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Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000.
To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer.
Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a “test and treat” strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro‐oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non‐steroidal anti‐inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non‐invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non‐invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth‐containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility.
The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.
The European Helicobacter Study Group (EHSG), founded in 1987 to promote multidisciplinary research into the pathogenesis of Helicobacter pylori, has organised successful annual meetings and arranged task forces on paediatric issues and clinical trials. Consensus meetings have been convened on who to treat, and how and when to treat patients with H pylori infection. The most active area of research is into the link between H pylori and gastric cancer, a major public health issue. The Third Maastricht Consensus Conference was convened to update guidelines on the management of H pylori infection. Fifty experts from 26 countries, including primary care physicians, were involved in formulating the consensus held in March 2005. The experts were chosen based on their expertise and contribution to the published literature.
Current guidelines from Japan, China, North America, and Europe were reviewed at an introductory plenary session.
Working groups examined the following three topics relating to H pylori infection:
The recommendations were debated and modified according to a standard template. The strength of recommendations and evidence to support them were graded (table 11).). 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 interpretation of the studies by the experts led to a different grade of recommendation than expected from the level of evidence.
The statements and recommendations were edited and finally agreed at the concluding plenary session. Consensus was considered to have been reached if 70% or more of the experts supported the recommendation. The recommendations/statements resulting from this rigorous process are reported in this manuscript.
There is a negative association between the prevalence of H pylori and GORD, but the nature of this relationship is uncertain.
Profound acid suppression affects the pattern and distribution of gastritis favouring corpus dominant gastritis. It may accelerate the process of loss of specialised glands, leading to atrophic gastritis.
H pylori eradication halts the progression of atrophic gastritis and may lead to regression of atrophy. The effect on intestinal metaplasia is uncertain.
Subsequent to Maastricht II, important new data have been published which have strengthened the indication for H pylori eradication therapy in gastric MALT lymphoma.
Predictors of response to eradication therapy in patients with low grade gastric MALT lymphoma are: H pylori positivity; Lugano classification stage I; lymphoma confined to the stomach; gastric wall invasion confined to mucosa/submucosa; and the absence of gene t (11, 18) (q21; q21), translocation with fusion of API2 and MALT1. Fusion of both leads to suppression of apoptosis and strongly predicts failure to respond to eradication therapy.
The Maastricht III‐2005 consensus report concluded that H pylori eradication is the treatment of first choice for H pylori infected patients with stage I low grade gastric MALT lymphoma.
A “test and treat” strategy is recommended in adult patients under the age of 45 years presenting with persistent dyspepsia (the age cut off point may vary between countries, depending on the prevalence of gastric cancer). A test and treat strategy has been validated by a primary care study on uninvestigated dyspepsia in Canada.4
H pylori eradication gives modest, but significant benefit in non‐ulcer dyspepsia.5 Economic modelling suggests that this benefit is cost effective.6 Twelve to 15 infected patients need to be treated to cure one patient with non‐ulcer dyspepsia.6 This compares favourably with any other treatment available for non‐ulcer dyspepsia. The eradication of H pylori infection is carried out once and leads to long term symptom improvement; it also reduces the risk of developing peptic ulcer disease, atrophic gastritis, and gastric cancer.
H pylori eradication is of value in chronic NSAID users but is insufficient to prevent NSAID related ulcer disease completely.
In areas of low H pylori prevalence7 (<20%) proton pump inhibitor (PPI) empirical treatment or a test and treat strategy were considered to be equivalent options (box 1).
The prevalence of H pylori in patients with GORD is lower than in those without reflux disease.8 Most countries with a high prevalence of H pylori also have a low prevalence of GORD. The falling prevalence of H pylori infection and related diseases, including peptic ulcer disease and gastric cancer, in developed countries has been paralleled by an increase in GORD and its complications. The nature of this negative association is unclear.9,10
In an American study on H pylori infection and, in particular, infection with CagA positive strains, the prevalence of H pylori infection was reported to be lower in patients with Barrett's oesophagus and adenocarcinoma of the cardia.11 This association has been confirmed in most but not all studies.12,13 Severe inflammation involving the fundus of the stomach is associated with reduced gastric acid secretion and is inversely correlated with GORD and its complications.
