Malfertheiner Р., Megraud F., O'Morain С.А., еt al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence Consensus Report // Gut 2012 Мау; 61(5): 646-664.

Accepted 22 February 2012

Peter Malfertheiner¹, Francis Megraud², Colm A O'Morain³, John Atherton⁴, Anthony T R Axon⁵, Franco Bazzoli⁶, Gian Franco Gensini⁸, Javier P Gisbert⁹, David Y Graham¹⁰, Theodore Rokkas¹¹, Emad M El-Omar⁷, Ernst J Kuipers¹², The European Helicobacter Study Group (EHSG)  

Author Affiliations
¹Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany
²Department of Bacteriologie, INSERM U853, Université Bordeaux Segalen 2, Bordeaux, France
³Department of Gastroenterology, Adelaide and Meath Hospital, Trinity College, Dublin, Ireland
⁴School of Clinical Sciences, University of Nottingham, Nothingham, UK
⁵Spire Leeds Hospital, Leeds, UK
⁶Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
⁷Division of Applied Medicine, Aberdeen University, Aberdeen, UK
⁸University of Firenze, Firenze, Italy
⁹Hospital Universitario de La Princesa, IP and CIBEREHD Madrid, Spain
¹⁰VA Medical Center Houston, Texas, USA
¹¹Department of Gastroenterology, Henry-Dunant Hospital, Athens, Greece
¹²Erasmus MC University Medical Center, Rotterdam, The Netherlands

Correspondence to
Professor Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Str 44, Magdeburg 39120, Germany; peter.malfertheiner@ med.ovgu.de

Contributors LP Andersen (Denmark), J Atherton (UK), A Axon (UK), F Bazzoli (Italy), A Burette (Belgium), X Calvet (Spain), F Chan (Hongkong), L Coelho (Brazil), JC Delchier (France), F Di Mario (Italy), E El-Omar (UK), W Fischbach (Germany), KM Fock (Singapore), G Gasbarrini (Italy), G Gensini (Italy), J Gisbert (Spain), KL Goh (Malaysia), DY Graham (USA), P Hungin (UK), R Hunt (Canada), VA Isakov (Russia), M Kist (Germany), S Koletzko (Germany), EJ Kuipers (The Netherlands), L Kupcinskas (Kaunas), S Ladas (Greece), A Lanas (Spain), M Leja (Latvia), JC Machado (Portugal), V Mahachai (Thailand) P Malfertheiner (Germany), K McColl (England), F Megraud (France), Y Niv (Israel), C O'Morain (Ireland), A Pilotto (Italy), A Ristimaki (Finland), T Rokkas (Greece), M Rugge (Italy), R Stockbrügger (Italy), K Sugano (Japan), D Vaira (Italy), N Vakil (USA), M Vieth (Germany). 

 

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Abstract 

Management of Helicobacter pylori infection is evolving and in this 4th edition of the Maastricht consensus report aspects related to the clinical role of H pylori were looked at again in 2010. In the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took active part and examined key clinical aspects in three subdivided workshops: (1) Indications and contraindications for diagnosis and treatment, focusing on dyspepsia, non-steroidal anti-inflammatory drugs or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of the infection. (2) Diagnostic tests and treatment of infection. (3) Prevention of gastric cancer and other complications. The results of the individual workshops were submitted to a final consensus voting to all participants. Recommendations are provided on the basis of the best current evidence and plausibility to guide doctors involved in the management of this infection associated with various clinical conditions.

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Management of Helicobacter pylori infection is evolving and so is our understanding of the role of the bacterium in various clinical conditions.

The European Helicobacter Study Group first took the initiative in 1996 in Maastricht to gather dedicated experts in the field and to review and discuss all relevant clinical data to arrive at recommendations for the clinical management of H pylori infection. [1] The Maastricht conference has since been repeated at intervals of 4–5 years. [2, 3]    

Aspects related to the clinical role of H pylori were re-examined in Florence 2010 with the Maastricht methodology. The meeting focused on indications, diagnostics and treatments of H pylori infection with additional emphasis on disease prevention—in particular, prevention of gastric cancer.

In the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took active part. Experts invited were chosen for their expertise and contribution to H pylori research and/or guideline methodology.

Methodology and structure of conference process

Current guidelines from Japan, Asia-Pacific, North America and Europe, as well as the ‘Maastricht methodology’ were reviewed at an introductory plenary session.

Working groups examined the following three topics relating to H pylori infection:

• Indications and contraindications for diagnosis and treatment, focusing on dyspepsia, non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of the infection. 
• Diagnostic tests and treatment of infection.
• Prevention of gastric cancer and other complications. 

