradicationwas successful or not [382]. In conclusion, after exclusion of an ul-cer there is no evidence that H. pylori infection in children is thecause for relapsing abdominal pain.

4. If upper gastrointestinal endoscopy is done in children withsevere upper abdominal pain, biopsies for histology should betaken. In addition, if a Helicobacter pylori infection is suspec-ted, a rapid urea test and bacterial culture should be done (Re-commendation grade C, evidence level 4, strong consensus).Comment: The goal of an upper endoscopy in children with se-vere upper abdominal pain or dyspeptic symptoms is the searchfor or the exclusion of organ diseases. Biopsies from the duode-num and stomach are standard, because even with normal mac-roscopic results the histology can indicate primary diseases. Ifthe histology of stomach biopsies shows a H. pylori infection,the parents and perhaps the patient must be informed aboutthe results. In this situation treatment will be offered (seeVI.13.). Bacteria should be cultured if a H. pylori infection is sus-pected so that an antibiogram-based therapy is possible (seeVI.15.).H. pylori infection in childhood and adolescence is often visuallydiagnosed by the endoscopist, because up to 80% of infected chil-dren have mucosal nodularity in the antrum (so-called goosebumps). Nodularity is more pronounced if bacterial density andgastritis activity is high [383–385], but independent of the pre-sence and severity of symptoms [386]. Since antral nodularity is re-latively specific for H. pylori positive gastritis it allows the exami-ner to take targeted additional biopsies for bacterial culture. Tosave costs of negative cultures of non-infected children an addi-tional biopsy for a rapid urease test that is readable within anhour may be taken. The biopsy immersed in transport medium isonly sent to the microbiology laboratory if the quick test is positive.

5. If other causes have been excluded (occult blood loss, celiacdisease, parasite infection), an examination for Helicobacterpylori infection in children and adolescents with refractoryiron deficiency anemia should be done (Recommendationgrade B, evidence level 2b, strong consensus).Comment: Iron deficiency anemia in children and adolescentscan have numerous causes. If the cause cannot be found withnon-invasive diagnostic tests and/or iron deficiency anemia isrefractory to oral iron administration, an endoscopy is indicated.In this case, stomach biopsies should be taken for histology, arapid urease test, and bacterial culture, because in some casesH. pylori infection can be the cause of refractory anemia [387,388]. The patients with anemia as a complication of H. pylori gas-tritis described in the literature often had no gastrointestinalsymptoms [389]. Anemia improved after bacterial eradicationalso without iron administration in some subjects [390]. A Turkishstudy in 140 children age 6 to 16 years also showed that anemiaand iron status improved after bacterial eradication monotherapywithout iron administration [391]. However, this positive effect ofbacterial eradication was not demonstrated in all studies on H. py-lori infected children with iron deficiency anemia [392].

6. There is no confirmed evidence that Helicobacter pylori in-fection causes sudden infant death syndrome (SIDS), otitismedia, chronic urticaria, idiopathic thrombocytopenic purpura,microsoma, or food allergies in childhood or adolescence (Re-commendation grade D, evidence level 5, consensus).Comment: Studies that showed a positive correlation betweenthe abovementioned extragastrointestinal diseases and H. pyloriinfection in infants and children were of very different quality.So far, prospective intervention studies that demonstrate or ex-clude a causality of H. pylori infection for these extraintestinalmanifestations do not exist.In part questionable methods were used for the H. pylori status[393, 394] so that the study results and conclusions were stronglychallenged [395, 396]. Since H. pylori infection is more frequent inpopulations with low social structure, the analysis must be socialstatus-adjusted. In addition, the analysis must be adjusted for in-fluencing factors that are associated with low social status. This in-cludes pre- and postpartum exposure to passive smoke, weight atbirth, postpartum diet, and parents’ height [397]. These factorswere not considered in most of the studies on growth retardation[398, 399], sudden infant death syndrome [393], or respiratory in-fections [400].

Which diagnostic tests are suitable?For studies on non-invasive diagnostic tests before initial ther-apy to be qualitatively high ranking two invasive diagnosticmethods are required as reference standards. All applied inva-sive methods must be negative for the status to be H. pylori ne-gative. To confirm the infection two tests or bacterial culturemust be positive. For non-invasive tests after therapy the refer-ence standard is a 13C-urea breath test. It should be done atleast 4 weeks after completion of drug treatment. Other qualitycriteria for diagnostic tests are the number of H. pylori positiveand negative children in the different age groups (toddlers andpreschool children, school children, school children age 6 to 12years, and adolescents age 13 to 18 years) studied.

7. In children and adolescents the 13C-urea breath test is suita-ble for non-invasive detection of Helicobacter pylori infectionand for monitoring therapy success (Recommendation gradeA, evidence level 1b, strong consensus).Comment: The 13C-urea breath test was compared to an estab-lished reference standard in numerous pediatric high qualitystudies on children and adolescents before and after treatment[401–405]. The test shows a consistently high accuracy with a sen-sitivity and specificity of > 95% despite high variability of tracerdose and application, test meal, fasting time, type and time ofbreath sampling, method of breath gas analysis, and determinationof limits [406]. The test should be done on an empty stomach i.e. atleast 3 hours after the last meal. The tracer should be taken with anacidic beverage (apple or orange juice, citric acid solution) andchased with pure test solution. The breath test shows a clear depen-dence on age with lower specificity for infants, toddlers, and schoolchildren [401, 403, 407]. False positive values in this age group re-sult from the low distribution volume in young children and ureasepositive bacteria in the mouth [407]. A high specificity can also beachieved in young children if special care is taken when doing thetest and by correcting for the CO2 production rate [408]. Antibioticsand acid suppressing drugs especially proton pump inhibitors im-pair the test accuracy and should be discontinued 4 and 2 weeks,respectively, before testing [409, 410].