Screening for H pylori in patients with GORD needs more formal study, including a cost effectiveness analysis, and is currently not recommended.
Profound acid suppression affects the pattern and distribution of gastritis, favouring corpus dominant gastritis.19 Profound acid suppression with PPIs or high dose histamine 2 receptor antagonists in the presence of H pylori positive corpus gastritis may accelerate the loss of specialised glands, leading to atrophic gastritis and, potentially, gastric cancer. In patients with reflux oesophagitis receiving long term acid suppression, eradication of H pylori infection decreases inflammation and gastritis activity, and reverses corpus gastritis (box 2).18
H pylori infection should be sought for and treated in patients with:
H pylori has no proven role in other extraintestinal diseases.
The relationship between H pylori infection and NSAIDs in gastroduodenal pathology is complex: H pylori and NSAIDs independently and significantly increase the risk of peptic ulcer bleeding by 1.79‐ and 4.86‐fold, respectively. The risk of ulcer bleeding is increased by 6.13‐fold when both factors are present.20
Serology should be considered as a diagnostic test when others could be false negative, such as in patients with:
Results of H pylori eradication in NSAIDs users are conflicting. Part of the problem is that both NSAIDs and H pylori can cause peptic ulcers. H pylori eradication can only be expected to prevent recurrence of H pylori ulcers and while it may also reduce the incidence of ulcers among those with both H pylori and NSAID use, the effect will vary depending on the proportion with true H pylori ulcers in the population studied. In chronic NSAID users with peptic ulcer, H pylori eradication was no better than placebo for maintaining a remission of peptic ulcer with PPI treatment at six months.21 PPI maintenance treatment is better than H pylori eradication alone in preventing upper gastrointestinal bleeding.22 In contrast, in patients with H pylori infection who are naive NSAID users, H pylori eradication is better than placebo in preventing peptic ulcer and upper gastrointestinal bleeding at six months.23,24
Patients who are receiving long term aspirin and have ulcer disease and a history of significant bleeding should be tested for H pylori infection and, if positive, be given eradication therapy.22,25 Patients receiving long term PPI treatment for prevention of NSAID ulcers should be tested for H pylori to reduce the PPI‐H pylori interaction leading to accelerated loss of specialised glands and atrophic gastritis (box 3).
The detection of H pylori pathogenic factors and the study of host genetic polymorphisms is currently not recommended in the management of H pylori infection.
Some studies suggest that H pylori infection may cause iron deficiency anaemia (IDA) and idiopathic thrombocytopenic purpura (ITP). Possible pathogenetic mechanisms involved in IDA in patients with H pylori infection include: occult blood loss secondary to chronic erosive gastritis; decreased iron absorption secondary to chronic gastritis of the corpus causing hypo‐ or achlorhydria; increased iron uptake and use by bacteria.26H pylori eradication reverses IDA in patients with asymptomatic gastritis27 and improves oral iron absorption.28
Some studies suggest that there is a higher prevalence of H pylori infection in patients with ITP than in controls.29 Moreover, a review of published data on H pylori infection and ITP confirmed that eradication therapy induces a significant positive platelet response in a proportion of patients with ITP.30,31,32,33 It was recommended that H pylori infection should be sought for and treated in patients with unexplained IDA and in those with ITP. H pylori infection has no proven role in other extraintestinal diseases (box 4).
A positive rapid urease test is sufficient to initiate treatment.
Recurrent abdominal pain is not an indication for a test and treat strategy for H pylori infection in children. The primary goal of a diagnostic investigation in recurrent abdominal pain should be to determine the cause of the presenting gastrointestinal symptoms, and not the presence of H pylori infection.
H pylori eradication should be confirmed at least four weeks after treatment.
However, children with upper gastrointestinal symptoms should be tested for H pylori infection (after exclusion of other causes of the symptoms) and should be treated if they have the infection.
