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Original Articles: Gastro-esophageal Disorders

The Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland

Smith, Sineada,b; Boyle, Breidac; Brennan, Denisea; Buckley, Martini; Crotty, Paule; Doyle, Maevej; Farrell, Richardg; Hussey, Marya; Kevans, Davida,d; Malfertheiner, Peterl; Megraud, Francism,n; Nugent, Seank; O’Connor, Anthonyf; O’Morain, Colma,h; Weston, Shiobhanh; McNamara, Deirdrea,f

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European Journal of Gastroenterology & Hepatology: May 2017 - Volume 29 - Issue 5 - p 552-559
doi: 10.1097/MEG.0000000000000822
  • Open



Helicobacter pylori is implicated in the development of chronic gastritis, duodenal and gastric ulcers, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Although the prevalence of H. pylori is decreasing in many parts of the world, management of H. pylori infection has become a challenge 1. It has been suggested that H. pylori therapies should aim to eradicate infection in at least 90% of treated patients 2. However, eradication rates have decreased, largely because of antibiotic-resistant bacteria and issues with patient compliance. The European Helicobacter pylori Study Group and Consensus Panel have just published the Maastricht 5/Florence Consensus report on the management of H. pylori at the European level 3. As the prevalence of H. pylori infection and rates of antibiotic resistance have been shown to vary among different countries 4,5, key treatment recommendations of the Maastricht 5/Florence Consensus Report are determined by the local prevalence of antibiotic resistance. Indeed, various efforts at the national level have been made recently to best manage H. pylori infection in a given population 6–10. The aim of this consensus process was to establish a national Irish Helicobacter pylori Working Group (IHPWG), with the support of international experts in the field, to review the literature relating to the management of H. pylori infection and provide updated recommendations most appropriate for the treatment of H. pylori in adult patients in Ireland.


Establishment of the Irish Helicobacter pylori Working Group

Experts in the areas of gastroenterology and microbiology based in Ireland and Europe were invited to join the IHPWG. Upon acceptance of the invitation to participate, members were assigned with reference to their expertise to one of three subgroups to address the key domains of (a) diagnosis of H. pylori infection in symptomatic adults, (b) first-line H. pylori therapy and (c) H. pylori rescue therapy.

Data review and assessment of evidence

Each subgroup was initially responsible for generating and defining focused healthcare questions of relevance to their domain in terms of Population, alternative management strategies (Interventions) and Comparators and Outcomes (PICO). Subsequently, each subgroup reviewed any available local data, the published literature and current European and international guidelines relevant to their respective PICO-based questions. At a meeting that took place on 22 June 2016 in Dublin, Ireland, summarized data associated with each of the three key domains were presented. Following a thorough discussion of the data, recommendation statements were established to address each PICO-based question 11. The Grading of Recommendations Assessment, Development and Evaluation approach 12 was used to define questions of importance, rate the quality of the available evidence and grade the resulting recommendations.

The strength of each recommendation and the strength of the supporting evidence were also assessed using the Grading of Recommendations Assessment, Development and Evaluation approach 12. The quality of evidence for each PICO was evaluated across studies as a body of evidence. Aspects related to the implementation of the recommendations in clinical practice in Ireland were also considered. Consensus for a recommendation was defined as support by more than 90% of the experts. The recommendations resulting from this process are reported below.


Domain 1: diagnosis of H. pylori infection in symptomatic adults

Statement 1: all patients with symptoms related to the upper gastrointestinal tract should be tested for H. pylori

Recommendation: strong. Quality of evidence: high.

On the basis of the links between H. pylori infection and ulcers, gastric cancer and MALT lymphoma, H. pylori detection and treatment is recommended in all symptomatic patients. Eradication of H. pylori infection provides a long-term cure for both duodenal and gastric ulcers in the majority of patients whose ulcers are not associated with NSAID use 13,14. Evidence also suggests that H. pylori eradication reduces the development of atrophic gastritis and the risk of cancer progression in infected individuals without premalignant gastric lesions 15–22. In addition, eradication of infection leads to regression of most localized gastric MALT lymphomas 23–26.

