Update S2k-Guideline Helicobacter pylori and gastroduodenal ulcer disease of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS)

Key word

therapy - diagnostics - eradication - resistance - antibiotics

Abbreviations

ACG: American College of Gastroenterology

AEG: Adenocarcinoma of the oesophagogastric junction

AG: Working Group

AMO: Amoxicillin

ARDS: Acute respiratory distress syndrome

ASGE : American Society for Gastrointestinal Endoscopy

ASA: Acetylsalicylic acid

AWMF: Association of the Scientific Medical Societies in Germany

cagA: Cytotoxin-associated antigen

CHOP: Cyclophosphamide, hydroxydaunorubicin, oncovin, prednisolone

CI: Confidence interval

CLA: Clarithromycin

CML : Chronic myeloid leukaemia

CMV: Cytomegalovirus

COI: Conflict of interest

DLBCL : Diffuse large B-cell-lymphoma

DOAC: Direct oral anticoagulants

EBV: Epstein-Barr-Virus

EMA : European Medicines Agency

ESGE: European Society of Gastrointestinal Endoscopy

ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition

EuroPedHP-Registers: European Paediatric Helicobacter Pylori Register

FDA: Food and Drug Administration

5-FU: Fluorouracil

H. pylori : Helicobacter pylori

HSV: Herpes-simplex-Virus

IARC: International Agency for Research on Cancer

IgG: Immunoglobulin-G

IgAV : Immunoglobulin-A-vasculitis

IM: Intestinal metaplasia

ITP: Idiopathic thrombocytopaenic purpura

ITT: Intention-to-treat

KIGGS: German Health Interview and Examination Survey for Children and Adolescents

MALT : Mucosa-associated lymphoid tissue

MEN-1: Multiple endocrine neoplasia type 1

MET: Metronidazole

MTX : Methotrexate

NAP: Neutrophil-activating protein

NASPGHAN : North American Society for Paediatric Gastroenterology, Hepatology & Nutrition

NET: Neuroendocrine tumour

NNH: Number-needed-to-harm

NNT: Number-needed-to-treat

NPV: Negative predictive value

NSAIDs : Non-steroidal anti-inflammatory drugs

nsNSAIDs: Non-selective NSAIDs

NUD: Non-ulcer dyspepsia

OGD: Oesophagogastroduodenosocopy

OLGA : Operative Link of Gastritis Assessment

OLGIM : Operative Link for Gastric Intestinal Metaplasia Assessment

OR: Odds ratio

PCR: Polymerase chain reaction

PPI: Proton pump inhibitor

PUD : Peptic ulcer disease

QALY : Quality adjusted life years

RCT: Randomized controlled trial

RR: Relative risk

RUT: Rapid urease-test

SAT: Stool antigen test

SIRT: Selective internal radiation therapy

SQT: Sequential therapy

SSRI : Selective serotonin receptor inhibitors

STT: Standard triple therapy

TACE: Transarterial chemoembolisation

TLR1: Toll-like-receptor 1

TTT: Tailored triple therapy

UBT: Urea breath test

VKA: Vitamin-K-antagonists

vacA : Vacuolating toxin A

WG: Working group

WHO: World Health Organisation

Index of Tables

[Table 1] Steering committee.	264
[Table 2] Members of the working groups.	265
[Table 3] Grading of reocmmendations.	266
[Table 4] Grading of strength of consensus.	266
[Table 5] Sensitivity and specificity of different test methods [strong consensus (5 votes withheld due to COI)].	273
[Table 6] gives an overview and summary of the recommendations 3.1 to 3.19 with regards to indication for H. pylori testing [strong consensus].	282
[Table 7] Risk groups for the development of gatsric cancer.	285
[Table 8] Preneoplastic risk stratification according to the OLGA system.	285
[Table 9] Standard dosing for triple therapy according to body weight [strong consensus].	290
[Table 10] Dosing for high dose amoxicillin therapy according to body weight. Dosing for PPI and metronidazole according to Table 9 [strong consensus].	293
[Table 11] Rare Causes of Gastric and/or Duodenal Ulcers.	296
[Table 12] Association of non-H. pylori risk factors with gastroduodenal ulcers or ulcer bleeding/complications, respectively.	297
[Table 13] Recommendation for PPI prophylaxis depending on the clinical scenario and the current medication [strong consensus].	298

 

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Index of Figures

[Fig. 1] Biopsy sites for histology according to the Sydney-system [strong consensus]].	272
[Fig. 2] Management of patients with gastric MALT lymphoma after successful eradication therapy [strong consensus].	277
[Fig. 3] Algorithm for testing and follow-up of patients with dyspepsia [strong consensus].	278
[Fig. 4] Algorithm for H. pylori eradication therapy.	287
[Fig. 5] Flow chart for the selection of first line antibiotic therapy depending on individual antibiotic resistance [strong consensus].	293

 

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1 Information about this guideline

1.1 Editors

 

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Responsible organisation

German Society of Gastroenterology, Digestive and Metabolic Diseases (Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, DGVS)

 

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1.2 Scope of application and rationale for the selected guideline topic

The prevalence of Helicobacter pylori infection in Germany is approximately 30 % and it represents the main cause for gastroduodenal ulcer disease. Prescription of aspirin and other pain killers further contribute to the development of gastroduodenal ulcer disease and other associated conditions.

However, many patients with H. pylori infection will remain asymptomatic throughout their lifetime. Previous strategies to prevent H. pylori-related diseases were mainly aimed at pathogen detection and eradication. More recently, it has been debated if general eradication of H. pylori infection could be contributing to long term adverse effects and if H. pylori infection could have beneficial aspects for its host (Weißbuch Gastroenterologie 2020/21).

To clarify these open questions and to further improve diagnosis and therapy, an update of the guideline is considered particularly important by the experts.

 

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1.3 Aim of the guideline

It is the aim of the guideline to be easily applicable in general practice, internal medicine, infectious diseases, rheumatology, microbiology, pathology, paediatrics and gastroenterology. In addition, the guideline is intended to provide a course of action for common decisions.

The target patient population includes patients with H. pylori infection or H. pylori-related diseases of any age as well as patients with H. pylori-negative gastroduodenal ulcer disease.

 

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1.4 Area of care

Outpatient and inpatient sector, addressing primary care as well as specialist care across internal medicine, infectious diseases, cardiology, rheumatology, microbiology, pathology, paediatrics and gastroenterology.

 

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1.5 User target group

This guideline is aimed at all medical specialties involved in the diagnosis and treatment of H. pylori and H. pylori-related diseases as well as (gastroenterologists, infectious disease specialists, microbiologists, cardiologists, rheumatologists, paediatricians, pathologists and general medical physicians) as well as patient representatives, affected individuals, relatives, and shall inform service providers (including insurance bodies).

The German College of General Practitioners and Family Physicians (DEGAM) declined an invitation to contribute to this guideline. However, the guideline is also relevant for general practitioners and family physicians.

 

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1.6 Composition of the guideline committee and participation of interest groups

The guideline was created under the leadership of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS), which commissioned Prof. Dr. Wolfgang Fischbach (Aschaffenburg) and PD Dr. Christian Schulz (Munich) as co-ordinators.

PD Dr. Petra Lynen-Jansen and Pia Lorenz from the DGVS office in Berlin were responsible for the methodology. Dr. Monika Nothacker from the Association of the Scientific Medical Societies (AWMF) in Berlin provided methodological advice and served as a neutral guideline expert to moderate the consensus conference. Torsten Karge supported the guideline portal and provided technical assistance for the consensus conference.

The guideline project was advertised in “Zeitschrift für Gastroenterologie” and the AWMF website and professional bodies and organisations were encouraged to contribute. The relevant professional bodies and patient organisations were contacted directly and invited to nominate contributors.

 

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1.7 The following organisations and professional bodies contributed to this guideline

• German Society of Hygiene and Microbiology (Deutsche Gesellschaft für Hygiene und Mikrobiologie e. V.; DGHM)
  M. Gerhard (Munich), S. Suerbaum (Munich)

• German Society of Infectious Diseases (Deutsche Gesellschaft für Infektiologie e. V.; DGI)
  C. Lübbert (Leipzig)

• German Society of Internal Medicine (Deutsche Gesellschaft für Innere Medizin e. V.; DGIM)
  J. Labenz (Siegen), W. Schepp (Munich)

• German Society of Cardiology and Reserch on Heart and Circulation (Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e. V.; DGK)
  T. Voigtländer (Frankfurt)

• German Society of Pathology (Deutsche Gesellschaft für Pathologie e. V.; DGP) and Federal Association of German Pathologists (Bundesverband Deutscher Pathologen e. V.; BDP)
  M. Eck (Aschaffenburg), C. Röcken (Kiel)

• German Society of Rheumatology (Deutsche Gesellschaft für Rheumatologie e. V.; DGRh)
  L. Bossaller (Greifswald)

• German Society of Paediatrics and Adolescent Medicine (Deutsche Gesellschaft für Kinder- uznd Jugendmedizin; DGKJ)
  S. Koletzko (Munich)

• Society of Paediatric Gastroenterology and Nutrition (Gesellschaft für Pädiatrische Gastroenterologie und Ernährung e. V., GPGE)
  P. Bufler (Berlin), S. Koletzko (Munich), T. Le Thi (Munich), C. Posovszky (Ulm)

• National Reference Centre (Nationales Referenzzentrum; NRZ)
  K. Dichtl (Munich)

The German Society of General Practice and Family Medicine (DEGAM) and the Robert Koch Institute (RKI) were also invited to participate in the guideline, but were unable to support the project due to personnel constraints.

 

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1.8 Representativeness of the guideline committee: patient contribution

A. Madisch (Hannover), B. Terjung (Bonn) of Gastro-Liga (patient representation)

A steering committee ([Table 1]) and seven working groups were established. The working groups were assigned to one or two leads ([Table 2]). Gastroenterologists, infectious diseases physicians, microbiologists, cardiologists, rheumatologists, paediatricians, pathologists and internal medicine physicians contributed to the working groups.

Table 1 Steering committee.

Name	Location	Professional body
W. Fischbach	Aschaffenburg	DGVS
C. Schulz	Munich	DGVS
J. Bornschein	Oxford	DGVS
J. Hoffmann	Ludwigshafen	DGVS
S. Koletzko	Munich	GPGE, DGKJ
A. Link	Magdeburg	DGVS
P. Malfertheiner	Munich	DGVS
K. Schütte	Osnabrück	DGVS
D. Selgrad	Fürstenfeldbruck	DGVS
S. Suerbaum	Munich	DGHM

Table 2 Members of the working groups.

WG 1: Epidemiology of H. pylori-infection	WG-Lead	A. Link, Magdeburg (DGVS)
	WG-Members	L. Macke, Munich (DGVS) M. Storr, Starnberg (DGVS) M. Venerito, Magdeburg (DGVS)
WG 2: Diagnosis of H. pylori- infection	WG-Lead	S. Suerbaum, Munich (DGHM)
	WG-Members	K. Dichtl, Munich (NRZ) M. Eck, Aschaffenburg (DGPathologie/BDP) M. Gerhard, Munich (DGHM) D. Mainz, Saarlouis (DGVS) U. Peitz, Münster (DGVS) B. Terjung, Bonn (Gastro-Liga)
WG 3: Indication for treatment of H.pylori-infection	WG-Lead	J. Bornschein, Oxford (DGVS)
	WG-Members	L. Bossaller, Greifswald (DGRh) W. Fischbach, Aschaffenburg (DGVS) H. Mönnikes, Berlin (DGVS) M. Sigal, Berlin (DGVS) C. Spinner, Munich (DGVS)
WG 4: Prevention and aftercare	WG-Lead	P. Malfertheiner, Munich, Magdeburg (DGVS)
	WG-Members	A. Beyer, Altötting (DGVS) S. Daum, Berlin (DGVS) U. Denzer, Marburg (DGVS) M. Ebert, Mannheim (DGVS) C. Röcken, Kiel (DGPathologie/BDP)
WG 5: Treatment of H. pylori- infection	WG-Lead	D. Selgrad, Fürstenfeldbruck (DGVS)
	WG-Members	J. Labenz, Siegen (DGIM) C. Lübbert, Leipzig (DGI) A. Madisch, Hannover (Gastro-Liga) S. Miehlke, Hamburg (DGVS) C. Schulz, Munich (DGVS)
WG 6: Special considerations for the treatment of children and young adults	WG-Lead	S. Koletzko, Munich (GPGE, DGKJ)
	WG-Members	P. Bufler, Berlin (GPGE) T. Le Thi, Munich (GPGE) C. Posovszky, Ulm (GPGE)
WG 7: Non-H. pylori associated ulcer disease (epidemiology, prevention, clinical management and therapy)	WG-Lead	J. Hoffmann, Ludwigshafen (DGVS) K. Schütte, Osnabrück (DGVS)
	WG-Members	L. Bossaller, Greifswald (DGRh) M. Gross, Munich (DGVS) A. Kandulski, Regensburg (DGVS) W. Schepp, Munich (DGIM) T. Voigtländer, Frankfurt (DGKardiologie)
Guideline committee office		L. Macke, Munich (DGVS)
Co-ordinators		W. Fischbach, Aschaffenburg (DGVS) C. Schulz, Munich (DGVS)

 

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2 Methods

2.1 Evidence synthesis

2.1.1 Methodology

Literature search

A literature search was conducted by each working group independently. Details are outlined in the guideline report.

 

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Grading of recommendations

The strength of each recommendation is determined by the wording used (must or has to/should/can) according to the grading in [Table 3]. The strength of consensus was determined according to [Table 4].

Table 3 Grading of recommendations.

description	term
strong recommendation	must/has to
recommendation	should
recommendation open	can

Table 4 Grading of strength of consensus.

strength of consensus	% agreement
strong consensus	≥ 95
consensus	≥ 75–95
majoritarian agreement	≥ 50–75
no consensus	< 50

If recommendations were adapted from the previous guideline without changes, this was reflected with “reviewed 2021”. Recommendations which were modified from the previous guideline are marked as “modified 2021”. Recommendations which were included in the guideline for the first time are marked as “new 2021”.

 

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Statements

Statements in this guideline relate to specific situations or clinical questions without immediate recommendations. These are agreed in a formal consensus discussion and are either based on published study results or expert opinion.

 

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“Choose wisely”

Recommendations marked as “choose wisely” were selected for the “choose wisely” (Klug entscheiden) initiative of the German Society of Internal Medicine (DGIM). These recommendations are aimed to provide direct support to guide indications for diagnostic tests and therapeutic interventions for an appropriate level of investigations and treatment. Further information can be found online https://www.klug-entscheiden.com/ (German only).

 

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2.2 External validation and approval

2.2.1 Approval by the executive boards of the publishing professional societies/organisations

The complete guideline was reviewed and agreed upon by all professional societies and organisations. It was available online for review and comments by the expert community for four weeks in March/April 2022, which was advertised through the DGVS newsletter. All proposed changes are available in the guideline report.

 

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2.2.2 Editorial independence and funding of the guideline

This guideline was written with full editorial independence. The DGVS funded use of the guideline portal, the online kick-off-meeting and the online consensus conferences. There was no financial involvement of third-parties. Mandated individuals and experts worked solely on a voluntary basis.

 

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2.2.3 Conflict of interests policy

All contributors and experts declared their conflicts of interests in accordance with the AWMF-rules for dealings with conflicts of interests by completing the AWMF-forms (Formblatt 2018). Any conflicts of interests were reviewed by the guideline co-ordinators as well as Mr Macke (guideline office) and Ms Nothacker (AWMF). These were then categorised in accordance with the AWMF-criteria as minor, moderate or high in relation to the specific recommendations. This process was discussed and agreed by all contributing parties at the beginning of the consensus conference.

Remuneration of contributors for talks and/or educational activities as well as paid authorship and/or co-authorship by companies with interests in diagnostic tools or therapeutic agents for Helicobacter pylori were considered as low conflict of interest and did not result in consequences on consensus discussions.

The following conflicts of interest were considered as moderate:

• Consulting, appraising or paid employment on a scientific board of a healthcare company (e. g. pharmaceutical industry, medical product industry), a commercially orientated research organisation or an insurance body

• Contribution or membership to a scientific advisory board

• Conducting clinical research with third-party financial contribution for scientific projects or direct financial support of employees of the institution by a healthcare company, a commercially orientated research organisation or insurance body

The following companies were considered to have potential conflicts of interest:

⎝ Pharmaceutical product companies: Mayoly Spindler, Kibion and Imevax GmBH

⎝ Pharmaceutical companies: Abbvie and Allergan

A high conflict of interest was defined as personal financial interest (patent, copyright, shares/stocks, investment funds with shares in healthcare industry). High conflicts of interest in relation to the present guideline were not identified.

By applying the above conflicts of interest framework, five experts were identified as having low conflicts of interest and eight experts were identified as having moderate conflicts of interest. Experts with moderate conflicts of interests were not admitted to vote in the relevant sections of the consensus agreements or two separate votes were documented (once with and once without the affected experts participating in an anonymous vote). The interdisciplinary composition of the guideline committee, as well as the structured consensus process discussions under neutral moderation were considered as protective factors against the bias by conflicts of interest. The vast majority of recommendations (93 %, i. e. 99/106) reached a “strong consensus”, further ensuring that potential conflicts of interest did not significantly influence the guideline.

All conflicts of interest are available in the guideline report.

 

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2.3 Distribution and implementation of the guideline

2.3.1 Concept for distribution and implementation

The guideline is published in “Zeitschrift für Gastroenterologie”, on AMBOSS and on the homepage of the DGVS (www.dgvs.de) and AWMF (www.awmf.de).

 

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2.3.2 Period of validity and update process

The guideline was last updated in May 2022. The validity of the guideline is approximately five years and is due for a further update by 30. April 2027. The DGVS will oversee this update. The steering committee will assess the need for further updates on a yearly basis. Ms Lorenz at the DGVS office can be contacted by email on [e-mail].

 

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2.4 Editorial Note

2.4.1 Participatory decision-making

All recommendations in this guideline are to be understood as recommendations to be implemented in a participatory decision-making process between physicians and patients and, if applicable, their families.

 

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2.5 Special considerations

The medical field is constantly evolving all information presented here, especially regarding diagnostic and therapeutic procedures, can only correspond to the state of knowledge at the time of publication of the guideline.

The recommendations regarding treatment options, selection and dosing of drugs were made with utmost care. We ask the guideline user to consult the manufacturer information and national formularies as well as an expert colleague should any doubt arise. Please inform the DGVS if there are any discrepancies. The responsibility for diagnostic and therapeutic application, choice of medication and dose lies with the guideline user. This guideline does not specifically highlight registered trademarks and brand names and it should not be assumed that only generic names are used. Any use outside the scope of the copyright law is prohibited and punishable without the written consent of DGVS. No part of the work may be reproduced in any form without written permission. This applies in particular to duplications, translations, microfilming and the storage, use and exploitation in electronic systems, intranets and the internet.

 

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3 Guideline – Preamble

Comment: 

H. pylori is a bacterial pathogen of the stomach and H. pylori gastritis is an infectious disease. H. pylori infection can present with or without symptoms and can lead to complications and sequelae such as peptic ulcer disease, adenocarcinoma of the stomach or marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) [1]. This is in concordance with international expert recommendation and consensus reports [1] [2].

 

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4 Guideline – Topic complex 1: Epidemiology

Comment: 

Infection with H. pylori induces chronic-active gastritis. Possible complications and related diseases are gastro-duodenal ulcer disease, gastric adenocarcinoma and the marginal-zone B-cell lymphoma of MALT (mucosa-associated lymphoid tissue) [3] [4] [5].

Infection with H. pylori increases the risk of distal gastric cancer by a factor of 2–3 (OR 1.92–2.56) compared to non-infected individuals. The association of H. pylori infection with different types of gastric cancer is comparable: intestinal type OR 2.49–4.45; diffuse type OR 2.58–3.39 [6] [7] [8] [9] [10]. The relative risk is higher if serum samples used for H. pylori diagnosis were taken at a timepoint longer before the cancer diagnosis (OR 5.9)Thus, the association between H. pylori and gastric cancer could be underestimated due to elimination of the bacteria during progression of the disease [3] [11]. If a previous infection is confirmed by (usually longer) persistent CagA antibodies in the serum, then the predicted risk for gastric cancer rises to 18–20fold [12].

The incidence of MALT lymphoma correlates with the prevalence of H. pylori infection. The relative risk of developing a primary gastric lymphoma is increased 6-fold in cases with serological evidence for H. pylori in large case-control studies [13]. Helicobacter heilmannii which is detected mainly in animals with a prevalence of 0.5 % in humans is also associated with an increased risk for a gastric MALT lymphoma [14] [15].

The NHANES-III study from the USA demonstrated that H. pylori infection is not associated with an increased mortality rate and even has protective effects on the development of stroke [16]. Although there is an increased risk of gastric cancer with H. pylori, this has no impact on cohort mortality due to the low gastric cancer prevalence. Association studies showed an inverse correlation between H. pylori infection and gastrooesophageal reflux disease as well as eosinophilic oesophagitis [17] [18] [19] [20] [21]. In the early studies, adenocarcinoma of the oesophagus was shown to be inversely associated with H. pylori infection, although a plausible cause for this has not yet been identified [22]. There is no association between H. pylori eradication and Barrett’s- oesophagus or adenocarcinoma of the oesophagus [23].

Recent publications highlight a positive correlation between H. pylori infection and colorectal cancer. The underlying mechanism remains to be determined. A meta-analysis demonstrated the risk for colorectal adenomas with an OR 1.49 and for colorectal carcinoma with an OR 1.44 [24]. The data needs to be interpreted with caution and the risk of selection bias has to be considered as the incidence for colorectal neoplasia does not correlate with the incidence of H. pylori infection.

A negative association between H. pylori infection and eosinophil oesophagitis was demonstrated in a German case-control study as well as a recent meta-analysis [25] [26]. There is also an inverse association between H. pylori infection and coeliac disease in the paediatric as well as adult population (OR 0.56; 95 %CI 0.45–0.70) [27] [28] [29].

In addition, infection with H. pylori has been associated with idiopathic thrombocytopaenic purpura (ITP) [30], iron deficiency anaemia [31] and Vitamin B12 deficiency [32]. Eradication of H. pylori infection is associated with a significant improvement in thrombocytopenia in positive individuals [33]. Several dermatological conditions such as chronic urticaria, rosacea, alopecia areata among others have been associated with H. pylori in multiple publications including meta-analyses, although the level of statistical significance was mostly not reached [34].

A meta-analysis of five case-control studies confirmed a higher prevalence of H. pylori in patients with migraine with an OR of 1.92. The underlying mechanism remains unclear at present [35]. A smaller randomised clinical study added that eradication of H. pylori infection has a positive effect on the course of disease [36].

Systematic reviews have identified associations between H. pylori and obesity [37], type II diabetes mellitus [38], cardiovascular disease such as acute coronary syndrome [39], Parkinson’s disease and Alzheimer’s disease [40], decline in cognitive function [41] and Guillain-Barré syndrome [42]. There are some case reports on H. pylori and IgA vasculitis, but a clear association has not been established [43].

Comment: 

A systematic review with meta-analysis of the global prevalence of H. pylori infection demonstrates a strong variation of infection between different regions and countries [44]. The highest prevalence is found in Africa (70.1 %, 95 %CI, 62.6–77.7), the lowest in Oceania (24.4 % 95 %CI 18.5–30.4). Western European countries with a prevalence of 34.3 % (95 %CI 31.3–37.2) are considered regions with low prevalence. Within Europe, the prevalence varies greatly with Portugal (86.4 %), Estonia (82.5 %) und Lithuania (79.2 %) being the most affected countries and Switzerland (18.9 %), Denmark (22.1 %) and Sweden (26.2 %) being the least affected countries. Germany has a prevalence of 35.3 % (95 %, CI 31.2–39.4). Available data from the last decade demonstrate a seroprevalence of 44–48 % in adults [45] [46], more recent data show a seroprevalence of 28.9 % in blood donors with a trend towards lower prevalence in younger people [47]. The prevalence of H. pylori infection in non-migrant children in Germany is 3 % at the age of 4 [48] and 5–7 % between the age of 5–7 [49].

Comment: 

Differences in prevalence between geographic and ethnic groups are often a consequence of differences in intensity of exposure to H. pylori (socio-economic factors, hygiene, food and environmental factors) [50] [51] [52]. Data are available for several countries demonstrating a higher prevalence of H. pylori infection in migrants and people with lower socio-economic status (work, income, housing situation) [54]. Hygiene conditions and level of education have a further influence on H. pylori prevalence [55]. It is likely that these data are transferable to Germany.

Considering in the increased migration inside and outside of Europe during recent years, changes in the H. pylori prevalence, at least regional, are possible. Currently, no data are available on H. pylori prevalence in this context or H. pylori associated epidemiological aspects, respectively. In addition to the above-mentioned factors, host genetics and virulence factors of the pathogen are also likely to play a role in the predisposition for H. pylori infection. A genome wide association study identified a polymorphism in the Toll-like-receptor 1 gene (TLR1) as a susceptibility gene in two independent population-based cohorts [56]. Polymorphisms in two fucosyltransferase genes (lewis and secretor genes) have also been associated with susceptibility for H. pylori infection [57].

Comment: 

Several studies have reported an age dependent increase in H. pylori infection with the highest prevalence in older adults and lowest in younger adults [45] [47]. This is interpreted as an expression of a birth cohort effect [58] [59]. Although previous studies highlighted a higher prevalence of H. pylori infection in males, more recent publications did not show a direct correlation [45] [47]. The main factor for the transmission is infection within the family. For example, one of the most important factors for infection in children is the infection status of the mother (OR 13.0; 95 %KI 3.0–55.2) [48]. A stable low prevalence of 9 % in children aged 7–9 has been reported over the last decade [60]. A meta-analysis showed that relatives of patients with stomach cancer had an up to 2-fold higher prevalence of H. pylori infection [61]. Interestingly, the risk of H. pylori infection increases with the number of siblings in Germany (OR 1.65). However, if corrected for age, sex, level of education, incidence of stomach cancer in the family, smoking status (nicotine) and alcohol intake, the prevalence does not show any increase anymore [62]. IN view of migration background, a dependency of the prevalence of H. pylori infection and ethnic origin and country of birth in Germany. Cohorts without migration background had a lower infection prevalence (13 %) in direct comparison with a cohort with a Turkish background (30 %) and a cohort in Turkey (44.5 %) [63].

Comment: 

In addition to social and environmental factors host genetics and virulence factors of the bacteria are possible contributors to the susceptibility for H. pylori associated diseases. Recently, a genome wide association study identified 9 genes (MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST, CCKBR) which play a role in the homeostasis of the gastric mucosa and are associated with peptic ulcer disease [64].

Different strains of H. pylori differ in virulence factors such as cytotoxin-associated antigen (cagA) and vacuolating toxin A (vacA). The virulence factors can be associated with an increased risk of H. pylori associated diseases. Infection with cagA-positive H. pylori is associated with more severe gastritis and a higher risk of gastric cancer in comparison to cagA-negative strains [10] [65]. In Germany, up to 93 % of H. pylori strains are cagA-positive. Anti-CagA-IgG is often used as a surrogate marker for cagA-positive strains and the seropositivity of CagA is 30–44.4 % [45] [47] [66] [67]. Confirmation of a CagA-positive strain cannot be used as confirmation for a functional type-4 secretory system and could explain the low seropositivity for CagA. VacA induces vacuole formation inside cells and is also associated with gastric cancer and ulcer disease. The vacA gene polymorphism s1i1m1 has a higher risk compared to s2i2m2 [68]. A German prospective cohort study confirmed the association of more severe mucosal inflammation [66]. Infection with a more aggressive strain of H. pylori with polymorphism vacA s1m1 occurs in 42 %, with vacA s1m2 in 23 % and vacA s2m2 in 34 % [66]. There are no studies available investigating the effect of these virulence factors on clinical practice. Currently cag-A positivity, anti-CagA-IgG serology or vacA polymorphism don’t influence clinical management of H. pylori infection.

Comment: 

The transmission of H. pylori within a family is well documented [69] [70] [71] [72]. There is a high molecular concordance of H. pylori strains between mothers and infected children [73] [74]. Interestingly, a recent study with 50 participants in 13 Irish families demonstrated that 37.7 % of participants were infected with multiple H. pylori strains. In three families with three to four members, all family members were infected with different strains, highlighting the likelihood of additional ways of transmission [75]. Family size and the size of living quarters are considered additional risk factors [76]. Breastfeeding does not influence transmission of H. pylori [77] [78]. Older infected siblings are a predictor for H. pylori infection [79]. The incidence of H. pylori infection is highest in children under 3 years of age and significantly decreases in children older than 5 [80]. Genetic factors and composition of the microbiome are considered as a possible reason for the increased rate of transmission in families [56] [81]. Interestingly, a meta-analysis of 16 studies of children in nursery and pre-school demonstrated that transmission of H. pylori outside the family does not occur in the same way [82].

Transmission of H. pylori between adult partners is possible. However, it is only confirmed when proof of the same strain in both individuals has been obtained [83]. A serological study on 389 married couples in the United Kingdom confirmed an increased risk of infection for the partner [84]. In a German study with 670 married couples, the partner’s risk of infection with H. pylori was significantly increased only in couples with non-German background. These data support the hypothesis of an increased risk of transmission in groups with high prevalence of H. pylori infection (both partners born in Germany: OR 1.10; 95 % KI 0.47–2.61; one partner not born in Germany: OR 1.57; KI 0.72–3.45; both partners not born in Germany: OR 6.05; KI 1.31–17.96;) [85]. The risk of infection is significantly elevated in case of gastrooesophageal reflux disease in the infected partner (OR 4.41) [86]. Studies from Asia demonstrate increased relapse rates in patients where another member of the household was infected with H. pylori (OR 4.231) and reduced relapse rates if all members of the household received eradication therapy (6.08 % vs. 0.96 %) [87] [88].

Comment: 

H. pylori can be isolated and cultured from and confirmed by molecular methods in vomitus, faeces and saliva [89] [90] [91]. Stomach content in particular has a high bacterial density [92]. H. pylori transmission to individuals in contact of people with outbreaks of acute gastrointestinal infection was observed [93]. H. pylori can be found in niches of the oral cavity and is associated with chronic periodontitis [94] [95] [96]. The association of H. pylori infection of the stomach with other diseases of the oral cavity is not clear, though [97]. The faecal-oral route of transmission is supported by a serological association of H. pylori with Hepatitis A and with confirmation of Giardia lamblia in faeces as both pathogens have a known faecal-oral transmission [98] [99].

Epidemiological observations suggest a possible contribution of sewage, agricultural products and animals for the transmission of H. pylori. The pathogen has been confirmed in multiple non-human reservoirs. There is controversy about the importance of waterways and sewers as possible sources of infection but is unlikely to be of relevance in developed regions [100] [101] [102] [103]. H. pylori has been confirmed in sewers and drink water samples with molecular biological methods as well as with bacterial culture [104] [105] [106]. An Iranian study detected H. pylori with PCR and in bacterial culture from bottled water [107]. Transmission through agricultural products and food has been discussed since H. pylori was detected in sheep’s milk, on fruits and vegetables and other foods [108] [109] [110] [111]. Even though H. pylori can be found in primates, farm animals, pets, honey bees and flies, there is no clear evidence of zoonotic transmission of H. pylori [112] [113] [114] [115].

Comment: 

Early studies demonstrate an increased risk of infection for healthcare workers, although heterogeneous or missing controls limited the interpretation and impact of the data [116]. More recent studies demonstrate that the direct contact of doctors or nurses with H. pylori positive patients is not a significant risk factor for infection [117]. A meta-analysis of 15 studies shows only a mildly increased risk for H. pylori infection among gastroenterologists (RR 1.6; 95 %CI: 1.3–2.0) and endoscopy staff (RR 1.4; 95 % CI: 1.1–1.8) [118].

Comment: 

Recurrence of H. pylori infection can be a result of recrudescence or re-infection. Recrudescence is characterised by a recurrence of the original H. pylori strain after a false negative eradication confirmation. Re-infection is an infection with a new strain after successful eradication therapy [119]. In case of infection within the first year after eradication therapy, in 60 % the same strain is identified, whereas in cases of detection of the infection after more than 12 months, a new strain is usually isolated [120]. Thus, it is likely that recurrence within 12 months represents recrudescence in most cases, and infection after more than a year rather re-infection [120].

A large meta-analysis of 132 studies across 5 continents gave a global annual recurrence rate of 4.3 % with a recrudescence of 2.2 % and a re-infection rate of 3.1 %. In Europe, the annual recurrence rate is 2.7 % and in Germany 1.4 %. There are limited data available on re-infection rates in Germany. One study with 108 infected patients, the 25 for who ¹³C-breath tests were available 12 and 24 months after eradication did not have a re-infection [121].

Recurrence rates are inversely correlated with the human developmental index, a surrogate marker for socio-economic and hygienic parameters, which is directly correlated with prevalence of H. pylori infection. The global recurrence rates have remained stable over the past 3 decades, albeit with strong regional fluctuations [122]. After successful systemic eradication treatment, H. pylori can persist in the oral cavity and could serve as a reservoir for recrudescence or re-infection [123] [124]. The recurrence rate after eradication therapy was increased in a paediatric (OR 2.283) and an adult cohort (OR 4.231) in China if further H. pylori infected people lived in the same household [87] [124]. The recurrence rate was low when all family members received eradication therapy (6.08 % vs. 0.96 %, P = 0.035).