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8. Of the currently available stool tests only the ELISA based onmonoclonal antibodies is suitable for non-invasive diagnosticsand therapy control of Helicobacter pylori infection in childrenand adolescents (Recommendation grade B, evidence level 1 or2 [after therapy], consensus).Comment: Stool tests are based on H. pylori antigen or DNA de-tection in feces. They are especially suited for children under6 years of age and disabled children and adolescents, becausecooperation of the patient is not necessary. The stool tests werethe only non-invasive measures that showed no age-dependencein children in high quality studies [411–414]. Thus, results fromstudies in adults can be extrapolated for the use in children. This isespecially necessary for post-therapy studies, because so far onlysmall case numbers of H. pylori positive children exist [413].A systematic review with meta-analysis of studies in childrenand adults showed a significant superiority of the monoclonalantibody ELISA compared to the commercially available polyclo-nal antibody ELISA [415]. The former is also available in Germany.Furthermore, a poor sensitivity and reproducibility due to batchvariability was shown in pediatric studies with polyclonal anti-body tests done in Germany and Austria [416, 417]. Sensitivityand specificity are comparable before and after therapy for themonoclonal ELISA and the 13C-urea breath test. As for the polyclo-nal ELISA, the following stool tests cannot be recommended becausethey are not suited or not sufficiently validated: so-called quicktests (immunochromatographic methods) [413, 418] as well asPCR-based procedures [417, 419].

9. Methods that detect specific antibodies against Helicobacterpylori in serum, whole blood, urine, or saliva are not suitablefor diagnostics of the infection in children (Recommendationgrade B, evidence level 2b, strong consensus).Comment: The detection of specific antibodies using ELISA or im-munoblot is less sensitive for children in the first decade of lifethan in adolescents or adults [420–422]. This is the case for IgGantibody tests and even more so for IgA based ones, which onlyidentify 20–50% of the H. pylori infected children [421]. Althoughnewer ELISA-tests or immunoblot procedures are better, they can-not reach the sensitivity of the 13C-urea breath test or the mono-clonal stool test [403, 423–425]. Quick tests using whole blood,serum, or urine are completely unsuitable.

10. Before treating children and adolescents for Helicobacterpylori infection resistance testing based on pathogen cultureand antibiogram should be done (Recommendation grade B,evidence level 2b, strong consensus).Comment: Since many reserve drugs for eradication therapysuch as bismuth salts, tetracycline, gyrase inhibitors, and rifabu-tin have not been approved or are contraindicated for children,it is even more important than for adults that the first therapyreach an eradication rate that is as high as possible. One ormore therapy failures are particularly stressful for children: in-duction of anxiety, perhaps another endoscopy to isolate biopsiesin case of unclear resistance, and other therapy cycles with theirside effects.The success of the therapy depends especially on the sensitivityof the pathogen to the applied antibiotic, dose and duration oftreatment, and compliance. A resistance to clarithromycin ishighly predictive of therapy failure if clarithromycin is part ofthe therapy regimen [426]. Investigations on antibiotic resistanceof H. pylori showed large differences in various populations. A Eu-ropeanmulticenter study in 1037 children and adolescents showed,

that before the first therapy children from southern Europe hadclarithromycin resistant bacteria more often than children fromnorthern, eastern, or middle Europe (adjusted OR2.25, 95%CI1.3–3.3) [357]. Within a geographic region younger children(< 6 years) were significantly more often infected with clarithor-mycin-resistant strains. A preceding monotherapy with new gen-eration macrolides for other indications e.g. airway infections in-crease the chance that mutants with macrolide resistances exist inH. pylori infected patients. In German children that were includedin the study 20% showed a primary clarithromycin resistance. Thisis a significantly higher percentage than in studies on Germanadults [427, 428]. Metronidazol resistances were seen more oftenin children that were born in Asia or Africa (adjusted OR 2.42,95% CI1.6–3.7). The high resistance rate against clarithromycinexplains why clarithromycin based triple therapies are less effec-tive in children than in adults [360, 361, 429]. Data from the Eur-opean therapy register which include 19 participating clinics showthat primary pathogen eradication therapy using a combination ofPPI, amoxicillin, and clarithromycin was successful in only 60.5% ofthe children. Using a combination of PPI, amoxicillin, and metroni-dazole the eradication rate was 66.7% [361]. However, if the tripletherapy was based on an antibiogram, eradication can be achievedin > 90% of the cases [430].Culturing of the bacteria from a gastric biopsy with subsequentresistance testing is currently the procedure of choice. Clarithro-mycin resistances can be determined molecular genetically withhigh accuracy by directly detecting mutations in fresh or paraf-fin embedded gastric biopsies with fluorescence in situ hybridi-zation (FISH) [431, 432]. The detection of clarithromycin resistantmutants using real time PCR in feces still has low sensitivity [66].

Who should be treated?11. Children and adolescents with confirmed Helicobacter py-lori infection and the following complications must have pa-thogen eradication: stomach and duodenal ulcers, MALT-lym-phoma (Recommendation grade B, evidence level 2b, strongconsensus).Comment: Peptic ulcers and MALT-lymphoma are serious, poten-tially lethal complications of H. pylori infection. In children andadolescents placebo controlled therapy studies are not allowedfor ethical reasons, because intervention studies in adultsshowed a significant benefit of bacterial eradication for healingand relapse rate of peptic ulcers (see III.1., IV.6.–7.). If the patho-gen is not eradicated, H. pylori induced ulcers often recur [433].If an ulcer or MALT-lymphoma is detected in H. pylori infected chil-dren or adolescents, it is not enough to initiate anti-H. pylori ther-apy. It is also necessary to ensure that pathogen eradication wassuccessful with corresponding follow-up tests.