The test-and-treat strategy involves the noninvasive testing of patients with dyspepsia to detect the presence of H. pylori, followed by treatment in cases where H. pylori is detected. Current European Guidelines recommend the test-and-treat strategy in countries where the prevalence of H. pylori is at least 20% and in situations where there is a low risk of the patient having gastric cancer, such as those up to 45 years and without alarm symptoms, such as weight loss, dysphagia, overt gastrointestinal bleeding, abdominal mass or iron-deficient anaemia 3,27. Noninvasive tests for H. pylori include the urea breath test (UBT), the stool antigen test and serology. Recent data from the Irish healthcare setting indicate infection rates of 36–37% among patients referred for the UBT 28,29 and 19–36% among patients referred for endoscopy 30 [and unpublished data Adelaide and Meath Hospital incorporating the National Children’s Hospital (AMNCH; D. McNamara and S. Smith) and Whitfield Clinic, Waterford (S. Nugent)].

An endoscope-and-treat strategy is recommended in patients with an increased risk of gastric cancer, such as those of at least 45 years or with alarm symptoms and those with a family history of gastric cancer 3,27. It should also be considered in dyspeptic patients in low-prevalence (<20%) H. pylori populations 3. The diagnosis of H. pylori infection at endoscopy is made by means of the rapid urease test, histology and/or culture using biopsy specimens.

Statement 2: the urea breath test is the recommended noninvasive test for H. pylori

Recommendation: strong. Quality of evidence: high.

The UBT involves the ingestion of 13C or 14C-labelled urea. If present, the H. pylori enzyme urease converts the C-labelled urea into labelled carbon dioxide, which is detected in a breath sample 31. Fasting for at least 4 h before testing is recommended 32. The UBT is easy to perform and accurate with reported sensitivities and specificities of 88–96 and 93–100%, respectively 33,34, and is the recommended noninvasive test for H. pylori where available.

The stool antigen test detects H. pylori antigens in stool samples, with enzyme-linked immunosorbent assay laboratory-based stool antigen tests showing superior accuracy to in-office kits. Sensitivity and specificity of 95 and 97%, respectively, have been reported for monoclonal stool antigen enzyme-linked immunosorbent assay-based tests in a meta-analysis by Gisbert et al. 35. Local evidence from AMNCH, demonstrated inferior results using the stool antigen test compared with the UBT, with a sensitivity of 62% (and specificity 99%) for the Premier Platinum HpSA PLUS test (Meridian Bioscience, Cincinnati, Ohio, USA) 28. Problems with sample storage and transport may have impacted the sensitivity of the test. However, in a facility with limited resources, introduction of a stool antigen test that is validated locally and Irish National Accreditation Board accredited is acceptable, provided processes are in place to minimise the impact of sample storage and transport on the accuracy of the kit.

Serologic tests detect immunoglobulin G antibodies to H. pylori. There is significant variability in the accuracy of serology test kits for H. pylori, with sensitivities and specificities of 79–85 and 79–82%, respectively 36,37. As such, serology tests should be validated locally before use.

Statement 3: a combination of histology taken from the antrum and corpus and a rapid urease test are recommended for invasive H. pylori testing

Recommendation: strong. Quality of evidence: high.

When endoscopy is performed, H. pylori infection may be diagnosed by histological examination of the biopsy specimens, the rapid urease test/CLO test and/or culture. Although histological examination of biopsy samples requires highly trained personnel, this method enables the accurate detection of bacteria, the assessment of the degree of inflammation and the diagnosis of chronic active gastritis, intestinal metaplasia or malignancy. To account for the patchy distribution of H. pylori, histological sampling for H. pylori diagnosis should include an antrum biopsy (2–3 cm in front of the pylorus) and a corpus biopsy 38. Most cases of H. pylori infection can be diagnosed from gastric biopsies using histochemical staining with haematoxylin and eosin or Giemsa. In cases of chronic (active) gastritis in which H. pylori has not been detected by histochemistry, immunohistochemical staining of H. pylori is recommended. In case of normal histology, no immunohistochemical staining should be performed 3.