Comment: 

The Pasitos study followed Hispanic new-borns in Mexico and Texas in 6-monthly intervals with H. pylori breath tests. Of the 218 children who tested positive, 168 children (77 %) were negative on a follow up test [126]. In a study in Germany with 2235 pre-school children, the infection could not be confirmed anymore after two years in 30 of 104 children who initially tested positive. For 25 of these 30 children, parents were available for a follow-up interview. Most children received a triple H. pylori eradication therapy (18/25) or antibiotics for other reasons (4/25), 3 children (3/25) were thought to have spontaneously eliminated the pathogen [127]. A study in China followed school children between 7 and 12 years of age and a spontaneous elimination rate of 2.9 %/year was described [128]. A study in Mexico observed a spontaneous elimination rate of 4.74 % in children aged 6–12 years. However, antibiotic therapy was not captured [129]. The effect of incidental antibiotic therapy on H. pylori elimination could be overestimated: the above mentioned Pasitos-study collected detailed data on intake of antibiotics. The proportion of children, who eliminated H. pylori without any antibiotic therapy was 66 %, with at least one antibiotic therapy 72 % and with H. pylori effective antibiotic therapy 79 %. The adjusted risk difference per antibiotic therapy cycle was 7 % for any antibiotic therapy prescription and 8 % for H. pylori effective antibiotic therapy [130]. Most studies in children and adults don’t capture data on incidental antibiotic therapy [129] [131].

Spontaneous elimination of H. pylori after partial gastrectomy was observed in 39–55 %. However, the data on the effect of the type of the surgical procedure (e. g. Billroth-I vs Billroth-II vs Roux-en-Y) on the elimination rate are contradictory [132] [133] [134] [135]. The loss of the antrum with secondary achlorhydria is considered to be a mechanism of spontaneous H. pylori elimination [136]. Entero-gastric bile reflux is associated with reduced H. pylori colonisation [137]. A further mechanism for the spontaneous elimination of H. pylori infection in adults is achlorhydria associated with severe atrophy of the mucosa of the body of the stomach, as pathognomonic for advanced H. pylori infection and in autoimmune gastritis [138] [139].

Comment: 

At present, no effective vaccine is available for H. pylori. In a placebo-controlled phase I/II study in Germany intramuscular immunisation with an antigen-based vaccine (with VacA, cagA and neutrophil-activating protein (NAP)) led to a strong antibody response. However, this was not associated with additional protection after H. pylori challenge of healthy individuals [140]. In a placebo-controlled phase III study with 4464 children in China, an oral recombinant vaccine against H. pylori demonstrated efficacy [141]. The success rate was 71.8 % (95 % CI 48.2–85.6), the rate of adverse effects was under 1 % after 3 years follow up. However, long-term data has not been published and the vaccine is no longer in development.

 

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5 Guideline – Topic complex 2: Diagnosis

The aforementioned methods are sufficiently validated but differ in their test accuracy and field of application [142] [143] [144] [145] [146] [147] [148]. No single method alone is completely accurate. For a reliable H. pylori diagnosis, two positive results should be obtained with two different methods. This is required due to the low and reducing prevalence of H. pylori infection in industrialised countries [158] [159]. In case of low prevalence, a steady proportion of false positive tests has a more significant impact resulting in a low positive predictive value. In certain clinical scenarios a second test method is not necessarily required:

1. Histological proof of H. pylori in combination with chronic-active gastritis is close to 100 % specific. The distinct bacterial morphology in combination with characteristic inflammation of chronic gastritis is sufficient for diagnosis. A combination of a urease breath test and histology can speed up the diagnosis at the time of endoscopy before the result of the histological analysis is available.

2. Due to the high prevalence of H. pylori in the presence of duodenal ulcer disease, a combination of endoscopic confirmation of duodenal ulcer and one positive test is sufficient for the diagnosis of H. pylori infection.

3. A positive culture of H. pylori alone is per definition 100 % specific and sufficient for the diagnosis. A negative culture does not exclude infection and if clinical suspicion remains high further tests are required.

For each test modality there are more or less limitations regarding the test accuracy. Studies validating new diagnostic methods use results of multiple established methods as a reference [142] [143] [144].

The sensitivity and specificity of each method, assuming there are not confounding factors, are listed in [Table 5].

Table 5 Sensitivity and specificity of different test methods [strong consensus] (5 votes withheld due to COI).

			Sensitivity (%)	Specificity (%)
Invasive methods	Culture		70–90	100
	Histology		80–98	90–98
	Rapid urease test		90–95	90–95
	PCR		90–95	90–95
Non-invasive methods	Urea breath test		85–95	85–95
	Faecal antigen test[*]
		ELISA	85–95	85–95
		rapid stool test	70–95	85–95
	IgG-antibody detection in serum[†]		> 95	> 90

^* monoclonal antibody test.

^† IgG antibody detection in serum is not appropriate for treatment follow-up as it does not differentiate between currently active and previously eradicated infection.

Furthermore, the different tests have specific areas of use depending on the clinical scenario, the medical history, and the presence of complicating factors. The test selection should follow the clinical indication. A decision between endoscopy-based and non-invasive test should take risk, cost and time required for each method into account.

In case of a gastroscopy, histology is the most informative test. The histological appearance of chronic active gastritis in combination with the distinct bacterial morphology leads to a certain H. pylori diagnosis and allows a precise assessment of the inflammatory changes guiding, predictions regarding treatment outcome, prognosis of the infection and an estimate of the individual gastric cancer risk. A gastroscopy should therefore not be performed without taking biopsies for histology.

The direct confirmation of the bacteria includes methods that detect the whole bacteria (histology, culture), a representative antigen ((quick/point-of-care) test for H. pylori antigens in stool) or due to specific bacterial metabolic abilities (detection of urease activity of the bacteria by the rapid urease test or the urea breath test). For the detection of antigens in stool, only (quick) tests should be used that are based on monoclonal antibody detection [145] [147] [149] [150] [151] [152] [153].

Indirect pathogen detection with serum IgG antibodies can nowadays be done with various test modalities with high sensitivity (ELISA, Western Blot, LineBlot, Lateral Flow Assay) [154] [155] [156] [157]. Serological tests don’t discriminate between currently active and previous, eradicated infection, leading to a reduction in specificity. Serum antibodies can persist months, sometimes even years after eradication therapy or even gastrectomy. Therefore, serology is clinically useful in cases where patients in whom a history of previous H. pylori-effective antibiotic therapy (eradication treatment) has been ruled out. Furthermore, antibody detection is useful in case of bleeding gastric lesions, when a PPI treatment has already been initiated. In addition to this, IgG-ELISA tests are available for the detection of antibodies in saliva and urine. The performance of these tests does mostly not achieve the level of serological tests, with lower sensitivity in particular [158] leading to a very low NPV in Germany. Further validation in larger cohorts is recommended.

Comment: 

The biopsy sites are in concordance with the Sydney classification of gastritis [161]. These are shown schematically in [Fig. 1]. The inhomogeneous density and the partly patchy distribution of H. pylori in the stomach explain why the sensitivity of histology increases with the number of biopsies taken [162] [163]. Histological studies with multiple biopsies (“mapping”) demonstrate the high diagnostic accuracy of the above sampling strategy for determination of the H. pylori status. In addition, the recommended biopsy strategy can diagnose the topographical distribution of gastritis as well as the histological parameters atrophy and intestinal metaplasia, which are associated with a higher risk of cancer. Thus, the prognosis as well as ulcer and gastric cancer risk and cancer risk can be estimated more precisely. Antrum-dominant H. pylori gastritis leads more often to duodenal ulcers. Pangastritis, in particular when atrophy and intestinal metaplasia is present, is associated with a significantly increased risk of gastric ulcer and stomach cancer. The risk of stomach cancer is also increased in body-dominant gastritis.

Fig. 1 Biopsy sites for histology according to the Sydney-system. [strong consensus]. [rerif]

Thus, it is indicated to send biopsies from antrum and body in separately labelled containers to the pathology laboratory. Biopsies from greater and lesser curves of the same region of the stomach, however, can be sent in the same container. The rationale for taking these biopsies of opposing areas is that atrophy and intestinal metaplasia are more often found at the lesser than the greater curvature [164] [165] [166]. If there is a specific question about premalignant lesions, then a separate biopsy from the incisura should be taken, as this area has the highest prevalence of these lesions [161] [167] [168] [169] (for risk stratification by OLGA and OLGIM system please see topic complex 4). Lesions like erosions, ulcers and polyps must be biopsied separately. Biopsies for the diagnosis of H. pylori should be taken from mucosa that appears endoscopically as normal as possible as changes of the mucosa (ulceration, erosions but also atrophy and intestinal metaplasia) are associated with a significantly reduced H. pylori-density.

Endoscopic-optical features of an H. pylori infection in the stomach can be used as additional means of diagnosis but do not replace the aforementioned test methods. The use of “advanced endoscopic imaging” techniques and virtual chromo-endoscopy with improved visualisation of fine structural mucosal and microvascular changes in case of H. pylori colonization are described in various international guidelines. [170] [171] [172] [173]. This may increase the sensitivity and specificity for detection of focal atrophy, intestinal metaplasia and early forms of gastric cancer compared to high-resolution white light endoscopy. However, a clear recommendation for general use is not made [171] [172].

Antrum: one biopsy from the greater (A1) and one biopsy from the lesser curve (A2), 2–3 cm proximal to the pylorus;

Body: one biopsy from the greater curve, approximal 8 cm distal to the cardia (C1) and one biopsy from the lesser curve, approximal 4 cm proximal of the incisura angularis;

Incisura angularis/angular fold (AF): one biopsy for dedicated investigation of pre-malignant lesions

Comment: 

Modified Giemsa staining is the preferred special stain for detection of H. pylori due to its high sensitivity, simple technical applicability and low cost. Although Warthin-Starry staining and immunohistochemistry have the highest sensitivity, they are reserved for special indications due to their technical complexity and high cost. These include:

• Positive stool antigen detection or positive urease test with concomitant negative histology.

• Confirmation of eradication in case of ongoing gastritis activity without H. pylori detection, unclear H. pylori detection with immediately preceding PPI or antibiotic treatment [174] [175], confirmation of successful eradication in case of H. pylori- associated MALT lymphoma, at least if the lymphoma persists.

Comment: 

Biopsies for microbiological testing methods should only be taken from areas of the stomach with high bacterial density (greater curve > lesser curve). Sampling from areas with visible metaplasia must be avoided if possible[176].

Although a higher bacterial density is more often found in the antrum when compared to the body, H. pylori can be detected in corpus biopsies only in case of hypochlorhydria [177]. For the rapid urease test (RUT), biopsies from both the antrum and body of the stomach have shown to increase the sensitivity by about one-third compared to the use of antral biopsies alone [178]. The biopsies can be placed together in a single test cassette [179] [180].

Biopsies from the antrum and body may also differ in terms of prevalence of bacterial resistance, so biopsies from both areas of the stomach are more representative for culture and resistance testing [181] [182] [183].

For RUT CE-certified tests are recommended. Different tests differ in their reaction speed and hence in the time interval during which they are ready for read-out. Newer tests have significantly shorter read-out times without loss of sensitivity [184] [185] [186] [187]. Exceeding the recommended interval can lead to false positive results due to other urease-producing bacteria [188]. Superiority of any one of the available tests has not been demonstrated [176] [185].

H. pylori infection can be demonstrated with PCR even at very low bacterial densities when other tests methods might be negative [189] [190] [191] [192] [193]. In the absence of complicating factors (e. g. bleeding ulcer) which also impact the performance of other test methods, this sensitivity is over 90 % depending on the chosen PCR target sequence. Various CE-certified PCR kits are commercially available and suitable for use in routine laboratories.

Reusing a biopsy that has previously been put into a RUT test medium for PCR to confirm H. pylori (in case of negative RUT), for molecular testing of clarithromycin resistance (in case of positive RUT) or for a bacterial culture is feasible [194] [195] [196].

Comment: 

Urease dependent tests include the ¹³C-urea breath test and the urease rapid test. Urease cleaves urea into CO2 and ammonia. While H. pylori is characterized by a very high urease activity, other bacteria in the GI tract are also capable of urea hydrolysis. Bacterial overgrowth of the stomach or small intestine with urease-producing bacteria other than H. pylori can occur especially in case of delayed gastrointestinal motility, hypochlorhydria and PPI therapy. These conditions can occasionally lead to false-positive tests [188] [197] [198] [199] [200] [201] [202] [203].

The sensitivity of all tests for the detection of current infection (with the exception of serology) is reduced under conditions of decreased bacterial density [177] [181]. Decreased bacterial density is observed in particular on PPI therapy or H. pylori sensitive antibiotic therapy. However, H2 blockers and antacids reduce sensitivity only slightly. Reduced bacterial density is also found in hypochlorhydria and mucosal atrophy, stomach cancer and MALT lymphoma of the stomach [204] [205].

The sensitivity of all direct tests is reduced by approximately 5–30 % during acute upper gastrointestinal bleeding, with considerable heterogeneity between different studies, also with regards to the “gold standard” applied [206]. The underlying reasons are partly not known. A major cause of reduced sensitivity is PPI treatment. Sensitivity decreases with duration of PPI therapy on a day to day basis [206], also for stool testing [207]. PCR seems to be the most sensitive method in this setting but is not widely available [191] [192] [208]. Among direct methods, histology has the highest sensitivity [209].

Specificity of direct test methods is also reduced in some situations. Cross-reactivity with blood can be a reason for reduced specificity of SAT [210]. It is not clear if a reduction of specificity of serology down to 50 % in case of gastrointestinal bleeding [209] is real or due to false negative results with the compared direct reference test methods.

In clinical practice, early histological diagnosis should be applied in scenarios with upper gastrointestinal bleeding, ideally at first endoscopy. However, this is often limited by the emergency situation and potential concomitant coagulopathies. Testing in case of a bleed often remains incomplete [211] [212]. Since sensitivity of serology is not altered in GI bleeding, a positive result is suitable to increase the sensitivity of the complete set of H. pylori diagnostics A lower specificity [209] is acceptable if omitting or delaying H. pylori eradication would be considered more detrimental to the patient compared to the consequences of an unnecessary eradication therapy. A negative H. pylori status in the acute situation should be re-checked when the acute episode is over [213].

After partial gastrectomy, the sensitivity of the urea breath test in particular is impaired. The reduced surface area of the gastric mucosa and accelerated gastric emptying contribute to this [214]. Also, in this condition, histology is the preferred test method.

Comment: 

After discontinuation of therapy with acid-suppressive or antibiotic treatment, several days to weeks are required for the bacterial density to return to its baseline level. This is also dependent on intensity and duration of the preceding treatment. During this time, the sensitivity of all direct tests is reduced. In clinical practice, this poses a significant problem as dyspepsia is often treated with PPI before the indication for H. pylori diagnostic or endoscopy is made [215] [216]. In the current version of the Maastricht Consensus, a minimum of 7-day break, but ideally 14 days, between last PPI intake and H. pylori diagnostic tests (SAT, UBT) is recommended [2]. The respective studies are heterogeneous and do not provide a reliable evidence-based recommendation. As alternative for PPIs, H2 receptor antagonists or antacids could be used for bridging therapy in case of symptoms as these have no or at most minimal interaction with individual test methods (SAT, UBT) for H. pylori [2] [215] [217] [218] [219] [220] [221].

If the mentioned time intervals are adhered to, all test methods (see recommendation 2.1) for detection of a current infection and confirmation of successful eradication of H. pylori infection are suitable [146] [222].

Comment: 

Pathogenic factors of H. pylori have an influence on the development of complications associated with H. pylori induced gastritis like gastroduodenal ulcer disease or gastric carcinoma. However, the knowledge about the existence of these virulence factors is not relevant for the clinical management [223].

Comment: 

Due to the current approach of only conducting resistance testing after failed therapies, data on primary resistance in Germany is limited. The latest research into primary resistance to clarithromycin suggests that the previously observed increase has continued and that a resistance rate of ≥ 15 % has to be assumed [224] [225] [226]. Thus, clarithromycin-based triple therapy is no longer suitable as first-line treatment (see recommendation 5.7). Already after the first treatment failure, secondary resistance rates to clarithromycin rise to about 60 %, and to 80 % after two unsuccessful attempts [224]. More than 60 % of H. pylori isolates show combined resistance to clarithromycin and metronidazole after two failed treatment cycles. Furthermore, resistance to quinolones is increasing [224] [226] [227]. These developments limit the success rate using empirical treatment regimens significantly. Thus, H. pylori culture and sensitivity testing allow targeted therapy.

The antimicrobial sensitivity of H. pylori against relevant antibiotics can be determined after culture from an endoscopic biopsy by agar diffusion testing and similar techniques (e. g. agar dilution). The E-test is a well-standardized agar diffusion test for determination of resistance [228]. The validity and reproducibility of the results have been confirmed in recent years through international comparisons between various reference laboratories. E-tests are plastic or paper strips that are coated with a concentration gradient of a specific antibiotic. After placement of the strip on a H. pylori culture on a fixed culture medium, the antibiotic diffuses into the culture medium according to the gradient, enabling a precise read-out of the minimal inhibitory concentration. This makes stratification into sensitive and resistant possible, according to the European Committee for Antimicrobial Sensitivity Testing (www.eucast.org). E-tests are commercially available for the antibiotics routinely used in eradication therapy, such as clarithromycin, metronidazole, levofloxacin, tetracycline and amoxicillin. In the case of testing for rifabutin, a rifampicin test strip can be used as a substitute. Since resistance to tetracycline is rare and resistance to amoxicillin does generally not occur in Germany [224], respective results should be critically evaluated and verified. Confirming such unexpected resistances in a reference laboratory (e. g. National Reference Centre for H. pylori) ensures the high quality of microbiological diagnostics and contributes to resistance surveillance.

Sensitivity testing for H. pylori gives results on the in-vitro resistance. According to experience, the actual clinical relevance of such resistance requires confirmation within clinical studies due to the particular pharmacokinetic conditions within the stomach. Therefore, antibiotics for eradication therapy should not just be combined based on the sensitivity testing, but also based on the experience from clinical studies.

If a high clarithromycin resistance is expected (e. g. in patients with an unsuccessful previous eradication, in patient with migration background and in young patients) sensitivity testing can be performed before first- or second-line therapy. Such sensitivity testing can be done in a microbiological laboratory using molecular or phenotypic (culture-based) methods [229]. For the latter, gastric biopsies can also be used that have been obtained for pathology or for the rapid urease test [230] [231].

Except for metronidazole the molecular mechanisms of resistance against antibiotics used in eradication therapies are known. These are due to mutations of the respective microbial receptor molecules and allow genotypic resistance testing in individual cases [181]. As resistance to clarithromycin is usually based on a few mutations in the 23S rRNA gene, it can be detected with high sensitivity and specificity with molecular tests. There is a very good concordance between the results of phenotypic and genotypic resistance testing for clarithromycin [232] [233] [234]. These tests are commercially available and sufficiently validated. Alternatively, validated in-house methods can be applied. Such methods of molecular-genetic resistance testing can be sufficient to guide appropriate first- or second-line therapy [235]. Resistance predictions based on whole-genome sequencing are currently being developed [186] [236].

 

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6 Guideline – Topic complex 3: Indication for diagnostic testing

Comment: 

There are several homogenous meta-analyses that have demonstrated a benefit of eradication therapy in peptic ulcer disease of the stomach and duodenum with and without complications [237] [238] [239] [240] [241] [242] [243].

A recent meta-analysis showed that eradication therapy is superior to other medical treatment for H. pylori-positive duodenal ulcers but this has not been demonstrated for H. pylori-positive gastric ulcers. When compared to no treatment, eradication therapy prevents effectively recurrences of gastric and duodenal ulcers [244].

The association between H. pylori and gastric and duodenal ulcer disease is decreasing on the background of decresing prevalence in Western industrial countries while the increasing frequency of Aspirin/NSAID-associated ulcers is increasing. This makes testing for H. pylori mandatory.

Comment: 

The common practice of the endoscopic/bioptic follow-up of gastric ulcers is controversial due to the underlying evidence and therefore receives little consideration in national and international Guidelines. The German S2k guideline on “Gastrointestinal Bleeding” recommends confirmatory biopsies of lesions if these are suspicious for malignancy. In accordance with the respective guidelines for the diagnosis and treatment of oesophageal, gastric and colorectal cancers, a sufficient number of biopsies should be taken. Biopsy sampling can be done during the initial “endoscopy depending on the severity of bleeding and the capacity of the patient’s coagulation system” [245].

The American Society for Gastrointestinal Endoscopy (ASGE) published in its recommendations in 2010 that the common practice of endoscopic ulcer control in the United States is not in line with the available evidence and that it is not considered cost-effective [246]. It is further recommended to decide individually if follow-up endoscopy and biopsies are required. This should be influenced by the macroscopic appearance at index endoscopy, histology results and presence of further risk factors (e. g. NSAID use, H. pylori status, age). Similarly, more recent studies highlight the relevance of endoscopic appearance and authors suggest not arranging follow-up in cases with benign appearance and corresponding histology [247] [248]. However, if there is a suspicion of malignancy based on endoscopic appearance (e. g. raised or irregular edges), a follow-up endoscopy is recommended even in case of negative histology at the time of the index endoscopy. A follow-up endoscopy was also considered reasonable in patients with persistent symptoms despite adequate therapy and in patients without a clear cause for the ulcer.

In light of the obvious uncertainties due to confounding factors, the authors of this guideline recommend endoscopic follow-up with biopsies as is currently common practice. Prospective studies to clarify the evidence are still urgently needed.

Follow-up of duodenal ulcers is still not recommended [249], but this can be considered in individual cases of complicated duodenal ulcers.

Comment: 

This recommendation was already made in the Sk2 guideline in 2016, but it has now been updated with the addition “independent of H. pylori status and stage”. The current recommendation is in line with other guidelines [2] [250] [251]. Recent publications continue to support this recommendation [252] [253]

All gastric MALT lymphomas, regardless of stage, are initially be treated with H. pylori eradication therapy. This is the first-line therapy with curative intent [254]. According to a meta-analysis, successful H. pylori eradication in stages I and II leads to complete lymphoma remission in 77.5 % of cases (78 % in stage I and 56 % in stage II) [255]. The majority of patients are cured with this treatment [256] [257]. Even patients with negative H. pylori status should receive eradication therapy, as it can also lead to complete remission of the lymphoma [258] [259].

Three scenarios can occur after H. pylori eradication: (1) Complete lymphoma remission; (2) Normalisation of macroscopic endoscopic findings but residual MALT lymphoma on histology; (3) Persistent endoscopic and histological residual evidence of MALT lymphoma. [Fig. 2] shows the further management in this situation. It has been shown that even in endoscopic and histological residual MALT lymphoma, most patients have a very good long-term outcome so a watch-and- wait strategy is recommended in these situations [260] [261]. The same approach is probably also feasible in initially H. pylori negative MALT lymphomas, but there is no data available for long-term observation with larger case numbers.

Fig. 2 Management of patients with gastric MALT lymphoma after successful eradication therapy [strong consensus]. [rerif]

Comment: 

The relevant studies on this topic are already cited in the S2k-LL 2016. The other guidelines do not address this issue. According to the EGILS consensus recommendations, patients with H. pylori positive stage I DLBCL can be treated with eradication therapy alone under strict monitoring of clinical and endoscopic parameters [254]. If there are no definitive signs of lymphoma regression after H. pylori eradication, patients should receive early immune-chemotherapy with the anti-CD20-antibody rituximab and chemotherapy according to the CHOP protocol. This approach is considered safe [254].

Comment: 

The Kyoto Consensus Report stratifies endoscopically assessed “non-ulcer-dyspepsia” into H. pylori-induced dyspepsia and H. pylori-negative functional dyspepsia in the stricter sense (1). The corresponding nomenclature and the resulting recommendations have also been adopted in the European Maastricht V guidelines (2). Therefore, testing for H. pylori is recommended for a pragmatic therapeutic approach ([Fig. 3]). Depending on the patient’s complaints, age (> 50 years) and presence of any risk factors (e. g. weight loss, anaemia), this can be done initially by endoscopy ([Fig. 3a]). Alternatively, non-invasive tests are also an option ([Fig. 3b]). In the case of H. pylori detection by non-invasive tests, an oesophagogastroduodenoscopy (OGD) should be performed if there is no improvement in symptoms after eradication, or if symptoms relapse within 6 months. This is to rule out serious pathology in the stomach (e. g. ulcer, carcinoma).

Fig. 3 Algorithm for testing and follow-up for patients with dyspepsia [strong consensus]. a depicts the algorithm for further testing and follow-up of dyspeptic patients who were diagnosed with H. pylori infection during an index gastroscopy. The algorithm is mainly derived from the Kyoto Consensus Report and corresponds to the recommendations listed there, which allow for a distinction between H. pylori dyspepsia and functional dyspepsia in the stricter sense (1). b shows a modified scheme for patients in whom the initial detection of the pathogen was performed non-invasively. It should be noted that in these patients, in case of persistent symptoms or symptom recurrence, an endoscopic investigation is required. [rerif]

Eliminating H. pylori infection in patients with long-standing dyspeptic symptoms (> 4 weeks) and negative endoscopic findings leads to sustained symptom improvement in up to 10 %. The number-needed-to-treat (NNT) is 12–15 [147] [264]. A meta-analysis of 14 randomized controlled trials showed a significant improvement of dyspeptic symptoms after eradication compared to controls: OR 1.38; 95 % CI 1.18–1.62; p < 0.001 [265]. This therapeutic advantage applies to populations in America, Asia and Europe. Further more recent studies, some of which were not yet included in the meta-analysis, show different effects of H. pylori eradication on general symptom improvement or on individual symptoms of functional dyspepsia [266] [267] [268] [269] [270] [271] [272].

In addition to patient preference and subjective symptoms, other arguments can be considered regarding the individual decision for H. pylori eradication: lack of therapeutic alternatives [273]; aspects of cancer prevention (see topic complex 4); reduction of physician visits [274] and endoscopies [275]. On the other hand, the likelihood of gastrointestinal side effects from eradication therapy is approximately 10–25 % and these are usually only transient.

Commentary: 

Epidemiological studies suggest a negative association between H. pylori and reflux disease [276] [277] [278] [279]. Barrett’s oesophagus and oesophageal adenocarcinomas are also less frequently observed in H. pylori-infected individuals, although a recent meta-analysis did not show a clear association between H. pylori and Barrett’s oesophagus [280] [281]. This could lead to the conclusion that H. pylori is protective and that eradicating the bacterium could be associated with the development or worsening of reflux disease. However, the majority of previous studies have not demonstrated a negative impact of H. pylori eradication on reflux symptoms or reflux oesophagitis [282] [283] [284] [285] [286]. Recent meta-analyses suggest that H. pylori eradication may lead to the development of erosive esophagitis, but the overall data are contradictory [287] [288] [289] [290]. Therefore, the decision to perform an H. pylori diagnostic test can be made independently of the presence of reflux symptoms or reflux disease.

Comment: 

Long-term PPI therapy requires H. pylori eradiation since atrophic changes in the gastric body mucosa and body-dominant H. pylori gastritis can develop under long-term treatment [291] [292]. Body-dominant H. pylori gastritis is considered a risk factor for development of gastric cancer. Similarly, an increased progression of pre-existing inflammatory changes (especially in the body) in H. pylori-positive patients is seen on PPI therapy [293]. While these effects were demonstrated in animal experiments on Mongolian gerbils [294], a Cochrane analysis published in 2014 did not confirm a significant association between long-term PPI therapy and glandular atrophy and intestinal metaplasia [295]. However, this was attributed to heterogeneous study designs and partially incomplete data.

It is currently assumed that long-term therapy with PPI and H. pylori infection have a synergistic effect on gastric acid secretion [296]. This not only leads to a shift in H. pylori colonization from antrum to body, but also to an increased presence of non-H. pylori organisms in the gastric mucosa [297]. The altered cytokine expression supports mucosal remodelling processes and the development of body-dominant atrophic gastritis. This effect on the gastric microflora increases with the duration of PPI intake [298]. The profile of bile acids in the stomach, altered by the pH-increase, also influences bacterial colonization, thereby promoting inflammatory processes in the body [299].

While long-term PPI therapy in H. pylori-positive patients is associated with an increased risk of atrophic gastritis, the association with further progression to gastric cancer remains controversial [300]. Data from larger cohorts (in particular from Asia) propose such an association and suggest that this effect may persist even after H. pylori eradication [301] [302] [303]. However, a detailed discussion of this aspect is beyond the scope of this guideline.

Comment: 

Our recommendation is in line with other guidelines [2] [250] [251]. A more recent meta-analysis supports the “must” recommendation and confirms two systematic literature reviews cited in the previous guideline [304] [305]. The meta-analysis is based on 6 randomized studies with 241 patients. Patients with successful eradication had significantly higher platelet levels than placebo-treated patients (OR 1.93; 95 % CI 1.01–3.71; p = 0.05). No significant increase was found in children (OR 1.80; 95 % CI 0.88–3.65; p = 0.11) [306].

Comment: 

The evidence for this recommendation is undoubtedly low. As a result, the ACG guideline expresses its reluctance to recommend routine testing for H. pylori. The other guidelines do not address lymphocytic gastritis. However, a randomized, double-blind, placebo-controlled study with a positive effect is available and was cited in the last guideline version of 2016 [307]. A recent review article on rare forms of gastritis highlighted a possible indication for eradication therapy in light of the pathogenic significance of H. pylori infection for lymphocytic gastritis [308].

The same applies to Menetrier’s disease. In the German guideline of 2016, only a few uncontrolled case reports were cited [309] [310] [311] [312] [313] [314]. In other guidelines, Menetrier’s disease is not addressed at all. For certain forms of Menetrier’s disease, CMV and H. pylori infection are discussed as possible pathogenic factors. Since gastroscopy and biopsy are routinely performed in the differential diagnosis of Menetrier’s disease, H. pylori infection will inevitably be encountered. In the absence of alternative treatment options, eradication therapy appears reasonable, as described in a recent review article [315].

Comment: 

In a recently published meta-analysis with 619 patients with Sjögren syndrome [316], a significantly higher rate of H. pylori infection was found in the study cohort compared to the general population. However, there are no studies to date that demonstrate the success of eradicating H. pylori in the prevention of MALT lymphomas in Sjögren patients [317] [318] [319] [320].

Comment: 

Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura, is the most common form of vasculitis in children. Although the pathogenesis is still largely unknown, it is believed that infections play an important role in triggering IgAV, as the disease often occurs after bacterial or viral infections during the autumn season. Although no pathogen has been clearly identified as a trigger, an association has been made between H. pylori infection and the disease. In IgAV patients with H. pylori infection, the vasculitis improved after successful eradication (4 studies with 266 HSP children, RR = 0.38, 95 % CI: 0.25–0.58, p < 0.001), while recurrence of IgA vasculitis was associated with H. pylori recolonization. H. pylori-infected children also had a 3.8-fold higher likelihood of developing IgAV compared to uninfected children [321] [322].

Comment: 

Two meta-analyses on this topic are available [323] [324]. According to these there is an increased risk for iron deficiency (OR 1.33; 1.15–1.54; 30 studies) and iron deficiency anaemia (OR 1.72; 95 % confidence interval 1.23–2.42) in H. pylori-infected individuals [323]. The association of H. pylori infection with iron deficiency anaemia was confirmed in a meta-analysis of 15 observational studies (OR 2.22; 1.52–3.24; p < 0.0001), despite overall heterogeneous results. In five randomized controlled intervention studies, H. pylori eradication did not significantly improve haemoglobin and serum ferritin levels [324].

Further data also suggest an association between iron deficiency (anaemia) and H. pylori infection. In 311 children, H. pylori correlated with ferritin and haemoglobin [325]. H. pylori eradication plus oral iron supplementation also increased the functional iron pool in children [326]. However, a randomized clinical trial showed no effect of H. pylori eradication on iron absorption [327].

Comment: 

H. pylori infection increases the risk of bleeding in patients taking aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) [328]. A new meta-analysis confirmed an increased ulcer risk in patients taking aspirin, due to H. pylori infection [329]. In NSAID-naive patients, H. pylori eradication significantly reduces the risk of developing gastroduodenal ulcers [330] [331]. However, patients already on long-term NSAID medication do not benefit from H. pylori eradication [332] [333] [334].

In the previous version of this guideline, testing for H. pylori before taking aspirin and NSAIDs was only recommended in cases with a positive ulcer history. However, there are other well-defined risk factors for the development of ulcers and ulcer complications, which are discussed in detail in statements 7.4 and 7.5. In patients with at least one risk factor for the development of an ulcer and/or an ulcer complication (see 7.3 and [Table 10]) in addition to age, testing and, if positive, eradication therapy should be initiated. Depending on the individual situation, a non-invasive (breath test, stool antigen test) or invasive H. pylori test may be chosen. Reimbursement for non-invasive diagnostics in this situation is explicitly recommended.

Comment: 

Oral anticoagulants such as warfarin/coumarin or direct oral anticoagulants (DOACs) are associated with an increased risk of upper gastrointestinal bleeding [335]. Unlike antiplatelet therapy (platelet aggregation inhibitors), the additional influence of H. pylori on the likelihood of bleeding is generally unclear, especially in the absence of gastro-duodenal ulcers [336] [337]. Nevertheless, H. pylori eradication has favourable effects on the safety of oral anticoagulant use [338]. An observational study showed lower and less complicated bleeding rates in patients where H. pylori was eradicated compared to non-eradicated patients, particularly in older patients (with previous history of peptic ulcer [339].

Comment: 

While a retrospective cohort study did not demonstrate an increased risk of upper gastrointestinal bleeding with SSRI use in the presence of H. pylori infection [336], a population-based study from Denmark demonstrated a significant increase in risk in this constellation with an OR of 2.73 (95 % CI, 1.17–6.36) [340]. Even after successful eradication therapy, the risk of upper GI bleeding remains elevated with SSRI use [341]. Data from prospective interventional studies that demonstrate a therapeutic advantage of eradication therapy before long-term SSRI therapy in at-risk patients are not available.