In children and adolescents, IDA refractory to iron supplementation is an indication to test for H pylori infection and for eradication therapy if positive. This should be carried out after exclusion of other causes, such as coeliac disease and inflammatory bowel disease.
Non‐invasive tests for the diagnosis of H pylori infection include: the 13C‐urea breath test (UBT); stool antigen tests (polyclonal antibody, monoclonal antibody, and office based); and immunological tests (laboratory and office based tests and tests on saliva and urine) (table 44).
The diagnostic accuracy of the UBT is >95% in studies. The UBT is an accurate, practical, and readily available test.36
The stool antigen test is appropriate when multiple specimens are tested as a batch. However, it is necessary to store stool samples at –20°C before testing. The sensitivity of the stool antigen test decreased to 69% after 2–3 days at room temperature. In a systematic review of 89 studies evaluating the stool antigen test the sensitivity and specificity were 91% and 93%, respectively.37
Serology is a widely available and inexpensive non‐invasive test, but the diagnostic accuracy is low (80–84%).38 Tests that detect active infection, although more expensive, are preferable to serology as these reduce the number of patients inappropriately treated for presumed H pylori infection.39,40 Some kits for serology with a high accuracy (>90%) are recommended in validated settings.
Rescue treatment should be based on antimicrobial susceptibility testing.
PPI treatment can result in false negative invasive and non‐invasive diagnostic tests. PPI should be stopped for at least two weeks before testing. However, this does not apply to serology.41,42,43,44,45,46 A positive serological test with negative histology and UBT suggests the presence of an unrecognised H pylori infection, and additional investigations to confirm whether the serological test is false positive or reflects active infection should be carried out. False positive non‐invasive tests are more common in low prevalence populations, requiring additional confirmation before treatment.47,48
Serological tests are recommended to assess H pylori in patients with a bleeding ulcer and conditions associated with a low bacterial density (extensive mucosal atrophy45 and MALT lymphoma)46 (box 5). The rapid urease test, culture, and histology as well as UBT have shown a limited sensitivity in patients presenting with acute bleeding peptic ulcer. Polyclonal stool antigen tests have a low specificity owing to cross reactivity with blood products. Serological tests, and in particular detection of antibodies against the specific antigen CagA, which is immunogenic and long lasting, are also the best method to document the link of gastric cancer with H pylori infection.49
Office based serological tests or near patient tests are extremely convenient, but they are not accurate and are currently not recommended50 (box 6).
Kits are available to diagnose H pylori antibodies in urine and saliva. Their main advantage is their non‐invasiveness and convenience. Unfortunately, their sensitivity is low. Therefore they are not useful in patient management but can be useful in epidemiological studies.
Some strains of H pylori are more virulent than others.51 Important pathogenic factors are CagA, a product of a gene of the cag pathogenicity island; VacA, a cytotoxin produced in various amounts; and BabA2, an adhesin which recognises the blood group antigen A and allows H pylori to adhere to gastric epithelial cells. Other factors, for example, OipA and SabA, may also determine disease. Furthermore, host genetic factors may determine disease outcome52 The association with H pylori pathogenic factors and host genetic factors is real in Western populations, but the limited strength of the association does not allow a reliable prediction of the outcome at an individual level. Moreover, the tests are cumbersome and expensive and of little relevance in the management of H pylori infection (box 7).
The rapid urease test can detect the presence of H pylori, within one hour with a satisfactory accuracy (>90%).53 False negative results can occur in patients taking antisecretory drugs. It is acceptable to initiate eradication therapy on the basis of a positive rapid urease test (box 8).
Non‐invasive tests should be employed for confirmation of eradication except in cases where repeat endoscopy is indicated, for example in patients with gastric ulcer. Systematic reviews of the studies performed in this context indicate that UBT is the best option, with a sensitivity of 94% and a specificity of 95%.36,54 The accuracy of the stool antigen tests is less than that of the UBT.55,56,57,58 However, when a UBT is not available, a stool test can be used. There are a number of stool tests available (one using monoclonal antibodies, laboratory and office based and the other polyclonal antibodies). The sensitivity of the test is lower if polyclonal antibodies59 or an office test is used. Confirmation of H pylori eradication should be performed at least four weeks after treatment (box 9).