The rapid urease test is easy to perform, enables a quick diagnosis and allows for the immediate prescription of treatment when H. pylori is detected. The rapid urease test has shown sensitivity and specificity values of 78–97 and 94–100%, respectively 39–41. Data from AMNCH indicate that the sensitivity and specificity for the rapid urease test (Tri-Med Distributors Pty Ltd, Leederville, Washington, USA) compared with histology are 80 and 90%, respectively 42. Data from Connolly Hospital Blanchardstown indicate sensitivity and specificity values of 88 and 97% for the rapid urease test (Kimberly Clark, Irving, Texas, USA) and 78 and 97% for the quick test 43. Despite the quick test being cheaper and faster, the sensitivity was inferior to the CLO test; almost a quarter of patients with H. pylori infection were not diagnosed using the quick test without concurrent gastric biopsies taken for histology. Therefore, the exclusive use of rapid urease testing, in particular, the quick test, cannot be recommended 43.

Culture of H. pylori from biopsy specimens is of interest, largely because of the opportunity to perform antimicrobial susceptibility testing. Although culture is highly specific, H. pylori is a fastidious organism with very specific growth requirements. As a result, culture is time-consuming and requires trained personnel. Culture positivity rates of between 55 and 93% have been reported 44,45.

Statement 4: a corpus and antrum biopsy sample should be taken for the rapid urease test

Recommendation: strong. Quality of evidence: low or very low.

To account for the patchy distribution of H. pylori, a biopsy from the antrum and the corpus should be taken for the rapid urease test. Emerging evidence from abroad and Ireland suggests that testing the antrum and corpus biopsies either separately 40 or combined within the same test 30,39,43 significantly increases the diagnostic accuracy of the rapid urease test compared with single antrum biopsy testing. In addition, the combined approach reduces the reaction time of the test resulting in a more rapid diagnosis 39.

Statement 5: if H. pylori cultures are required, a corpus and an antrum biopsy should be taken

Recommendation: strong. Quality of evidence: low or very low.

Because of the lack of widespread availability of H. pylori culture and antimicrobial susceptibility testing in the Irish healthcare setting, H. pylori culture is only recommended following treatment failure (see Statements 10 and 13 below). Similar to the other invasive H. pylori diagnostic tests, dedicated biopsies should be taken from both the antrum and the corpus for culture to increase the likelihood of successful H. pylori detection 46. It is noteworthy that differences in the antimicrobial susceptibility profiles of H. pylori isolated from the corpus compared with the antrum have been reported 47. As a result, resistant H. pylori may be missed if only a single sample from one anatomic site of the stomach is taken.

Biopsy specimens should be transported in special transport containers (e.g. Portagerm pylori; Biomerieux, Nürtingen, Germany) to prevent contact with air and dessication. They should be processed for culture as soon as possible following endoscopy, ideally within 6 h 48. If processing is delayed, refrigeration is recommended 46,48. Biopsy specimens are used to inoculate Columbia blood agar plates (Columbia blood agar base; 10% laked horse blood) and incubated under microaerobic conditions at 37°C for 7–10 days 49, although colonies are usually visible after 3–5 days 48. Antimicrobial supplements may be added to the growth media to limit overgrowth with contaminating bacteria and/or fungi 49,50. Following culture, the presence of H. pylori should be confirmed by the Gram stain, and positive oxidase, urease and catalase tests 5. Current identification systems also include matrix assisted laser desorption ionization time-of-flight technology. Clinical breakpoints for H. pylori antimicrobial resistance are available from the European Committee on Antimicrobial Susceptibility Testing ( and are due to be updated in early 2017.