Comment: 

A randomized study showed that the probability of recurrent ulcer bleeding on aspirin is comparable after H. pylori eradication or on long-term omeprazole medication (1.9 % and 0.9 %, respectively, in 6 months) is comparable [342]. Another study from Hong Kong found a reduction in the risk of recurrent ulcer bleeding in patients taking low-dose aspirin (< 160 mg/d) after H. pylori eradication [343]. In contrast, H. pylori-negative patients with ulcer bleeding on aspirin had still a high risk of recurrent ulcer bleeding. Therefore, it can be concluded only to prescribe permanent PPI treatment to those patients with additional risk factors for ulcer recurrence beyond aspirin intake after successful H. pylori eradication. H. pylori-negative patients, on the other hand, require permanent PPI protection after ulcer bleeding if they continue to take aspirin, P₂Y₁₂ inhibitors, or DOACs (see also topic complex 7, statement 7.11).

Comment 

Given the fact that H. pylori and NSAIDs are independent risk factors for gastroduodenal ulcers and their complications, a protective effect of eradication can be assumed. However, this is lower than that of PPI maintenance therapy. In the randomized study from Hong Kong, the risk of recurrent ulcer bleeding (after ulcer healing with omeprazole) with continued use of naproxen alone after eradication was 18.8 % and 4.4 % with concurrent omeprazole therapy [342]. Therefore, after ulcer bleeding on NSAIDs with continued use of this (otherwise contraindicated) medication, concurrent PPI therapy is always indicated (see also Statement 7.9). The question of whether PPI plus H. pylori eradication further reduces the risk of recurrence in this situation has not been studied ([Table 6]).

Table 6 gives an overview and summary of the recommendations 3.1 to 3.19 with regards to indication for H. pylori testing [strong consensus].

Indication	Must	Should	Can
Gastric/duodenal ulcer	X
Gastric MALT lymphoma	X
Gastric diffuse large cell B-cell lymphoma (DLBCL)			X
Dyspepsia	X
PPI long term therapy		X
Idiopathic thrombocytopaenic purpura (ITP)	X
Menetrier’s disease, lymphocytic gastritis		X
Sjögren’s syndrome			X
IgA vasculitis		X
Iron deficiency anaemia of unclear cause	X
Aspirin long term therapy	X[1]
NSAID long term therapy	X[1]
Anticoagulation (VKA, DOAC, heparin, fondaparinux)		X[2]
SSRI long term therapy			X[1]
Upper GI bleeding while on aspirin, P2Y12 inhibitors and or anticoagulation (VKA, DOAC, heparin, fondaparinux)	X
Upper GI bleeding while on NSAIDs	X

¹ In scenarios with increased risk for ulcer and ulcer complications.

² In scenarios with increased risk constellation.

 

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7 Guideline – Topic complex 4: Prevention and Follow-up

Comment: 

H. pylori was first classified as a class 1 carcinogen by the WHO in 1994 based on epidemiological studies. In an updated version of IARC, H. pylori is considered a causal and most important risk factor for the development of gastric cancer based on numerous additional evidence-based studies [344].

H. pylori is the initial trigger for the development of both histological types (intestinal and diffuse, according to Lauren) of gastric cancer. However, the multifactorial pathogenesis also involves host factors [345] [346] [347] [348] [349] [350], environmental factors [351] and bacterial virulence factors [356] [357] [358]. Diet also plays an important role in H. pylori-triggered gastric carcinogenesis [356] [357] [358].

Current evidence indicates that the cause of gastric cancer is attributable to infection with H. pylori in approximately 90 % of cases. Accordingly, the incidence of gastric cancer can be significantly reduced by H. pylori eradication [344] [359] [360].

The carcinogenic potential of H. pylori also applies to a subgroup of tumours at the oesophagogastric junction. For Siewert classification type III junctional cancers, the role of H. pylori as carcinogen has been confirmed [361] [362].Type II tumours, “classic cardia cancers”, seem to comprise two different entities: H. pylori- and reflux-associated carcinomas [363] [364] [365] [366]. A differentiation of these subtypes is currently only possible using surrogate parameters [367] [368]. Tumours that are located more proximally are of different aetiology and are considered as adenocarcinomas of the oesophagus [369].

Comment: 

Despite a recent decline in incidence, gastric cancer still causes significant morbidity and mortality in Germany, with approximately 15,000 new cases in 2016 according to data from the Robert Koch Institute. The median age at diagnosis is 72 for men and 75 for women. Due to the late stage at diagnosis, the case-specific mortality rate for gastric cancer is very high. Considering all tumour related deaths in 2016, for example, more than twice as many women (3.7 %) died from gastric cancer than from cervical cancer (1.5 %). With an age-specific incidence of 7–10/100 000, depending on the region, Germany is considered to be an area with low/intermediate incidence of gastric cancer compared to other countries [370].

In Germany, H. pylori can vary prevalence depending on age, with 9 % in those aged 20 and 47 % in those over 60 years [371] [372]. Primary prevention of gastric cancer in the asymptomatic population through eradication therapy of H. pylori infection is effective and feasible for Germany. However, randomized controlled studies on prevention, as summarized in a recent meta-analysis, are primarily from Asia. The NNT to prevent a case of gastric cancer was 72 and for tumour-related death from gastric cancer 135 [373]. For the first time, a European study has now also demonstrated a positive preventive effect of H. pylori eradication on gastric cancer [374]. The largest population-based cohort study on the effect of primary prevention comes from the Matsu Islands in Taiwan. In a high-risk population, using non-invasive methods in sequential order of serology and UBT followed by eradication treatment, it was possible to reduce the prevalence of H. pylori infection from 64.2 % to 15.0 %, compared to a historical control group, as well as to reduce the incidence and mortality of gastric cancer by 53 % and 25 %, respectively [375].

Systematic reviews suggest that a screen & treat strategy may be cost-effective even in case low incidence of H. pylori infection, if additional H. pylori-induced comorbidities (NUD, PUD) are also considered [376] [377]. In Western countries, cost-effectiveness is higher in the population older than 50 compared to younger age groups [378]. In countries with high prevalence of H. pylori infection (42.25 %), model calculations suggest that a screen & treat strategy is not only cost-effective but associated with cost savings in the context of possible H. pylori related diseases [377].

For Western countries, nine studies calculated long-term costs and life years or quality-adjusted life years (QALY) for an H. pylori screen & treat strategy using a single H. pylori serology test [378]. They concluded that such a strategy could be cost-effective also in Western countries, but that there is still insufficient evidence to support widespread implementation.

The rising cost of individualized oncological multimodal therapy for gastric cancer has not been considered in the above cost-effectiveness analyses. The cost-effectiveness of a screen & treat strategy will therefore further improve. “Opportunistic” screening for H. pylori with eradication in case of a positive result could therefore be considered from the age of 50. The opportunity to link screening for patients at increased risk of gastric cancer to colon cancer screening should be considered. To date, only few studies have addressed this. As part of such a strategy, patients with low serum pepsinogen and the then likely preneoplastic changes of the gastric mucosa (e. g. severe atrophy) could be further assessed with gastroscopy [379] [380]. The argument that carcinogenic cascade is already in a stage irreversible by H. pylori eradication in patients over 50 has been refuted [381]. It therefore appears reasonable and practical to incorporate screening for colorectal and gastric cancer in a combined approach.

Comment: 

Asymptomatic patients with low risk for gastric cancer can be offered screening for H. pylori with non-invasive tests (UBT, stool antigen test) and eradication in case of a positive result. In low-incidence regions for gastric cancer, gastroscopy with the aim of prevention is not cost-effective [380]. Further research into non-invasive screening tests for pre-neoplastic and neoplastic lesions of the stomach is needed.

In addition to H. pylori serology, serology for pepsinogen I as well as the calculation of the ratio of pepsinogen I to pepsinogen II (PgI/II ratio) can be used to identify patients with advanced gastric mucosal atrophy who should undergo further evaluation by endoscopy and histology. Pg I is produced exclusively in the chief cells of the body, while Pg II is secreted by the cardia, pylorus and duodenal Brunner’s glands [382]. A decreased PgI/II ratio is indicative of advanced glandular atrophy with a sensitivity of 66.7–84.6 % and a specificity of 73.5–87.1 % [383] [384].

A Japanese meta-analysis of 40 studies with more than 30,000 individuals showed that serum PgI/II ratio testing can identify individuals at increased risk of gastric cancer who would benefit from further diagnostic measures [385]. In Japan, individuals are classified into different risk groups based on their pepsinogen and H. pylori serology tests to allow for individual risk stratification and more cost-effective endoscopic surveillance. This led to a reduction in gastric cancer-related deaths of up to 76 % [386] [387]. A meta-analysis of studies from Asia describes that the risk of developing gastric cancer is 6–60 times higher with a pathological serum pepsinogen test and positive H. pylori serology [388]. Several cohort studies with long follow-up of up to 14 years confirm the effectiveness of this strategy [389] [390] [391] [392].

In populations in Western industrial countries, especially in Europe and North America, the outcome regarding pepsinogen testing are not clear. The current German gastric cancer guideline, and the American as well as the Japanese guidelines highlight that the existing data do not support a reliable conclusion [393] [394] [395] [396]. However, more recent meta-analyses suggest a benefit of pepsinogen serology for assessing individual risk of gastric cancer and possible precursor lesions [397] [398]. In a large cohort of smoking men in Finland, low serum pepsinogen was significantly associated with increased gastric cancer risk [399]. In a German study that combined pepsinogen testing with colorectal cancer screening, low serum pepsinogen levels were significantly associated with pre-cancerous histological changes in the stomach [379]. Despite its limitations, serum pepsinogen testing is currently the only non-invasive method for detecting severe atrophic gastritis or gastric mucosal atrophy, which is associated with an increased risk of gastric cancer. Therefore, serology can be offered to asymptomatic individuals as part of health screening. Pathologically low pepsinogen I levels indicate the likely presence of pre-neoplastic lesions of the stomach and a corresponding increased risk of gastric cancer. In all cases, these changes must then be confirmed or ruled out by endoscopy.

Comment: 

Patients with a positive family history of gastric cancer in first-degree relatives have an increased risk and must undergo screening for H. pylori, followed by eradication treatment in case of a positive result. The genetic predisposition and increased family risk of H. pylori-associated gastric cancer have long been established [400] [401]. Clinical proof of the effectiveness of testing and H. pylori eradication intervention for the prevention of gastric cancer in high-risk families has been demonstrated in a large South Korean study [402]. In this context, it should be noted that this should not be confused with the very rare hereditary gastric carcinoma [403].

Under the age of 40, H. pylori-associated gastric cancer does not usually occur in the context of a positive family history. Therefore, the search for H. pylori can be performed using non-invasive methods. With older age, the risk of developing preneoplastic gastric mucosal changes increases and the international consensus of endoscopy with biopsy should be followed [360] [403].

The primary endoscopic diagnostic assessment should be done with HD endoscopy. This yields a specificity of over 90 % for the diagnosis of intestinal metaplasia, with sensitivity ranging from 75 % to 53 % [404] [405] [406]. Chromoendoscopy, real and virtual, and appropriate training can improve the detection of pre-malignant lesions [403]. The current ESGE guideline therefore recommends examination with HD endoscopy and, if possible, virtual chromoendoscopy.

During initial endoscopy, biopsies must be taken for the diagnosis of H. pylori infection and atrophic gastritis. For this purpose, two biopsies should be taken from the antrum and body at the greater and lesser curve, respectively, as well as additional biopsies from endoscopically suspicious lesions [403]; (see also recommendation 2.3 and [Fig. 1]). In this context, the ESGE guidelines correspond to the recommendations of the previous German guideline from 2016. The update of the Sydney protocol recommends a fifth biopsy from the incisura angularis. Due to this, individual studies reported an increased detection of pre-malignant lesions with an upgrade of patients to a high-risk stage (OLGA III/IV or OLGIM III/IV) [407] [408] [409]. Other studies have not shown a clinically significant benefit through an additional biopsy from the incisura angularis [410].

The phenotypes of gastritis with an increased risk of gastric cancer are histologically characterized as follows: advanced stage of atrophy with/and without intestinal metaplasia (OLGA 3/4, OLGIM 3/4) and body-dominant severe inflammation. In the presence of these changes, the term “risk gastritis” is also used. Although H. pylori can often no longer be found due to severe mucosal damage, a reliable exclusion of the pathogen must still be made even in these advanced stages [2].

Patients from high-risk areas should be screened for H. pylori infection [410] [411]. An increased risk for H. pylori-associated gastric cancer should be considered in particular in immigrants from countries with a high incidence of gastric cancer. A recent US study demonstrated a positive cost-benefit ratio for primary endoscopic screening with biopsy for residents with African American, Hispanic and Asian background [412]. This calculation also included endoscopic surveillance upon detection of atrophic gastritis with intestinal metaplasia.

In case of suspected autoimmune gastritis, endoscopy is recommended. If the diagnosis is confirmed, patients with this condition require less frequent monitoring [403]. The large US-SEER database confirmed an increased incidence of gastric cancer in patients with pernicious anaemia (OR 2.18, 95 %CI 1.94–2.45) and to a greater extend neuroendocrine tumours (NET) (OR 11.43, 95 %CI 8.90–14.69) [413]. Incidence of gastric cancer in autoimmune gastritis is much lower in comparison to H. pylori associated gastric cancer (Rugge et al, GUT 2022 submitted).

[Table 7] summarizes the risk groups for developing gastric cancer, as listed above and supplemented in section 4.6.

Table 7 Risk groups for the development of gastric cancer.

First-degree relatives of patients with gastric cancer

Individuals born and/or raised in areas with high prevalence of H. pylori and high incidence of gastric cancer: Asia, Eastern Europe, Central and South America

Patients with advanced, body-dominant atrophic gastritis with or without intestinal metaplasia (OLGA 3/4, OLGIM 3/4)

Patients with previous gastric neoplasms (adenoma, early carcinoma) after endoscopic resection or partial gastrectomy.

Comment: 

The risk of developing gastric cancer increases five-fold with intestinal metaplasia (IM) and/or atrophy [415]. For risk stratification in cases of active H. pylori gastritis systems such as OLGA and/or OLGIM can be used, which stratify gastritis into stages based on the Sydney classification [416] [417] [418] ([Table 8]). Although OLGIM has shown less interobserver variability, the combination of both schemes appears to provide the most optimal results for predicting risk (highest risk in stages III and IV) [419] [420] [421] [422] [423]. In cases of detection of pre-/paraneoplastic changes such as atrophy and IM, endoscopic surveillance and biopsies should be performed with the caveat that progression to gastric cancer can occur despite successful H. pylori eradication [415] [424] [425] [426] [427] [428]. Endoscopic surveillance is recommended at an interval of (2-)3 years in international guidelines (MAPS II) for severe atrophic gastritis/intestinal metaplasia in the antrum and body (OLGA/OLGIM III/IV) [403]. In a large prospective cohort study, the 5-year neoplasia risk was 36.5 per 1000 patient-years for OLGA III and 63.1 per 1000 patient-years for OLGA IV [419]. A three-year surveillance interval in patients with advanced gastric atrophy or IM has been described as cost-effective in Europe [429]. In contrast, OLGA I and II almost never show progression to dysplastic changes or gastric cancer [430].

Table 8 Preneoplastic Risk Stratification according to the OLGA System.

The staging is based on the mucosal changes graded according to the updated Sydney classification.
		Body
	Atrophy score	No atrophy	Mild atrophy	Moderate atrophy	Severe Atrophy
Antrum (incl. incisura angularis)	No atrophy	Stage 0	Stage I	Stage II	Stage II
	Mild atrophy	Stage I	Stage I	Stage II	Stage III
	Moderate atrophy	Stage II	Stage II	Stage III	Stage IV
	Severe Atrophy	Stage III	Stage III	Stage IV	Stage IV

Comment: 

Endoscopic en-bloc resection is the curative treatment of choice for intraepithelial neoplasia and well-to-moderately differentiated (G1 / G2) early gastric carcinomas with a diameter < 2 cm [393]. However, the risk gastritis underlying the cancer development persists, so these patients not only have a risk of local recurrence but also a risk of metachronous carcinomas. In studies from Asian and European countries, the incidence rate of metachronous lesions is reported to be 1–3.5 % per year [431] [432]. The benefit of H. pylori eradication in the prevention of metachronous gastric cancer has been confirmed in several randomized controlled trials and summarized in a review [360] [433] [434]. This applies to both endoscopic resection of early carcinoma and subtotal gastric resection [435]. The final evidence for the necessity of H. pylori eradication was provided in a large prospective randomized study from South Korea on patients after endoscopic resection of early gastric carcinoma. The number of metachronous gastric carcinomas after successful H. pylori eradication was halved compared to the control group during a follow-up period of almost 6 years. The severity of atrophy also decreased in a significant number of patients after H. pylori eradication [436]. In the final assessment of this approach, it remains necessary to regularly monitor patients in the long term with endoscopy and biopsy even after successful H. pylori eradication [437].

Comment: 

Besides the prevention of gastric cancer through H. pylori eradication, a significant reduction in the incidence and mortality of gastroduodenal ulcer diseases has been demonstrated in both European and non-European populations [438] [439] [440]. This effect is particularly evident in risk groups for the development of peptic ulcers and associated complications (bleeding or perforation), such as those with a positive ulcer history, long-term use of NSAIDs, aspirin and oral anticoagulants, or after surgical ulcer repair [441] [442] [443] [444] [445].

 

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8 Guideline – Topic complex 5: Therapy

Comment: 

The statement is based on explorative analysis of clinical studies. Correct prescription, a treatment regimen that can be applied as simply as possible, motivation for compliance as well as smoking cessation are means which can improve treatment success. Acid suppressants need to be prescribed in adequately high doses. The degree of acid suppression is decisive for the efficacy of clarithromycin and amoxicillin [446] [447].

Compliance can be improved by detailed consenting about indication and the course of treatment as well as potential side effects. The extent of the acid suppression is defined by the selection, dosage and frequency of intake of the respective proton pump inhibitor (PPI) as well as by genetic polymorphisms in the cytochrome-P450 2C19 gene (affects mainly racemic omeprazole and lansoprazole; with impact also on other PPIs under certain conditions). With increasing age there are changes in kidney and liver function which can result in much higher drug levels for similar dosing.

Comment: 

There is a relative contra-indication to treatment, if the benefit-risk-ratio is poor. This can be the case for proven or assumed drug intolerance or allergy, which increase treatment related risks. This should be considered before testing for H. pylori. Previous pseudomembranous colitis is not a contra-indication.

It is, however, contra-indicated to merely repeat the therapy regimen that has previously been applied correctly, but which has been unsuccessful.

In scenarios with increased risk constellationAntibiotic resistance of H. pylori is an important risk factor for treatment failure [448]. Primary clarithromycin resistance reduces the eradication rate of first-line therapy with standard triple therapy with clarithromycin and amoxicillin by 66 % and that of standard triple therapy with clarithromycin and metronidazole by 35 % [449]. The latter is also negatively affected by primary metronidazole resistance. In a German multicentre study (ResiNet), the rate of primary clarithromycin resistance increased from 4.8 % in the years 2001/2002 to 10.9 % in the years 2011/2012 [450]. Across Europe, there is a wide range of primary resistance rates against clarithromycin from 5.6 % to 36.6 %, with resistance rates > 20 % mainly observed in southern and eastern European countries [449]. Worldwide, primary and secondary resistance rates against the most widely used antibiotic clarithromycin are > 15 % [451]. A recent European study, which collected data from 18 countries over the period 2008–2017, showed a further increase in resistance to clarithromycin (21.4 %) and levofloxacin (15.8 %) [452]. The most recent German data from 2015–2018 confirm the trend of increasing resistance, with a clarithromycin resistance rate of 11.3 % and a levofloxacin resistance rate of 13.4 % [453]. There continues to be a lack of documented regional resistance data for Germany.

Comment: 

Aim of first line eradication treatment of patients with H. pylori infection should be an eradication rate > 90 %. This goal is desirable but currently not realistic in view of the available drugs, regulatory approval status and the low compliance often encountered in clinical practice [454]. However, therapies with an eradication rate of at least 80 % in intention-to-treat (ITT) analyses in randomized, controlled therapy studies should be used while minimising the possibility of significant adverse events. This recommendation was first given in the Maastricht consensus report, with the 80 % threshold being arbitrary [2]. Regulatory agencies (e. g. FDA, EMA) apply partially different criteria.

Several recent meta-analyses and RCTs have shown that clarithromycin resistance significantly impacts on the effectiveness of clarithromycin-based standard triple therapy. In many countries, including Germany, resistance rates have been increasing in recent years, leading to reduced effectiveness of clarithromycin-based standard triple therapy. In the absence of well-documented local resistance data for Germany, the use of clarithromycin-based triple therapy in first-line treatment is no longer recommended. The desired effectiveness of bismuth-containing quadruple therapy has been demonstrated in several multicentre studies [455] [456] [457].

Comment: 

After a failed first-line treatment, further untargeted and therefore often unsuccessful therapy attempts lead to increased burden for patients and can lead to adverse events. In addition, the risk of developing further resistance increases. Previous treatments with antibiotics – including for other indications – should be appropriately considered when selecting eradication therapy. Resistance to clarithromycin, the key antibiotic of the standard triple therapy, is the main reason for therapy failure. In Germany, there has been an increasing resistance to antibiotics used in eradication therapy in recent decades [448] [453]. Pre-therapeutic resistance to amoxicillin is currently extremely rare. In case of resistance against so-called reserve antibiotics (levofloxacin, moxifloxacin, rifabutin) a further resistance-associated loss of efficacy has to be assumed [449] [453].

Comment: 

Therapy adapted to resistance test results has a significantly higher efficacy than empiric treatment. This was demonstrated in a case-control study with 1232 patients. Eradication rates with resistance-adapted therapy were significantly higher, with an eradication rate of 80.7 % compared to empirical therapy attempts (69.5 %, 214/308; p < 0.01; 71.1 %, 219/308; p = 0.01) [458]. Furthermore, two recently published studies show that resistance-adapted therapies are significantly more cost-effective than empiric therapies [459].

Comment: 

The selection of available antibiotic therapy options after a failed resistance-directed second-line treatment is significantly reduced. Only so-called reserve regimens are available, which should be prescribed by a specialist.

Comment: 

Intravenous eradication therapy is not necessary. There are no data supporting a beneficial effect of eradication on prognosis in the acute setting. Single small studies suggest that H. pylori therapy (omeprazole, amoxicillin, metronidazole) can be given intravenously, however there is no medical indication for this. The vital treatment for complicated ulceration, besides any necessary endoscopic therapy, is profound acid inhibition. Since this does not diminish the treatment success of an oral eradication therapy significantly, eradication treatment should start with oral refeeding once the acute complications are controlled [460] [461].

Comment: 

Peptic ulcer disease can lead to life-threatening complications that can often be prevented by eradication therapy [462]. Therefore, it is necessary to evaluate the success of H. pylori therapy using adequate methods. In case of an uncomplicated duodenal ulcer, this can be a non-invasive breath or stool test. In case of a complicated duodenal ulcer and in any case of a gastric ulcer, a repeat endoscopy is necessary and should be timed in a way that eradication success and ulcer healing can be evaluated at the same time. In case of a MALT lymphoma, confirmation of eradication by invasive test methods (endoscopy is mandatory anyway) is compulsory, because progression of the tumour disease is possible if eradication fails, with alternative treatment options being available (see [Fig. 2]). It is advisable to confirm success of eradication also for other indications, since detection of persistent H. pylori infection has prognostic relevance, patient compliance is likely to be increased by systematic planning of assessment of treatment success and the therapist keeps track on the efficacy of the prescribed eradication therapies (quality assurance).

If the interval between finishing an antibiotic treatment and assessment of treatment success is less than 4 weeks, a “negative finding” of bacteria is not reliable, since this can be the result of suppression of the bacteria below the detection threshold and not a permanent elimination (= eradication). The consequence of this situation would be incorrect prediction of the further course of the disease (also see 2.7).

If the time interval between the end of PPI therapy and evaluation of therapeutic success is less than 2 weeks, a false negative test may result in up to 80 % of cases due to the PPI given, since these lead to suppression of H. pylori. H₂-receptor antagonists in a standard once daily dose or antacids generally do not lead to false negative results (see also 2.7).

Comment: 

The arguments for this approach can be found in the comment to recommendation 5.9.

Comment: 

If there is no indication for a repeat endoscopy then the ¹³C-urea breath test and the monoclonal stool antigen test are considered equivalent options for ensuring eradication non-invasively. A serological result would be only usable if a relevant decrease of the titre (more than 50 %) compared to the pre-therapeutic test can be demonstrated with an identical test kit. However, it can take up to one year until such a decrease can be seen. In some patients there is no such effect at all despite successful eradication. Therefore, serology is generally not recommended to check successful eradication (see also 2.1).

Comment: 

Data from industrial countries suggest a low likelihood of reinfection (< 1 % per year) if eradication has been performed with a recommended therapy (see above), the eradication success is checked with a combination of reliable methods no earlier than 4 weeks after completion of antibiotic therapy and confounding factors, such as pathogen suppression by PPI at the time of diagnosis, are excluded [463] [464]. With this approach, routine follow-up is not recommended. In cases of “vital” indication (e. g. history of ulcer bleeding, MALT lymphoma), a repeat check of permanent eradication, e. g. after one year, may be advisable.

 

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9 Guideline – Topic complex 6: Specifics for children and adolescents

Multiple recommendations from the last German S2k guideline 2016 (AWMF registration number: 021–001) remain unchanged. The literature cited there is not listed here again. The literature from 2015 onwards has been considered. Included in this update are the evidence-based guidelines of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN and NASPGHAN) [465], which the Latin American guideline [466] also follows, as well as the updated Japanese guideline for children and adolescents [467]. It should be noted that decisions on the diagnosis and treatment of H. pylori infection strongly depend on the patient’s age (preschool age, primary school age or teenager) and are also influenced by parents’ concerns and wishes for or against H. pylori eradication therapy. This explains the seemingly divergent recommendations and recommendation strengths within this chapter and compared to those regarding adults in the other section of this guideline.

Comment: 

In countries with low prevalence like Germany, chronic infection with H. pylori is mostly acquired at during early childhood. New infection after the age of 6 years old are rather rare [468]. The observed immunological reaction against the infection is usually milder in children compared to adults. This is due to a down regulation of the immune response and an increase of regulatory T-cells and anti-inflammatory cytokines, e. g. IL-10, which inhibit increased pro-inflammatory immune responses and associated tissue damage. Recent studies and a meta-analysis show an inverse relationship between infection and atopy (OR = 0.82; 95 % CI: 0.73–0.91; p = 0.01) and childhood asthma (OR = 0.68; 95 % CI: 0.54–0.87; p = 0.002), especially in infection with CagA(+) strains (OR = 0.54; 95 % CI: 0.35–0.96; p = 0.034) [469] [470] [471] [472] [473]. An inverse association of H. pylori infection has also been shown for inflammatory bowel disease [474] [475]. These potentially positive long-term effects of early infection on overall health must be weighed against the possible risks of ulcer disease or gastric cancer later in life and influence the timing of when preventive eradication therapy should be performed. Chronic H. pylori infection is rarely symptomatic in childhood. The risk for an ulcer is 6–7 % in symptomatically infected children and adolescents. [476]. Gastric cancers caused by H. pylori-infection do not occur at this age [477]. In addition, the available treatment options in childhood are more limited compared to adults, as reserve antibiotics are mostly not approved for these age groups.

In conclusion, there is a different benefit-risk-consideration in children and adolescents compared to adults, resulting in different recommendations for this age group. Therefore, testing for the infection in children and adolescents should be restricted to individuals who have a high likelihood to directly benefit from eradication therapy. Treatment with the aim of prevention of complications at a later age should be postponed until adulthood.

Comment: 

Abdominal pain is a common complaint among children and adolescents. Out of the 15,241 participants (aged 3–17 years) of the KIGGS study, a health survey of children and adolescents in Germany, 69.3 % of 3–10-year-old children and 59.6 % of 11–17-year-old adolescents reported abdominal pain in the last 3 months [478]. Recurring symptoms were reported by 35.9 % of children and 28.5 % of adolescents, with the prevalence decreasing significantly with age. The frequency did not differ among children with migration background and was independent of social class, with the exception that adolescent girls with migration background reported abdominal pain more frequently compared to their age-matched peers without migration background. The abdominal pain is usually functional and stress-related [479]. The definitions of functional gastrointestinal disorders (Rome criteria) depend on age. Complicating the stratification is the fact that children under 8 years of age often cannot provide detailed information on the severity, character and location of the pain. A systematic review cited in the last guideline found no association between abdominal symptoms and H. pylori infection in children and adolescents [480]. New prospective studies involving over 2000 children and adolescents who were tested for the presence of H. pylori infection using ¹³C-urea breath testing test came to the same conclusion [481] [482] [483]. If children and adolescents presenting with abdominal pain were tested for H. pylori using a non-invasive test, the rejection of a “test and treat” strategy would lead to a large number of children requiring endoscopy, in particular among children with migration background.

These children would not benefit from H. pylori eradication treatment as abdominal pain in H. pylori-positive children is usually functional and H. pylori-induced ulcers are rare. Eradication therapy for the prevention of gastric cancer should be postponed until adulthood.

In summary, paediatric gastroenterologists advise against routine non-invasive H. pylori diagnostics in patients with abdominal pain for the above-mentioned reasons (for exceptions see recommendation 6.3). Testing for H. pylori in children and adolescents with suspected functional abdominal pain, along with possibly subsequent endoscopy, is usually not indicated.

Comment: 

Chronic ITP in childhood is a chronic autoimmune disease with antibodies against and destruction of platelets resulting in thrombocytopenia (< 100 × 10⁹/L) over a duration of at least 12 months. Since the last guidelines, some uncontrolled studies [484] [485] [486] and one controlled study with 22 patients with H. pylori infection have been published [487]. In the latter, children with successful bacterial eradication had a better platelet response compared to the control group. This, albeit small, evidence justifies non-invasive testing for H. pylori in paediatric patients with chronic ITP. In positive cases, a decision for endoscopy prior to eradication therapy should be made on a case-by-case basis depending on platelet count.

For children with recurrent Henoch-Schönlein purpura with gastrointestinal involvement, there are case reports which justify testing and possibly treating H. pylori [488] [489]. Like Henoch-Schönlein purpura, the aetiology of chronic urticaria is unclear and trigger factors are largely unknown. The disease is much less common in children than in adults. Although the infection rates of H. pylori in children are low at around 20 % [490] [491] [492], uncontrolled studies reported a high percentage of resolution of urticaria in infected children and adults after successful eradication treatment [493]. Due to the high disease burden of chronic urticaria, affected paediatric patients should be offered a non-invasive test even if this is based on low evidence.

The recommendation for testing children or grandchildren of gastric cancer patients is also controversial, as eradication therapy can be performed for cancer prevention from the age of 18 years old. The offer of testing a schoolchild or adolescent whose parent or grandparent died of gastric cancer is rather based on psychological reasons. The probability of infection in grandchildren of affected individuals is rather low and a negative test would alleviate anxiety. Therefore, the decision for or against testing must be made depending on the age of the child, the overall situation and any associated illnesses and must be discussed with the legal guardians and the child/adolescent.

Comment: 

Since the last guideline published in 2016, no new publications have emerged that would change this recommendation. Iron deficiency anaemia in children and adolescents has numerous causes and its evaluation should follow the usual guidelines. H. pylori infection as the sole cause of iron deficiency anaemia is very rare [494] [495]. The synthesis of hepcidin appears to be upregulated in H. pylori-infected children with iron deficiency [496]. Asymptomatic H. pylori infection has usually no effect on iron absorption from food [497]. Therefore, a non-invasive test for the presence of H. pylori infection must not be performed in the initial diagnosis [465]. If an upper endoscopy is performed to evaluate iron deficiency anaemia for other reasons (e. g., therapy-refractory course, suspected occult bleeding, unclear enteropathy or Crohn’s disease), biopsies for H. pylori diagnosis, including antibiotic resistance testing, should be taken (see recommendation 6.6.). Eradication therapy for iron deficiency anaemia should be combined with iron replacement therapy [465].

Comment: 

No publications have been published since the last guidelines in 2016 that would change this recommendation. H. pylori infection is only one of many causes of ulcers or erosions in the stomach or duodenum of children and adolescents [498] [499]. However, the infection is easily treatable and recurrences are rare after successful therapy. If an ulcer is found during endoscopy, numerous biopsies should be taken from the antrum and corpus for antibiotic resistance testing, histology and rapid urease test. Sensitivity for pathogen detection is reduced in case of bleeding. Serology for IgG antibodies against H. pylori may be helpful in cases of suspicion of a false negative finding in histology, culture or the rapid urease test [467].

Until the results of the antibiotic resistance tests are obtained, standard dose PPI (see [Table 9]) must be given after endoscopy to reduce or prevent symptoms and complications, respectively. This 1–2-week pre-treatment with PPI does not negatively affect the success of subsequent eradication therapy. In cases of deep ulcers, PPI can be continued for an additional 2–4 weeks after the 2-week course of antibiotics [465]. Eradication therapy must confirmed and testing should be performed no sooner than four weeks after stopping antibiotics or two weeks after stopping PPI (see recommendation 6.21). In most cases, repeat endoscopy is not necessary in children and adolescents with ulcers after successful treatment of the infection. If the therapy fails, treatment should continue until bacterial eradication is confirmed.

Table 9 Standard dosing for triple therapy according to body weight [strong consensus].

Medication	Body weight	Morning	Evening
PPI (Es)Omeprazole) [*]	15 to 24 kg	20 mg	20 mg
	25 to 34 kg	30 mg	30 mg
	> 35 kg	40 mg	40 mg
Amoxicillin	15 to 24 kg	500 mg	500 mg
	25 to 43 kg	750 mg	750 mg
	> 35 kg	1000 mg	1000 mg
Clarithromycin	15 to 24 kg	250 mg	250 mg
	25 to 43 kg	500 mg	250 mg
	> 35 kg	500 mg	500 mg
Metronidazole	15 to 24 kg	250 mg	250 mg
	25 to 43 kg	500 mg	250 mg
	> 35 kg	500 mg	500 mg

PPI = proton pump inhibitor.

^* for other PPI, the equivalent dose for (es)omeprazole must be calculated (see comment).