Individual questions were submitted to all participants, debated and modified according to a standard template. After a thorough discussion of each statement in one of the three working groups the strength of recommendations and the strength of the supporting evidence were graded according to the slightly modified system, used in our previous report [3] (table 1). In a few statements where there are only experimental studies in support of the biological plausibility but no treatment studies, we did not quote the evidence, but graded the recommendation for the statement. For some statements the grade of recommendation did not match the level of evidence because either studies focusing on the same topic reported conflicting results or the interpretation of the studies by the experts led to a different grade of recommendation than expected from the level of evidence. Aspects related to the implementation of recommendations in daily clinical practice have also been taken into account.

Grades of recommendation and evidence levels in support of the recommendations formulated in the Maastricht IV / Florence Consensus Report 

Grade of recom­men­dation*	Evi­dence level		Type of studies
A	1	1a	Systematic review of randomised controlled trial (RCT) of good methodological quality and with homogeneity
		1b	Individual RCT with narrow CI
		1c	Individual RCT with risk of bias
B	2	2a	Systematic review of cohort studies (with homogeneity)
		2b	Individual cohort study (including low quality RCT, eg <80% follow-up)
		2c	Non-controlled cohort studies/ecological studies
	3	3a	Systematic review of case–control studies (with homogeneity)
		3b	Individual case–control study
C	4		Case series/poor quality cohort or case–control studies
D	5		Expert opinion without explicit critical appraisal or based on physiology, bench research or ‘first principles’

* The highest grade of recommendation does not always correspond to the highest evidence level.

 
H pylori is the most successful human pathogen infecting an estimated 50% of the global population. It is a common and potentially curable cause of dyspepsia and peptic ulcer disease. Test and treat is a strategy involving a non-invasive test being carried out in patients with dyspepsia to assess whether H pylori is present and then treatment of the infection if it is found; it thus avoids the cost, inconvenience and discomfort of endoscopy. The test-and-treat strategy is appropriate in situations where the risk of the patient having gastric cancer is low; in most countries this means dyspeptic patients below a locally determined age cut-off point (depending on local incidence of gastric cancer in different age groups) and without so-called ‘alarm’ symptoms or signs which are associated with an increased risk of gastric cancer. These include weight loss, dysphagia, overt GI bleeding, abdominal mass and iron deficient anaemia. In young patients with dyspepsia, testing for and treating H pylori is preferable to a strategy of just prescribing a proton pump inhibitor where the H pylori prevalence is ≥20%. The Urea Breath Test (UBT) and stool antigen testing are acceptable non-invasive tests for H pylori infection in this setting. For UBT, sensitivity is 88–95% and specificity 95%–100%. [4] Stool antigen testing may be somewhat less acceptable to patients in some cultures but is equally valid, with a sensitivity of 94% and a specificity of 92%. [5] A significant symptom benefit can be obtained from a test-and-treat strategy. This has been validated in a primary care cohort, which is the setting where most dyspeptic patients present. [6] Test and treat must be used cautiously in populations with a low H pylori prevalence as it becomes less accurate in this setting. [7] In patient groups with an increased risk of gastric cancer (over a local age cut-off point or with alarm symptoms or signs), the test-and-treat strategy is not recommended and a strategy of ‘endoscope and treat’ is preferred. [8] In addition, non-invasive tests are less accurate in older adults. [9]    

 
Many dyspeptic patients found to be infected by H pylori have functional dyspepsia (FD) rather than peptic ulcer disease. The benefit from eradication treatment is less clear in these patients than in those with peptic ulcer. At a population level, there is a significant improvement in the resolution of persistent symptoms in the H pylori eradication group (95% CI 6% to 14%) compared with placebo, with a number needed to treat of 12. [10] Treatment response is difficult to predict for the individual patient. H pylori eradication led to a 25% reduction in dyspepsia consultations between 2 and 7 years of follow-up in a randomised controlled trial. [11] Another study suggested that H pylori eradication provides a similar long-term symptom reduction in patients with dyspepsia and duodenal ulcer. [12] The cost-effectiveness of H pylori eradication in FD varies between regions. In Europe H pylori eradication is cost-effective compared with offering no treatment but in the USA it is less certain that this is a cost-effective approach owing to the higher cost of eradication treatment. [13] Overall response, however, is much better in regions where H pylori is highly prevalent and this is where it may be most cost-effective. Patients with FD in Asia would benefit from treatment for H pylori infection with an increased chance of symptom resolution as high as 3.6–13 after its eradication. [14, 15] 