Numerous clinical trials have been published since the last Maastricht conference. Table 55 shows the recommendations for treatment of H pylori infection formulated at the Maastricht III Consensus Conference. Standard triple therapy composed of PPI, clarithromycin and amoxicillin/or metronidazole is more successful if extended to more than seven days. Increased resistance to antibiotics used in the PPI triple therapy needs to be considered in the selection of treatment. Recently, sequential treatment consisting of five days of a PPI plus amoxicillin followed by five additional days of a PPI plus clarithromycin plus tinidazole has been shown to be better than the combination of a PPI plus amoxicillin and clarithromycin for seven days60,61 and deserves further evaluation in different regions.
The mechanism of resistance of H pylori strains to clarithromycin is well understood. Its methods of detection are reliable and its clinical relevance has been proved.
The prevalence of clarithromycin resistance in Europe was measured in a European study in 1997–98 and was, overall, 10%, with important differences between northern (4%) and southern European countries (18.5%).62 There was a correlation between the prevalence of H pylori clarithromycin resistance and the consumption of macrolides in the corresponding regions expressed as the daily dose per 1000 inhabitants in 1997.63
Clarithromycin resistance is increasing. It is the main risk factor for treatment failure.64,65,66 Treatment should achieve an eradication rate of 80%.67 The threshold of clarithromycin resistance at which this antibiotic should not be used, or a clarithromycin susceptibility test should be performed, is 15–20%.
In vitro resistance to metronidazole may not accurately reflect in vivo resistance.68 For this reason metronidazole testing is not recommended routinely in clinical practice (box 10).
In susceptible strains the combination of PPI‐clarithromycin‐metronidazole is more successful than the combination of PPI‐clarithromycin‐amoxicillin (97% v 88%, respectively). In the case of clarithromycin resistance alone, the eradication rates are also higher with PPI‐clarithromycin‐metronidazole than with PPI‐clarithromycin‐amoxicillin (50% v 18%, respectively). In cases of metronidazole resistance when a PPI‐clarithromycin‐metronidazole regimen is used, there is a 25% decrease in eradication rate (72% v 97%).69
Based on these data, the predicted eradication rates for the PPI‐clarithromycin‐metronidazole combination show a better efficacy than PPI‐clarithromycin‐amoxicillin, which is nullified only when metronidazole resistance reaches 40%.70
A 14 day treatment led to a 12% (95% confidence interval 7 to 17%) higher eradication rate based on a single meta‐analysis.71 Few studies have compared the cost effectiveness of these different strategies.72 Numerous studies with PPI triple therapy for seven days, mainly from European countries, confirm that this is still a valid duration for this treatment.70
Bismuth‐containing quadruple therapy (10 or 14 days) is an option for the first line treatment. It leads to satisfactory eradication rates despite the increased resistance to both clarithromycin and metronidazole.
First choice treatment in various geographical regions world wide was also examined and finally, a global statement including the different points mentioned above was voted upon (box 11).
Bismuth based quadruple therapy is a preferred option as second choice treatment if not previously used. However, the participants highlighted the fact that bismuth is not currently available in many countries.
PPI triple treatments have been tested as second choice treatment. Clarithromycin should not be used unless phenotypic or genotypic tests show that the strain is susceptible. The eradication rate obtained with the combination PPI‐amoxicillin‐metronidazole was 89% and 64% for metronidazole susceptible and resistant strains, respectively. In a clinical trial using this combination as a second choice treatment, the global eradication rate was 64%.73 Another combination, for which limited data exist, is PPI‐tetracycline‐metronidazole with an eradication of 91% (box 12).74
Two other classes of antibiotics have emerged in the treatment of H pylori infection: a fluoroquinolone, levofloxacin; and a rifamycin, rifabutin.