Comment: 

Compared to adults, H. pylori infection in children and adolescents is a visual diagnosis during endoscopy. In the international European registry study of 1333 unselected H. pylori-infected children and adolescents (median age 12.6 years) who underwent endoscopy due to complaints, nodularity in the antrum typical of the infection was found in 78 %, a gastric or duodenal ulcer in 5.1 % and erosions in 12.8 % [476]. The main indications for upper endoscopy were dyspeptic symptoms or abdominal pain in 81.2 % of cases.

In most European countries, during upper endoscopy of paediatric patients’ systematic biopsies are taken for histology from four levels (two biopsies each from the duodenum, antrum, body and distal oesophagus, respectively), even if the macroscopic findings are inconspicuous. Indications for OGD where routine biopsies are not taken include: immediate repeat endoscopic evaluation of oesophageal findings, removal of a foreign body, or other interventions (bougie dilation, feeding tube replacement). H. pylori infection is diagnosed histologically regardless of the indication for endoscopy or the age of the child and parents and patients must be informed of the diagnosis. Even though antral nodularity is not correlated with pain [500] and in the majority of symptomatic children with H. pylori gastritis, the symptoms are likely to be functional in nature, most parents of children with a confirmed infection choose eradication therapy. For successful treatment, individual selection of antibiotics based on antibiotic resistance testing is important (see recommendation 6.16). Therefore, in cases of endoscopy and incidental finding of antral nodularity, biopsies should be taken for resistance testing. In individual cases where parents decide against therapy, e. g. in very young children under 6 years with an increased risk of reinfection or because antibiotic therapy is refused, it is recommended to take at least two additional biopsies from the antrum and corpus for culture/PCR and antibiotic resistance testing if antral nodularity is present [501].

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this recommendation. As stated in the introduction, the indication for treatment depends on the age of the child and the context. In children and adolescents, one biopsy is usually taken from the corpus and antrum even in with mucosa looking normal. If H. pylori positive gastritis is found in children incidentally on histology in routine biopsies, the advice to parents of preschool aged children would be against eradication, e. g. if endoscopy was performed for assessment of coeliac disease, but, in contrast, treatment would be recommended, if the patient is, for example, a 16-year old adolescent undergoing endoscopy for assessment of Crohn’s disease.

Histology also influences the decision for or against eradication therapy (e. g. moderate to severe active body gastritis versus mild chronic antrum gastritis). The “can” recommendation provides the required flexibility in different clinical scenarios with different benefit-risk assessment for isolated H. pylori gastritis.

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this recommendation. After failed treatment, the presence of a resistant bacterium to one or both of the antibiotics used is very likely [476] [502]. If there are no symptoms and only H. pylori gastritis was present, eradication therapy can be postponed for cancer prevention until after the age of 18, for example, when a bismuth-based therapy with Pylera is feasible and approved.

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this recommendation.

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this statement. More recent publications on rapid stool antigen tests [503] [504] [505] [506] or detection of H. pylori in stool by real-time PCR [507] show that these are inferior in their diagnostic accuracy compared to the ¹³C-urea breath test and to earlier studies on laboratory-based ELISA tests.

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this recommendation. Recently, Kusano et al. suggested in 2021 that the accuracy of the serum antibody test would be sufficient for practical use in children aged 13–14 years [508]. However, the sample size was small and with a specificity of 99.5 % (95 % CI: 98.2–99.9), the sensitivity was only 93.3 % (95 % CI: 68.1–99.8) with a large confidence interval. Therefore, serological tests should be applied only in individual clinical scenarios, for example, when an infection cannot be detected by other methods in case of long-term acid suppression [467].

Comment: 

In the paediatric European and North American guidelines on H. pylori infection, a primary eradication rate of at least 90 % is recommended as therapeutic aim to avoid further invasive investigations and antibiotic treatments in those affected [465]. A primary high eradication rate of > 95 % (optimal) or at least > 90 % in compliant patients is in keeping with the aims set by antibiotic stewardship, which is more and more required for the therapy of H. pylori infections [509]. Repeated and simultaneous administration of different antibiotics has potential negative effects on the microbiome in the medium to long term. Every failed therapy has a high risk of the patient developing antibiotic-resistant H. pylori. Mutations for clarithromycin resistance occur particularly rapidly under macrolide therapy. Thus, every further therapy has a lower likelihood for bacterial eradication. The higher target value in this statement compared to 80 % in adults follows the strict demands of antibiotic stewardship in paediatrics and also arises from the lack of approval of bismuth combinations (Pylera) and most reserve antibiotics (levofloxacin, rifabutin) for paediatric patients [476] [510] [511] [512] [513].

Comment: 

Since the last guidelines published in 2016, no publications have been added that would change this recommendation. Data of the EuroPedHP registry show a high primary antibiotic resistance in children and adolescents (n = 1168) in European countries including Germany, with an average of 25 % for clarithromycin and 21 % for metronidazole [476]. Resistances vary from country to country, for example, above-average clarithromycin resistance rates are reported in children from southern Europe [514] [515] and Poland [516], while Israel has a particularly high primary metronidazole resistance of 33 % [517]. In a Turkish study, the primary resistance against clarithromycin in children was 27 %, while that for fluoroquinolones was already 15 % [511]. The latter suggests that the children acquired the resistant bacteria from their parents. There are therefore significant differences between countries, which are reflected in different resistance patterns in Germany in children and adolescents from migrant families compared to German children without a migration background. Therefore, regional or national recommendations for children make little sense.

With the help of the EuroPedHP registry, it was also shown that a primary eradication rate of 90 % can be achieved if a triple therapy that is tailored to individual antibiotic resistance is administered for 2 weeks at a sufficiently high dose for PPI and antibiotics in accordance with the guidelines. When taking at least 90 % of the prescribed doses, the eradication rate increased to 93 %. Results from Slovenia [542] and Japan [518] confirm the high success rates of the antimicrobial susceptibility-guided triple therapy. When comparing four different treatment regimens in children in China, only a bismuth-based quadruple therapy achieved eradication rates of 90 %, while the standard triple therapy, sequential therapy and concomitant therapy missed the target with 74 %, 69 % and 85 %, respectively [513]. Both sequential and concomitant therapy involved administering three antibiotics with PPI. One of the three antibiotics used did not contribute to eradication success which is against antibiotic stewardship recommendations [509].

Comment: 

Newer publications support the unchanged recommendation from the 2016 published guideline [519] [520] [521] [522] [523].

Comment: 

As stated in recommendation 6.16, in children and adolescents, standard triple therapy (STT) with PPI, amoxicillin and clarithromycin or metronidazole for 7–14 days only achieves unsatisfactory eradication rates due to the high primary antibiotic resistance rates in Europe [476], if the individual antibiotic resistance situation is not considered when selecting antibiotics. In Germany, a bismuth-based therapy is not available for children and adolescents, except in the form of Pylera, which is only available off-label for adolescents due to its tetracycline content. Therefore, a so-called “tailored triple therapy” (TTT) for 14 days, which is based on the results of antibiotic resistance testing, is the first-choice treatment for children and adolescents [465] [512] [518] (see [Fig. 5]). The dosage is determined based on the child’s body weight, as shown in [Table 10]. The dose per kg body weight is higher in younger children weighing up to 35 kg compared to adolescents or adults.

Fig. 5 Flow chart for the selection of first line antibiotic therapy depending on individual antibiotic resistance [strong consensus]. AMO: Amoxicillin; CLA: Clarithromycin. MET: Metronidazole. PPI: Proton-pump inhibitor. [rerif]

Table 10 Dosing for high dose amoxicillin therapy according to body weight. Dosing for PPI and metronidazole according to [Table 9] [strong consensus].

Medication	Body weight	Morning	Evening
Amoxicillin	15 to 24 kg	750 mg	750 mg
	25 to 34 kg	1000 mg	1000 mg
	> 35 kg	1500 mg	1500 mg

Comment: 

In a meta-analysis published in 2016 on sequential therapy (SQT; PPI with amoxicillin for 5 days, followed by PPI with clarithromycin and metronidazole for 5 days) in children, data from 14 RCTs with 1698 participants, of which 718 received SQT and 980 received standard triple therapy (STT), were evaluated [524]. The intention-to-treat (ITT) analysis yielded an eradication rate of 73 % (95 % CI: 70–78) for SQT and 66 % (95 % CI: 64–70) for STT. Although SQT was significantly more effective than STT (RR 1.15, 95 % CI 1.09–1.23), it was still far from the desired treatment aim of 90 % eradication success. Studies published thereafter confirm the unsatisfactory eradication rates of SQT in paediatric patients, especially when resistance to one of the antibiotics was present [525] [526] [527]. A meta-analysis in adults demonstrated a trend towards decreasing effectiveness of SQT since 2008 [527]. In an analysis of multinational data by the ESPHGAN Study Group for Helicobacter pylori by Schwarzer et al. 2016, SQT in children with fully sensitive strains showed an eradication rate of only 85.8 % (115/134). The success rate significantly decreased to 72.6 % (45/62) when the children were infected with strains resistant to clarithromycin or metronidazole [525]. A study by Zhou et al. 2020 showed that SQT over 10 days (PPI with amoxicillin for 5 days, followed by PPI with clarithromycin and metronidazole for 5 days) achieved a lower treatment success rate of 69.5 % (41/59, [95 % CI: 57.8 %-81.2 %]) than standard triple therapy with 74.1 % (43/58, [95 % CI: 62.8 %-85.5 %]) [513]. Like concomitant therapy, sequential therapy has the disadvantage that children are exposed to three different antibiotics, compared to only two antibiotics in triple therapy. In summary, recent publications support the recommendation not to use sequential therapy in children and adolescents.

Comment: 

If no resistance results are available before initiation of first-line therapy of H. pylori infection, European and North American guidelines recommend a metronidazole-based triple therapy over 14 days with an increased amoxicillin dose according to [Table 10] [465]. This therapy also has a relatively high success rate of 66 % even in the presence of double resistance [529]. In older adolescents, the bismuth-based fixed combination would be an alternative. However, patients and parents should be informed about the off-label use.

Comment: 

Since the last guideline was published in 2016, no publications have been added that would change this recommendation [530]. It should be noted that in some population groups, high resistance rates to reserve antibiotics already exist, even in children. Rifabutin should be avoided as much as possible as it is an important part of tuberculosis therapy and tuberculosis infections are increasing, in particular in the paediatric population with migration background, which is also affected by higher incidence of H. pylori infection in Germany.

Comment: 

Poor compliance is a significant risk factor for treatment failure. The study by Kotilea et al. 2017 showed that with high compliance, i. e. taking over 90 % of the prescribed doses of medication, a success rate of 89.9 % was achieved, while patients with poor compliance had a treatment success rate of only 36.8 % [531]. The importance of reliable and complete medication intake for treatment success must be explained to parents and children. Flyers in numerous languages have been created by ESPGHAN and can be downloaded free of charge. https://www.espghan.org/knowledge-center/education/H-Pylori-Patient-Parent-Guide

Comment: 

Since the last guideline was published in 2016, no publications have been added that would change this recommendation. In paediatric patients, a change in symptoms after therapy does not necessarily indicate successful eradication of the bacteria. However, the result of checking eradication success has consequences for individual recommendations, which is why a mandatory recommendation (must) has been made.

Comment: 

In a systematic meta-analysis by Feng et al. of 29 RCTs with a total of 3122 paediatric participants, 17 different probiotic treatment regimens were identified [532]. Compared to placebo, there was a significant improvement in the eradication rate ((RR) = 1.19; 95 % CI: 1.13–1.25) and a reduction of side effects (RR = 0.49; 95 % CI: 0.38–0.65). However, it should be noted that studies with different probiotics should not be pooled. Lactobacillus casei was identified as the best probiotic strain in terms of eradication rate (p = 0.84) and the combination of Lactobacillus acidophilus and Lactobacillus rhamnosus was identified as best in reducing side effects (p = 0.93) [532]. In the meta-analysis by Fang et al., five paediatric RCTs with 484 participants who received triple therapy with amoxicillin, clarithromycin and PPI, as well as various strains of Lactobacillus (L. acidophilus with L. rhamnosus, L. reuteri, L. casei and L. GG) were analyzed [533]. The eradication rate was significantly higher in the supplementation group (RR = 1.19, 95 % CI: 1.07–1.33) and was higher at a dosage ≥ 5 × 109 with RR = 1.36 (95 % CI: 1.15–1.60) compared to 1.08 (95 % CI 0.86–1.35) at a lower dosage. In addition, the duration of supplementation affected the eradication rate. In two RCTs (n = 110), Lactobacillus was administered for longer than ≥ 4 weeks and achieved better eradication rates (RR = 1.24; 95 % CI: 1.06–1.46) than at short supplementation duration (3 RCTs ≥ 2 weeks; n = 374; RR = 1.17; 95 % CI: 0.96–1.44) compared to placebo. Similarly, the administration of Lactobacillus significantly reduced the incidence of diarrhoea (RR = 0.30; 95 % CI: 0.10–0.85) [533]. A randomized study in which the combination of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, Streptococcus thermophilus, Bifidobacterium infantis and Bifidobacterium breve was administered showed significantly higher eradication rates (p = 0.040) and lower side effects (nausea/vomiting p = 0.020 and diarrhoea p = 0.039) [534]. Particularly in children, Lactobacillus rhamnosus GG showed a significant reduction in antibiotic-associated diarrhoea (5 RCTs, n = 445; RR = 0.48; 95 % CI: 0.26–0.89) [535]. However, the combination of Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium lactis did not show any improvement compared to the placebo group [536]. The meta-analysis by Szajewska et al. examined the effects of Saccharomyces boulardii as a supplementation to H. pylori eradication treatment in 11 RCTs [537]. In two RCTs conducted on children (n = 330), a better eradication rate was observed (RR = 1.13, 95 % CI: 1.03–1.35). Saccharomyces boulardii significantly reduced the incidence of side effects in both studies (p < 0.05).

In summary, individual probiotics or probiotic combinations reduce side effects, especially antibiotic-associated diarrhoea, which can occur during eradication therapy and improve eradication rates in sub-group analyses in children [538] [539] [540]. Whether this is a direct or indirect effect through improving compliance remains unclear. Due to the heterogeneity and methodological limitations of some studies, further improved, rigorous, clinical studies are needed to provide recommendations for supplementation with defined probiotic strains, their dosage and duration [541].

 

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10 Guideline – Topic complex 7: Non-Helicobacter pylori-associated ulcers

10.1 Preamble

Gastroduodenal ulcers can also be caused by factors other than H. pylori infection (see statements 7.1 to 7.2). Non-steroidal anti-inflammatory drugs (NSAIDs) are particularly noteworthy. These can be divided into non-selective NSAIDs (nsNSAIDs) and selective, COX-2-specific NSAIDs (coxibs). All NSAIDs are characterized by potential nephro- and hepatotoxicity as well as possible cardiovascular risks. Therefore, contraindications and side effects must be considered for both subgroups. Differences between the two groups exist with regards to the frequency of gastroduodenal ulcers and intestinal ulcers [542] [543] [544] [545].

Prophylactic use of PPIs can be considered for intake of NSAIDs, acetylsalicylic acid (Aspirin) and for other reasons (see statement 7.2). Comparative studies on the dosage of different PPIs in this indication field only exist for NSAID therapy [546] [547] [548] [549]. In addition, the Korean guideline from 2020 compared randomized, controlled studies on both lower and higher doses with a similar protective effect [550]. Thus, direct and indirect evidence shows no advantage for a higher dose than 15 mg lansoprazole, 20 mg omeprazole, esomeprazole, or pantoprazole. There are no head-to-head dose studies on PPI prophylaxis in case of aspirin intake, but efficacy was proven in form of a meta-analysis, with similarly low dosages (10–20 mg rabeprazole, 15 mg lansoprazole, 20 mg omeprazole, esomeprazole, or pantoprazole) [551]. Regarding PPI dosage for the prophylaxis of bleeding on oral anticoagulation, no dose recommendations can be derived from existing studies [552]. Therefore, PPI should be used at the minimum dose as outlined above.

It needs to be taken into account that many studies on the efficacy of PPI used for prophylaxis have been conducted in Asian populations. These patients are less likely to have a genetic polymorphism that leads to faster PPI metabolism [553] [554]. Therefore, doubling the above-mentioned dosage may be useful for some Europeans, at least in secondary prophylaxis.

Comment: 

In addition to H. pylori infection, the use of nsNSAIDs is a major cause of gastroduodenal ulcers. Another important cause is the use of aspirin, even in low dose as long-term treatment [555]. Overall, the data on the epidemiology of uncomplicated gastroduodenal ulcers is limited, but extensive data exits on gastroduodenal ulcer bleeding [542] [543] [545] [556] [557] [558] [559] [560] [561]. For these, the risk associated with long-term therapy with nsNSAIDs and low-dose aspirin is particularly well established. In some regions, these drugs exceed already the importance of H. pylori infection as the causative factor in ulcer bleeding [562].

Table 11 Rare Causes of Gastric and/or Duodenal Ulcers.

Inflammatory diseases:  Eosinophilic gastroenteritis Crohn’s disease Behcet’s disease Sarcoidosis Vasculitis Idiopathic  Infections:  CMV HSV Candida, EB virus, Helicobacter heilmannii, Mucorales, Mycobacteria, Treponema pallidum Ischemia or necrosis:  Recent transarterial chemoembolization (TACE) Recent percutaneous radiotherapy or radioembolization (SIRT) Recent coiling (at the stomach or duodenum) Crack/cocaine abuse Amphetamine abuse Medication-induced or -associated:  SSRIs Bisphosphonates, potassium Sirolimus, mycophenolate Chemotherapy (e. g., 5-FU or MTX) Spironolactone Neuroendocrine tumours or mediator-induced:  Gastrinomas (including MEN-1) Systemic mastocytosis Basophilia in myeloproliferative disorders (basophilic leukaemia, CML) Obstruction:  Duodenal stenosis, e. g. in annular pancreas Postoperative:  Antrum exclusion Gastric bypass Severe illnesses (“stress ulcers”):  Acute Respiratory Distress Syndrome (ARDS) Shock with hypotension, sepsis, polytrauma, burns, traumatic brain injury with neurosurgery Liver/kidney failure Prolonged mechanical ventilation Tumour infiltration:  e. g. in pancreatic cancer

Comment: 

In addition to H. pylori infection and the intake of aspirin/NSAIDs, numerous other diseases are considered rare causes of gastroduodenal ulcers. These rare causes include: Crohn’s disease, eosinophilic gastroduodenitis, systemic mastocytosis, vasculitis and ischemia, as well as tumours (e. g. gastrinomas), metastases and other consuming diseases. In immunocompromised or immunosuppressed patients (HIV infection, after organ transplantation), viral infections or reactivations (CMV, EBV, HSV) with gastroduodenal ulcers occur more frequently [563] [564] [565] [566]. Increased exposure to radiation from a previous radiotherapy or internal radiotherapy (e. g. as part of selective internal radiotherapy (SIRT)) can cause gastrointestinal ulcers throughout the gastrointestinal tract [567] [568] [569] [570] [571] [572]. As a side effect of immunooncological therapy, gastroduodenal ulcers are rare compared to other side effects, but due to the increasingly broader application of modern oncological treatment concepts, their frequency is increasing [567] [568] [569].

Treatment is based on the underlying disease or the management of side effects, but usually involves PPI therapy until the lesions have healed, without evidence from controlled studies to support this. In a small proportion of patients, no cause of the ulcers is found despite careful investigation (idiopathic ulcers).

Comment: 

Risk factors for uncomplicated gastroduodenal ulcers include advanced age, a history of ulcer and the presence of common or rare ulcer causes [555]. There is no fixed age limit of 60 or 65 years, but rather an increasing frequency with increasing age [573]. More literature is available for gastroduodenal ulcer complications, particularly bleeding [558] [561] [573] [574] [575] [576]. Risk factors include severe comorbidities [574]. Other risk factors include smoking [555] and particularly severe psychosocial stress situations (e. g. after earthquakes) [577] [578] [579]. However, these risk factors are only mentioned in the commentary as the effectiveness of PPI prophylaxis for these factors has not been demonstrated ([Table 12]).

Table 12 Association of non-H. pylori risk factors with gastroduodenal ulcers or ulcer bleeding/complications, respectively.

	Gastroduodenal Ulcer	Ulcer bleeding/complications
	Age > 60	Age > 60
Risk factors	History of ulcers	History of ulcers
	Medication: nsNSAIDs, aspirin	Medication: nsNSAIDs, aspirin, SSRI, P2Y12 inhibitors (DOAC, VKA, heparin, selective factorX inhibitors), systemic steroids
	Other risk factors: significant co-morbidities[#], significant psychosocial stress factors, smoking	Other risk factors: significant co-morbidities[#]

Even though smoking is a risk factor, positive smoking status in itself is not an indicator for PPI prophylaxis (see 7.5 and 7.9).

^# see Table 11.

Comment: 

Risk factors for ulcer complications include age > 60 years, a history of ulcers and the use of anticoagulants [544] [580] [581] [582] [583]. Anticoagulants that are considered a risk factor for ulcer complications include both vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs), selective factor Xa inhibitors (fondaparinux) and heparins. Other risk factors for ulcer complications include the presence of malignancy, advanced kidney, liver, lung and/or cardiovascular disease or diabetes mellitus [544] [581] [584] [585] [586] [587] [588] [589].

Note: 

Please see recommendation 3.16 regarding testing for H. pylori infection prior to anticoagulation.

Comment: 

Numerous non-selective nonsteroidal anti-inflammatory drugs (nsNSAIDs) are known to cause gastroduodenal ulcers and ulcer bleeding [542]. Prospective randomized studies [549] [590] [591] as well as two meta-analyses [592] [593] have shown that concomitant administration of a PPI, an H₂ receptor antagonist or misoprostol reduces the likelihood of developing an ulcer and the rate of ulcer bleeding significantly. PPIs are by far the most effective class of drugs among gastroprotective agents. [593] [594] ([Table 13]).

Table 13 Recommendation for PPI prophylaxis depending on the clinical scenario and the current medication [strong consensus].

Clinical scenario		PPI Prophylaxis
Presence of risk factors independent of age	nsNSAID long term treatment	Must
	Coxib – long term treatment	Should
	Long term monotherapy: aspirin, P2Y12 Inhibitors, DOAC, VKA	Should
	Long-term monotherapy with SSRI	Can
Gastroduodenal bleeding  (PPI prophylaxis when continuing therapy)	While on nsNSAIDs	Must
	While on aspirin, P2Y12 -Inhibitors, DOAC, VKA	Must
	While on systemic steroid treatment	Should
Therapy with two agents affecting coagulation		Must
SSRI Therapy	Co-medication: nsNSAIDs, coxib, aspirin, P2Y12 -inhibitors, Co-	Should
	Co-medication: DOAC, VKA	Can
Intensive care patients	Risk factors: Invasive ventilation > 48 h or if at least two of the following risk factors apply: ITU stay > 1 week sepsis ARDS liver failure kidney failure polytrauma burns high dose steroid therapy	Should

Comment: 

Compared to nsNSAIDs, Coxibs show a significantly reduced rate of gastroduodenal ulcers and ulcer bleeding [593]. Therefore, for most patients with planned long-term NSAID treatment, they are an equivalent alternative to a combination of nsNSAIDs with a PPI [592] [595]. However, in high-risk patients, the combination of a Coxib with a PPI is safer than monotherapy with a Coxib [596]. For several risk groups, it has been shown that the combination of a Coxib with PPI therapy significantly reduces the incidence of gastroduodenal ulcers or ulcer bleeding compared to monotherapy with a Coxib or nsNSAID plus PPI therapy. This affects in particular patients over the age of 60 years [549], patients with a history of ulcers or ulcer bleeding [549] [596] [597] and patients receiving anticoagulation with a VKA [598] [599]. When analysing combination therapies, the combination of Coxibs with an SSRI was shown to be significantly more dangerous (in addition to the dangerous combination of nsNSAIDs with corticosteroids or anticoagulants), whereas the combination of a Coxib with corticosteroids did not show an increased rate of ulcer bleeding in this study [599].

Comment: 

A randomized study demonstrated that ranitidine therapy alone led not to significant healing of nsNSAID induced ulcers if the nsNSAID therapy was continued. However, when the nsNSAID was discontinued at the same time, a significantly higher rate of healing was achieved compared to nsNSAID plus placebo [600].

Reference to recommendation 3.19: 

Patients who develop a gastroduodenal bleeding on nsNSAID therapy should be tested for H. pylori infection and, if the bacterium is detected, undergo eradication therapy.

Comment: 

A prospective randomized study from Hong Kong compared an eradication therapy only to omeprazole therapy only in patients with gastro-duodenal bleeding and H. pylori infection. The PPI was much more effective than the eradication therapy (4.4 % versus 18.8 %) [601]. Therefore, long-term PPI prophylaxis is crucial. It has not yet been investigated to what extent prior eradication therapy is advantageous in this situation. Therefore, sole PPI prophylaxis would be a justifiable treatment. However, a case-control study showed a relative risk of 8 in patients with a gastro-duodenal ulcer bleeding who also had an H. pylori infection and took an NSAID [602]. Therefore, eradication therapy may have a positive effect.

Comment: 

Long-term treatment with aspirin increases the risk of developing gastroduodenal ulcers [603] [604] [605] [606]. The risk of gastroduodenal bleeding is also increased with other anticoagulant medications [607] [608] [609] [610] [611] [612] [613] [614]. For aspirin, the risk increases with higher doses and in the presence of H. pylori infection [615].

Limited evidence from case-control and cohort studies suggests a possible association between the aldosterone antagonist spironolactone and the occurrence of gastrointestinal bleeding. However, due to a lack of causality and insufficient evidence a reliable recommendation cannot be made.

Both, population-based data and prospective randomized studies demonstrate the effectiveness of PPI prophylaxis in reducing severe bleeding events [616] [617]. Meta-analyses of published prospective studies show that PPIs are superior to H₂ receptor antagonists in the prevention of ulcers and bleeding [551] [594] [618] [619].

Reference to recommendation 3.18 

Patients who develop gastroduodenal bleeding under aspirin, P₂Y₁₂ inhibitors or DOACs should be tested for H. pylori infection and treated with eradication therapy if the bacterium is present.

Comment: 

Only one prospective randomized study investigated whether H. pylori testing plus eradication is useful in patients on coagulation-effective medication after gastroduodenal bleeding. This study showed for low-dose aspirin, that re-bleeding is rare after H. pylori-positive ulcer eradication plus aspirin [620]. Therefore, eradication has presumably a positive effect. However, it is more important to highlight the high-risk situation in patients with negative test results. These patients should receive long-term PPI prophylaxis. Therefore, patients with a history of ulcer bleeding and negative H. pylori test results must be treated consistently over the long term. In addition, eradication therapy may also reduce the risk of recurrent bleeding in patients taking DOACs [621]. There not studies on P2Y12 inhibitors and VKAs with regards to this issue (indirect evidence).

Comment: 

The optimal management of patients who develop an ulcer bleeding while taking a different platelet aggregation inhibitor than aspirin for secondary prevention of a cardiovascular event has not been investigated in prospective clinical studies. A change in platelet aggregation inhibition should be made on an individualized basis and with strict consideration of the indication for treatment. If it is acceptable from a cardiovascular perspective, switching to a P₂Y₁₂ inhibitor with lower bleeding risk should be considered [622]. Although clopidogrel therapy increases the risk of peptic ulcer bleeding, continuation of clopidogrel treatment after ulcer bleeding is not associated with increased mortality [623]. In a retrospective longitudinal cohort study of patients with a history of peptic ulcer, 12 % of patients on clopidogrel therapy experienced ulcer complications (bleeding or perforation) within one year [624]. A population-based retrospective cohort study of 14,627 patients who had previously experienced a severe complication of peptic ulcer and were taking a platelet aggregation inhibitor for secondary prevention of a cardiovascular event (12,001 aspirin, 2,626 clopidogrel) showed an incidence of hospital readmission due to a severe gastrointestinal complication of 0.125 per person-year on aspirin, 0.103 per person-year on aspirin and PPI, 0.128 per person-year on clopidogrel and 0.152 per person-year on clopidogrel and PPI. The additional use of a PPI with aspirin significantly reduced the risk of hospitalization due to GI complications (hazard ratio [HR] = 0.76; 95 % CI, 0.64–0.91). This effect was not documented for the additional use of a PPI with clopidogrel (HR = 1.08; 95 % CI, 0.89–1.33) [625]. A systematic review with meta-analysis of published studies on the recurrence of gastrointestinal complications with clopidogrel, clopidogrel plus PPI and aspirin plus PPI shows no difference between the three regimens. Due to cost-effectiveness, the authors recommend aspirin plus PPI for secondary prevention of cardiovascular events in patients at high risk of upper GI bleeding [626]. There are no data from high-quality studies on newer P₂Y₁₂ inhibitors.

Comment: 

Although systemic corticosteroids are not inherently ulcerogenic, they can significantly increase the risk of gastroduodenal ulcer bleeding, especially in hospitalised patients [627]. This affects particularly patients taking NSAIDs at the same time [599] and is very likely for patients with relevant comorbidities. Eradication of H. pylori infection may also have a favourable effect on the course, although a retrospective case series did not demonstrate this conclusively [561]. Whenever possible, systemic corticosteroids should be discontinued or replaced with other therapies for the duration of ulcer healing. If this is not possible, a dose-response relationship should be assumed and the lowest possible steroid dose should be used together with PPI prophylaxis.

Comment: 

Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, fluoxetine, citalopram and sertraline are used to treat depression and anxiety. The release of serotonin from platelets plays an important role in regulating the haemostatic response to vascular injury. The largest serotonin store in our body is in platelets. Serotonin is taken up from the circulation by serotonin transporters into platelets, as well as into neuronal structures. In therapeutic dose, Fluoxetine and other SSRIs block the uptake of serotonin into platelets.

Several population-based studies and meta-analyses show an increased risk of non-variceal upper gastrointestinal bleeding with SSRI therapy with an OR of about 1.55 (95 % CI 1.35–1.78) [628] [629] [630]. Concurrent use of NSAIDs, oral anticoagulants, or P₂Y₁₂ inhibitors increases the risk significantly [628] [629] [631] [632] [633]. A meta-analysis of four observational studies involving a total of 153,000 patients showed a doubling of the relative risk of gastrointestinal bleeding with SSRI (odds ratio 2.36), a tripling with NSAIDs (odds ratio 3.16) and a 6-fold increase with the combination of SSRI and NSAIDs (odds ratio 6.33). The number needed to harm (NNH) was 318 per year for patients over 50 years of age using SSRIs and 82 per year for patients using SSRIs plus NSAIDs. Patients with a history of ulcer disease had an even higher risk: these had an NNH of 70 per year with SSRIs and 19 per year with SSRIs plus NSAIDs. A subgroup analysis of 101 cases showed that bleeding occurred on average after a treatment duration of 25 weeks [628].

Concomitant use of a PPI reduces this risk significantly [630] [634]. A case-control study of 1,321 patients with upper GI bleeding and 10,000 controls showed that acid-suppression lowers the (OR for bleeding to 1.4 (95 % CI, 0.8–2.3) compared to an OR of 2.0 (95 % CI, 1.5–2.8) without acid-suppression. This effect is even more pronounced when taking NSAIDs (OR, 9.1; 95 % CI, 4.8–17.3 without acid suppression vs. OR, 1.1; 95 % CI, 0.3–3.4 with acid suppression), or P₂Y₁₂ inhibitors in combination with SSRIs (OR 4.7; 95 % CI, 2.6–8.3 without acid suppression vs. OR, 0.8; 95 % CI, 0.3–2.5 with acid suppression) [634].

Comment: 

If it is clinically necessary to give long-term treatment with aspirin or another coagulation active substance and an upper gastrointestinal bleed occurs while on this treatment, the risk of a recurrent bleed after continuation of the treatment can be reduced by the addition of a PPI [635] [636] [637]. This is in concordance with the Maastricht V/Florence consensus report [2]. In addition, the indication for long-term aspirin treatment should be re-evaluated and discontinued in case of primary prevention, as three recent studies do not show a clear benefit of aspirin therapy regarding primary prevention of cardiovascular events and this not being recommended in the current ESC guidelines [638] [639] [640] [641] [642]. However, timely continuation of aspirin treatment is of great importance for secondary prevention in cardiovascular risk patients (e. g. after PCI) [643] [644]. In case of ulcer bleeding during therapy with a DOAC or VKA due to atrial fibrillation, implantation of a LAA occluder is an option [645].

Two prospective randomized, double-blind studies have shown that combination of aspirin with a PPI is more effective in reducing the risk of gastroduodenal ulcers and bleeding than switching to monotherapy with clopidogrel [646] [647]. The healing rates of ulcers do not differ between a combination therapy of PPI with aspirin and a combination therapy of PPI with clopidogrel [648]. The results of randomized studies show contradictory results regarding the superiority of PPI therapy over H₂ receptor antagonists in case of ulcer bleeding on aspirin [649] [650]. After an ulcer bleeding while on P₂Y₁₂ inhibitors (clopidogrel, prasugrel, ticagrelor), treatment with a PPI but not with H₂ receptor antagonists reduces the risk of recurrent bleeding in prospective studies [649] [650] [651] [652]. A population-based study shows a risk reduction for bleeding in patients with ulcer history on dabigatran by PPI therapy [653]. Although there are no studies on this, it can be assumed that the same applies to other DOACs and VKAs.