12. Children and adolescents with confirmed Helicobacter pyloriinfection and the following complications should have pathogeneradication: erosive gastritis and duodenitis, iron deficiency ane-mia, ulcer or gastric carcinoma in 1st degree relatives (Recom-mendation grade C, evidence level 3, consensus).Comment: Erosive gastritis or duodenitis may be precursors ofpeptic ulcers and can be the cause for occult blood loss. Insome cases iron deficiency anemia after excluding other causescan be the result of an H. pylori infection (see VI. 5.). If a 1st

degree relative (parent or sibling) has had an ulcer or gastriccancer, the risk of the infected child for sequelae is increased.Certain pathogenic factors of H. pylori predispose for ulcers orcancer. Children usually acquire the pathogen within the family


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[434]. Their risk of complications due to H. pylori infection is highernot only because of highly pathogenic bacteria but also because ofgenetic predispositions or environmental factors that they sharewith relatives that have ulcers or gastric cancer.

13. An eradication therapy should be done in children and ado-lescents with endoscopically confirmed Helicobacter pylori in-fection without ulcers/erosion (Recommendation grade C, evi-dence level 3, consensus).Comment: The parents and patients must be informed of the re-sults if an H. pylori infection was detected during upper endo-scopy as part of diagnostic clarification in children and adoles-cents. Even if there is no evidence that H. pylori gastritis causespain in the absence of an ulcer, eradication therapy should beoffered. The advantages and disadvantages of the procedureshould be discussed. The knowledge of the infection induces fearof later complications in some parents and children. Fear mayenhance functional symptoms. In the end it cannot be excludedthat an ulcer that has developed as a result of the infection isresponsible for later stomach pain episodes. Parents usually de-cide on a therapy for their children. Therefore to reach a higheradication rate, if visible nodularity is present in the antrumor during endoscopy to clarify upper stomach symptoms, a biop-sy should be taken for bacterial culture (see VI.4. and VI.10.).

14. A test-and-treat-strategy i.e. screening with a non-invasivetest for Helicobacter pylori and eradication therapy in case ofpositive test results should not be done in symptomatic childrenand adolescents (Recommendation grade C, evidence level 3,consensus).Comment: The goal of diagnostic clarification in symptomaticchildren is to identify the cause for the symptoms and not toconfirm or exclude a H. pylori infection. As explained in recom-mendation VI.3. the relationship between H. pylori gastritis andabdominal symptoms is not confirmed. A test-and-treat-strategyhas the risk of over-treatment of children with functional symp-toms in populations with high infection prevalence (immi-grants). There is also the problem of low eradication rates with“blind” therapy. However, organic diseases that are responsiblefor the symptoms would be identified with delay especially inpopulations with a high prevalence. The test-and-treat strategyis not cost efficient in populations with low H. pylori prevalence(< 5%) and low ulcer rates. To identify a child with H. pylori in-duced ulcer > 200 children would have to be tested with a highlysensitive diagnostic test.

15. An eradication therapy does not have to be repeated inchildren and adolescents with only Helicobacter pylori gastri-tis, who continue to be infected after therapy but are asymp-tomatic (Recommendation grade C, evidence level 4, strongconsensus).Comment: As described in VI. 3. ulcers are even found in < 10%of children who have endoscopy because of symptoms [357].H. pylori infection may be a coincidence in children with functionalsymptoms or organic diseases. Open and controlled therapy studiesshowed that the symptoms in children decrease or subside aftereradication therapy independent of whether the eradication wassuccessful or not [382]. The question how to handle symptom-freechildren whose eradication therapy has failed is very controversialand is dealt differently by doctors. Advantages and disadvantagesof repeated therapy must be discussed with the parents and pa-tients. The choice of the antibiotic combination for repeated ther-

apy depends on the previous therapy regimen and the resistancetesting before failed treatment. Another endoscopy for the sole pur-pose of taking a biopsy for bacterial culture is usually in poor rela-tion to the risk-benefit or costs.

How should Helicobacter pylori infection be treated inchildren and adolescents?16. A one week triple therapy of PPI plus amoxicillin and eitherclarithromycin or metronidazole at a sufficiently high dose andaccording to the results of the antibiotic sensitivity test is thetherapy of choice for children and adolescents with confirmedHelicobacter pylori infection (Recommendation grade B, evi-dence level 2b, strong consensus).Comment: An eradication rate of > 90% can be reached with aone week triple therapy based on an antibiogram if there is nodouble resistance to clarithromycin and metronidazole [430]. Foramoxicillin 50mg/kg body weight and for clarithromycin and me-tronidazole 20mg/kg body weight each given in 2 doses is consid-ered a sufficiently high daily dose with in vitro sensitive pathogens.The success rate is not expected to improve if the duration of treat-ment of a sensitive pathogen is longer.