Statement 6: posteradication testing must be performed. If gastroscopy is not required, a urea breath test is recommended for posteradication testing

Recommendation: strong. Quality of evidence: high.

As eradication rates for H. pylori are decreasing and symptoms are not a good indicator of treatment success, posteradication testing must be performed. Testing for H. pylori eradication should be performed at least 4 weeks following the completion of any therapy for H. pylori. The UBT is considered the best option for confirmation of H. pylori eradication 34,51. The monoclonal stool antigen test may be used as an alternative, but is less accurate 35,52, likely because of issues with stool sample storage and transport before testing. As antibodies persist for months following infection, serology testing is not recommended for eradication confirmation. When endoscopy is required, the sensitivity and specificity of the rapid urease test for H. pylori detection posteradication has been shown to be in the ranges of 44–88 and 98–100%, respectively 39,53. A biopsy from the antrum and the corpus should be taken for the rapid urease test.

Statement 7: proton pump inhibitors significantly reduce the accuracy of the recommended H. pylori tests; therefore, proton pump inhibitors should be stopped 14 days before testing

Recommendation: strong. Quality of evidence: low or very low.

Acid-suppressing proton pump inhibitors (PPIs) should be avoided 2 weeks before diagnostic testing by the UBT, stool antigen test or endoscopy as they increase the gastric pH, leading to a decrease in bacterial load 3,27,49,54. PPIs have been shown to reduce the sensitivity and specificity of the UBT, the stool antigen test and endoscopic tests, and thus increase the risk of false-negative results 54–57. Although a 7-day withdrawal has been shown to be sufficient, 14 days are recommended as a ‘safety’ interval 58. To a lesser extent, H2 receptor antagonists may also slightly decrease the load of H. pylori, but their use is not considered a problem during H. pylori diagnosis 3,27. Antimicrobials should be avoided for 4 weeks before testing (UBT, stool antigen test or endoscopy) as these agents also suppress infection and reduce test sensitivity 3,27.

Domain 2: first-line H. pylori therapy

Statement 8: standard triple therapy for a duration of 7 days can no longer be recommended

Recommendation: strong. Quality of evidence: moderate.

Eradication rates for the empirical 7-day clarithromycin-based triple therapy have decreased in many countries in recent years 6, with eradication rates as low as 55% reported from countries in Western Europe 59. Indeed, a recent study on patients in Ireland has indicated an eradication rate for clarithromycin-based triple therapy of just 57% 60. As intention-to-treat rates of less than 80% are considered unacceptable according to consensus guidelines 27, standard triple therapy for 7 days cannot be recommended nationally.

Statement 9: 14-day clarithromycin-based triple therapy with a high-dose proton pump inhibitor is recommended. Bismuth quadruple therapy for 14 days is an alternative if available

Recommendation: strong. Quality of evidence: moderate.

Numerous factors contribute toward treatment failure, including high bacterial load, low gastric pH and impaired mucosal immunity; however, treatment failure is largely associated with the emergence of antibiotic-resistant H. pylori and with poor patient compliance 5,61–63. Current Maastricht consensus guidelines recommend abandoning clarithromycin-containing triple therapy without previous susceptibility testing when the local clarithromycin resistance rate is higher than 15% 3. The most recent published Irish data on clarithromycin resistance in 2010 reported a clarithromycin resistance rate of 9.3% 64. Although more recent findings from AMNCH indicate that this rate has increased considerably 65,66, the Working Group believed that the lack of nationwide data on the prevalence of clarithromycin resistance precluded its abandonment among H. pylori-infected patients in Ireland at this point in time.