Comment: 

Simultaneous administration of aspirin and clopidogrel increases the odds ratio for gastroduodenal bleeding from 1.8 (aspirin) and 1.1 (clopidogrel) to 7.1 [654] [655]. Similarly, the incidence of bleeding increases significantly by simultaneous administration of aspirin and VKA [656] [657] [658]. Furthermore, a combination of oral anticoagulation therapy with dual antiplatelet therapy further increases the risk of gastrointestinal bleeding compared to a combination with single antiplatelet therapy [659]. Two prospective randomized studies show that the administration of a PPI in dual antiplatelet therapy reduces the frequency of gastrointestinal bleeding significantly without increasing cardiovascular mortality [660] [661]. Since some PPIs inhibit cytochrome P450 2C19 (CYP2C19), which biotransforms clopidogrel and prasugrel into their active metabolites, the safety of combining PPIs with these substances has been questioned. Statements from meta-analyses on the question of a higher risk of cardiovascular events with the combination of clopidogrel and PPIs are contradictory [662] [663]. A meta-analysis on the subject concludes that the positive effects of PPI medication outweigh the risks [610].

In vitro studies show that PPIs differ in the extent of their inhibitory effects on the action of clopidogrel [664]. This interaction was more pronounced with omeprazole than with pantoprazole. This could lead to reduced activation of clopidogrel on PPI therapy [665] [666]. For this reason, there is still no uniform recommendation from the European Society of Cardiology (ESC). Part of the current ESC statements recommends routine PPI therapy in patients on dual antiplatelet therapy and in the combination of dual antiplatelet therapy with oral anticoagulation [667]. Another consensus paper also recommends PPI medication for dual antiplatelet therapy (DAPT) as well as for dual therapy with a P₂Y₁₂ inhibitor and a DOAC for the duration of dual therapy [668]. On the other hand, the 2019 guideline for chronic coronary syndrome recommends the additional administration of a PPI only in the presence of a further risk factor for gastrointestinal bleeding [669].

A potential interaction via the cytochrome system requires the simultaneous presence of both drugs in the plasma. With the plasma half-life of clopidogrel and PPIs being only a few hours each, the risk of interaction could be minimized by taking the two preparations at different time points (one in the morning, the other in the evening) [670] [671].

Commentary: 

There are no studies that have systematically investigated the treatment of Crohn’s-associated gastroduodenal ulcers. Generally, the efficacy of steroid treatment on inflammatory ulcers is documented in European and American studies [672] [673]. Thus, reservations against the use of steroids in this situation are likely not justified. Case series have shown that PPI can have a positive influence on the healing of Crohn’s-associated gastro-duodenal ulcers [674] [675].

In general, involvement of the upper gastrointestinal tract is associated with a more severe disease course [676] [677]. In a retrospective case series, 11 out of 19 patients were treated with anti-TNF-α antibodies (10 with infliximab and 1 with adalimumab). After 12 weeks, mucosal healing was observed in 72.7 % of the anti-TNF-α-treated patients compared to only 12.5 % in the control group [7]. There are no reports yet on the efficacy of other biologicals.

Comment: 

With the decrease in the prevalence of H. pylori infection, the relative proportion of H. pylori-negative ulcers is increasing. At least in Asia, the absolute number of idiopathic ulcers seems to be increasing as well [678]. Prospective multicentre studies show that 12–30 % of patients with peptic ulcers have no identifiable cause, such as H. pylori infection or use of ulcerogenic drugs [678] [679] [680]. Careful exclusion of other possible causes is necessary for categorizing an ulcer as idiopathic (see Statement 7.2). Due to the low incidence of idiopathic ulcers, there are only a few studies on their clinical characteristics [681]. The proportion of idiopathic ulcers is reported to be 25 % in a retrospective study. Risk factors for the occurrence of idiopathic ulcers include age (OR 3.52, 95 % CI 1.63–7.59), male gender (OR 3.13, 95 % CI 1.89–5.18), hospitalization (OR 2.97, 95 % CI 1.93–4.58) and number of medications taken (OR 2.81, 95 % CI 1.18–6.74). The most common location is the antrum [682].

The healing rates of idiopathic ulcers under acid-suppressive therapy are lower than those of H. pylori or NSAID-induced ulcers [683]. Although most studies on PPI therapy for peptic ulcers have been conducted in patients with H. pylori infection or NSAID-induced ulcers, it can be assumed that effective acid suppression, e. g. with omeprazole 2 × 40 mg or another equipotent PPI dosage, leads to accelerated healing of idiopathic ulcers [681] [683]. A retrospective case-control study shows a healing rate of 97.6 % for idiopathic ulcers on high-dose PPI treatment [684].

Idiopathic peptic ulcers show higher recurrence rates than H. pylori or NSAID-induced ulcers [685].

Patients with bleeding from an idiopathic ulcer have a significantly higher rate of recurrent ulcer bleeding and show a higher mortality than those with H. pylori-associated ulcers. Without acid-suppressive treatment, recurrent bleeding occurs with an incidence of 6.0 % to 13.4 % within one year [686] [687]. In a prospective randomized study, the incidence of recurrent bleeding from idiopathic ulcers within 24 months was 0.88 % on long-term treatment with 30 mg lansoprazole/day and 2.63 % on treatment with the H2 receptor antagonist famotidine 40 mg/day, without these results reaching statistical significance [688]. Therefore, PPI maintenance treatment is justified after bleeding from an idiopathic ulcer [689] [690].

Comment: 

Stress ulcers occur in the stomach or proximal duodenum as a result of mucosal perfusion disturbances in the splanchnic area, which can be caused by various severe diseases or pathophysiological conditions. Independent risk factors include coagulation disorders and mechanical ventilation > 48 hours, as well as the presence of > 2 of the following conditions: intensive care treatment > 1 week, sepsis, hypotensive shock, ARDS, liver or kidney failure, extensive burns, polytrauma, severe head injury with neurosurgical interventions, recent organ transplantation, high-dose steroid therapy > 250 mg/day, positive ulcer history [691] [692] [693] [694]. Stress ulcer bleeding significantly increases the already high mortality rate of these high-risk patients. However, advances in intensive care have significantly reduced the incidence and mortality of stress ulcer bleeding [695]. Therefore, pharmacological stress ulcer prophylaxis should be limited to the aforementioned high-risk constellations, especially if early enteral feeding is not possible [696] [697].

Extensive meta-analyses of newer studies (2010–2017) show that pharmacological prophylaxis (PPIs, H2 receptor antagonists, antacids, sucralfate) reduces the incidence of clinically relevant stress ulcer bleeding by approximately 50 % when compared to no prophylaxis or placebo. The benefit of stress ulcer prophylaxis is not compromised by an increased rate of nosocomial pneumonia [698] [699] [700]. A prospective randomized study comparing PPI and placebo also reached the same conclusion [161]. In direct comparison between PPIs and H₂ receptor antagonists, PPIs are found to be significantly more effective in meta-analyses and in a new, very large, strongly powered, randomized, direct comparison study. The protection provided by H₂ receptor antagonists shows an effect similar to sucralfate [699] [700]. The more effective stress ulcer prevention by PPIs vs. H₂ receptor antagonists is also not compromised by a higher rate of nosocomial pneumonia [698] [699] [700]. Therefore, the preferred use of PPIs for stress ulcer prophylaxis in clinical practice is in line with current evidence.