17. If results of an antibiotic sensitivity test are missing, thepatient should be treated for 1–2 weeks with PPI/amoxicillin/clarithromycin, PPI/amoxicillin/metronidazole, or PPI/metroni-dazole/clarithromycin. The therapy that is chosen should takeprevious therapies and a child’s country of origin into consid-eration (Recommendation grade B, evidence level 2b, consen-sus).Comment: As described in VI.10. the risk of children in Germanyto be infected with a clarithromycin-resistant pathogen is 20%[357] and in Austria even higher [435]. The risk is especially highif the child has already been treated with a new generation macro-lide for another indication. The failure rate is expected to be high forblind triple therapy that includes clarithromycin. This is so regard-less of whether amoxicillin or metronidazole is used as a secondantibiotic [361]. If PPI is administered with amoxicillin and clari-thromycin, a 2-week treatment seems to have no advantage com-pared to a 1-week treatment [361]. However, randomized com-parative studies do not exist. A combination of PPI withclarithromycin and metronidazole only showed a medium successrate of 63% in studies other than from Canada [360]. In childrenwhose families have not immigrated from Asia or Africa a combi-nation of PPI, amoxicillin, and metronidazole for 2 weeks seems tobe the most successful choice if resistance testing is missing. An invitro resistance to metronidazole can be overcome in vivo in a highpercentage of patients by longer and higher dose applications[428]. Therefore, a 2-week therapy is recommended if triple ther-apy includes metronidazole.In a randomized Italian study in 75 children sequential therapy(omeprazol plus amoxicillin for 5 days followed by 5 days ofomeprazol plus clarithromycin plus tinidazol) was compared toa 1-week therapy with omeprazol, amoxicillin, and metronida-zole [436]. The eradication rate was significantly higher with thesequential therapy than with the triple therapy (97.3% vs. 75.7%,respectively, p < 0.02). A prospective study should clarify whetherit [437] is also a better alternative for children living in Germany.


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18. For Helicobacter pylori infection with a pathogen that is re-sistant to clarithromycin and metronidazole an individual ther-apy decision must be made depending on the child’s age andthe resistance results to reserve antibiotics (Recommendationgrade C, evidence level 3, strong consensus).Comment: So far there are no published studies on the treat-ment of children and adolescents who are infected with a patho-gen that is resistant to metronidazole and clarithromycin. Tetra-cycline can be used for children over 12 years of age. As foradults a high dose therapy with a dual therapy of PPI andamoxicillin [438] or a triple therapy plus metronidazole can alsobe attempted. The doses have to be adjusted to the body weight ofthe child. For children from countries with a high prevalence of tu-berculosis H. pylori eradication therapy should not be treated withRifabutin.

19. Success of eradication should be checked with a non-inva-sive test 4 weeks at the earliest after discontinuation of PPIand antibiotics (Recommendation grade C, evidence level 4,strong consensus).Comment: Eradication success should be checked even if childrenare free of symptoms after therapy, because the absence ofsymptoms does not mean successful treatment. A control ismandatory for complicated H. pylori infections (see VI. 11), be-cause eradication failure would mean another therapy attempt.Suitable tests for therapy control are 13C-urea breath tests andthe stool test based on monoclonal antibodies. Both tests can befalse negative [439] under acid suppression and antibiotic admin-istration. Therefore, the interval of the last medication intake mustbe at least 4 weeks.

20. Endoscopic control should only be done after complicatedulcers, if other differential diagnoses are suspected as causal(e.g. eosinophilic gastroenteropathy, Crohn’s disease) or ifbiopsies are necessary for bacterial culture (Recommendationgrade C, evidence level 3, strong consensus).Comment: After successful eradication relapsing ulcers are veryrare in children [440]. This is similar to adults. Repetition of endo-scopy is not necessary if the non-invasive test is negative and thereare no symptoms. If there are indications due to the anamnesis, his-tology, or other tests that other organic diseases are the cause of theulcer, an endoscopic follow-up examination should be done inde-pendent of the H. pylori status.

21. The antibiotic resistance situation of Helicobacter pyloristrains in children and adolescents in Germany should be mon-itored (Recommendation grade: not applicable, evidence level:missing, strong consensus).Comment: In the last 15 years an increase in primary clarithro-mycin resistance of H. pylori strains was seen [435, 441]. Even iftherapies that are based on an antibiogram are first choice, it willalways be the case that for various reasons no antibiogram isavailable. Therefore, the information on the resistance status ofH. pylori strains from children living in Germany is important.

VII. Topic complex “Gastroduodenal ulcer diseases notassociated with Helicobacter pylori ”!

Preliminary remark: Causes aside from Helicobacter pylori in-fection can also lead to gastroduodenal ulcers. An importantone is the use of traditional non-steroidal antirheumatics

(tNSAR). Numerous studies on tNSAR-induced gastroduodenalulcers have shown that especially older patients and patientswith a history of ulcer bleeding have a higher risk for uppergastrointestinal bleeding [442–444]. Short-term NSAR therapyis defined as treatment that is planned for a maximum of onemonth. This differentiates it from long-term treatment withNSAR.

1. If at least one risk factor for gastroduodenal ulcers exists,when treatment with traditional non-steroidal antirheumatics(tNSAR) is started proton pump inhibitor should be used con-comitantly (Recommendation grade A, evidence level 1b, con-sensus).Comment: Numerous studies confirm that depending on the dosetNSAR lead to gastroduodenal ulcers with frequent occurrence ofbleeding [442–445]. Aside from age (over 60 or 65 years), risk fac-tors for upper gastrointestinal bleeding are male gender, previousgastrointestinal bleeding or history of gastroduodenal ulcers, oralanticoagulation, and use of corticosteroids [442–444, 446]. Pro-spective randomized, double-blind studies have shown that therisk for such bleeding can be significantly reduced by taking PPI[447–451]. Many experts estimate the risk of under-treatment,i. e. that a patient receiving tNSAR-therapy is not offered comedica-tion with PPI, as being higher than for over-treatment, becausetNSAR is particularly administered to older patients. A general PPIcomedication for tNSAR was not sufficiently agreed on. Thus, pa-tients under 60 years of age should be asked specifically about riskfactors. If they exist, PPI comedication in addition to tNSAR shouldbe given.