These antibiotics have been evaluated for the most part in first choice treatments with PPI and amoxicillin rather than rescue treatments, with a good success rate.
However, rifabutin is an antibiotic which can select resistance among Mycobacteria, so it must be used cautiously. H pylori resistance to rifabutin may occur but is rare.
Many studies have included levofloxacin and obtained good eradication rates.75,76 Unfortunately, none of them tested for fluoroquinolone susceptibility. One can assume that the strains were susceptible. Recent data showed that levofloxacin resistance reached 20% in some areas and can result in eradication failure.
Owing to the variety of clinical situations and antibiotics available in different countries, no specific recommendation was given for third choice treatment except to perform susceptibility testing.
Culture for the management of H pylori infection has been neglected for a long time, despite the fact that several studies have shown that higher eradication rates are obtained when antibiotics are chosen based on susceptibility testing rather than chosen empirically.73,77,78 This may be a cost effective approach.79 The high impact of clarithromycin resistance led to the proposal to perform culture and antimicrobial susceptibility testing when the resistance rate reaches 15–20%. Culture and sensitivity may help in decision making after the failure of a second choice treatment. We recommend that monitoring of primary antibiotic resistance be carried out in different regions in order to appreciate the risk of failure linked to antimicrobial resistance (box 13).
Gastric cancer is a major public health issue and the global burden of gastric cancer is increasing, particularly in developing countries (table 66).). H pylori infection is the major cause of chronic gastritis, a condition that initiates the pathogenic sequence of events leading to atrophic gastritis, metaplasia, dysplasia and subsequently, cancer. Pooled analyses of prospective seroepidemiological studies have shown that people with H pylori infection are at a statistically significantly increased risk of developing non‐cardiac gastric cancer.80 It is also well established that both the intestinal and diffuse histological types of gastric cancer are significantly associated with the H pylori infection. Non‐randomised clinical follow‐up studies in Japan have shown that gastric cancer rates are significantly higher in patients with H pylori infection than in those in whom the infection was eradicated.81 Metachronous tumour rates are also higher in those with persisting infection than in those without, after endoscopic resection for early gastric cancer.82
Furthermore, follow‐up studies in Sweden and Denmark of patient cohorts undergoing hip replacement procedures show statistically significantly lower rates of gastric cancer. This may be explained by the possibility that high doses of prophylactic antibiotics incidentally eradicate H pylori infection.83 Thus, it was agreed that H pylori infection is the most common proven risk factor for human non‐cardiac gastric cancer.
Infection with cagA positive strains of H pylori increases the risk for gastric cancer over the risk associated with H pylori infection alone. Determining the cagA status in H pylori infection may confer additional benefit in identifying populations at greater risk for gastric cancer.84 Interleukin 1 gene cluster polymorphisms are associated with a higher risk of hypochlorhydria (odds ratio=9.1) and of gastric cancer (odds ratio=1.9).52 Potential extrinsic and intrinsic factors in gastric carcinogenesis include: hereditary/family history, both direct and indirect (social inheritance); autoimmune (H pylori may trigger the onset of autoimmune atrophic gastritis in some patients with pernicious anaemia in diabetes type I, autoimmune chronic gastritis is common and rarely associated with H pylori infection); environmental (occupational exposure/nitrate/nitrite/nitroso compounds); nutritional (salt, pickled food, red meat, smoking); general (low socioeconomic status, geography); pharmacological (gastric acid inhibition).85,86,87,88,89,90 All these lines of evidence suggest that bacterial virulence factors, host genetic factors, and environmental factors contribute to the risk of developing gastric cancer.91
H pylori eradication prevents development of pre‐neoplastic changes (atrophic gastritis and intestinal metaplasia) of the gastric mucosa.92,93,94 Evidence that H pylori eradication may reduce the risk of gastric cancer is based on non‐randomised controlled studies in animal and humans.95,96 Several randomised control studies show regression of precancerous lesions or, at least, a decrease of progression as compared with control groups after H pylori eradication.97 One RCT did not demonstrate reduction of cancer incidence at five years but showed a significant reduction in the group without pre‐neoplastic lesions.98 The consensus report concluded that eradication of H pylori has the potential to reduce the risk of gastric cancer development; moreover, the optimal time to eradicate H pylori is before pre‐neoplastic lesions (atrophy, intestinal metaplasia) are present. It was also agreed, that the potential for gastric cancer prevention globally is restricted by currently available treatments.96,97,98,99 Thus, new treatments are desirable for a global strategy of gastric cancer prevention.