However, the statistical reliability of the meta-analyses is limited by partially underpowered studies and by heterogeneity of results and bias risks. Additionally, neither the meta-analyses nor the prospective studies available to date can demonstrate a significant reduction in overall mortality with acid suppressive medication. Therefore, further high-quality, randomized, sufficiently powered studies are necessary, in which the definition of nosocomial pneumonia is uniformly handled and the measures for its diagnosis and prevention are standardized, in order to allow for a more precise assessment of the effect of stress ulcer prophylaxis on overall mortality.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Sugano KJ, Tack J, Kuipers EJ. et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015; 64 (09) 1353-1367
• 2 Malfertheiner P, Megraud F, O`Morain CAO. et al. Management of Helicobacter pylori infection – the MaastrichtV/Florence Consensus Report. Gut 2017; 66: 6-30
• 3 Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet 2009; 374: 1449-1461
• 4 Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49 (03) 347-335
• 5 Fischbach W. Gastric mucosal-associated lymphoid tissue lymphoma. Gastroenterol Clin North Am 2013; 2 (02) 371-380
• 6 Huang JQ, Sridhar S, Chen Y. et al. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998; 114 (06) 1169-1179
• 7 Danesh J. Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies. Aliment Pharmacol Ther 1999; 13 (07) 851-856
• 8 Eslick GD, Lim LL, Byles JE. et al. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999; 94 (09) 2373-2379
• 9 Xue FB, Xu YY, Wan Y. et al. Association of H. pylori infection with gastric carcinoma: a Meta analysis. World J Gastroenterol 2001; 7 (06) 801-804
• 10 Huang JQ, Zheng GF, Sumanac K. et al. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003; 125 (06) 1636-1644
• 11 Brenner H, Arndt V, Stegmaier C. et al. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer?. Am J Epidemiol 2004; 159 (03) 252-258
• 12 Siman JH, Engstrand L, Berglund G. et al. A. Helicobacter pylori and CagA seropositivity and its association with gastric and oesophageal carcinoma. Scand J Gastroenterol 2007; 42 (08) 933-940
• 13 Parsonnet J, Hansen S, Rodriguez L. et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 1994; 330 (18) 1267-1271
• 14 Morgner A, Lehn N, Andersen LP. et al. Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Gastroenterology 2000; 118 (05) 821-828
• 15 Solnick JV, Schauer DB. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin Microbiol Rev 2001; 14 (01) 59-97
• 16 Chen Y, Segers S, Blaser MJ. Association between Helicobacter pylori and mortality in the NHANES III study. Gut 2013; 62 (09) 1262-1269
• 17 Erőss B, Farkas N, Vincze A. et al. Helicobacter pylori infection reduces the risk of Barrett’s esophagus: A meta-analysis and systematic review. Helicobacter 2018; 23 (04) e12504
• 18 Shah SC, Tepler A, Peek RM. et al. Association Between Helicobacter pylori Exposure and Decreased Odds of Eosinophilic Esophagitis-A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17 (11) 2185-2198 e2183
• 19 Yalaki S, Pulat H, Ilhan A. Localization of Helicobacter pylori gastritis and the relation of existing histopathological features with reflux esophagitis. Scand J Gastroenterol 2020; 55 (01) 27-33
• 20 Usui G, Sato H, Shinozaki T. et al. Association Between Helicobacter pylori Infection and Short-segment/Long-segment Barrett’s Esophagus in a Japanese Population: A Large Cross-Sectional Study. J Clin Gastroenterol 2020; 54 (05) 439-444
• 21 Sugimoto M, Murata M, Mizuno H. et al. Endoscopic Reflux Esophagitis and Reflux-Related Symptoms after Helicobacter pylori Eradication Therapy: Meta-Analysis. J Clin Med 2020; 9 (09) 3007
• 22 Xie FJ, Zhang YP, Zheng QQ. et al. Helicobacter pylori infection and esophageal cancer risk: an updated meta-analysis. World J Gastroenterol 2013; 19 (36) 6098-6107
• 23 Doorakkers E, Lagergren J, Santoni G. et al. Helicobacter pylori eradication treatment and the risk of Barrett’s esophagus and esophageal adenocarcinoma. Helicobacter 2020; 25 (03) e12688
• 24 Choi DS, Seo SI, Shin WG. et al. Risk for Colorectal Neoplasia in Patients With Helicobacter pylori Infection: A Systematic Review and Meta-analysis. Clin Transl Gastroenterol 2020; 11 (02) e00127
• 25 von Arnim U, Wex T, Link A. et al. Helicobacter pylori infection is associated with a reduced risk of developing eosinophilic oesophagitis. Aliment Pharmacol Ther 2016; 43 (07) 825-830
• 26 Shah SC, Tepler A, Peek RM. et al. Association Between Helicobacter pylori Exposure and Decreased Odds of Eosinophilic Esophagitis-A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17 (11) 2185-2198 e2183
• 27 Narang M, Puri AS, Sachdeva S. et al. Celiac disease and Helicobacter pylori infection in children: Is there any Association?. J Gastroenterol Hepatol 2017; 32 (06) 1178-1182
• 28 Bayrak NA, Tutar E, Volkan B. et al. Helicobacter pylori infection in children with celiac disease: Multi-center, cross-sectional study. Helicobacter 2020; 25 (03) e12691
• 29 Amlashi FI, Norouzi Z, Sohrabi A. et al. A systematic review and meta-analysis for association of Helicobacter pylori colonization and celiac disease. PLoS One 2021; 16 (03) e0241156
• 30 Franchini M, Cruciani M, Mengoli C. et al. Effect of Helicobacter pylori eradication on platelet count in idiopathic thrombocytopenic purpura: a systematic review and meta-analysis. J Antimicrob Chemother 2007; 60 (02) 237-246
• 31 Marignani M, Angeletti S, Bordi C. et al. Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol 1997; 32 (06) 617-622
• 32 Suter PM, Golner BB, Goldin BR. et al. Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 1991; 101 (04) 1039-1045
• 33 Lee AJ, Chung HH, Koh Y. et al. Helicobacter pylori eradication affects platelet count recovery in immune thrombocytopenia. Sci Rep 2020; 10 (01) 9370
• 34 Jorgensen AR, Egeberg A, Gideonsson R. et al. Rosacea is associated with Helicobacter pylori: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2017; 31 (12) 2010-2015
• 35 Su J, Zhou XY, Zhang Gy. Association between Helicobacter pylori infection and migraine: a meta-analysis. World J Gastroenterol 2014; 20 (40) 14965-14972
• 36 Faraji F, Zarinfar N, Zanjani AT. et al. The effect of Helicobacter pylori eradication on migraine: a randomized, double blind, controlled trial. Pain Physician 2012; 15 (06) 495-498
• 37 Xu X, Li W, Qin L. et al. “Relationship between Helicobacter pylori infection and obesity in Chinese adults: A systematic review with meta-analysis.”. PLoS One 2019; 14 (09) e022107
• 38 Mansori K, Dehghanbanadaki H, Naderpour S. et al. A systematic review and meta-analysis of the prevalence of Helicobacter pylori in patients with diabetes. Diabetes Metab Syndr 2020; 14 (04) 601-607
• 39 Fang Y, Fan C, Xie H. Effect of Helicobacter pylori infection on the risk of acute coronary syndrome: A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98 (50) e18348
• 40 Fu P, Gao M, Yung KKL. Association of Intestinal Disorders with Parkinson’s Disease and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. ACS Chem Neurosci 2020; 11 (03) 395-405
• 41 Cardenas VM, Boller F, Roman GC. Helicobacter pylori, Vascular Risk Factors and Cognition in U.S. Older Adults. Brain Sci 2019; 9 (12) 370
• 42 Dardiotis E, Sokratous M, Tsouris Z. et al. Association between Helicobacter pylori infection and Guillain-Barre Syndrome: A meta-analysis. Eur J Clin Invest 2020; 50 (05) e13218
• 43 Xiong LJ, Mao M. Current views of the relationship between Helicobacter pylori and Henoch-Schonlein purpura in children. World J Clin Pediatr 2016; 5 (01) 82-88
• 44 Hooi JKY, Lai WY, Ng WK. et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017; 153 (02) 420-429
• 45 Wex T, Venerito M, Kreutzer J. et al. Serological prevalence of Helicobacter pylori infection in Saxony-Anhalt, Germany, in 2010. Clin Vaccine Immunol 2011; 18 (12) 2109-2112
• 46 Michel A, Pawlita M, Boeing H. et al. Helicobacter pylori antibody patterns in Germany: a cross-sectional population study. Gut Pathog 2014; 6: 10
• 47 Franck C, Hoffmann A, Link A. et al. Prevalence of Helicobacter pylori infection among blood donors in Saxony-Anhalt, Germany–a region at intermediate risk for gastric cancer. Zeitschrift für Gastroenterologie 2017; 55 (07) 653-656
• 48 Weyermann M, Rothenbacher D, Brenner H. Acquisition of Helicobacter Pylori Infection in Early Childhood: Independent Contributions of Infected Mothers, Fathers and Siblings. The American Journal of Gastroenterology 2008; 104 (01) 182-189
• 49 Grimm W, Fischbach W. Helicobacter pylori infection in children and juveniles: an epidemiological study on prevalence, socio-economic factors and symptoms. Dtsch Med Wochenschr 2003; 128 (37) 1878-1883
• 50 Graham DY, Malaty HM, Evans DG. et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Gastroenterology 1991; 100 (06) 1495-1501
• 51 Malaty HM, Evans DG, Evans DJ. et al. Helicobacter pylori in hispanics: Comparison with blacks and whites of similar age and socioeconomic class. Gastroenterology 1992; 103 (03) 813-816
• 52 Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut 1994; 35 (06) 742-745
• 53 Perez-Perez GI, Olivares AZ, Foo FY. Seroprevalence of Helicobacter pylori in New York City populations originating in East Asia. J Urban Health 2005; 82 (03) 510-516
• 54 Malaty HM, Kim JG, Kim SD. et al. Prevalence of Helicobacter pylori infection in Korean children: inverse relation to socioeconomic status despite a uniformly high prevalence in adults. Am J Epidemiol 1996; 143 (03) 257-262
• 55 Nouraie M, Latifi-Navid S, Rezvan H. et al. Childhood hygienic practice and family education status determine the prevalence of Helicobacter pylori infection in Iran. Helicobacter 2009; 14 (01) 40-46
• 56 Mayerle J, den Hoed CM, Schurmann C. et al. Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA 2013; 309 (18) 1912-1920
• 57 Ikehara Y, Nishihara S, Yasutomi H. et al. Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiol Biomarkers Prev 2001; 10 (09) 971-977
• 58 Banatvala N, Mayo K, Megraud F. et al. The cohort effect and Helicobacter pylori. J Infect Dis 1993; 168 (01) 219-221
• 59 Roosendaal R, Kuipers EJ, Buitenwerf J. et al. Helicobacter pylori and the birth cohort effect: evidence of a continuous decrease of infection rates in childhood. Am J Gastroenterol 1997; 92 (09) 1480-1482
• 60 den Hoed CM, Vila AJ, Holster IL. et al. Helicobacter pylori and the birth cohort effect: evidence for stabilized colonization rates in childhood. Helicobacter 2011; 16 (05) 405-409
• 61 Rokkas T, Sechopoulos P, Pistiolas D. et al. Helicobacter pylori infection and gastric histology in first-degree relatives of gastric cancer patients: a meta-analysis. Eur J Gastroenterol Hepatol 2010; 22 (09) 1128-1133
• 62 Lei G, Melanie NW, Elke R. et al. Sibship size, Helicobacter pylori infection and chronic atrophic gastritis: A population-based study among 9444 older adults from Germany. International Journal of Epidemiology 2010; 39: 129-134
• 63 Porsch-Ozcürümez M, Doppl W, Hardt PD. et al. Impact of migration on Helicobacter pylori seroprevalence in the offspring of Turkish immigrants in Germany. Turk J Pediatr 2003; 45 (03) 203-208
• 64 Wu Y, Murray GK, Byrne EM. et al. “GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression.”. Nat Commun 2021; 12 (01) 1146
• 65 Odenbreit S, Püls J, Sedlmaier B. et al. “Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.”. Science 2000; 287: 1497-1500
• 66 Link A, Langner C, Schirrmeister W. et al. Helicobacter pylori vacA genotype is a predominant determinant of immune response to Helicobacter pylori CagA. World J Gastroenterol 2017; 23 (26) 4712-4723
• 67 Gutwerk A, Wex T, Stein K. et al. Helicobacter Pylori Serology in Relation to Hepatitis C Virus Infection and IL28B Single Nucleotide Polymorphism. J Clin Med 2018; 7 (03) 44
• 68 Basso D, Zambon CF, Letley DP. et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008; 135 (01) 91-99
• 69 Tindberg Y, Bengtsson C, Granath F. et al. Helicobacter pylori infection in Swedish school children: lack of evidence of child-to-child transmission outside the family. Gastroenterology 2001; 121 (02) 310-316
• 70 Rothenbacher D, Winkler M, Gonser T. et al. Role of infected parents in transmission of helicobacter pylori to their children. Pediatr Infect Dis J 2002; 21 (07) 674-679
• 71 Rocha GA, Rocha AM, Silva LD. et al. Transmission of Helicobacter pylori infection in families of preschool-aged children from Minas Gerais, Brazil. Trop Med Int Health 2003; 8 (11) 987-991
• 72 Kivi M, Johansson AL, Reilly M. et al. Helicobacter pylori status in family members as risk factors for infection in children. Epidemiol Infect 2005; 133 (04) 645-652
• 73 Han SR, Zschausch HC, Meyer HG. et al. Helicobacter pylori: clonal population structure and restricted transmission within families revealed by molecular typing. J Clin Microbiol 2000; 38 (10) 3646-3651
• 74 Kivi M, Johansson AL, Sorberg M. et al. Concordance of Helicobactrer pylori strainsw within families. J Clin Microbiol 2003; 41 (12) 5604-5608
• 75 Dolan B, Burkitt-Gray L, Shovelin S. et al. The use of stool specimens reveals Helicobacter pylori strain diversity in a cohort of adolescents and their family members in a developed country. Int J Med Microbiol 2018; 308 (02) 247-255
• 76 Mendall MA, Goggin PM, Molineaux N. et al. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet 1992; 339: 896-897
• 77 Carter F, Seaton T, Yuan Y. et al. Prevalence of Helicobacter pylori infection in children in the Bahamas. West Indian Med J 2023; 61 (07) 698-702
• 78 Jafar S, Jalil A, Soheila N. et al. Prevalence of helicobacter pylori infection in children, a population-based cross-sectional study in west iran. Iran J Pediatr 2013; 23 (01) 13-18
• 79 Goodman KJ, Correa P. Transmission of Helicobacter pylori among siblings. The Lancet 2000; 355: 358-362
• 80 Rowland M, Daly L, Vaughan M. et al. Age-specific incidence of Helicobacter pylori. Gastroenterology 2006; 130 (01) 65-72; quiz 211
• 81 Osaki T, Zaman C, Yonezawa H. et al. Influence of Intestinal Indigenous Microbiota on Intrafamilial Infection by Helicobacter pylori in Japan. Front Immunol 2018; 9: 287
• 82 Bastos J, Carreira H, La Vecchia C. et al. Childcare attendance and Helicobacter pylori infection. European Journal of Cancer Prevention 2013; 22 (04) 311-319
• 83 Luman W, Zhao Y, Ng HS. et al. Helicobacter pylori infection is unlikely to be transmitted between partners: evidence from genotypic study in partners of infected patients. Eur J Gastroenterol Hepatol 2002; 14 (05) 521-528
• 84 Stone MA, Taub N, Barnett DB. et al. Increased risk of infection with Helicobacter pylori in spouses of infected subjects: observations in a general population sample from the UK. Hepatogastroenterology 2000; 47 (32) 433-436
• 85 Brenner H, Weyermann M, Rothenbacher D. Clustering of Helicobacter pylori infection in couples: differences between high- and low-prevalence population groups. Ann Epidemiol 2006; 16 (07) 516-520
• 86 Sgambato D, Visciola G, Ferrante E. et al. Prevalence of Helicobacter pylori infection in sexual partners of H. pylori-infected subjects: Role of gastroesophageal reflux. United European Gastroenterol J 2018; 6 (10) 1470-1476
• 87 Zhou LY, Song ZQ, Xue Y. et al. Recurrence of Helicobacter pylori infection and the affecting factors: A follow-up study. J Dig Dis 2017; 18 (01) 47-55
• 88 Zhou G. Helicobacter pylori Recurrence after Eradication Therapy in Jiangjin District, Chongqing, China. Gastroenterol Res Pract 2020; 2020: 7510872
• 89 Parsonnet J, Hansen S, Rodriguez L. et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 1994; 330 (18) 1267-1271
• 90 Castro-Munoz LJ, Gonzalez-Diaz CA, Munoz-Escobar A. et al. Prevalence of Helicobacter pylori from the oral cavity of Mexican asymptomatic children under 5 years of age through PCR. Arch Oral Biol 2017; 73: 55-59
• 91 Vasapolli R, Schutte K, Schulz C. et al. Analysis of Transcriptionally Active Bacteria Throughout the Gastrointestinal Tract of Healthy Individuals. Gastroenterology 2019; 157 (04) 1081-1098.e3
• 92 Leung WK, Siu KL, Kwok CK. et al. Isolation of Helicobacter pylori from vomitus in children and its implication in gastro-oral transmission. Am J Gastroenterol 1999; 94 (10) 2881-2884
• 93 Laporte R, Pernes P, Pronnier P. et al. Acquisition of Helicobacter pylori infection after outbreaks of gastroenteritis: prospective cohort survey in institutionalised young people. Bmj 2004; 329: 204-205
• 94 Schulz C, Schutte K, Koch N. et al. The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut 2018; 67 (02) 216-225
• 95 Chen Z, Cai J, Chen YM. et al. A meta-analysis of the association between the presence of Helicobacter pylori and periodontal diseases. Medicine (Baltimore) 2019; 98 (22) e15922
• 96 Wei X, Zhao HQ, Ma C. et al. The association between chronic periodontitis and oral Helicobacter pylori: A meta-analysis. PLoS One 2019; 14 (12) e0225247
• 97 Payao SL, Rasmussen LT. Helicobacter pylori and its reservoirs: A correlation with the gastric infection. World J Gastrointest Pharmacol Ther 2016; 7 (01) 126-132
• 98 Moreira ED, Nassri VB, Santos RS. et al. Association of Helicobacter pylori infection and giardiasis: results from a study of surrogate markers for fecal exposure among children. World J Gastroenterol 2005; 11 (18) 2759-2763
• 99 Bui D, Brown HE, Harris RB. et al. Serologic Evidence for Fecal-Oral Transmission of Helicobacter pylori. Am J Trop Med Hyg 2016; 94 (01) 82-88
• 100 Klein PD, Graham DY, Gaillour A. et al. Water source as risk factor for Helicobacter pylori infection in Peruvian children. Gastrointestinal Physiology Working Group. Lancet 1991; 337: 1503-1506
• 101 Nurgalieva ZZ, Malaty HM, Graham DY. et al. Helicobacter pylori infection in Kazakhstan: effect of water source and household hygiene. Am J Trop Med Hyg 2002; 67 (02) 201-206
• 102 Aziz RK, Khalifa MM, Sharaf RR. Contaminated water as a source of Helicobacter pylori infection: A review. J Adv Res 2015; 6 (04) 539-547
• 103 Farhadkhani M, Nikaeen M, Hassanzadeh A. et al. Potential transmission sources of Helicobacter pylori infection: detection of H. pylori in various environmental samples. J Environ Health Sci Eng 2019; 17 (01) 129-113
• 104 Hulten K, Han SW, Enroth H. et al. Helicobacter pylori in the drinking water in Peru. Gastroenterology 1996; 110 (04) 1031-1035
• 105 Lu Y, Redlinger TE, Avitia R. et al. Isolation and genotyping of Helicobacter pylori from untreated municipal wastewater. Appl Environ Microbiol 2002; 68 (03) 1436-1439
• 106 Bai X, Xi C, Wu J. Survival of Helicobacter pylori in the wastewater treatment process and the receiving river in Michigan, USA. J Water Health 2016; 14 (04) 692-698
• 107 Ranjbar R, Khamesipour F, Jonaidi-Jafari N. et al. Helicobacter pylori in bottled mineral water: genotyping and antimicrobial resistance properties. BMC Microbiol 2016; 16: 40
• 108 Dore MP, Sepulveda AR, Osato MS. et al. Helicobacter pylori in sheep milk. The Lancet 1999; 354
• 109 Dore MP, Sepulveda AR, El-Zimaity H. et al. Isolation of Helicobacter pylori from sheep-implications for transmission to humans. Am J Gastroenterol 2001; 96 (05) 1396-1401
• 110 Zamani M, Vahedi A, Maghdouri Z. et al. Role of food in environmental transmission of Helicobacter pylori. Caspian J Intern Med 2017; 8 (03) 146-152
• 111 Siavoshi F, Sahraee M, Ebrahimi H. et al. Natural fruits, flowers, honey, and honeybees harbor Helicobacter pylori-positive yeasts. Helicobacter 2018; 23 (02) e12471
• 112 Dubois A, Fiala N, Heman-Ackah LM. et al. Natural gastric infection with Helicobacter pylori in monkeys: a model for spiral bacteria infection in humans. Gastroenterology 1994; 106 (06) 1405-1417
• 113 Handt LK, Fox JG, Dewhirst FE. et al. Helicobacter pylori isolated from the domestic cat: public health implications. Infect Immun 1994; 62 (06) 2367-2374
• 114 Momtaz H, Dabiri H, Souod N. et al. Study of Helicobacter pylori genotype status in cows, sheep, goats and human beings. BMC Gastroenterol 2014; 14: 61
• 115 Junqueira ACM, Ratan A, Acerbi E. et al. The microbiomes of blowflies and houseflies as bacterial transmission reservoirs. Sci Rep 2017; 7 (01) 16324
• 116 Kheyre H, Morais S, Ferro A. et al. The occupational risk of Helicobacter pylori infection: a systematic review. Int Arch Occup Environ Health 2018; 91 (06) 657-674
• 117 Kim HY, Kim N, Kim SM. et al. Seroprevalence of Helicobacter pylori Infection in Korean Health Personnel. Gut Liver 2013; 7 (06) 648-654
• 118 Peters C, Schablon A, Harling M. et al. The occupational risk of Helicobacter pylori infection among gastroenterologists and their assistants. BMC Infect Dis 2011; 11: 154
• 119 Sjomina O, Pavlova J, Niv Y. et al. Epidemiology of Helicobacter pylori infection. Helicobacter 2018; 23 (Suppl. 01) e12514
• 120 Take S, Mizuno M, Ishiki K. et al. Reinfection rate of Helicobacter pylori after eradication treatment: a long-term prospective study in Japan. J Gastroenterol 2012; 47 (06) 641-646
• 121 Knippig C, Arand F, Leodolter A. et al. Prevalence of H. pylori-infection in family members of H. pylori positive and its influence on the reinfection rate after successful eradication therapy: a two-year follow-up. Z Gastroenterol 2002; 40 (06) 383-387
• 122 Hu Y, Wan JH, Li XY. et al. Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. Aliment Pharmacol Ther 2017; 46 (09) 773-779
• 123 Gebara EC, Faria CM, Pannuti C. et al. Persistence of Helicobacter pylori in the oral cavity after systemic eradication therapy. J Clin Periodontol 2006; 33 (05) 329-333
• 124 Sun Y, Zhang J. Helicobacter pylori recrudescence and its influencing factors. J Cell Mol Med 2019; 23 (12) 7919-7925
• 125 Zhang Y, Dong Q, Tian L. et al. Risk factors for recurrence of Helicobacter pylori infection after successful eradication in Chinese children: A prospective, nested case-control study. Helicobacter 2020; 25 (05) e12749
• 126 Goodman KJ, O’Rourke K, Day RS. et al. Dynamics of Helicobacter pylori infection in a US-Mexico cohort during the first two years of life. Int J Epidemiol 2005; 34 (06) 1348-1355
• 127 Rehmann A, Muller D, Krumbiegel P. et al. Spontaneous elimination of helicobacter pylori infection in children. Klin Padiatr 2005; 217 (01) 15-17
• 128 Zhou Y, Ye Z, Huang J. et al. High prevalence and low spontaneous eradication rate of Helicobacter pylori infection among schoolchildren aged 7–12 years. Acta Paediatr 2018;
• 129 Duque X, Vilchis J, Mera R. et al. Natural history of Helicobacter pylori infection in Mexican schoolchildren: incidence and spontaneous clearance. J Pediatr Gastroenterol Nutr 2012; 55 (02) 209-216
• 130 Broussard CS, Goodman KJ, Phillips CV. et al. Antibiotics taken for other illnesses and spontaneous clearance of Helicobacter pylori infection in children. Pharmacoepidemiol Drug Saf 2009; 18 (08) 722-729
• 131 Luzza F, Suraci E, Larussa T. et al. High exposure, spontaneous clearance, and low incidence of active Helicobacter pylori infection: the Sorbo San Basile study. Helicobacter 2014; 19 (04) 296-305
• 132 Danesh J, Appleby P, Peto R. How often does surgery for peptic ulceration eradicate Helicobacter pylori? Systematic review of 36 studies. Bmj 1998; 316: 746-747
• 133 Bair MJ, Wu MS, Chang WH. et al. Spontaneous clearance of Helicobacter pylori colonization in patients with partial gastrectomy: correlates with operative procedures and duration after operation. J Formos Med Assoc 2009; 108 (01) 13-19
• 134 Suh S, Nah JC, Uhm MS. et al. Changes in prevalence of Helicobacter pylori infection after subtotal gastrectomy. Hepatogastroenterology 2012; 59 (114) 646-648
• 135 Yoon K, Kim N, Kim J. et al. Dynamic Changes in Helicobacter pylori Status Following Gastric Cancer Surgery. Gut Liver 2017; 11 (02) 209-215
• 136 Lin YS, Chen MJ, Shih SC. et al. Management of Helicobacter pylori infection after gastric surgery. World J Gastroenterol 2014; 20 (18) 5274-5282
• 137 O’Connor HJ, Dixon MF, Wyatt JI. et al. Effect of duodenal ulcer surgery and enterogastric reflux on Campylobacter pyloridis. Lancet 1986; 2: 1178-1181
• 138 Venerito M, Radunz M, Reschke K. et al. Autoimmune gastritis in autoimmune thyroid disease. Aliment Pharmacol Ther 2015; 41 (07) 686-693
• 139 Weise F, Vieth M, Reinhold D. et al. Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the star project on gastric cancer research. United European Gastroenterol J 2020; 8 (02) 175-184
• 140 Malfertheiner P, Selgrad M, Wex T. et al. Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. The Lancet Gastroenterology & Hepatology 2018; 3 (10) 698-707
• 141 Zeng M, Mao XH, Li JX. et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2015; 386: 1457-1464
• 142 Cutler AF, Havstad S, Ma CK. et al. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995; 109 (01) 136-141
• 143 Thijs JC, van Zwet AA, Thijs WJ. et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996; 91 (10) 2125-2129
• 144 Laheij RJ, de Boer WA, Jansen JB. et al. Diagnostic performance of biopsy-based methods for determination of Helicobacter pylori infection without a reference standard. J Clin Epidemiol 2000; 53 (07) 742-746
• 145 Gisbert JP, de la Morena F, Abraira V. Accuracy of monoclonal stool antigen test for the diagnosis of H. pylori infection: a systematic review and meta-analysis. Am J Gastroenterol 2006; 101 (08) 1921-1930
• 146 Calvet X, Lario S, Ramirez-Lazaro MJ. et al. Comparative accuracy of 3 monoclonal stool tests for diagnosis of Helicobacter pylori infection among patients with dyspepsia. Clin Infect Dis 2010; 50 (03) 323-328
• 147 Deguchi R, Matsushima M, Suzuki T. et al. Comparison of a monoclonal with a polyclonal antibody-based enzyme immunoassay stool test in diagnosing Helicobacter pylori infection after eradication therapy. J Gastroenterol 2009; 44 (07) 713-716
• 148 Gisbert JP, Pajares JM. Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection -- a critical review. Aliment Pharmacol Ther 2004; 20 (10) 1001-1017
• 149 Korkmaz H, Kesli R, Karabagli P. et al. Comparison of the diagnostic accuracy of five different stool antigen tests for the diagnosis of Helicobacter pylori infection. Helicobacter 2013; 18 (05) 384-391
• 150 Lario S, Ramirez-Lazaro MJ, Montserrat A. et al. Diagnostic accuracy of three monoclonal stool tests in a large series of untreated Helicobacter pylori infected patients. Clin Biochem 2016; 49 (09) 682-687
• 151 Fang YJ, Chen MJ, Chen CC. et al. Accuracy of rapid Helicobacter pylori antigen tests for the surveillance of the updated prevalence of H. pylori in Taiwan. J Formos Med Assoc 2020; 119 (11) 1626-1633
• 152 Veijola L, Myllyluoma E, Korpela R. et al. Stool antigen tests in the diagnosis of Helicobacter pylori infection before and after eradication therapy. World J Gastroenterol 2005; 11 (46) 7340-7344
• 153 Gatta L, Perna F, Ricci C. et al. A rapid immunochromatographic assay for Helicobacter pylori in stool before and after treatment. Aliment Pharmacol Ther 2004; 20 (04) 469-474
• 154 Best LM, Takwoingi Y, Siddique S. et al. Non-invasive diagnostic tests for Helicobacter pylori infection. Cochrane Database Syst Rev 2018; 3: CD012080
• 155 Formichella L, Romberg L, Bolz C. et al. A novel line immunoassay based on recombinant virulence factors enables highly specific and sensitive serologic diagnosis of Helicobacter pylori infection. Clin Vaccine Immunol 2013; 20 (11) 1703-1710
• 156 Skrebinska S, Daugule I, Santare D. et al. Accuracy of two plasma antibody tests and faecal antigen test for non-invasive detection of H. pylori in middle-aged Caucasian general population sample. Scand J Gastroenterol 2018; 53 (07) 777-783
• 157 Schulz C, Kalali B, Vasapolli R. et al. New accurate Helicobacter pylori rapid blood test based on combined FliD and CagA antibodies [accepted for conference presentation]. Digestive Disease Week 2021;
• 158 Gong Y, Li Q, Yuan Y. Accuracy of testing for anti-Helicobacter pylori IgG in urine for H. pylori infection diagnosis: a systematic review and meta-analysis. BMJ Open 2017; 7 (04) e013248
• 159 Sjomina O, Pavlova J, Niv Y. et al. Epidemiology of Helicobacter pylori infection. Helicobacter 2018; 23 (Suppl. 01) e12514
• 160 Venneman K, Huybrechts I, Gunter MJ. et al. The epidemiology of Helicobacter pylori infection in Europe and the impact of lifestyle on its natural evolution toward stomach cancer after infection: A systematic review. Helicobacter 2018; 23 (03) e12483
• 161 Dixon MF, Genta RM, Yardley JH. et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20 (10) 1161-1181
• 162 Genta RM, Graham DY. Comparison of biopsy sites for the histopathologic diagnosis of Helicobacter pylori: a topographic study of H. pylori density and distribution. Gastrointest Endosc 1994; 40 (03) 342-345
• 163 El-Zimaity HM, Graham DY. Evaluation of gastric mucosal biopsy site and number for identification of Helicobacter pylori or intestinal metaplasia: role of the Sydney System. Hum Pathol 1999; 30 (01) 72-77
• 164 Sudraba A, Daugule I, Rudzite D. et al. Performance of routine Helicobacter pylori tests in patients with atrophic gastritis. J Gastrointestin Liver Dis 2011; 20 (04) 349-354
• 165 Lan HC, Chen TS, Li AF. et al. Additional corpus biopsy enhances the detection of Helicobacter pylori infection in a background of gastritis with atrophy. BMC Gastroenterol 2012; 12: 182
• 166 Craanen ME, Blok P, Dekker W. et al. Subtypes of intestinal metaplasia and Helicobacter pylori. Gut 1992; 33 (05) 597-600
• 167 Stolte M, Muller H, Talley NJ. et al. In patients with Helicobacter pylori gastritis and functional dyspepsia, a biopsy from the incisura angularis provides useful diagnostic information. Pathol Res Pract 2006; 202 (06) 405-413
• 168 Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacterand Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019. Endoscopy 2019; 51: 365-388
• 169 Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol 2005; 36 (03) 228-233
• 170 Ono S, Dohi O, Yagi N. et al. Accuracies of Endoscopic Diagnosis of Helicobacter pylori-Gastritis: Multicenter Prospective Study Using White Light Imaging and Linked Color Imaging. Digestion 2020; 101 (05) 624-630
• 171 East JE, Vleugels JL, Roelandt P. et al. Advanced endoscopic imaging: European Society of Gastrointestinal Endoscopy (ESGE) Technology Review. Endoscopy 2016; 48 (11) 1029-1045
• 172 Banks M, Graham D, Jansen M. et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut 2019; 68 (09) 1545-1575
• 173 Gupta S, Li D, El Serag HB. et al. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology 2020; 158 (03) 693-702
• 174 Laine L, Lewin DN, Naritoku W. et al. Prospective comparison of H&E, Giemsa, and Genta stains for the diagnosis of Helicobacter pylori. Gastrointest Endosc 1997; 45 (06) 463-467
• 175 Fallone CA, Loo VG, Lough J. et al. Hematoxylin and eosin staining of gastric tissue for the detection of Helicobacter pylori. Helicobacter 1997; 2 (01) 32-35
• 176 Graham DY, Miftahussurur M. Helicobacter pylori urease for diagnosis of Helicobacter pylori infection: A mini review. Journal of advanced research 2018; 13: 51-57
• 177 Guidelines for clinical trials in Helicobacter pylori infection. Working Party of the European Helicobacter pylori Study Group. Gut 1997; 41 (Suppl. 02) S1-S9
• 178 Parihar V, Holleran G, Hall B. et al. A combined antral and corpus rapid urease testing protocol can increase diagnostic accuracy despite a low prevalence of Helicobacter pylori infection in patients undergoing routine gastroscopy. United European Gastroenterol J 2015; 3 (05) 432-436
• 179 Uotani T, Graham DY. Diagnosis of Helicobacter pylori using the rapid urease test. Annals of translational medicine 2015; 3 (01) 9
• 180 Moon SW, Kim TH, Kim HS. et al. United Rapid Urease Test Is Superior than Separate Test in Detecting Helicobacter pylori at the Gastric Antrum and Body Specimens. Clinical endoscopy 2012; 45 (04) 392-396
• 181 Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev 2007; 20 (02) 280-322
• 182 Selgrad M, Tammer I, Langner C. et al. Different antibiotic susceptibility between antrum and corpus of the stomach, a possible reason for treatment failure of Helicobacter pylori infection. World J Gastroenterol 2014; 20 (43) 16245-16251
• 183 Ailloud F, Didelot X, Woltemate S. et al. Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps. Nat Commun 2019; 10 (01) 2273
• 184 McNicholl AG, Ducons J, Barrio J. et al. Accuracy of the Ultra-Rapid Urease Test for diagnosis of Helicobacter pylori infection. Gastroenterologia y hepatologia 2017; 40 (10) 651-657
• 185 Dechant FX, Dechant R, Kandulski A. et al. Accuracy of Different Rapid Urease Tests in Comparison with Histopathology in Patients with Endoscopic Signs of Gastritis. Digestion 2020; 101 (02) 184-190
• 186 Koumi A, Filippidis T, Leontara V. et al. Detection of Helicobacter pylori: A faster urease test can save resources. World J Gastroenterol 2011; 17 (03) 349-353
• 187 Perna F, Ricci C, Gatta L. et al. Diagnostic accuracy of a new rapid urease test (Pronto Dry), before and after treatment of Helicobacter pylori infection. Minerva gastroenterologica e dietologica 2005; 51 (03) 247-254
• 188 Brandi G, Biavati B, Calabrese C. et al. Urease-positive bacteria other than Helicobacter pylori in human gastric juice and mucosa. Am J Gastroenterol 2006; 101 (08) 1756-1761
• 189 Ramírez-Lázaro MJ, Lario S, Calvet X. et al. Occult H. pylori infection partially explains “false-positive” results of (13)C-urea breath test. United European Gastroenterol J 2015; 3 (05) 437-442
• 190 Lo CC, Lai KH, Peng NJ. et al. Polymerase chain reaction: a sensitive method for detecting Helicobacter pylori infection in bleeding peptic ulcers. World J Gastroenterol 2005; 11 (25) 3909-3914
• 191 Ramírez-Lázaro MJ, Lario S, Casalots A. et al. Real-time PCR improves Helicobacter pylori detection in patients with peptic ulcer bleeding. PLoS One 2011; 6 (05) e20009
• 192 Saez J, Belda S, Santibáñez M. et al. Real-time PCR for diagnosing Helicobacter pylori infection in patients with upper gastrointestinal bleeding: comparison with other classical diagnostic methods. J Clin Microbiol 2012; 50 (10) 3233-3237
• 193 Bénéjat L, Ducournau A, Lehours P. et al. Real-time PCR for Helicobacter pylori diagnosis. The best tools available. Helicobacter 2018; 23 (05) e12512
• 194 Hyde DK, Lee J, Buckley M. et al. Evaluation of antral biopsies used in the rapid urease test for Helicobacter pylori culture. Eur J Clin Microbiol Infect Dis 1999; 18 (01) 73-75
• 195 Chung WC, Jeon EJ, Oh JH. et al. Dual-priming oligonucleotide-based multiplex PCR using tissue samples from the rapid urease test kit for the detection of Helicobacter pylori in bleeding peptic ulcers. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2016; 48 (08) 899-903
• 196 Milani M, Moaddab Y, Sharifi Y. One piece biopsy for both rapid urease test and cultivation of Helicobacter pylori. J Microbiol Methods 2019; 164: 105674
• 197 Urita Y, Hike K, Torii N. et al. Influence of urease activity in the intestinal tract on the results of 13C-urea breath test. J Gastroenterol Hepatol 2006; 21 (04) 744-747
• 198 Gurbuz AK, Ozel AM, Narin Y. et al. Is the remarkable contradiction between histology and 14C urea breath test in the detection of Helicobacter pylori due to false-negative histology or false-positive 14C urea breath test?. The Journal of international medical research 2005; 33 (06) 632-640
• 199 Osaki T, Mabe K, Hanawa T. et al. Urease-positive bacteria in the stomach induce a false-positive reaction in a urea breath test for diagnosis of Helicobacter pylori infection. J Med Microbiol 2008; 57 (07) 814-819
• 200 Arroyo Vázquez JA, Henning C, Park PO. et al. Bacterial colonization of the stomach and duodenum in a Swedish population with and without proton pump inhibitor treatment. JGH open: an open access journal of gastroenterology and hepatology 2020; 4 (03) 405-409
• 201 Del Piano M, Anderloni A, Balzarini M. et al. The innovative potential of Lactobacillus rhamnosus LR06, Lactobacillus pentosus LPS01, Lactobacillus plantarum LP01, and Lactobacillus delbrueckii Subsp. delbrueckii LDD01 to restore the “gastric barrier effect” in patients chronically treated with PPI: a pilot study. J Clin Gastroenterol 2012; 46: S18-S26
• 202 Del Piano M, Pagliarulo M, Tari R. et al. Correlation between chronic treatment with proton pump inhibitors and bacterial overgrowth in the stomach: any possible beneficial role for selected lactobacilli?. J Clin Gastroenterol 2014; 48 (Suppl. 01) S40-S46
• 203 Levine A, Shevah O, Shabat-Sehayek V. et al. Masking of 13C urea breath test by proton pump inhibitors is dependent on type of medication: comparison between omeprazole, pantoprazole, lansoprazole and esomeprazole. Aliment Pharmacol Ther 2004; 20 (01) 117-122
• 204 Capurso G, Carnuccio A, Lahner E. et al. Corpus-predominant gastritis as a risk factor for false-negative 13C-urea breath test results. Aliment Pharmacol Ther 2006; 24 (10) 1453-1460
• 205 Lehours P, Ruskone-Fourmestraux A, Lavergne A. et al. Which test to use to detect Helicobacter pylori infection in patients with low-grade gastric mucosa-associated lymphoid tissue lymphoma?. Am J Gastroenterol 2003; 98 (02) 291-295
• 206 Vörhendi N, Soós A, Anne Engh M. et al. Accuracy of the Helicobacter pylori diagnostic tests in patients with peptic ulcer bleeding: a systematic review and network meta-analysis. Therap Adv Gastroenterol 2020; 13: 1756284820965324
• 207 Peitz U, Leodolter A, Kahl S. et al. Antigen stool test for assessment of Helicobacter pylori infection in patients with upper gastrointestinal bleeding. Alimentary pharmacology & therapeutics 2003; 17 (08) 1075-1084
• 208 Rimbara E, Sasatsu M, Graham DY. PCR detection of Helicobacter pylori in clinical samples. Methods Mol Biol 2013; 943: 279-287
• 209 Choi YJ, Kim N, Lim J. et al. Accuracy of diagnostic tests for Helicobacter pylori in patients with peptic ulcer bleeding. Helicobacter 2012; 17 (02) 77-85
• 210 van Leerdam ME, van der Ende A, ten Kate FJ. et al. Lack of accuracy of the noninvasive Helicobacter pylori stool antigen test in patients with gastroduodenal ulcer bleeding. The American journal of gastroenterology 2003; 98 (04) 798-801
• 211 Kim JJ, Lee JS, Olafsson S. et al. Low adherence to Helicobacter pylori testing in hospitalized patients with bleeding peptic ulcer disease. Helicobacter 2014; 19 (02) 98-104
• 212 Sánchez-Delgado J, Gené E, Suárez D. et al. Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta-regression. The American journal of gastroenterology 2011; 106 (03) 398-405
• 213 Sung JJY, Laine L, Kuipers EJ. et al. Towards personalised management for non-variceal upper gastrointestinal bleeding. Gut 2021; 70: 818-824
• 214 Tian XY, Zhu H, Zhao J. et al. Diagnostic performance of urea breath test, rapid urea test, and histology for Helicobacter pylori infection in patients with partial gastrectomy: a meta-analysis. J Clin Gastroenterol 2012; 46 (04) 285-292
• 215 Gatta L, Vakil N, Ricci C. et al. Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection. Am J Gastroenterol 2004; 99 (05) 823-829
• 216 Malfertheiner P. Diagnostic methods for H. pylori infection: Choices, opportunities and pitfalls. United European Gastroenterol J 2015; 3 (05) 429-431
• 217 Stoschus B, Domínguez-Muñoz JE, Kalhori N. et al. Effect of omeprazole on Helicobacter pylori urease activity in vivo. Eur J Gastroenterol Hepatol 1996; 8 (08) 811-813
• 218 Parente F, Sainaghi M, Sangaletti O. et al. Different effects of short-term omeprazole, lansoprazole or pantoprazole on the accuracy of the (13)C-urea breath test. Aliment Pharmacol Ther 2002; 16 (03) 553-557
• 219 Kodama M, Murakami K, Okimoto T. et al. Influence of proton pump inhibitor treatment on Helicobacter pylori stool antigen test. World J Gastroenterol 2012; 18 (01) 44-48
• 220 Savarino V, Bisso G, Pivari M. et al. Effect of gastric acid suppression on 13C-urea breath test: comparison of ranitidine with omeprazole. Aliment Pharmacol Ther 2000; 14 (03) 291-297
• 221 Murakami K, Sato R, Okimoto T. et al. Influence of anti-ulcer drugs used in Japan on the result of (13)C-urea breath test for the diagnosis of Helicobacter pylori infection. J Gastroenterol 2003; 38 (10) 937-941