2. With regard to gastroduodenal complications selective COX-2 inhibitors may be applied as an alternative procedure to thecombination of tNSAR and PPI (Recommendation grade B(downgrading from A), evidence level 1b, majority agree-ment).Comment: Three prospective randomized, double-blind studiesconfirm that selective COX-2 inhibitors have a lower complica-tion rate than unselective tNSAR [452–454]. With regard to ul-cers and upper gastrointestinal bleeding a prospective randomized,double-blind study demonstrated no significant difference betweenpatients using celecoxib versus diclofenac plus omeprazol [455]. Ameta-analysis showed that the use of selective Cox-2 inhibitorsmay prevent NSAR-induced ulcers [456]. The cardiovascular sideeffects profile of selective COX-2 inhibitors and tNSAR (with the ex-ception of naproxen) are similar [457]. Nonetheless, many expertsprefer the combination of non-selective tNSAR and PPI. This is re-flected in the lack of consensus (only majority agreement) of thisstatement.

3. If long-term therapy is implemented using selective COX-2inhibitors and acetylsalicylic acid (ASS), concomitant therapywith PPI should be employed if there is a history of previousgastrointestinal bleeding or the presence of other risk factors(see VII.1.). The combination therapy ASS and tNSAR should al-ways be accompanied by PPI-comedication (Recommendationgrade B (downgrading from A), evidence level 1b, consensus).Comment: While COX-2 selective inhibitors significantly reducethe ulcer and upper gastrointestinal bleeding rate compared totNSAR, the concomitant use of ASS annuls this effect [452, 458].In high risk patients that take selective COX-2 inhibitors PPI signif-icantly reduces the rate of ulcers and complications [459]. In con-trast similar ulcer rates were found in patients that took ASS plus


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celecoxib or ASS plus naproxen and lansoprazol [460]. So far, stu-dies on patients that took ASS plus selective COX-2 inhibitors withandwithout PPI do not exist. Thus, the abovementioned recommen-dation has been extrapolated and is indirect.

4. A test to detect Helicobacter pylori infection is not obliga-tory before NSAR-therapy (Recommendation grade B (down-grading from A), evidence level 1a, consensus).Comment: H. pylori infection as well as tNSAR-therapy are inde-pendent risk factors for the development of gastroduodenal ul-cers [442–445, 461]. An eradication therapy can reduce the riskof developing gastroduodenal ulcers significantly if a patient hasboth risk factors [462, 463]. However, PPI comedication is consid-erably more effective than eradication therapy alone [464]. It isgenerally administered to patients that are treated with tNSAR.Thus, H. pylori testing can be done but is not mandatory. For prac-tical reasons it is important that treatment with tNSAR is not post-poned because of testing for H. pylori. Since the meta-analysis citedhere does not directly investigate the recommended procedure onlyan indirect applicability for the evidence exists. Thus, the recom-mendation was downgraded from A to B.

5. When upper gastrointestinal bleeding occurs under long-term NSAR treatment, a concomitant long-term PPI therapyshould be given if NSAR therapy will be continued. In addition,testing for Helicobacter pylori infection and, if positive, com-plementary eradication therapy seem meaningful (Recommen-dation grade A/D, evidence level 1a/indirect, consensus).Comment: If long-term NSAR therapy is clinically necessary andif under treatment upper gastrointestinal bleeding occurs, therisk of recurrent bleeding is significantly reduced by the co-ad-ministration of PPI [463, 465–467]. The question whether addi-tional eradication of concomitant H. pylori infection reduces the re-currence of bleeding further has not been investigated. However, itcan be indirectly concluded that eradication would be beneficial,because they are independent cofactors. If ulcers occurred undertNSAR, repeated use of tNSAR is contraindicated according to thedrug licensing. For the COX-2 inhibitor celecoxib a prospective ran-domized study showed that PPI-comedication significantly reducesupper gastrointestinal bleeding compared to celecoxib monother-apy in patients at very high risk [459].

6. Helicobacter pylori testing and possibly eradication therapycannot be generally recommended before planned ASS long-term therapy (Recommendation grade B [downgrading fromA], evidence level 1b, consensus).Comment: Low dose ASS long-term therapy increases the risk ofgastroduodenal ulcers [468–471]. The risk rises with higher dosesand the presence of H. pylori infection [472]. Altogether, the risk ofdeveloping ASS long-term therapy induced upper gastroduodenalbleeding is small. Thus, a general recommendation for testing andpossibly eradication is not warranted from amedical and economicviewpoint.

7. Long-term PPI therapy should be initiated if ASS is continu-ally given and gastrointestinal bleeding is present. Concomi-tantly Helicobacter pylori testing and if necessary eradicationtherapy should be done (Recommendation grade B [downgrad-ing from A], evidence level 1b, strong consensus).Comment: Two prospective, randomized, double-blind studies de-monstrated that PPI as secondary prophylaxis significantly re-

duces recurrence of gastroduodenal bleeding in patients thatneed ASS long-term therapy [467, 473]

8. A switch to clopidogrel monotherapy should not be consid-ered if ASS is continually given and gastrointestinal bleeding ispresent. Instead PPI should be given in addition to ASS (Re-commendation grade A, evidence level 1b, consensus).Comment: Two prospective, randomized, double-blind studies de-monstrated that an ASS and PPI combination therapy was betterwith regard to gastroduodenal bleeding and ulcers than a switchto clopidogrel monotherapy [474, 475].