The meeting was made possible by generous grants offered by Altana, AstraZeneca, Janssen Cilag, Takeda, and Malesci (main sponsor for the local event).
BabA2 - blood group antigen binding adhesin 2
CagA - cytotoxin associated gene A
EHSG - European Helicobacter Study Group
GORD - gastro‐oesophageal reflux disease
IDA - iron deficiency anaemia
ITP - idiopathic thrombocytopenic purpura
MALT - mucosa associated lymphoid tissue
NSAIDs - non‐steroidal anti‐inflammatory drugs
OipA - outer inflammatory protein A
PPIs - proton pump inhibitors
RCT - randomised controlled trial
SabA - sialic acid binding adhesion
UBT - 13C‐urea breath test
VacA - vacuolating associated gene A
Andersen, Leif, Copenhagen, Denmark; Atherton, John, Nottingham, UK; Asaka, Masahiro, Sapporo, Japan; Bazzoli, Franco, Bologna, Italy; Bytzer, Peter, Glostrup, Denmark; Chan, Francio, Shatin, HongKong; Coelho, Luiz Gonzaga Vaz, Belo Horizonte, Brazil; de Wit, Niek, Utrecht, The Netherlands; Delchier, Jean Charles, Paris, France; Di Mario, Francesco, Padova, Italy; El‐Omar, Emad, Aberdeen, UK; Fock, Kwong Ming, Singapore; Forman, David, Leeds, UK; Fujioka, Toshio, Oita, Japan; Gasbarrini, Giovanni, Roma, Italy; Genta, Robert, Geneva, Switzerland; Goh, KL, Kuala Lumpur, Malaysia; Graham, David Y, Houston, Texas, USA; Hirschl, Alexander, Wien, Austria; Hungin, Pali, Durham, UK; Hunt, Richard, Ontario, Canada; Isakov, Vassili A, Moscow, Russia; Jones, Roger, London, UK; Kist, Manfred, Freiburg, Germany; Koletzko, Sibylle, München, Germany; Kuipers, Ernst J, Amsterdam, The Netherlands; Kupcinskas, Limas, Kaunas, Lithuania; Ladas, Spiros, Athens, Greece; Lanas, Angel, Zaragoza, Spain; Machado, Jose, Porto, Portugal; Malfertheiner, Peter, Magdeburg, Germany; McColl, Kenneth E. L., Glasgow, Scotland, UK; Mégraud, Francio, Bordeaux, France; Michetti, Pierre, Lausanne, Schwitzerland; Moayyedi, Paul, Hamilton, Canada; ÓMorain, Colm, Dublin, Ireland; Pilotto, Alberto, Vicenza, Italy; Quina, Mario, Lisboa, Portugal; Rokkas, Theodore, Athens, Greece; Sharma, Patreek, Missouri, USA; Simsek, Ylkay, Izmir, Turkey; Sipponen, Pentii, Esposo, Finland; Sollano, J., Manila, Philippines; Stockbrügger, Reinold, Maastricht, The Netherlands; Sugano, Kentaro, Yakushiji Tochigi, Japan; Vaira, Dino, Bologna, Italy; Vakil, Nimish, Milwaukee, WI, USA; Vieth, Michael, Bayreuth, Germany; Xiao, Shudong, Shanghai, China.
Extracts in abstract form and comments have been published in Italian. Short extracts have been published in GI Forefront, based on a presentation to the Japanese Society of Gastroenterology and a European short version release.
Since the Maastricht conference new additional publications in support of the recommendations and statements, are included to update the manuscript.
Competing interests: None