• 222 Shimoyama T, Kato C, Kodama M. et al. Applicability of a monoclonal antibody-based stool antigen test to evaluate the results of Helicobacter pylori eradication therapy. Japanese journal of infectious diseases 2009; 62 (03) 225-227
• 223 Haley KP, Gaddy JA. Helicobacter pylori: Genomic Insight into the Host-Pathogen Interaction. International journal of genomics 2015; 2015: 386905
• 224 Wüppenhorst N, Draeger S, Stüger HP. et al. Prospective multicentre study on antimicrobial resistance of Helicobacter pylori in Germany. J Antimicrob Chemother 2014; 69 (11) 3127-3133
• 225 Hofreuter D, Behrendt J, Franz A. et al. Antimicrobial resistance of Helicobacter pylori in an eastern German region. Helicobacter 2021; 26 (01) e12765
• 226 Mégraud F, Bruyndonckx R, Coenen S. et al. Helicobacter pylori resistance to antibiotics in Europe in 2018 and its relationship to antibiotic consumption in the community. Manuscript submitted for publication 2021;
• 227 Wueppenhorst N, Stueger HP, Kist M. et al. High secondary resistance to quinolones in German Helicobacter pylori clinical isolates. J Antimicrob Chemother 2013; 68 (07) 1562-1566
• 228 Best LM, Haldane DJ, Keelan M. et al. Multilaboratory comparison of proficiencies in susceptibility testing of Helicobacter pylori and correlation between agar dilution and E test methods. Antimicrob Agents Chemother 2003; 47 (10) 3138-3144
• 229 Grignon B, Tankovic J, Mégraud F. et al. Validation of diffusion methods for macrolide susceptibility testing of Helicobacter pylori. Microbial drug resistance (Larchmont, NY) 2002; 8 (01) 61-66
• 230 Perna F, Gatta L, Figura N. et al. Susceptibility of Helicobacter pylori to metronidazole. Am J Gastroenterol 2003; 98 (10) 2157-2161
• 231 Schmitt BH, Regner M, Mangold KA. et al. PCR detection of clarithromycin-susceptible and -resistant Helicobacter pylori from formalin-fixed, paraffin-embedded gastric biopsies. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 2013; 26 (09) 1222-1227
• 232 Cambau E, Allerheiligen V, Coulon C. et al. Evaluation of a new test, genotype HelicoDR, for molecular detection of antibiotic resistance in Helicobacter pylori. J Clin Microbiol 2009; 47 (11) 3600-3607
• 233 Oleastro M, Ménard A, Santos A. et al. Real-time PCR assay for rapid and accurate detection of point mutations conferring resistance to clarithromycin in Helicobacter pylori. J Clin Microbiol 2003; 41 (01) 397-402
• 234 Miendje Deyi VY, Burette A, Bentatou Z. et al. Practical use of GenoType HelicoDR, a molecular test for Helicobacter pylori detection and susceptibility testing. Diagn Microbiol Infect Dis 2011; 70 (04) 557-560
• 235 Liou JM, Chen CC, Chang CY. et al. Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial. J Antimicrob Chemother 2013; 68 (02) 450-456
• 236 Lauener FN, Imkamp F, Lehours P. et al. Genetic Determinants and Prediction of Antibiotic Resistance Phenotypes in Helicobacter pylori. Journal of clinical medicine 2019; 8 (01)
• 237 Ford AC, Delaney BC, Forman D. et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2006; (02) CD003840
• 238 Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Am J Gastroenterol 1998; 93 (09) 1409-1415
• 239 Leodolter A, Kulig M, Brasch H. et al. A meta-analysis comparing eradication, healing and relapse rates in patients with Helicobacter pylori-associated gastric or duodenal ulcer. Aliment Pharmacol Ther 2001; 15 (12) 1949-1958
• 240 Liu CC, Lee CL, Chan CC. et al. Maintenance treatment is not necessary after Helicobacter pylori eradication and healing of bleeding peptic ulcer: a 5-year prospective, randomized, controlled study. Arch Intern Med 2003; 163 (17) 2020-2024
• 241 Malfertheiner P, Megraud F, O’Morain C. et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007; 56 (06) 772-781
• 242 Sharma VK, Sahai AV, Corder FA. et al. Helicobacter pylori eradication is superior to ulcer healing with or without maintenance therapy to prevent further ulcer haemorrhage. Aliment Pharmacol Ther 2001; 15 (12) 1939-1947
• 243 Sonnenberg A, Olson CA, Zhang J. The effect of antibiotic therapy on bleeding from duodenal ulcer. Am J Gastroenterol 1999; 94 (04) 950-954
• 244 Ford AC, Gurusamy KS, Delaney B. et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people. Cochrane Database Syst Rev 2016; 4 (04) CD003840
• 245 Götz M, Anders M, Biecker E. et al. S2k Leitlinie Gastrointestinale Blutung. Z Gastroenterol 2017; 55: 883-936
• 246 Banerjee S, Cash BC, Dominitz JA. et al. ASGE Practice Guideline: The role of endoscopy in the management of peptic ulcer disease. Gastrointest Endosc 2010; 71 (04) 663-668
• 247 Gielisse EAR, Kuyvenhoven JP. Follow-up endoscopy for benign-appearing gastric ulcers has no additive value in detecting malignancy. Gastric Cancer 2015; 18 (04) 803-809
• 248 Lee YB, Han J, Cho JH. et al. Clinicasl outcomes of endoscopic surveillance for gastric ulcers in populations with a high prevalence of gastric cancer. Turk J Gastroenterol 2016; 27 (05) 421-427
• 249 Rodriguez-de-Santiago E, Frazzoni L, Fuccio L. et al. Digestive findings that do not require endoscopic surveillance – Reducing the burden of care: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy 2020; 52 (06) 491-497
• 250 Chey WD, Leontiadis GI, Howden CW. et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 2017; 112: 212-238
• 251 El-Serag HB, Kao JY, Kanwal F. et al. Houston Consensus Conference on Testing for Helicobacter pylori Infection in the United States. Clin Gastroenterol Hepatol 2018; 16 (07) 992-1002
• 252 Sindel A, Al-Juhaishi T, Yazbeck V. Marginal zone lymphoma: State-of-the-art treatment. Curr Treat Options Oncol 2019; 20 (12) 90
• 253 Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood 2016; 127 (17) 2082-2092
• 254 Ruskoné-Fourmestraux A, Fischbach W, Aleman BMP. et al. EGILS consensus report. Gastric extranodal marginal zone B cell lymphoma of MALT. Gut 2011; 60: 747-758
• 255 Zullo A, Hassan C, Cristofari F. et al. Effects of Helicobacter pylori Eradication on Early Stage Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Clin Gastroenterol Hepatol 2010; 8: 105-110
• 256 Fischbach W, Goebeler-Kolve ME, Dragosics B. et al. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication: experience from a large prospective series. GUT 2004; 53: 34-37
• 257 Wündisch T, Dieckhoff P, Greene B. et al. Second cancers and Residual Disease in Patients Treated for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma by Helicobacter pylori Eradication and Followed for 10 Years. Gastroenterology 2012; 143: 936-942
• 258 Zullo A, Hassan C, Ridola L. et al. Eradication Therapy in Helicobacter pylori-negative, gastric low-grade Mucosa-associated Lymphoid Tissue lymphoma patients. A systematic Review. J Clin Gastroenterol 2013; 47 (10) 824-827
• 259 Al-Taie O, Al-Taie E, Fischbach W. Patients with Helicobacter pylori negative gastric marginal zone B-cell lymphoma (MZBCL) of MALT have a good prognosis. Z Gastroenterol 2014; 52: 1389-1393
• 260 Fischbach W, Goebeler ME, Ruskone-Fourmestraux A. et al. Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be safely managed by a watch-and-wait strategy. Experience from a large international series. Gut 2007; 56: 1685-1687
• 261 Fischbach W, Dorlöchter C. Patients with gastric MALT lymphoma revealing persisting endoscopic abnormalities after successful eradication of Helicobacter pylori can be safely managed by a watch-and-wit strategy. Z Gastroenterol 2019; 57: 593-599
• 262 Ferreri AJM, Gove S, Ponzoni M. The role of Helicobacter pylori eradication in the treatment of diffuse large B-cell and marginal zone lymphomas of the stomach. Curr Opin Oncol 2013; 25 (05) 470-479
• 263 Moayyedi P, Deeks J, Talley NJ. et al. An update of the Cochrane systematic review of Helicobacter pylori eradication therapy in nonulcer dyspepsia: resolving the discrepancy between systematic reviews. Am J Gastroenterol 2003; 98: 2621-2626
• 264 Kang SJ, Park B, Shin CM. Helicobacter pylori Eradication Therapy for Functional Dyspepsia: A Meta-Analysis by Region and H. pylori Prevalence. J Clin Med 2019; 8 (09) 1324
• 265 Zhao B, Zhao J, Cheng WF. et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia. A meta-analysis of randomized controlled studies with 12-month follow-up. J Clin Gastroenterol 2014; 48 (03) 241-247
• 266 Xu S, Wan X, Zheng X. et al. Symptom improvement after helicobacter pylori eradication in patients with functional dyspepsia – a multicenter, randomized, prospective cohort study. Int J Clin Exp Med 2013; 6 (09) 747-756
• 267 Zhao W, Zhong X, Zhuang X. et al. Evaluation of Helicobacter pylori eradication and drug therapy in patients with functional dyspepsia. Exp Ther Med 2013; 6 (01) 37-44
• 268 Kim SEK, Park YS, Kim N. et al. Effect of Helicobacter pylori eradication on functional dyspepsia. J Neurogastroenterol Motil 2013; 19 (02) 233-243
• 269 Sodhi JS, Javid G, Zargar SA. et al. Prevalence of Helicobacter pylori infection and the effect of ist eradication on symptoms of functional dyspepsia in Kashmir, India. J Gastroenterol Hepatol 2013; 28 (05) 808-813
• 270 Lan L, Yu J, Chen YL. et al. Symptom-based tendencies of Helicobacter pylori eradication in patients with functional dyspepsia. World J Gastroenterol 2011; 17: 3242-3247
• 271 Mazzoleni LE, Sander GB, Francesconi CF. et al. Helicobacter pylori Eradication in Functional Dyspepsia. HEROES Trial. Arch Intern Med 2011; 171 (21) 1929-1936
• 272 Koletzko L, Macke L, Schulz C. et al. Helicobacter pylori eradication in dyspepsia: New evidence for symptomatic benefit. Best Pract Res Clin Gastroenterol 2019; 40-41: 101637
• 273 Ford AC, Moayyedi P, Black CJ. et al. Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia. Aliment Pharmacol Ther 2021; 53 (01) 8-21
• 274 Harvey RF, Lane JA, Nair P. et al. Clinical trial: prolonged beneficial effect of Helicobacter pylori eradication on dyspepsia consultations – the Bristol helicobacter Project. Aliment Pharmacol Ther 2010; 32: 394-400
• 275 Suzuki H, Moayyedi P. Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol 2013; 10: 168-174
• 276 Cullen D, Hawkey G, Greenwood D. et al. H. pylori and gastroesophageal reflux disease: a community-based study. Helicobacter 2008; 13: 352-360
• 277 Nam SY, Choi IJ, Ryu KH. et al. Effect of Helicobacter pylori Infection and its Eradication on Reflux Esophagitis and Reflux Symptoms. Am J Gastroenterol 2010; 105: 2153-2162
• 278 Ashktorab H, Entezari O, Nouraie M. et al. Helicobacter pylori protection against reflux esophagitis. Dig Dis Sci 2012; 57: 2924-2928
• 279 Xie T, Cui X, Zheng H. et al. Meta-analysis: eradication of Helicobacter pylori infection is associated with the development of endoscopic gastroesophageal reflux disease. Eur J Gastroenterol Hepatol 2013; 25: 1195-1205
• 280 Rokkas T, Pistiolas D, Sechopoulos P. et al. Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin Gastroenterol Hepatol 2007; 5: 1413-1417
• 281 Wang C. et al. Helicobacter pylori Infection and Barrett’s Esophagus: A Systematic Review and Meta-Analysis. Am J Gastroenterol 2009; 104: 492-500
• 282 Yaghoobi M, Farrokhyar F, Yuan Y. et al. Is there an increased risk of GERD after Helicobacter pylori eradication?: a meta-analysis. Am J Gastroenterol 2010; 105: 1007-1013
• 283 Qian B, Shijie M, Shang L. et al. Effect of H. pylori eradication on gastroesophageal reflux disease. Helicobacter 2011; 121: 1120-1126
• 284 Rodriguez L, Faria CM, Geocze S. et al. Helicobacter pylori Eradication does not influence Gastroeosphageal Reflux Disease: a prospective, parallel, randomized, open-label, controlled trial. Arq Gastroenterol 2012; 49 (01) 56-63
• 285 Saad AM, Choudhary A, Bechtold ML. Effect of Helicobacter pylori treatment on gastroesopha-geal reflux disease (GERD): meta-analysis of randomized controlled trials. Scand J Gastroenterol 2012; 47: 129-135
• 286 Hirata K, Suzuki H, Matsuzaki J. et al. Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy. J Clin Biochem Nutr 2013; 52: 172-178
• 287 Wang XT, Zhang M, Chen CY. et al. Helicobacter pylori eradication and gastroesophageal reflux disease: a Meta-analysis. Zhonghua Nei Ke Za Zhi 2016; 55 (09) 710-716
• 288 Mitsushige S, Masaki M, Hitomi M. et al. Endoscopic Reflux Esophagitis and Reflux-Related Symptoms after Helicobacter pylori Eradication Therapy: Meta-Analysis. J. Clin. Med 2020; 9: 3007
• 289 Zhao Y, Li Y, Hu J. et al. The Effect of Helicobacter pylori Eradication in Patients with Gastroesophageal Reflux Disease: A Meta-Analysis of Randomized Controlled Studies. Dig Dis 2020; 38: 261-268
• 290 Kuipers EJ, Uyterlinde AM, Pena AS. et al. Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety. Am J Gastroenterol 1995; 90 (09) 1401-1406
• 291 Kuipers EJ, Lundell L, Klinkenberg-Knol EC. et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Eng J Med 1996; 334 (16) 1018-1022
• 292 Lundell L, Havu N, Miettinen P. et al. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther 2006; 23 (05) 639-647
• 293 Hagiwara T, Mukaisho KI, Nakayama T. et al. Long-term proton pump inhibitor administration worsens atrophic gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori. Gut 2011; 60 (05) 624-630
• 294 Song H, Zhu J, Lu DH. Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. Cochrane Database Syst Rev 2014; (12) CD010623
• 295 Tran-Duy A, Spaetgens B, Hoes AW. et al. Use of Proton Pump Inhibitors and Risks of Fundic Gland Polyps and Gastric Cancer: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2016; 14 (12) 1706-1719
• 296 Sanduleanu S, Jonkers D, De Bruine A. et al. Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis. Aliment Pharmacol Ther 2001; 15 (08) 1163-1175
• 297 Sanduleanu S, Jonkers D, De Bruine A. et al. Non-Helicobacter pylori bacterial flora during acid-suppressive therapy: differential findings in gastric juice and gastric mucosa. Aliment Pharmacol Ther 2001; 15 (03) 379-388
• 298 Mukaisho KI, Hagiwara T, Nakayama T. et al. Potential mechanism of corpus-predominant gastritis after PPI therapy in Helicobacter pylori-positive patients with GERD. World J Gastroenterol 2014; 20 (34) 11962-11965
• 299 Lundell L, Vieth M, Gibson F. et al. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharmacol Ther 2015; 42 (06) 649-663
• 300 Cheung KS, Chan EW, Wong AYS. et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut 2018; 67: 28-35
• 301 Jiang K, Jing X, Wen Y. et al. Relationship between long-term use of proton pump inhibitors and risk of gastric cancer: A systematic analysis. J Gastroenterol Hepatol 2019; 34 (11) 1898-1905
• 302 Seo SI, Park CH, You SCV. et al. Association between proton pump inhibitor use and gastric cancer: a population-based cohort study using two different types of nationwide databases in Korea. Gut 2021; 70 (11) 2066-2075
• 303 Arnold DM, Bernotas A, Nazi I. et al. Platelet count response to H pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review. Haematologica 2009; 94: 850-856
• 304 Stasi R, Sarpatwari A, Segal JB. et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: A systematic review. Blood 2009; 113: 1231-1240
• 305 Kim BJ, Kim HS, Jang HJ. et al. Helicobacter pylori Eradication in Idiopathic Thrombocytopenic Purpura: A Meta-Analysis of Randomized Trials. Gastroenterology Research and Practice 2018; 2018: 6090878
• 306 Madisch A, Miehlke S, Neuber F. et al. Healing of lymphocytic gastritis after Helicobacter pylori eradication therapy – a randomized, double-blind, placebo-controlled multicentre trial. Aliment Pharmacol Ther 2006; 23 (04) 473-479
• 307 Joo M. Rare Gastric Lesions Associated with Helicobacter pylori Infection: A Histopathological Review. J Pathol Med 2017; 51 (04) 341-551
• 308 Yoshimura M, Hirai M, Tanaka N. et al. Remission of severe anemia persisting for over 20 years after eradication of Helicobacter pylori in cases of Menetrier’s disease and atrophic gastritis: Helicobacter pylori as a pathogenic factor in iron-deficiency anemia. Intern Med 2003; 42 (10) 971-977
• 309 Kawasaki M, Hizawa K, Aoyagi K. et al. Menetrier’s disease associated with Helicobacter pylori infection: resolution of enlarged gastric folds and hypoproteinemia after antibacterial treatment. Am J Gastroenterol 1997; 92 (10) 1909-1912
• 310 Yamada M, Sumazaki R, Adachi H. et al. Resolution of protein-losing hypertrophic gastropathy by eradication of Helicobacter pylori. Eur J Pediatr 1997; 156 (03) 182-185
• 311 Bayerdörffer E, Ritter MM, Hatz R. et al. Healing of protein losing hypertrophic gastropathy by eradication of Helicobacter pylori--is Helicobacter pylori a pathogenic factor in Menetrier’s disease?. Gut 1994; 35 (05) 701-704
• 312 Madsen LG, Taskiran M, Madsen JL. et al. Menetrier’s disease and Helicobacter pylori. Normalization of Gastrointestinal Protein Loss after Eradication therapy. Dig Dis Sci 1999; 44 (11) 2307-2312
• 313 Badov D, Lambert JR, Finlay M. et al. Helicobacter pylori as a pathogenetic factor in Menetrier’s disease. Am J Gastroenterol 1998; 93 (10) 1976-1979
• 314 Huh WJ, Coffey RJ, Washington MK. Menetrier’s Disease: Its Mimickers and Pathogenesis. J Pathol Transl Med 2016; 50 (01) 10-16
• 315 Chen Q, Zhou X, Tan W. et al. Association between Helicobacter pylori infection and Sjögren syndrome: A meta-analysis. Medicine (Baltimore) 2018; 97 (49) e13528
• 316 Saghafi M, Abdolahi N, Orang R. et al. Helicobacter Pylori Infection in Sjogren’s Syndrome: Co-incidence or Causality?. Curr Rheumatol Rev 2019; 15 (03) 238-241
• 317 Prelipcean CC, Mihai C, Gogalniceanu C. et al. Extragastric manifestations of Helicobacter pylori infection. Rev Med Chir Soc Med Nat Iasi 2007; 111 (03) 575-583
• 318 Gasbarrini A, Franceschi F. Autoimmune diseases and Helicobacter pylori infection. Biomed Pharmacother 1999; 53 (05) 223-226
• 319 Bartoloni E, Alunno A, Gerli R. The dark side of Sjogren’s syndrome: the possible pathogenic role of infections. Curr Opin Rheumatol 2019; 31 (05) 505-511
• 320 Xiong L-J, Tong Y, Wang Z-L. et al. Is Helicobacter pylori infection associated with Henoch-Schonlein purpura in Chinese children? A meta-analysis. World J Pediatr 2012; 8: 301-308
• 321 Xiong L-J, Mao M. Current views of the relationship between Helicobacter pylori and Henoch-Schonlein purpura in children. World J Clin Pediatr 2016; 5: 82-88
• 322 Hudak L, Jaraisy A, Haj S. et al. An updated systematic review and meta-analysis on the association between Helicobacter pylori infection and iron deficiency anemia. Helicobacter 2017; 22 (01)
• 323 Qu XH, Huang XL, Xiong P. et al. Does Helicobacter pylori infection play a role in iron deficiency anemia?. World J Gastroenterol 2010; 16: 886-896
• 324 Queiroz DMM, Harris PR, Sanderson IR. et al. Iron Status and Helicobacter pylori infection in symptomatic children: An international Multicentered study. PLOS One 2013; 8 (07) e68833
• 325 Duque X, Moran S, Mera R. et al. Effect of eradication of Helicobacter pylori and iron supplementation on the iron status of children with iron deficiency. Arch Med Res 2010; 41 (01) 38-45
• 326 Herter-Aeberli I, Eliancy K, Rathon Y. et al. In Haitian women and preschool children, iron absorption from wheat flour-based meals fortified with sodium iron EDTA is higher than that from meals fortified with ferrous fumarate, and is not affected by Helicobacter pylori infection in children. Br J Nutr 2017; 118 (04) 273-279
• 327 Venerito M, Schneider C, Costanzo R. et al. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
• 328 Sarri GL, Grigg SE, Yeomans ND. Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis. J Gastroenterol Hepatol 2019; 34 (03) 517-525
• 329 Chan FK, To KF, Wu JC. et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 2002; 359: 9-13
• 330 Tang CL, Ye F, Liu W. et al. Eradication of Helicobacter pylori infection reduces the incidence of peptic ulcer disease in patients using nonsteroidal anti-inflammatory drugs: a meta-analysis. Helicobacter 2012; 17 (04) 286-296
• 331 Lai KC, Lam SK, Chu KM. et al. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in nonsteroidal anti-inflammatory drug users – a randomized trial. Aliment Pharmacol Ther 2003; 18: 829-836
• 332 Hawkey CJ, Tulassay Z, Szczepanski L. et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention. Lancet 1998; 352: 1016-1021
• 333 de Leest HT, Steen KS, Lems WF. et al. Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment: double-blind, randomized, placebo-controlled trial. Helicobacter 2007; 12: 477-485
• 334 Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. 2013 Available from: https://www.ncbi.nlm.nih.gov/books/NBK154370
• 335 Venerito M, Schneider C, Costanzo R. et al. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
• 336 Cheung KS, Leung WK. Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management. World J Gastroenterol 2017; 23 (11) 1954-1963
• 337 Lauffenburger JC, Rhoney DH, Farley JF. et al. Predictors of gastrointestinal bleeding among patients with atrial fibrillation after initiating dabigatran therapy. Pharmacotherapy 2015; 35 (06) 560-568
• 338 Suceveanu AI, Suceveanu AP, Parepa I. et al. Reducing upper digestive bleeding risk in patients treated with direct oral anticoagulants and concomitant infection with Helicobacter pylori. Exp Ther Med 2020; 20 (06) 205
• 339 Dall M, Schaffalitzky de Muckadell OB, Moller Hansen J. et al. Helicobacter pylori and risk of upper gastrointestinal bleeding among users of selective serotonin reuptake inhibitors. Scand J Gastroenterol 2011; 46: 1039-1044
• 340 Guo CG, Cheung KS, Zhang F. et al. Risks of hospitalization for upper gastrointestinal bleeding in users of selective serotonin reuptake inhibitors after Helicobacter pylori eradication therapy: a propensity score matching analysis. Aliment Pharmacol Ther 2019; 50: 1001-1008
• 341 Chan FKL, Chung SC, Suen BY. et al. Preventing Recurrent Upper Gastrointestinal Bleeding in Patients with Helicobacter pylori Infection who are taking Low-Dose Aspirin or Naproxen. N Engl J Med 2001; 344: 967-973
• 342 Chan FKL, Ching JYL, Suen BY. et al. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013; 144: 528-553
• 343 Group I.H.p.W. Helicobacter pylori eradication as a strategy for preventing gastric cancer. IARC Working Group Reports Volume 8. 2014. ISBN-13; 978-92-832-2454-9
• 344 Wang C, Yuan Y, Hunt RH. The association between Helicobacter pylori infection and early gastric cancer: a meta-analysis. Am J Gastroenterol 2007; 102 (08) 1789-1798
• 345 Derks S, Bass AJ. Mutational signatures in Helicobacter pylori-induced gastric cancer: lessons from new sequencing technologies. Gastroenterology 2014; 147 (02) 267-269
• 346 Shimizu T. et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology 2014; 147 (02) 07-17.e3
• 347 Stoicov C. et al. Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. Gene 2004; 341: 1-17
• 348 Kodaman N. et al. Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A 2014; 111 (04) 1455-1460
• 349 Bornschein J. et al. Molecular diagnostics in gastric cancer. Front Biosci (Landmark Ed) 2014; 19: 312-338
• 350 Ekström AM. et al. Occupational exposures and risk of gastric cancer in a population-based case-control study. Cancer Res 1999; 59 (23) 5932-5937
• 351 Miehlke S. et al. The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany. Int J Cancer 2000; 87 (03) 322-327
• 352 Basso D. et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008; 135 (01) 91-99
• 353 Jang S. et al. Epidemiological link between gastric disease and polymorphisms in VacA and CagA. J Clin Microbiol 2010; 48 (02) 559-567
• 354 Rizzato C. et al. Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention. PLoS One 2012; 7 (01) e29605
• 355 Ekström AM. et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based case-control study in Sweden. Int J Cancer 2000; 87 (01) 133-140
• 356 González CA. et al. Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2006; 98 (05) 345-354
• 357 González CA, López-Carrillo L. Helicobacter pylori, nutrition and smoking interactions: their impact in gastric carcinogenesis. Scand J Gastroenterol 2010; 45 (01) 6-14
• 358 Plummer M. et al. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer 2015; 136 (02) 487-490
• 359 Liou JM. et al. Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus. Gut 2020; 69 (12) 2093-2112
• 360 Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998; 85 (11) 1457-1459
• 361 Bornschein J. et al. H. pylori infection is a key risk factor for proximal gastric cancer. Dig Dis Sci 2010; 55 (11) 3124-3131
• 362 Cavaleiro-Pinto M. et al. Helicobacter pylori infection and gastric cardia cancer: systematic review and meta-analysis. Cancer Causes Control 2011; 22 (03) 375-387
• 363 Derakhshan MH. et al. Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer. Gut 2008; 57 (03) 298-305
• 364 Hansen S. et al. Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status. Gut 2007; 56 (07) 918-925
• 365 Peleteiro B. et al. Is cardia cancer aetiologically different from distal stomach cancer?. Eur J Cancer Prev 2011; 20 (02) 96-101
• 366 McColl KE, Watabe H, Derakhshan MH. Role of gastric atrophy in mediating negative association between Helicobacter pylori infection and reflux oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 2008; 57 (06) 721-723
• 367 Bornschein J. et al. Adenocarcinomas at different positions at the gastro-oesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. Eur J Gastroenterol Hepatol 2015; 27 (05) 492-500
• 368 Rice TW. et al. Cancer of the Esophagus and Esophagogastric Junction: An Eighth Edition Staging Primer. J Thorac Oncol 2017; 12 (01) 36-42
• 369 Arnold M, Park JY, Camargo MC. et al. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut 2020; 69 (05)
• 370 Hooi JKY. et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017; 153 (02) 420-429
• 371 Franck C, Hoffmann A, Link A. et al. Prevalence of Helicobacter pylori infection among blood donors in Saxony-Anhalt, Germany – a region at intermediate risk for gastric cancer. Z Gastroenterol 2017; 55 (07) 653-656
• 372 Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut 2020; 69 (12) 2113-2121
• 373 Doorakkers E, Lagergren J, Engstrand L. et al. Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population. Gut 2018; 67 (12) 2092-2096
• 374 Chiang TH. et al. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut 2021; 70 (02) 243-250
• 375 Lansdorp-Vogelaar I, Sharp L. Cost-effectiveness of screening and treating Helicobacter pylori for gastric cancer prevention. Best Pract Res Clin Gastroenterol 2013; 27 (06) 933-947
• 376 Chen Q. et al. Cost-effectiveness analysis of screen-and-treat strategy in asymptomatic Chinese for preventing Helicobacter pylori-associated diseases. Helicobacter 2019; 24 (02) e12563
• 377 Lansdorp-Vogelaar I, Meester RGS, Laszkowska M. et al. Cost-effectiveness of prevention and early detection of gastric cancer in Western countries. Best Pract Res Clin Gastroenterol 2021; 50-51: 101735
• 378 Selgrad M. et al. Combined Gastric and Colorectal Cancer Screening – A New Strategy. Int J Mol Sci 2018; 19 (12)
• 379 Areia M. et al. Endoscopic screening for gastric cancer: A cost-utility analysis for countries with an intermediate gastric cancer risk. United European Gastroenterol J 2018; 6 (02) 192-202
• 380 Leung WK. et al. Effects of Helicobacter pylori Treatment on Incidence of Gastric Cancer in Older Individuals. Gastroenterology 2018; 155 (01) 67-75
• 381 di Mario F, Cavallaro LG. Non-invasive tests in gastric diseases. Dig Liver Dis 2008; 40 (07) 523-530
• 382 Leja M. et al. The validity of a biomarker method for indirect detection of gastric mucosal atrophy versus standard histopathology. Dig Dis Sci 2009; 54 (11) 2377-2384
• 383 Kitahara F. et al. Accuracy of screening for gastric cancer using serum pepsinogen concentrations. Gut 1999; 44 (05) 693-697
• 384 Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer 2006; 9 (04) 245-253
• 385 Watabe H. et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut 2005; 54 (06) 764-768
• 386 Yoshihara M. et al. Reduction in gastric cancer mortality by screening based on serum pepsinogen concentration: a case-control study. Scand J Gastroenterol 2007; 42 (06) 760-764
• 387 Terasawa T. et al. Prediction of gastric cancer development by serum pepsinogen test and Helicobacter pylori seropositivity in Eastern Asians: a systematic review and meta-analysis. PLoS One 2014; 9 (10) e109783
• 388 Oishi Y. et al. The serum pepsinogen test as a predictor of gastric cancer: the Hisayama study. Am J Epidemiol 2006; 163 (07) 629-637
• 389 Yanaoka K. et al. Cancer high-risk subjects identified by serum pepsinogen tests: outcomes after 10-year follow-up in asymptomatic middle-aged males. Cancer Epidemiol Biomarkers Prev 2008; 17 (04) 838-845
• 390 Zhang X. et al. Low serum pepsinogen I and pepsinogen I/II ratio and Helicobacter pylori infection are associated with increased risk of gastric cancer: 14-year follow up result in a rural Chinese community. Int J Cancer 2012; 130 (07) 1614-1619
• 391 Lomba-Viana R. et al. Serum pepsinogen test for early detection of gastric cancer in a European country. Eur J Gastroenterol Hepatol 2012; 24 (01) 37-41
• 392 Moehler M. et al. S3-Leitlinie Magenkarzinom. Z Gastroenterol 2019; 57 (12) 1517-1632
• 393 Huang YK. et al. Significance of Serum Pepsinogens as a Biomarker for Gastric Cancer and Atrophic Gastritis Screening: A Systematic Review and Meta-Analysis. PLoS One 2015; 10 (11) e0142080
• 394 Gupta S. et al. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology 2020; 158 (03) 693-702
• 395 Hamashima C. Update version of the Japanese Guidelines for Gastric Cancer Screening. Jpn J Clin Oncol 2018; 48 (07) 673-683
• 396 Zagari RM. et al. Prevalence of upper gastrointestinal endoscopic findings in the community: A systematic review of studies in unselected samples of subjects. J Gastroenterol Hepatol 2016; 31 (09) 1527-1538
• 397 Bang CS, Lee JJ, Baik GH. Prediction of Chronic Atrophic Gastritis and Gastric Neoplasms by Serum Pepsinogen Assay: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy. J Clin Med 2019; 8 (05)
• 398 Song M. et al. Serum pepsinogen 1 and anti-Helicobacter pylori IgG antibodies as predictors of gastric cancer risk in Finnish males. Aliment Pharmacol Ther 2018; 47 (04) 494-503
• 399 El-Omar EM. et al. Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. Gastroenterology 2000; 118 (01) 22-30
• 400 Oh S. et al. Risk factors of atrophic gastritis and intestinal metaplasia in first-degree relatives of gastric cancer patients compared with age-sex matched controls. J Cancer Prev 2013; 18 (02) 149-160
• 401 Choi IJ. et al. Family History of Gastric Cancer and Helicobacter pylori Treatment. N Engl J Med 2020; 382 (05) 427-436
• 402 Venerito M, Vasapolli R, Malfertheiner P. Helicobacter pylori and Gastric Cancer: Timing and Impact of Preventive Measures. Adv Exp Med Biol 2016; 908: 409-418
• 403 Panteris V. et al. Diagnostic capabilities of high-definition white light endoscopy for the diagnosis of gastric intestinal metaplasia and correlation with histologic and clinical data. Eur J Gastroenterol Hepatol 2014; 26 (06) 594-601
• 404 Pimentel-Nunes P. et al. A multicenter prospective study of the real-time use of narrow-band imaging in the diagnosis of premalignant gastric conditions and lesions. Endoscopy 2016; 48 (08) 723-730
• 405 Ang TL. et al. A multicenter randomized comparison between high-definition white light endoscopy and narrow band imaging for detection of gastric lesions. Eur J Gastroenterol Hepatol 2015; 27 (12) 1473-1478
• 406 Kim YI. et al. Effect of biopsy site on detection of gastric cancer high-risk groups by OLGA and OLGIM stages. Helicobacter 2017; 22 (06)
• 407 Isajevs S. et al. The effect of incisura angularis biopsy sampling on the assessment of gastritis stage. Eur J Gastroenterol Hepatol 2014; 26 (05) 510-513
• 408 Varbanova M, Wex T, Jechorek D. et al. Impact of the angulus biopsy for the detection of gastric preneoplastic conditions and gastric cancer risk assessment. J Clin Pathol 2016; 69 (01) 19-25
• 409 Arnold M. et al. The burden of stomach cancer in indigenous populations: a systematic review and global assessment. Gut 2014; 63 (01) 64-71
• 410 De Vries AC. et al. Migrant communities constitute a possible target population for primary prevention of Helicobacter pylori-related complications in low incidence countries. Scand J Gastroenterol 2008; 43 (04) 403-409
• 411 Saumoy M. et al. Cost Effectiveness of Gastric Cancer Screening According to Race and Ethnicity. Gastroenterology 2018; 155 (03) 648-660
• 412 Murphy G. et al. Cancer Risk After Pernicious Anemia in the US Elderly Population. Clin Gastroenterol Hepatol 2015; 13 (13) 2282-2289. e1-4
• 413 Weise F, Vieth M, Reinhold D. et al. Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research. United European Gastroenterol J 2020; 8 (02) 175-184
• 414 Wong BC. et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291 (02) 187-194
• 415 Rugge M, Genta RM. Staging gastritis: an international proposal. Gastroenterology 2005; 129 (05) 1807-1808
• 416 Rugge M. et al. Gastritis staging in clinical practice: the OLGA staging system. Gut 2007; 56 (05) 631-636
• 417 Capelle LG. et al. The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointest Endosc 2010; 71 (07) 1150-1158
• 418 Rugge M. et al. Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients. Gut 2019; 68 (01) 11-17
• 419 Isajevs S. et al. Gastritis staging: interobserver agreement by applying OLGA and OLGIM systems. Virchows Arch 2014; 464 (04) 403-407
• 420 Leja M. et al. Interobserver variation in assessment of gastric premalignant lesions: higher agreement for intestinal metaplasia than for atrophy. Eur J Gastroenterol Hepatol 2013; 25 (06) 694-699
• 421 Marcos-Pinto R. et al. First-degree relatives of patients with early-onset gastric carcinoma show even at young ages a high prevalence of advanced OLGA/OLGIM stages and dysplasia. Aliment Pharmacol Ther 2012; 35 (12) 1451-1459
• 422 Rugge M. et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study. Aliment Pharmacol Ther 2010; 31 (10) 1104-1111
• 423 Take S. et al. The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori. J Gastroenterol 2011; 46 (03) 318-324
• 424 Yanaoka K. et al. Eradication of Helicobacter pylori prevents cancer development in subjects with mild gastric atrophy identified by serum pepsinogen levels. Int J Cancer 2009; 125 (11) 2697-2703
• 425 Kodama M. et al. Histological characteristics of gastric mucosa prior to Helicobacter pylori eradication may predict gastric cancer. Scand J Gastroenterol 2013; 48 (11) 1249-1256
• 426 Rokkas T. et al. The long-term impact of Helicobacter pylori eradication on gastric histology: a systematic review and meta-analysis. Helicobacter 2007; 12 (Suppl. 02) 32-38
• 427 Yoshida T. et al. Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer. Int J Cancer 2014; 134 (06) 1445-1457
• 428 Areia M, Dinis-Ribeiro M, Rocha Gonçalves F. Cost-utility analysis of endoscopic surveillance of patients with gastric premalignant conditions. Helicobacter 2014; 19 (06) 425-436
• 429 Rugge M, Genta RM, Fassan M. et al. OLGA Gastritis Staging for the Prediction of Gastric Cancer Risk: A Long-term Follow-up Study of 7436 Patients. Am J Gastroenterol 2018; 113 (11) 1621-1628
• 430 Kato M. et al. Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: a multicentre retrospective cohort study by Osaka University ESD study group. Gut 2013; 62 (10) 1425-1432
• 431 Pimentel-Nunes P. et al. Long-term follow-up after endoscopic resection of gastric superficial neoplastic lesions in Portugal. Endoscopy 2014; 46 (11) 933-940
• 432 Fukase K. et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392-397
• 433 Choi JM. et al. Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial. Gastrointest Endosc 2018; 88 (03) 475-485.e2
• 434 Choi Y, Kim N, Yoon H. et al. The Incidence and Risk Factors for Metachronous Gastric Cancer in the Remnant Stomach after Gastric Cancer Surgery. Gut Liver 2021;
• 435 Choi IJ. et al. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N Engl J Med 2018; 378 (12) 1085-1095
• 436 Malfertheiner P. Helicobacter pylori Treatment for Gastric Cancer Prevention. N Engl J Med 2018; 378 (12) 1154-1156
• 437 Sonnenberg A. Time trends of ulcer mortality in Europe. Gastroenterology 2007; 132 (07) 2320-2327
• 438 Sonnenberg A. Time trends of ulcer mortality in non-European countries. Am J Gastroenterol 2007; 102 (05) 1101-1107
• 439 Malfertheiner P, Schulz C. Peptic Ulcer: Chapter Closed?. Dig Dis 2020; 1-5
• 440 Van der Hulst RW. et al. Prevention of ulcer recurrence after eradication of Helicobacter pylori: a prospective long-term follow-up study. Gastroenterology 1997; 113 (04) 1082-1086
• 441 Venerito M, Schneider C, Costanzo R. et al. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
• 442 Hellström PM, Benno P, Malfertheiner P. Gastrointestinal bleeding in patients with Helicobacter pylori and dual platelet inhibition after myocardial infarction. Lancet Gastroenterol Hepatol 2021; 6 (09) 684-685
• 443 Gisbert JP. et al. Eradication of Helicobacter pylori for the prevention of peptic ulcer rebleeding. Helicobacter 2007; 12 (04) 279-278
• 444 Wong CS. et al. Eradication of Helicobacter pylori for prevention of ulcer recurrence after simple closure of perforated peptic ulcer: a meta-analysis of randomized controlled trials. J Surg Res 2013; 182 (02) 219-226
• 445 Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment Pharmacol Ther 2007; 26 (03) 343-357
• 446 Malfertheiner P, Selgrad M. Helicobacter pylori. Curr Opin Gastroenterol 2014; 30 (06) 589-595
• 447 Selgrad M, Meissle J, Bornschein J. et al. Antibiotic susceptibility of Helicobacter pylori in central Germany and its relationship with the number of eradication therapies. Eur J Gastroenterol Hepatol 2013; 25 (11) 1257-1260
• 448 Megraud F, Coenen S, Versporten A. et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut 2013; 62 (01) 34-42
• 449 Wüppenhorst N, Draeger S, Stüger HP. et al. Prospective multicentre study on antimicrobial resistance of Helicobacter pylori in Germany. J Antimicrob Chemother 2014; 69 (11) 3127-3133
• 450 Savoldi A, Carrara E, Graham DY. et al. Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. Gastroenterology 2018; 155 (05) 1372-1382.e17
• 451 Megraud F, Bruyndonckx R, Coenen S. et al. Helicobacter pylori resistance to antibiotics in Europe in 2018 and ist relationship to antibiotic consumption in the community. Gut 2021; 70: 1815-1822
• 452 Bluemel B, Goelz H, Goldmann B. et al. Antimicrobial resistance of Helicobacter pylori in Germany, 2015 to 2018. Clin Microbiol Infect 2020; 26 (02) 235-239
• 453 Kuo C-H, Lu C-Y, Shih H-Y. et al. CYP2C19 polymorphism influences Helicobacter pylori eradication. World J Gastroenterol 2014; 20 (43) 16029-16036
• 454 Nyssen OP, Perez-Aisa A, Castro-Fernandez M. et al. European Registry on Helicobacter pylori Management: single-capsule bismuth quadruple therapy is effective in real-world clinical practice. United Eur Gastroenterol J 2020;
• 455 Nyssen OP, McNicholl AG, Gisbert JP. Meta-analysis of three-in-one single capsule bismuth-containing quadruple therapy for the eradication of Helicobacter pylori. Helicobacter 2019; 24 (02) e12570
• 456 Nyssen OP, Perez-Aisa A, Castro-Fernandez M. et al. European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice. United Eur Gastroenterol J 2021; 9 (01) 38-46
• 457 Lee HJ, Kim JIl, Cheung DY. et al. Eradication of Helicobacter pylori according to 23S ribosomal RNA point mutations associated with clarithromycin resistance. J Infect Dis 2013; 208 (07) 1123-1130
• 458 Cho J-H, Jeon SR, Kim HG. et al. Cost-effectiveness of a tailored Helicobacter pylori eradication strategy based on the presence of a 23S ribosomal RNA point mutation that causes clarithromycin resistance in Korean patients. J Gastroenterol Hepatol 2019; 34 (04) 700-706
• 459 Amini M, Tajik A. Oral and intravenous eradication of Helicobacter pylori. Pakistan J Biol Sci PJBS 2009; 12 (10) 809-812
• 460 Schilling D, Demel A, Nüsse T. et al. Helicobacter pylori infection does not affect the early rebleeding rate in patients with peptic ulcer bleeding after successful endoscopic hemostasis: a prospective single-center trial. Endoscopy 2003; 35 (05) 393-396