9. Complementary PPI medication should be given if concomi-tant thrombocyte aggregation inhibition using ASS and clopi-dogrel is implemented (Recommendation grade C (downgrad-ing from B), evidence level 2a, consensus).Comment: By taking ASS and clopidogrel concomitantly the riskof gastroduodenal bleeding increases from 1.8 and 1.1, respec-tively, to 7.1 [476]. Thus, the majority of experts recommend con-comitant application of PPI even though no directly applicablestudy exists.

10. Crohn’s-associated gastroduodenal ulcers or their complica-tions should primarily be treated with glucocorticosteroids incombination with PPI (Recommendation grade C, evidence le-vel 2a/4, majority agreement).Comment: So far, no studies that systematically investigated thetherapy of Crohn’s-associated ulcers exist. In principle, accordingto the data of the large European and American studies the effi-cacy of steroid therapy for stenoses and inflammatory ulcers hasbeen proven [477, 478]. Whether this is also true for gastroduode-nal Crohn’s-associated ulcers can only be inferred. As far as isknown from case studies, PPI can positively influence the healingof Crohn’s-associated ulcers [479, 480]. Since this recommendationhas resulted from relatively weak data there was only majorityagreement on this statement.

11. Other causes for gastroduodenal ulcers should be consid-ered if there is no Helicobacter pylori infection and no applica-tion of NSAR medication (Recommendation grade C (upgradingfrom D), evidence level 5, strong consensus).Comment: Apart from H. pylori infection and NSAR medication,there are numerous other causes for gastroduodenal ulcers.These include taking thrombocyte aggregation inhibitors, vascu-litides, virus infections, neuroendocrine tumors (gastrinomes),and ischemia. Systematic investigations on this topic do not ex-ist. Ulcers caused by CMV infections are frequently observed inHIV-infected and transplanted patients. However, basically theycan also occur in immunocompetent patients [481–483].

12. If no cause for gastroduodenal ulcers (idiopathic ulcers) isfound, long-term PPI-medication should be administered (Re-commendation grade C (upgrading von D), evidence level 5,strong consensus).Comment: If rare but identified causes induce gastroduodenalulcers, emphasis is on specific therapies (e.g. virostatic therapyfor CMV ulcers). If no cause can be found, almost all experts re-commend long-term PPI-therapy because the positive effect ofulcer healing using acid suppression is considered to be proven.


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13. The occurrence of so-called stress ulcers and associated gas-trointestinal bleeding during serve diseases such as ARDS, shockwith hypotension, sepsis, polytrauma, burns, traumatic brain in-jury with neurosurgical interventions, liver/kidney failure, or con-tinuous artificial ventilation can be reduced by prophylactic pro-ton pump inhibitor administration (40mg p.o. or i. v./die). Lesseffective is stress ulcer prophylaxis with H2 blockers such as rani-tidin (3!50mg/d i.v. or 2!150mg p.o.) or sucralfate (4!1g/dp.o.) (Recommendation grade B/B, evidence level 1b/1b, consen-sus/majority agreement).Comment: So-called stress ulcers arise more often as part of se-vere disease in certain risk groups such as patients with burns,coagulopathy, heart surgery patients, or patients under artificialventilation [484–488]. Other risk factors are ARDS, sepsis, poly-trauma, traumatic brain injury, and liver and kidney failure. Ameta-analysis shows that sucralfate as well as H2-receptor block-ers reduce the probability of gastroduodenal stress ulcer bleeding[486, 489]. Corresponding analyses on PPI do not exist. However,since PPI is superior in acid suppression this indirectly implies thatit should be prophylactically used in this risk group. Therefore, H2-receptor blockers and sucralfate are only rarely used for this indica-tion. The consensus participants recommended them as an alterna-tive only by majority agreement.

Appendix A: Guideline classification (!" Tables 5–7)!

Appendix B (!" Table 8)!

Table 5 Recommendation grade and evidence level.

recommendation

grade

evidence-

level

comment

A 1 systematic overview (SR) withhomogenous (no heterogeneitywith regard to results of individualstudies) randomized controlledstudies (RCT)

B 2a systematic overview with homo-genous cohort studies

2b individual cohort studies plus RCTsof low quality(e. g. follow-up < 80%)

C 3 systematic overview with homo-genous case control studies as wellas individual case control studies:EG3

C 4 case series and cohort studies aswell as case control studies of lowquality (i. e. cohort: no clearly de-fined control group, no outcomeor exposure assessment in experi-mental and control groups, insuf-ficient follow-up; case controls: noclearly defined control group)

D 5 expert opinion or inconsistentand/or inconclusive studies of anyevidence level

Table 6 Recommendation grade classification.