Successful treatment of H pylori infection may increase, decrease or have no overall effect on acid secretion. The effect on acid secretion depends upon the initial pattern of gastritis. People with an antral-predominant, body-sparing, non-atrophic gastritis have high stimulated acid production due to low somatostatin production in the antrum, higher gastrin levels compared with non-infected controls and so higher acid production by the uninflamed gastric corpus. Clinically, duodenal ulcer and non-ulcer dyspepsia are common in this group. In contrast, people with body-predominant and atrophic gastritis affecting the gastric body have low acid production despite the same hormonal changes. This phenotype is associated with premalignant gastric lesions and with an increased risk for gastric cancer. [16, 17] Therefore it can be concluded that the pattern of gastritis and associated disturbance in acid secretion determine disease outcomes. In both situations, treatment of H pylori resolves the gastritis and leads to an, at least partial, correction of the high or low acid state. While interesting, these changes in acid production after H pylori treatment have no proven clinical relevance and they should not be used as an argument to treat or not to treat H pylori.

 
At a population level, H pylori and GORD are negatively associated, [18] and this is most marked for cytotoxin-associated gene product (CagA)-positive strains of H pylori. A review of 26 studies showed a rate of H pylori infection in patients with GORD of 39% compared with 50% in controls. [19] Similarly, the sequelae of GORD, such as Barrett's oesophagus and oesophageal adenocarcinoma, are also less common in infected individuals. [20] However, eradication of H pylori in populations of infected patients, on average, neither causes nor exacerbates GORD. [21–23] Therefore the presence of GORD should not dissuade practitioners from H pylori eradication treatment where indicated. In addition, the long-term efficacy of proton pump inhibitor (PPI) maintenance treatment for GORD is not influenced by H pylori status. [24] An interesting phenomenon has been observed whereby some H pylori-positive patients may develop a sudden-onset, transient epigastric pain shortly after the start of PPI treatment for reflux, but this again should not affect decisions on management, and more studies are needed to confirm and explore this phenomenon. [25] 

   
Both H pylori infection and NSAID use are independent risk factors for the development of peptic ulcer disease and associated bleeding and these conditions are uncommon in those who do not have either risk factor. It has been shown that there is an increased risk when these factors are both present. [26] There is a difference between naive users and those receiving long-term NSAID treatment in the benefits of searching for, and eradicating, H pylori. In naive users it is clearly beneficial to eradicate H pylori. [27, 28] In those who are already long-term users there is no clear benefit. [29–31] A meta-analysis showed, however, that eradication seems less effective than treatment with a maintenance PPI for preventing NSAID-associated ulcers. [32] Further research is needed on whether selective cyclo-oxygenase-2-inhibiting NSAIDs may be safer options. For aspirin, even given at low dose, H pylori eradication can prevent gastropathy and should be undertaken in patients with a history of peptic ulcers. [33, 34] In such patients, the residual risk of peptic ulcer bleeding due to continued aspirin use after H pylori has been successfully treated is very low. [35]    

 
Acid suppression affects the pattern and distribution of gastritis and favours corpus-predominant gastritis. It may accelerate the process of loss of specialised glands, leading to atrophic gastritis. In H pylori-positive patients, active inflammation increases in the corpus and decreases in the antrum during PPI treatment. [36, 37] This shift in gastritis appears to be accompanied by an increase in corpus atrophy. [38, 39] Studies in H pylori-infected Mongolian gerbils showed that PPI treatment accelerated the progression to gastric cancer. [40, 41] But there are no such data in humans. 

 
H pylori eradication has the potential to prevent gastric cancers. [42] A study on the effect of H pylori eradication on patients with premalignant lesions showed that eradication may prevent their progression. [43] It is thought though that a so-called ‘point of no return’ may exist in the histological cascade from chronic gastritis to adenocarcinoma after which eradication is unlikely to prevent gastric cancer. It appears that by the time intestinal metaplasia (IM) has become established eradication, although retarding the progression of IM, cannot completely prevent gastric cancer. [44, 45] This is not necessarily true for gastric atrophy, where there appears to be a discrepancy between the effect of eradication in the corpus and in the antrum. A meta-analysis of 12 studies on 2658 patients concluded that eradication of H pylori results in significant improvement in atrophy in the corpus but not in the antrum, but has no effect on gastric IM. [46] 

 
Low-grade MALT lymphoma accounts for approximately 50% of cases of gastrointestinal non-Hodgkin's lymphoma. Most are linked to H pylori infection and in the early (lugano I/II) stage low-grade MALT lymphoma can be cured by H pylori eradication in 60–80% of cases. [47–49] When the t(11,18) translocation is present, however, H pylori eradication is usually ineffective and these patients need adjunctive and alternative treatments. [50] All patients should be followed up intensively after H pylori treatment and given alternative treatments (chemotherapy or radiotherapy) if the lymphoma fails to respond or progresses. [51] 

 
The association of H pylori with unexplained iron-deficiency anaemia has been conclusively proved in adult and paediatric populations. Two s