• 461 Selgrad M, Meyer F, Malfertheiner P. Helicobacter pylori: Kurzabriss zu ausgewählten historischen Etappen des Erkenntnisprozesses und ihre Bedeutung für die klinische Medizin, insbesondere auch die Chirurgie – was der (Allgemein-/Viszeral-)Chirurg wissen sollte. Zentralblatt für Chir – Zeitschrift für Allg Visz Thorax- und Gefäßchirurgie 2014; 139 (04) 399-405
• 462 Hu Y, Wan J-H, Li X-Y. et al. Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. Aliment Pharmacol Ther 2017; 46 (09) 773-779
• 463 Gisbert JP. The recurrence of Helicobacter pylori infection: incidence and variables influencing it. A critical review. Am J Gastroenterol 2005; 100 (09) 2083-2099
• 464 Jones NL, Koletzko S, Goodman K. et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr 2017; 64 (06) 991-1003
• 465 Harris PR, Calderon-Guerrero OG, Vera-Chamorro JF. et al. [Adaptation to the reality of Latin America of the NASPGHAN/ESPGHAN 2016 Guidelines on the Diagnosis, Prevention and Treatment of Helicobacter pylori Infection in Pediatrics]. Rev Chil Pediatr 2020; 91 (05) 809-827
• 466 Kato S, Shimizu T, Toyoda S. et al. The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood. Pediatr Int 2020; 62 (12) 1315-1331
• 467 Rowland M, Clyne M, Daly L. et al. Long-term follow-up of the incidence of Helicobacter pylori. Clin Microbiol Infect 2018; 24 (09) 980-984
• 468 Elias N, Nasrallah E, Khoury C. et al. Associations of Helicobacter pylori seropositivity and gastric inflammation with pediatric asthma. Pediatr Pulmonol 2020; 55 (09) 2236-2245
• 469 Fouda EM, Kamel TB, Nabih ES. et al. Helicobacter pylori seropositivity protects against childhood asthma and inversely correlates to its clinical and functional severity. Allergol Immunopathol (Madr) 2018; 46 (01) 76-81
• 470 Lim JH, Kim N, Lim SH. et al. Inverse Relationship Between Helicobacter Pylori Infection and Asthma Among Adults Younger than 40 Years: A Cross-Sectional Study. Medicine (Baltimore) 2016; 95 (08) e2609
• 471 Taye B, Enquselassie F, Tsegaye A. et al. Is Helicobacter Pylori infection inversely associated with atopy? A systematic review and meta-analysis. Clin Exp Allergy 2015; 45 (05) 882-890
• 472 Chen Y, Zhan X, Wang D. Association between Helicobacter pylori and risk of childhood asthma: a meta-analysis of 18 observational studies. J Asthma 2021; 1-17
• 473 Imawana RA, Smith DR, Goodson ML. The relationship between inflammatory bowel disease and Helicobacter pylori across East Asian, European and Mediterranean countries: a meta-analysis. Ann Gastroenterol 2020; 33 (05) 485-494
• 474 Sayar R, Shokri Shirvani J, Hajian-Tilaki K. et al. The negative association between inflammatory bowel disease and Helicobacter pylori seropositivity. Caspian J Intern Med 2019; 10 (02) 217-222
• 475 Kori M, Le Thi TG, Werkstetter K. et al. Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016. J Pediatr Gastroenterol Nutr 2020; 71 (04) 476-483
• 476 Okuda M, Nomura K, Kato M. et al. Gastric cancer in children and adolescents in Japan. Pediatr Int 2019; 61 (01) 80-86
• 477 Schwille IJ, Giel KE, Ellert U. et al. A community-based survey of abdominal pain prevalence, characteristics, and health care use among children. Clin Gastroenterol Hepatol 2009; 7 (10) 1062-1068
• 478 Gulewitsch MD, Enck P, Schwille-Kiuntke J. et al. Rome III criteria in parents’ hands: pain-related functional gastrointestinal disorders in community children and associations with somatic complaints and mental health. Eur J Gastroenterol Hepatol 2013; 25 (10) 1223-1229
• 479 Chitkara DK, Rawat DJ, Talley NJ. The epidemiology of childhood recurrent abdominal pain in Western countries: a systematic review. Am J Gastroenterol 2005; 100 (08) 1868-1875
• 480 Chobot A, Porebska J, Krzywicka A. et al. No association between Helicobacter pylori infection and gastrointestinal complaints in a large cohort of symptomatic children. Acta Paediatr 2019; 108 (08) 1535-1540
• 481 Correa Silva RG, Machado NC, Carvalho MA. et al. Helicobacter pylori infection is high in paediatric nonulcer dyspepsia but not associated with specific gastrointestinal symptoms. Acta Paediatr 2016; 105 (05) e228-e231
• 482 Rejchrt S, Koupil I, Kopacova M. et al. The prevalence and sociodemographic determinants of uninvestigated dyspepsia in the Czech Republic: a multicentre prospective study accomplished 10 years after the first study from the same geographical areas. Eur J Gastroenterol Hepatol 2018; 30 (01) 76-82
• 483 Kim BJ, Kim HS, Jang HJ. et al. Helicobacter pylori Eradication in Idiopathic Thrombocytopenic Purpura: A Meta-Analysis of Randomized Trials. Gastroenterol Res Pract 2018; 2018: 6090878
• 484 Sheema K, Ikramdin U, Arshi N. et al. Role of Helicobacter pylori Eradication Therapy on Platelet Recovery in Chronic Immune Thrombocytopenic Purpura. Gastroenterol Res Pract 2017; 2017: 9529752
• 485 Abdollahi A, Shoar S, Ghasemi S. et al. Is Helicobacter pylori infection a risk factor for idiopathic thrombocytopenic purpura in children?. Ann Afr Med 2015; 14 (04) 177-181
• 486 Brito HS, Braga JA, Loggetto SR. et al. Helicobacter pylori infection & immune thrombocytopenic purpura in children and adolescents: A randomized controlled trial. Platelets 2015; 26 (04) 336-341
• 487 Wang JJ, Xu Y, Liu FF. et al. Association of the infectious triggers with childhood Henoch-Schonlein purpura in Anhui province, China. J Infect Public Health 2020; 13 (01) 110-117
• 488 Xiong LJ, Mao M. Current views of the relationship between Helicobacter pylori and Henoch-Schonlein purpura in children. World J Clin Pediatr 2016; 5 (01) 82-88
• 489 Cornillier H, Giraudeau B, Munck S. et al. Chronic spontaneous urticaria in children – a systematic review on interventions and comorbidities. Pediatr Allergy Immunol 2018; 29 (03) 303-310
• 490 Kudryavtseva AV, Neskorodova KA, Staubach P. Urticaria in children and adolescents: An updated review of the pathogenesis and management. Pediatr Allergy Immunol 2019; 30 (01) 17-24
• 491 Williams PV. Pharmacologic Management of Chronic Urticaria in Pediatric Patients: The Gap Between Guidelines and Practice. Paediatr Drugs 2020; 22 (01) 21-28
• 492 Akelma AZ, Cizmeci MN, Mete E. et al. A neglected cause for chronic spontaneous urticaria in children: Helicobacter pylori. Allergol Immunopathol (Madr) 2015; 43 (03) 259-263
• 493 Zahmatkeshan M, Karimi M, Geramizadeh B. et al. Association between Helicobacter pylori Infection and Iron Deficiency Anemia in School-aged Iranian Children. Indian Pediatr 2019; 56 (05) 387-389
• 494 Gheibi S, Farrokh-Eslamlou HR, Noroozi M. et al. Refractory iron deficiency anemia and Helicobacter Pylori Infection in pediatrics: A review. Iran J Ped Hematol Oncol 2015; 5 (01) 50-64
• 495 Mendoza E, Duque X, Hernandez Franco JI. et al. Association between Active H. pylori Infection and Iron Deficiency Assessed by Serum Hepcidin Levels in School-Age Children. Nutrients 2019; 11 (09)
• 496 Buerkli S, Fatou Ndiaye N, Cercamondi CI. et al. Asymptomatic Helicobacter Pylori Infection in Preschool Children and Young Women Does Not Predict Iron Bioavailability from Iron-Fortified Foods. Nutrients 2019; 11 (09)
• 497 Burgard M, Kotilea K, Mekhael J. et al. Evolution of Helicobacter pylori associated with gastroduodenal ulcers or erosions in children over the past 23 years: Decline or steady state?. Helicobacter 2019; 24 (05) e12629
• 498 Alper A, Hardee S, Rojas-Velasquez D. et al. Prevalence and Clinical, Endoscopic, and Pathological Features of Duodenitis in Children. J Pediatr Gastroenterol Nutr 2016; 62 (02) 314-316
• 499 Ganga-Zandzou PS, Michaud L, Vincent P. et al. Natural outcome of Helicobacter pylori infection in asymptomatic children: a two-year follow-up study. Pediatrics 1999; 104 (02) 216-221
• 500 Lazowska-Przeorek I, Kotowska M, Banasiuk M. et al. Value of Antral Nodularity for the Diagnosis of Helicobacter pylori Infection in Children. Med Sci Monit 2015; 21: 1827-1830
• 501 Koletzko S, Richy F, Bontems P. et al. Prospective multicentre study on antibiotic resistance of Helicobacter pylori strains obtained from children living in Europe. Gut 2006; 55 (12) 1711-1716
• 502 El-Shabrawi M, El-Aziz NA, El-Adly TZ. et al. Stool antigen detection versus (13)C-urea breath test for non-invasive diagnosis of pediatric Helicobacter pylori infection in a limited resource setting. Arch Med Sci 2018; 14 (01) 69-73
• 503 Calik Z, Karamese M, Acar O. et al. Investigation of Helicobacter pylori antigen in stool samples of patients with upper gastrointestinal complaints. Braz J Microbiol 2016; 47 (01) 167-171
• 504 Kalach N, Gosset P, Dehecq E. et al. A one-step immune-chromatographic Helicobacter pylori stool antigen test for children was quick, consistent, reliable and specific. Acta Paediatr 2017; 106 (12) 2025-2030
• 505 Moubri M, Burucoa C, Kalach N. et al. Performances of the IDEIA HpStAR Stool Antigen Test in Detection of Helicobacter pylori Infection Before and After Eradication Treatment in Algerian Children. J Trop Pediatr 2019; 65 (03) 210-216
• 506 Beer-Davidson G, Hindiyeh M, Muhsen K. Detection of Helicobacter pylori in stool samples of young children using real-time polymerase chain reaction. Helicobacter 2018; 23 (01)
• 507 Kusano C, Gotoda T, Ikehara H. et al. The Accuracy of the Serum Antibody Test for Helicobacter pylori Infection among Junior High School Students. Digestion 2021; 102 (02) 155-160
• 508 Graham DY, Liou JM. Primer for Development of Guidelines for Helicobacter pylori Therapy Using Antimicrobial Stewardship. Clin Gastroenterol Hepatol 2021;
• 509 Jansson L, Agardh D. Prevalence of clarithromycin-resistant Helicobacter pylori in children living in South of Sweden: a 12-year follow-up. Scand J Gastroenterol 2019; 54 (07) 838-842
• 510 Guven B, Gulerman F, Kacmaz B. Helicobacter pylori resistance to clarithromycin and fluoroquinolones in a pediatric population in Turkey: A cross-sectional study. Helicobacter 2019; 24 (03) e12581
• 511 Butenko T, Jeverica S, Orel R. et al. Antibacterial resistance and the success of tailored triple therapy in Helicobacter pylori strains isolated from Slovenian children. Helicobacter 2017; 22 (05)
• 512 Zhou Y, Ye Z, Wang Y. et al. Comparison of four different regimens against Helicobacter pylori as a first-line treatment: A prospective, cross-sectional, comparative, open trial in Chinese children. Helicobacter 2020; 25 (02) e12679
• 513 Lopo I, Libanio D, Pita I. et al. Helicobacter pylori antibiotic resistance in Portugal: Systematic review and meta-analysis. Helicobacter 2018; 23 (04) e12493
• 514 Tamayo E, Montes M, Fernandez-Reyes M. et al. Clarithromycin resistance in Helicobacter pylori and its molecular determinants in Northern Spain, 2013-2015. J Glob Antimicrob Resist 2017; 9: 43-46
• 515 Krzyzek P, Pawelka D, Iwanczak B. et al. High Primary Antibiotic Resistance of Helicobacter pylori Strains Isolated from Pediatric and Adult Patients in Poland during 2016–2018. Antibiotics (Basel) 2020; 9 (05)
• 516 Kori M, Yahav J, Berdinstein R. et al. Primary and Secondary Antibiotic Resistance of Helicobacter pylori in Israeli Children and Adolescents. Isr Med Assoc J 2017; 19 (12) 747-750
• 517 Miyata E, Kudo T, Ikuse T. et al. Eradication therapy for Helicobacter pylori infection based on the antimicrobial susceptibility test in children: A single-center study over 12 years. Helicobacter 2021; 26 (01) e12764
• 518 Lucero Y, George S, O’Ryan M. Indications for Helicobacter pylori Eradication: Do We Need to Consider to Screen and Treat Asymptomatic Children?. J Pediatr Gastroenterol Nutr 2018; 67 (04) e86-e87
• 519 Koletzko S, Jones N. No Screen and Treat in Children for Helicobacter pylori Infection. J Pediatr Gastroenterol Nutr 2018; 67 (04) e87-e88
• 520 Kotilea K, Kalach N, Homan M. et al. Helicobacter pylori Infection in Pediatric Patients: Update on Diagnosis and Eradication Strategies. Paediatr Drugs 2018; 20 (04) 337-351
• 521 Kori M, Daugule I, Urbonas V. Helicobacter pylori and some aspects of gut microbiota in children. Helicobacter 2018; 23 (Suppl. 01) e12524
• 522 Kaji E, Yoden A, Otani M. et al. Helicobacter pylori test-and-treat strategy for second-year junior high school students aimed at the prevention of gastric cancer in Takatsuki City. Helicobacter 2020; 25 (04) e12696
• 523 Huang Y, Zhan X. Sequential Therapy is Superior to Triple Therapy for Helicobacter pylori Infection in Children: A Meta-Analysis. Indian J Pediatr 2016; 83 (04) 307-315
• 524 Schwarzer A, Bontems P, Urruzuno P. et al. Sequential Therapy for Helicobacter pylori Infection in Treatment-naive Children. Helicobacter 2016; 21 (02) 106-113
• 525 Iwanczak BM, Borys-Iwanicka A, Biernat M. et al. Assessment of Sequential and Standard Triple Therapy in Treatment of Helicobacter pylori Infection in Children Dependent on Bacteria Sensitivity to Antibiotics. Adv Clin Exp Med 2016; 25 (04) 701-708
• 526 Dehghani SM, Nazari A, Javaherizadeh H. Effect of sequential therapy on treatment of Helicobacter pylori infection in children. Rev Gastroenterol Peru 2018; 38 (02) 128-130
• 527 Nyssen OP, McNicholl AG, Megraud F. et al. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database Syst Rev 2016; 2016 (06) CD009034
• 528 Schwarzer A, Urruzuno P, Iwanczak B. et al. New effective treatment regimen for children infected with a double-resistant Helicobacter pylori strain. J Pediatr Gastroenterol Nutr 2011; 52 (04) 424-428
• 529 Zhou Y, Ye Z, Lu J. et al. Long-term changes in the gut microbiota after 14-day bismuth quadruple therapy in penicillin-allergic children. Helicobacter 2020; 25 (05) e12721
• 530 Kotilea K, Mekhael J, Salame A. et al. Eradication rate of Helicobacter Pylori infection is directly influenced by adherence to therapy in children. Helicobacter 2017; 22 (04)
• 531 Feng JR, Wang F, Qiu X. et al. Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis. Eur J Clin Pharmacol 2017; 73 (10) 1199-1208
• 532 Fang HR, Zhang GQ, Cheng JY. et al. Efficacy of Lactobacillus-supplemented triple therapy for Helicobacter pylori infection in children: a meta-analysis of randomized controlled trials. Eur J Pediatr 2019; 178 (01) 7-16
• 533 Ahmad K, Fatemeh F, Mehri N. et al. Probiotics for the treatment of pediatric helicobacter pylori infection: a randomized double blind clinical trial. Iran J Pediatr 2013; 23 (01) 79-84
• 534 Szajewska H, Kolodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther 2015; 42 (10) 1149-1157
• 535 Akcam M, Koca T, Salman H. et al. The effects of probiotics on treatment of Helicobacter pylori eradication in children. Saudi Med J 2015; 36 (03) 286-290
• 536 Szajewska H, Horvath A, Kolodziej M. Systematic review with meta-analysis: Saccharomyces boulardii supplementation and eradication of Helicobacter pylori infection. Aliment Pharmacol Ther 2015; 41 (12) 1237-1245
• 537 Lau CS, Ward A, Chamberlain RS. Probiotics improve the efficacy of standard triple therapy in the eradication of Helicobacter pylori: a meta-analysis. Infect Drug Resist 2016; 9: 275-289
• 538 Lu M, Yu S, Deng J. et al. Efficacy of Probiotic Supplementation Therapy for Helicobacter pylori Eradication: A Meta-Analysis of Randomized Controlled Trials. PLoS One 2016; 11 (10) e0163743
• 539 Yu M, Zhang R, Ni P. et al. Efficacy of Lactobacillus-supplemented triple therapy for H. pylori eradication: A meta-analysis of randomized controlled trials. PLoS One 2019; 14 (10) e0223309
• 540 Hassan ST, Sudomova M. Probiotics as Dietary Supplements for Eradication of Helicobacter pylori Infection in Children: A Role Beyond Infection. Children (Basel) 2016; 3 (04)
• 541 Castellsague J, Riera-Guardia N, Calingaert B. et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012; 35 (12) 1127-1146
• 542 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115 (10) 787-796
• 543 Gutthann SP, Garcia Rodriguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997; 8 (01) 18-24
• 544 Henry D, Lim LL, Garcia Rodriguez LA. et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: 1563-1566
• 545 Campbell DR, Haber MM, Sheldon E. et al. Effect of H. pylori status on gastric ulcer healing in patients continuing nonsteroidal anti-inflammatory therapy and receiving treatment with lansoprazole or ranitidine. Am J Gastroenterol 2002; 97 (09) 2208-2214
• 546 Graham DY, Agrawal NM, Campbell DR. et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162 (02) 169-175
• 547 Regula J, Butruk E, Dekkers CP. et al. Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole. Am J Gastroenterol 2006; 101 (08) 1747-1755
• 548 Scheiman JM, Yeomans ND, Talley NJ. et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006; 101 (04) 701-710
• 549 Joo MK, Park CH, Kim JS. et al. Clinical Guidelines for Drug-Related Peptic Ulcer, 2020 Revised Edition. Gut Liver 2020; 14 (06) 707-726
• 550 Mo C, Sun G, Lu ML. et al. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World J Gastroenterol 2015; 21 (17) 5382-5392
• 551 Bang CS, Joo MK, Kim BW. et al. The Role of Acid Suppressants in the Prevention of Anticoagulant-Related Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis. Gut Liver 2020; 14 (01) 57-66
• 552 Hunfeld NG, Touw DJ, Mathot RA. et al. A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism. Aliment Pharmacol Ther 2010; 31 (01) 150-159
• 553 Lanas A, Chan FKL. Peptic ulcer disease. Lancet 2017; 390: 613-624
• 554 Gonzalez-Perez A, Saez ME, Johansson S. et al. Risk factors associated with uncomplicated peptic ulcer and changes in medication use after diagnosis. PLoS One 2014; 9 (07) e101768
• 555 Garcia Rodriguez LA, Martin-Perez M, Hennekens CH. et al. Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies. PLoS One 2016; 11 (08) e0160046
• 556 Hawkey CJ, Weinstein WM, Smalley W. et al. Effect of risk factors on complicated and uncomplicated ulcers in the TARGET lumiracoxib outcomes study. Gastroenterology 2007; 133 (01) 57-64
• 557 Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000; 160 (14) 2093-2099
• 558 Lanas A, Carrera-Lasfuentes P, Arguedas Y. et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015; 13 (05) 906-912 e2
• 559 Lanas A, Wu P, Medin J. et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011; 9 (09) 762-768 e6
• 560 Venerito M, Schneider C, Costanzo R. et al. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors. Aliment Pharmacol Ther 2018; 47 (11) 1464-1471
• 561 Nagasue T, Nakamura S, Kochi S. et al. Time trends of the impact of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs on peptic ulcer bleeding in Japanese patients. Digestion 2015; 91 (01) 37-41
• 562 Cheung AN, Ng IO. Cytomegalovirus infection of the gastrointestinal tract in non-AIDS patients. Am J Gastroenterol 1993; 88 (11) 1882-1886
• 563 Dorigo-Zetsma JW, van der Meer JT, Tersmette M. et al. Value of laboratory investigations in clinical suspicion of cytomegalovirus-induced upper gastrointestinal tract ulcerations in HIV-infected patients. J Med Virol 1996; 49 (01) 29-33
• 564 Itami H, Morita K, Nakai T. et al. Gastritis cystica profunda is associated with aberrant p53 and Epstein-Barr virus in gastric cancer: A clinicopathological, immunohistochemical and in situ hybridization study. Pathol Int 2021; 71 (01) 42-50
• 565 Peter A, Telkes G, Varga M. et al. Endoscopic diagnosis of cytomegalovirus infection of upper gastrointestinal tract in solid organ transplant recipients: Hungarian single-center experience. Clin Transplant 2004; 18 (05) 580-584
• 566 Haanen J, Carbonnel F, Robert C. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Suppl. 04) iv264-iv266
• 567 Kobayashi M, Yamaguchi O, Nagata K. et al. Acute hemorrhagic gastritis after nivolumab treatment. Gastrointest Endosc 2017; 86 (05) 915-916
• 568 Nishimura Y, Yasuda M, Ocho K. et al. Severe Gastritis after Administration of Nivolumab and Ipilimumab. Case Rep Oncol 2018; 11 (02) 549-556
• 569 Ricke J, Klumpen HJ, Amthauer H. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71 (06) 1164-1174
• 570 Shinoto M, Shioyama Y, Matsunobu A. et al. Dosimetric analysis of upper gastrointestinal ulcer after carbon-ion radiotherapy for pancreatic cancer. Radiother Oncol 2016; 120 (01) 140-144
• 571 Wasan HS, Gibbs P, Sharma NK. et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol 2017; 18 (09) 1159-1171
• 572 Lanas A, Perez-Aisa MA, Feu F. et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005; 100 (08) 1685-1693
• 573 Crooks CJ, West J, Card TR. Comorbidities affect risk of nonvariceal upper gastrointestinal bleeding. Gastroenterology 2013; 144 (07) 1384-1393 , 93 e1-2; quiz e18-9
• 574 Laine L, Bombardier C, Hawkey CJ. et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002; 123 (04) 1006-1012
• 575 Weil J, Langman MJ, Wainwright P. et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs. Gut 2000; 46 (01) 27-31
• 576 Kanno T, Iijima K, Koike T. et al. Accommodation in a refugee shelter as a risk factor for peptic ulcer bleeding after the Great East Japan Earthquake: a case-control study of 329 patients. J Gastroenterol 2015; 50 (01) 31-40
• 577 Levenstein S, Rosenstock S, Jacobsen RK. et al. Psychological stress increases risk for peptic ulcer, regardless of Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs. Clin Gastroenterol Hepatol 2015; 13 (03) 498-506 e1
• 578 Yamanaka K, Miyatani H, Yoshida Y. et al. Hemorrhagic gastric and duodenal ulcers after the Great East Japan Earthquake Disaster. World J Gastroenterol 2013; 19 (42) 7426-7432
• 579 Lee SJ, Shin DH, Hwang HJ. et al. Bleeding risk and major adverse events in patients with previous ulcer on oral anticoagulation therapy. Am J Cardiol 2012; 110 (03) 373-377
• 580 Chan FK, Hung LC, Suen BY. et al. Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial. Gastroenterology 2004; 127 (04) 1038-1043
• 581 Abraham NS, Noseworthy PA, Inselman J. et al. Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age. Clin Gastroenterol Hepatol 2020; 18 (02) 337-346 e19
• 582 Abraham NS, Noseworthy PA, Yao X. et al. Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study. Gastroenterology 2017; 152 (05) 1014-1022 e1
• 583 Hsu YC, Lin JT, Chen TT. et al. Long-term risk of recurrent peptic ulcer bleeding in patients with liver cirrhosis: a 10-year nationwide cohort study. Hepatology 2012; 56 (02) 698-705
• 584 Kim M, Kim CS, Bae EH. et al. Risk factors for peptic ulcer disease in patients with end-stage renal disease receiving dialysis. Kidney Res Clin Pract 2019; 38 (01) 81-89
• 585 Luo JC, Leu HB, Hou MC. et al. Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study. Aliment Pharmacol Ther 2012; 36 (06) 542-550
• 586 Peng YL, Leu HB, Luo JC. et al. Diabetes is an independent risk factor for peptic ulcer bleeding: a nationwide population-based cohort study. J Gastroenterol Hepatol 2013; 28 (08) 1295-1299
• 587 Selak V, Jackson R, Poppe K. et al. Personalized Prediction of Cardiovascular Benefits and Bleeding Harms From Aspirin for Primary Prevention: A Benefit-Harm Analysis. Ann Intern Med 2019; 171 (08) 529-539
• 588 Siva R, Birring SS, Berry M. et al. Peptic ulceration, Helicobacter pylori seropositivity and chronic obstructive pulmonary disease. Respirology 2013; 18 (04) 728-731
• 589 Labenz J, Blum AL, Bolten WW. et al. Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial. Gut 2002; 51 (03) 329-335
• 590 Stupnicki T, Dietrich K, Gonzalez-Carro P. et al. Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients. Digestion 2003; 68 (04) 198-208
• 591 Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013; 48 (07) 830-838
• 592 Rostom A, Muir K, Dube C. et al. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. Drug Healthc Patient Saf 2009; 1: 47-71
• 593 Scally B, Emberson JR, Spata E. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol 2018; 3 (04) 231-241
• 594 Wang X, Tian HJ, Yang HK. et al. Meta-analysis: cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal anti-inflammatory drugs with proton pump inhibitors in regard to gastrointestinal adverse events in osteoarthritis and rheumatoid arthritis. Eur J Gastroenterol Hepatol 2011; 23 (10) 876-880
• 595 Chan FK, Wong VW, Suen BY. et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007; 369: 1621-1626
• 596 Chan FKL, Ching JYL, Tse YK. et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet 2017; 389: 2375-2382
• 597 Cheetham TC, Levy G, Niu F. et al. Gastrointestinal safety of nonsteroidal antiinflammatory drugs and selective cyclooxygenase-2 inhibitors in patients on warfarin. Ann Pharmacother 2009; 43 (11) 1765-1773
• 598 Masclee GM, Valkhoff VE, Coloma PM. et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 2014; 147 (04) 784-792
• 599 Tildesley G, Ehsanullah RS, Wood JR. Ranitidine in the treatment of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drugs. Br J Rheumatol 1993; 32 (06) 474-478
• 600 Chan FK, Chung SC, Suen BY. et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001; 344 (13) 967-973
• 601 Sostres C, Carrera-Lasfuentes P, Benito R. et al. Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users. Am J Gastroenterol 2015; 110 (05) 684-689
• 602 Kelly JP, Kaufman DW, Jurgelon JM. et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348: 1413-1416
• 603 Slattery J, Warlow CP, Shorrock CJ. et al. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin--analysis of gastrointestinal bleeding during the UK-TIA trial. Gut 1995; 37 (04) 509-511
• 604 Weil J, Colin-Jones D, Langman M. et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995; 310: 827-830
• 605 Yeomans ND, Lanas AI, Talley NJ. et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther 2005; 22 (09) 795-801
• 606 de Abajo FJ, Gil MJ, Bryant V. et al. Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case-control study in a new general practice database. Eur J Clin Pharmacol 2013; 69 (03) 691-701
• 607 Grove EL, Wurtz M, Schwarz P. et al. Gastrointestinal events with clopidogrel: a nationwide population-based cohort study. J Gen Intern Med 2013; 28 (02) 216-222
• 608 Holster IL, Valkhoff VE, Kuipers EJ. et al. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013; 145 (01) 105-112 e15
• 609 Khan R, Lopes RD, Neely ML. et al. Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome. Heart 2015; 101 (18) 1475-1484
• 610 Lopez-Lopez JA, Sterne JAC, Thom HHZ. et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017; 359: j5058
• 611 Ray WA, Chung CP, Murray KT. et al. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. JAMA 2018; 320 (21) 2221-2230
• 612 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962
• 613 Sherwood MW, Nessel CC, Hellkamp AS. et al. Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial. J Am Coll Cardiol 2015; 66 (21) 2271-2281
• 614 Lanas A, Fuentes J, Benito R. et al. Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther 2002; 16 (04) 779-786
• 615 Lin KJ, Hernandez-Diaz S, Garcia Rodriguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011; 141 (01) 71-79
• 616 Moayyedi P, Eikelboom JW, Bosch J. et al. Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial. Gastroenterology 2019; 157 (02) 403-412 e5
• 617 Mo C, Sun G, Wang YZ. et al. PPI versus Histamine H2 Receptor Antagonists for Prevention of Upper Gastrointestinal Injury Associated with Low-Dose Aspirin: Systematic Review and Meta-analysis. PLoS One 2015; 10 (07) e0131558
• 618 Szabo IL, Matics R, Hegyi P. et al. PPIs Prevent Aspirin-Induced Gastrointestinal Bleeding Better than H2RAs. A Systematic Review and Meta-analysis. J Gastrointestin Liver Dis 2017; 26 (04) 395-402
• 619 Chan FK, Ching JY, Suen BY. et al. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013; 144 (03) 528-535
• 620 Suceveanu AI, Suceveanu AP, Parepa I. et al. Reducing upper digestive bleeding risk in patients treated with direct oral anticoagulants and concomitant infection with Helicobacter pylori. Exp Ther Med 2020; 20 (06) 205
• 621 Scott MJ, Veitch A, Thachil J. Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when?. Br J Haematol 2017; 177 (02) 185-197
• 622 Schmidt M, Riis AH, Christiansen CF. et al. Clopidogrel use and short-term mortality after peptic ulcer bleeding: a population-based cohort study. Am J Ther 2013; 20 (01) 13-20
• 623 Ng FH, Wong SY, Chang CM. et al. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther 2003; 18 (04) 443-449
• 624 Hsiao FY, Tsai YW, Huang WF. et al. A comparison of aspirin and clopidogrel with or without proton pump inhibitors for the secondary prevention of cardiovascular events in patients at high risk for gastrointestinal bleeding. Clin Ther 2009; 31 (09) 2038-2047
• 625 Wu W, Liu J, Yu H. et al. Antiplatelet therapy with or without PPIs for the secondary prevention of cardiovascular diseases in patients at high risk of upper gastrointestinal bleeding: A systematic review and meta-analysis. Exp Ther Med 2020; 19 (06) 3595-3603
• 626 Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 2014; 4 (05) e004587
• 627 Anglin R, Yuan Y, Moayyedi P. et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109 (06) 811-819
• 628 Jiang HY, Chen HZ, Hu XJ. et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015; 13 (01) 42-50 e3
• 629 Targownik LE, Bolton JM, Metge CJ. et al. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol 2009; 104 (06) 1475-1482
• 630 Labos C, Dasgupta K, Nedjar H. et al. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ 2011; 183 (16) 1835-1843
• 631 Quinn GR, Hellkamp AS, Hankey GJ. et al. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. J Am Heart Assoc 2018; 7 (15) e008755
• 632 Swart F, Bianchi G, Lenzi J. et al. Risk of hospitalization from drug-drug interactions in the Elderly: real-world evidence in a large administrative database. Aging (Albany NY) 2020; 12 (19) 19711-19739
• 633 de Abajo FJ, Garcia-Rodriguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65 (07) 795-803
• 634 Iwakiri R, Higuchi K, Kato M. et al. Randomised clinical trial: prevention of recurrence of peptic ulcers by rabeprazole in patients taking low-dose aspirin. Aliment Pharmacol Ther 2014; 40 (07) 780-795
• 635 Lai KC, Lam SK, Chu KM. et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346 (26) 2033-2038
• 636 Sugano K, Choi MG, Lin JT. et al. Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study. Gut 2014; 63 (07) 1061-1068
• 637 Gaziano JM, Brotons C, Coppolecchia R. et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018; 392: 1036-1046
• 638 Group ASC, Bowman L, Mafham M. et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018; 379 (16) 1529-1539
• 639 McNeil JJ, Wolfe R, Woods RL. et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. N Engl J Med 2018; 379 (16) 1509-1518
• 640 Piepoli MF, Hoes AW, Agewall S. et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37 (29) 2315-2381
• 641 Raber I, McCarthy CP, Vaduganathan M. et al. The rise and fall of aspirin in the primary prevention of cardiovascular disease. Lancet 2019; 393: 2155-2167
• 642 Garcia Rodriguez LA, Johansson S, Nagy P. et al. Use of proton pump inhibitors and the risk of coronary events in new users of low-dose acetylsalicylic acid in UK primary care. Thromb Haemost 2014; 111 (01) 131-139
• 643 Sung JJ, Lau JY, Ching JY. et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152 (01) 1-9
• 644 Hindricks G, Potpara T, Dagres N. et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42 (05) 373-498
• 645 Chan FK, Ching JY, Hung LC. et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005; 352 (03) 238-244
• 646 Lai KC, Chu KM, Hui WM. et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol 2006; 4 (07) 860-865
• 647 Luo JC, Huang KW, Leu HB. et al. Randomised clinical trial: rabeprazole plus aspirin is not inferior to rabeprazole plus clopidogrel for the healing of aspirin-related peptic ulcer. Aliment Pharmacol Ther 2011; 34 (05) 519-525
• 648 Chan FK, Kyaw M, Tanigawa T. et al. Similar Efficacy of Proton-Pump Inhibitors vs H2-Receptor Antagonists in Reducing Risk of Upper Gastrointestinal Bleeding or Ulcers in High-Risk Users of Low-Dose Aspirin. Gastroenterology 2017; 152 (01) 105-110 e1
• 649 Ng FH, Wong SY, Lam KF. et al. Famotidine is inferior to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. Gastroenterology 2010; 138 (01) 82-88
• 650 Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology 2011; 140 (03) 791-798
• 651 Hsu PI, Wu DC, Tsay FW. et al. Histamine-2 Receptor Antagonist Cannot Prevent Recurrent Peptic Ulcers in Patients With Atherosclerotic Diseases Who Receive Platelet ADP Receptor Antagonist Monotherapy: A Randomized-Controlled, Double-Blind, and Double-Dummy Trial. Am J Gastroenterol 2017; 112 (02) 282-289
• 652 Chan EW, Lau WC, Leung WK. et al. Prevention of Dabigatran-Related Gastrointestinal Bleeding With Gastroprotective Agents: A Population-Based Study. Gastroenterology 2015; 149 (03) 586-595 e3
• 653 Hallas J, Dall M, Andries A. et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006; 333: 726
• 654 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (07) 494-502
• 655 Hansen ML, Sorensen R, Clausen MT. et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170 (16) 1433-1441
• 656 Schalekamp T, Klungel OH, Souverein PC. et al. Effect of oral antiplatelet agents on major bleeding in users of coumarins. Thromb Haemost 2008; 100 (06) 1076-1083
• 657 Sorensen R, Hansen ML, Abildstrom SZ. et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009; 374: 1967-1974
• 658 Dewilde WJ, Oirbans T, Verheugt FW. et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381: 1107-1115
• 659 Bhatt DL, Cryer BL, Contant CF. et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363 (20) 1909-1917
• 660 Vaduganathan M, Bhatt DL, Cryer BL. et al. Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy. J Am Coll Cardiol 2016; 67 (14) 1661-1671
• 661 Bundhun PK, Teeluck AR, Bhurtu A. et al. Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: a systematic review and meta-analysis of recently published studies (2012–2016). BMC Cardiovasc Disord 2017; 17 (01) 3
• 662 Cardoso RN, Benjo AM, DiNicolantonio JJ. et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart 2015; 2 (01) e000248
• 663 Chen CH, Yang JC, Uang YS. et al. Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel. Biopharm Drug Dispos 2012; 33 (05) 278-283
• 664 Abrignani MG, Gatta L, Gabrielli D. et al. Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: a position paper of National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO). Eur J Intern Med 2021; 85: 1-13
• 665 Choi YJ, Kim N, Jang IJ. et al. Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea. Gut Liver 2017; 11 (04) 504-511
• 666 Valgimigli M, Bueno H, Byrne RA. et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur J Cardiothorac Surg 2018; 53 (01) 34-78
• 667 Lip GYH, Collet JP, Haude M. et al. Management of antithrombotic therapy in AF patients presenting with ACS and/or undergoing PCI: A Summary of the Joint Consensus Document of the European Heart Rhythm Association (EHRA), European Society of Cardiology Working Group on Thrombosis, European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). Eur Heart J 2018; 39 (31) 2847-2850
• 668 Knuuti J, Wijns W, Saraste A. et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
• 669 Fischbach W, Darius H, Gross M. et al. Concomitant use of thrombocyte aggregation inhibitors and proton pump inhibitors (PPIs). Z Gastroenterol 2011; 49 (03) 395-402
• 670 Furuta T, Sugimoto M, Kodaira C. et al. Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel. J Thromb Thrombolysis 2017; 43 (03) 333-342
• 671 Malchow H, Ewe K, Brandes JW. et al. European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86 (02) 249-266
• 672 Summers RW, Switz DM, Sessions Jr. JT. et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology 1979; 77 (04) 847-869
• 673 Dickinson JB. Is omeprazole helpful in inflammatory bowel disease?. J Clin Gastroenterol 1994; 18 (04) 317-319
• 674 Miehsler W, Puspok A, Oberhuber T. et al. Impact of different therapeutic regimens on the outcome of patients with Crohn’s disease of the upper gastrointestinal tract. Inflamm Bowel Dis 2001; 7 (02) 99-105
• 675 Moon JS, Lee JL, Yu CS. et al. Clinical Characteristics and Postoperative Outcomes of Patients Presenting With Upper Gastrointestinal Tract Crohn Disease. Ann Coloproctol 2020; 36 (04) 243-248
• 676 Wagtmans MJ, Verspaget HW, Lamers CB. et al. Clinical aspects of Crohn’s disease of the upper gastrointestinal tract: a comparison with distal Crohn’s disease. Am J Gastroenterol 1997; 92 (09) 1467-1471
• 677 Iijima K, Kanno T, Koike T. et al. Helicobacter pylori-negative, non-steroidal anti-inflammatory drug: negative idiopathic ulcers in Asia. World J Gastroenterol 2014; 20 (03) 706-713
• 678 Charpignon C, Lesgourgues B, Pariente A. et al. Peptic ulcer disease: one in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. Aliment Pharmacol Ther 2013; 38 (08) 946-954
• 679 Kanno T, Iijima K, Abe Y. et al. A multicenter prospective study on the prevalence of Helicobacter pylori-negative and nonsteroidal anti-inflammatory drugs-negative idiopathic peptic ulcers in Japan. J Gastroenterol Hepatol 2015; 30 (05) 842-848
• 680 Gisbert JP, Calvet X. Review article: Helicobacter pylori-negative duodenal ulcer disease. Aliment Pharmacol Ther 2009; 30 (08) 791-815
• 681 Iijima K, Kanno T, Abe Y. et al. Preferential location of idiopathic peptic ulcers. Scand J Gastroenterol 2016; 51 (07) 782-787
• 682 Freston JW. Review article: role of proton pump inhibitors in non-H. pylori-related ulcers. Aliment Pharmacol Ther 2001; 15 (Suppl. 02) 2-5
• 683 Dore MP, Soro S, Niolu C. et al. Clinical features and natural history of idiopathic peptic ulcers: a retrospective case-control study. Scand J Gastroenterol 2019; 54 (11) 1315-1321
• 684 Yoon H, Kim SG, Jung HC. et al. High Recurrence Rate of Idiopathic Peptic Ulcers in Long-Term Follow-up. Gut Liver 2013; 7 (02) 175-181
• 685 Wong GL, Au KW, Lo AO. et al. Gastroprotective therapy does not improve outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Clin Gastroenterol Hepatol 2012; 10 (10) 1124-1129
• 686 Wong GL, Wong VW, Chan Y. et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology 2009; 137 (02) 525-531
• 687 Wong GLH, Lau LHS, Ching JYL. et al. Prevention of recurrent idiopathic gastroduodenal ulcer bleeding: a double-blind, randomised trial. Gut 2020; 69 (04) 652-657
• 688 Chung CS, Chiang TH, Lee YC. A systematic approach for the diagnosis and treatment of idiopathic peptic ulcers. Korean J Intern Med 2015; 30 (05) 559-570
• 689 Quan C, Talley NJ. Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs. Am J Gastroenterol 2002; 97 (12) 2950-2961
• 690 Cook DJ, Fuller HD, Guyatt GH. et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330 (06) 377-381
• 691 Cook DJ, Reeve BK, Guyatt GH. et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996; 275 (04) 308-314
• 692 Marik PE, Vasu T, Hirani A. et al. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38 (11) 2222-2228
• 693 Tryba M, Cook D. Current guidelines on stress ulcer prophylaxis. Drugs 1997; 54 (04) 581-596
• 694 Krag M, Perner A, Wetterslev J. et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 2015; 41 (05) 833-845
• 695 Wang Y, Ge L, Ye Z. et al. Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated systematic review and network meta-analysis of randomized trials. Intensive Care Med 2020; 46 (11) 1987-2000
• 696 Zhou X, Fang H, Xu J. et al. Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in critically ill adults – a meta-analysis of randomized controlled trials with trial sequential analysis. BMC Gastroenterol 2019; 19 (01) 193
• 697 Alhazzani W, Alshamsi F, Belley-Cote E. et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med 2018; 44 (01) 1-11
• 698 Alshamsi F, Belley-Cote E, Cook D. et al. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care 2016; 20 (01) 120
• 699 Toews I, George AT, Peter JV. et al. Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units. Cochrane Database Syst Rev 2018; 6: CD008687
• 700 Krag M, Marker S, Perner A. et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med 2018; 379 (23) 2199-2208
• 701 Australian PIft, New Zealand Intensive Care Society Clinical Trials Group AHSCCSCN, the Irish Critical Care Trials G. et al. Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial. JAMA 2020; 323 (07) 616-626

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Article published online:
16 February 2024