A consistent studies with evidence level 1 availableB consistent studies with evidence level 2 or 3 and/or extrapolation

of studies with evidence level 1C studies with evidence level 4 or extrapolation of studies with evi-

dence level 2 or 3D expert opinion or inconsistent and/or inconclusive studies of any

evidence level

Table 7 Consensus size classification.

strong consensus Agreement of > 95% of participantsconsensus Agreement of > 75 – 95% of participantsmajority agreement Agreement of > 50 – 75% of participantsno consensus Agreement of < 50% of participants

Table 8 Chronological course of the guideline preparation.

task subtask time period

initiation Commissioning by DGVS guide-line committeeDesignation of topic complexesby the heads of the guidelineChoice and writing heads of taskforcesAssembling of task forces bytheir heads and the heads of theguidelineCompilation of key words andsearch terms by the heads of thetask forcesRegistration of the guideline pro-ject at the AWMFDesignation of the persons re-sponsible for the literaturesearch by the corresponding taskforce headConference on methodologicaltraining in systematic literaturesearchSystematic literature search andevaluation

5 /2005

6 /2005

06 /2005

7 – 8 /2005

8 /2005 – 12 /2005

8 /2006

11 /2006

1 /2007

2 – 5 /2007

delphi-questioning

Wording of questionnaireInternet based distribution ofquestionnairesInternet based answering ofquestionnairesEvaluation of questionnaires

6 – 7 /20078 /2007

9 /2007

10 /2007consensusconference

Wording of statements in thetask force meetingsPlenary session with voting

Nov. 30, 2007

Dec. 1, 2007follow-up Revision and writing comments

by task force headsEditorial revision of the task forcemanuscripts by the heads of theguidelineFinal version of the guidelineSubmission to the DGVS guide-line committee

1 – 6 /2008

7 – 8 /2008

Aug. 17, 2008Aug. 18, 2008


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Appendix C (!" Table 9)!

Table 9 Task force members.

guideline heads/organization committeeProf. Dr. W. Fischbach Medizinische Klinik II und Klinik für Palliativmedizin, Klinikum AschaffenburgProf. Dr. P. Malfertheiner Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburgtopic complex I: “Epidemiology”headsProf. Dr. W. E. Schmidt Medizinische Klinik I, Universtitätsklinik St. Josef-Hospital, Klinikum der Ruhr-Universität Bochumliterature searchDr. O. Götze Medizinische Klinik I, Universtitätsklinik St. Josef-Hospital, Klinikum der Ruhr-Universität BochummembersPD Dr. B. Braden Medizinische Klinik I, Universitätsklinikum Frankfurt/Maintopic complex II: “Diagnostics, typing, resistance situation, resistance testing”headsProf. Dr. M. Kist Institut für medizinische Mikrobiologie und Hygiene, Universität FreiburgPD Dr. U. Peitz Klinik für Innere Medizin II, Raphaelsklinik Münsterliterature searchPD Dr. A. Timmer Deutsches Cochrane-Zentrum Freiburg im BreisgaumembersDr. Ch. Haferland Praxis Innere Medizin/Gastroenterologie, GörlitzDr. R. Hillert Labor für medizinische Mikrobiologie, GörlitzDr. A. Leodolter Medizinische Klinik Evang. Jung-Stilling-Krankenhaus, SiegenProf. Dr. S. Suerbaum Institut für Medizinische Mikrobiologie, MMH, Hannovertopic complex III: “Indications for therapy of Helicobacter pylori-infection in benign diseases”headsProf. Dr. P. Layer Medizinische Klinik, Israelitisches Krankenhaus, Hamburgliterature searchDr. U. Rosien Medizinische Klinik, Israelitisches Krankenhaus, HamburgmembersProf. Dr. A. L. Blum CH-RomainmotierPD Dr. Ch. Fibbe Medizinische Klinik, Israelitisches Krankenhaus, HamburgProf. Dr. H. Koop Klinik für Innere Medizin II, HELIOS-Klinikum, Berlin-BuchProf. Dr. H. Mönnikes Medizinische Klinik m. S. Gastroenterologie, Charite, Campus Virchow, Berlintopic complex IV: “Prevention and Therapy of neoplastic gastric diseases (marginal zone-B-cell-lymphoma (MZBCL) of MALT-Type, gastric carcinoma)”headsPD Dr. A. Morgner Medizinische Klinik und Poliklinik I, Universtitätsklinikum DresdenPD Dr. M. Vieth Pathologisches Institut, Klinikum Bayreuthliterature searchDr. R. Schmelz Medizinische Klinik und Poliklinik I, Universtitätsklinikum DresdenDr. J. Bornschein Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum MagdeburgmembersPD Dr. D. Flieger I. Medizinische Klinik, Gesundheits- und Pflegezentrum Rüsselsheim gGmbHPD Dr. A. Meining II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU MünchenPD Dr. A. Schneider 2. Medizinische Abteilung, Klinikum Bogenhausen, Städtisches Klinikum MünchenPD Dr. J. Weismüller Gastroenterologische Gemeinschaftspraxis KoblenzPD Dr. Th. Wündisch Zentrum für Innere Medizin, Hämatologie und internistische Onkologie, Universitätsklinikum MarburgProf. Dr. R. Arnold Wittelsbacher Str. 6, MünchenProf. Dr. W. Fischbach Medizinische Klinik II und Klinik für Palliativmedizin, Klinikum AschaffenburgProf. Dr. P. Malfertheiner Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburgtopic complex V: “Therapy of Helicobacter pylori infection”headsProf. Dr. J. Labenz Medizinische Klinik Evang. Jung-Stilling-Krankenhaus, SiegenPD Dr. G. Treiber Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saarliterature searchDr. J. Maubach Medizinische Klinik Evang. Jung-Stilling-Krankenhaus, SiegenmembersDr. B. Birkner Gastroenterologie am Max-Weber-Platz, MünchenProf. Dr. St. Miehlke Medizinische Klinik und Poliklinik I, Universitätsklinikum DresdenPD Dr. K. Mörike Medizinische Klinik I, Universitätsklinikum TübingenProf. Dr. S. Wagner Medizinische Klinik II, Klinikum Deggendorftopic complex VI: “Characteristics of Helicobacter pylori infection in children and adolescents”headsProf. Dr. S. Koletzko Kinderklinik und Poliklinik Dr. von Hauner’sches Kinderspital, Münchenliterature searchDr. A. Schwarzer Kinderklinik und Poliklinik Dr. von Hauner’sches Kinderspital, München


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Appendix D (!" Table 10)!

Affiliations1 Medizinische Klinik II, Klinikum Aschaffenburg2 Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätklini-kum Magedeburg

3 Medizinische Klinik I, St. Marienkrankenhaus Ludwigshafen4 Klaus Miehlke-Klinik, Rheumatologie, Wiesbaden5 Medizinische Klinik I, Univ.-Klinik St. Josef-Hospital, Ruhr-Universität Bochum

6 Medizinische Klinik I, Charite Campus Benjamin Franklin, Berlin7 Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg8 Kinderklinik und Poliklinik, Dr. von Haunersches Kinderspital, München9 Medizinische Klinik, Evang. Jung-Stilling-Krankenhaus, Siegen

10 Medizinische Klinik, Israelitisches Krankenhaus, Hamburg11 Medizinische Klinik und Polklinik I, Universitätsklinikum Dresden12 Klinik für Innere Medizin II, Raphaelsklinik, Münster13 II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München14 Institut für Mikrobiologie, MHH Hannover15 Deutsches Cochrane-Zentrum, Freiburg im Breisgau16 Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/

Saar17 Pathologisches Institut, Klinikum Bayreuth

References1 Graham DY, Adam E, Reddy GT et al. Seroepidemiology of Helicobacter

pylori infection in India. Comparison of developing and developedcountries. Dig Dis Sci 1991; 36 (8): 1084–1088

2 Megraud F, Brassens-Rabbe MP, Denis F et al. Seroepidemiology ofCampylobacter pylori infection in various populations. J Clin Micro-biol 1989; 27 (8): 1870–1873

3 Redlinger T, O’Rourke K, Goodman KJ. Age distribution of Helicobacterpylori seroprevalence among young children in a United States/Mex-ico border community: evidence for transitory infection. Am J Epide-miol 1999; 150 (3): 225–230

4 Taylor DN, Blaser MJ. The epidemiology of Helicobacter pylori infec-tion. Epidemiol Rev 1991; 13: 42–59

5 Malaty HM, Graham DY. Importance of childhood socioeconomic sta-tus on the current prevalence of Helicobacter pylori infection. Gut1994; 35 (6): 742–745

6 Graham DY, Malaty HM, Evans DG et al. Epidemiology of Helicobacterpylori in an asymptomatic population in the United States. Effect ofage, race, and socioeconomic status. Gastroenterology 1991; 100 (6):1495–1501

7 Malaty HM, Evans DG, Evans Jr DJ et al. Helicobacter pylori in Hispa-nics: comparison with blacks and whites of similar age and socioeco-nomic class. Gastroenterology 1992; 103 (3): 813–816

8 Malaty HM, Engstrand L, Pedersen NL et al. Helicobacter pylori infec-tion: genetic and environmental influences. A study of twins. Ann In-tern Med 1994; 120 (12): 982–986

9 Perez-Perez GI, Olivares AZ, Foo FY et al. Seroprevalence of Helicobacterpylori in New York City populations originating in East Asia. J UrbanHealth 2005; 82 (3): 510–516

10 Malaty HM, Kim JG, Kim SD et al. Prevalence of Helicobacter pylori in-fection in Korean children: inverse relation to socioeconomic statusdespite a uniformly high prevalence in adults. Am J Epidemiol 1996;143 (3): 257–262

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Table 9 (Fortsetzung)

membersDr. St. Buderus Marienhospital, BonnDr. J. Crone Gentzgasse 7 /26, WienProf. Dr. M. J. Lentze Universitätskinderklinik Bonntopic complex VII: “Gastroduodenal ulcer disease not associated with Helicobacter pylori ”headsPD Dr. J. Hoffmann Medizinische Klinik I, St. Marienkrankenhaus, LudwigshafenProf. Dr. C. Prinz II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU Münchenliterature searchDr. J. Preiß Medizinische Klinik I, Charite, Campus Benjamin Franklin, BerlinmembersDr. W. Bolten Klaus Miehlke-Klinik, WiesbadenProf. Dr. M. Jung Hildegardis-Krankenhaus, Mainz

Table 10 Participants of the consensus conference on Nov. 30./Dec. 1.2007

name society/organiza-

tion

financial conflict of

interest

Braden, B. DGVS –Bornschein, J. – –

Buderus, S. – –

Fischbach, W. DGVS –Flieger, D. DGVS, DGHO –

Götze, O. DGVS –

Haferland, C. DGVS –

Hoffmann, J. DGVS –Höhne, W. – –

Jung, M. DGVS –

Kist, M. DGHM –

Koletzko, S. GPGE –Koop, H. DGVS –

Labenz, J. DGVS –

Layer, P. DGVS –

Lentze, M. GPGE –Leodolter, A. DGVS –

Maubach, J. DGVS –

Miehlke, S. DGVS –Morgner, A. DGVS –

Mörike, K. DGVS –

Peitz, U. DGVS –

Preiss, J. DGVS –Prinz, C. DGVS –

Rosien, U. DGVS –

Schmidt, W. DGVS –

Schneider, A. DGVS –Schwarzer, A. DGVS –

Suerbaum, S. DGHM –

Timmer, A. DeutschesCochrane-Zentrum

–

Treiber, G. DGVS –

Vieth, M. – –

Wagner, S. DGVS –


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S3-Guideline ”Helicobacter pylori and gastroduodenal ulcer disease” of the German Society for...

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