Several strategies have been shown to improve the success rate of standard triple therapy. Many meta-analyses and recent observational studies have shown that increasing the duration of first-line triple therapy enhances eradication success, with treatment durations of 14 days showing the most effective eradication 67–73. PPIs inhibit acid secretion in the stomach. As antibiotics are more stable in a less acidic environment, PPIs increase H. pylori eradication efficiency. Increasing the frequency of PPIs from once to twice daily has been shown to have a positive outcome on eradication rates 74,75. In addition, the newer generation PPIs show better overall H. pylori eradication rates than first-generation PPIs (omeprazole, lansoprazole and pantoprazole), with a 40 mg dose of esomeprazole twice daily showing the most pronounced clinical benefit 75,76.

European guidelines recommend bismuth quadruple therapy as a valid alternative to clarithromycin-based triple therapy 3. Intention-to-treat eradication rates of more than 95% have been reported for 14 days of bismuth quadruple therapy 77. Bismuth quadruple therapy is also effective in areas of dual clarithromycin and metronidazole resistance 3, which has been shown to impact all non-bismuth quadruple therapies (sequential, concomitant or hybrid therapy) 78. However, an issue with bismuth quadruple therapy is the lack of widespread availability in Ireland and therefore this regimen may not be an option for many. De-Noltab (bismuth subcitrate potassium 120 mg; Astellas Pharma, Leiden, The Netherlands), which is licensed and marketed in the UK, is not licenced in Ireland, where it is considered an Exempt Medicinal Product. As such, it needs to be sourced by pharmacists through a special wholesaler. De-Noltab is included in the Irish Health Service Executive list of Exempt Medicinal Products that may be reimbursed for patients under the General Medical Services Scheme or the Drugs Payment Scheme. Pylera (140 mg bismuth subcitrate potassium, 125 mg metronidazole, 125 mg tetracycline hydrochloride; Aptalis Pharma, Houdan, France) is licenced but not marketed in Ireland, making it currently very difficult for pharmacies to obtain.

The Working Group believed that sequential therapy (PPI and amoxicillin for 5 days, followed by PPI, clarithromycin and metronidazole for 5 days) should not be recommended in Ireland as it is not superior to 14 days of clarithromycin triple therapy 79,80 and a recent Irish study reported an eradication rate for sequential therapy of only 69% 60. First-line treatment options and descriptions are summarized in Table 1 and Fig. 1.

Table 1
Table 1:
Recommended treatment descriptions
Fig. 1
Fig. 1:
Treatment decision schematic.

Statement 10: currently, culture and antimicrobial susceptibility testing is not recommended before first-line therapy

Recommendation: weak. Quality of evidence: low or very low.

Although local 65 and published evidence provides a rationale for tailoring first-line treatment on the basis of antimicrobial susceptibility testing 81–84, H. pylori culture and susceptibility testing are not performed routinely in the majority of Irish hospitals. As a result, the Working Group believed that it would be unable to recommend widespread antimicrobial susceptibility testing before first-line therapy, but that a large effort should be made to encourage local antimicrobial susceptibility testing for H. pylori in the Irish healthcare setting going forward.

Statement 11: clarithromycin resistance can be monitored by molecular methods

Recommendation: strong. Quality of evidence: moderate.

Molecular testing for H. pylori offers an attractive alternative to culture and allows for molecular genetic identification of H. pylori and antibiotic resistance directly from biopsy samples. As such, it provides the opportunity for rapid analysis, enabling same-day diagnosis. Single-point mutations within the H. pylori rrl gene encoding the 23S ribosomal subunit result in clarithromycin resistance, with three major mutations described: A2146C, A2146G and A2147G (Genbank accession number NC_000915) 85,86. These mutations may be detected using PCR-based molecular methods. Several molecular testing kits are commercially available for the molecular detection of clarithromycin resistance, including the MutaREAL Helicobacter pylori kit (Immunodiagnostik, Benshiem, Germany), the ClariRes real-time PCR assay (Ingentix, Vienna, Austria), the Seeplex ClaR-H. pylori ACE detection system (Seegene, Eschborn, Germany) and the GenoType HelicoDR assay (Hain Lifescience, Nehren, Germany) 5,86. Accumulating evidence has shown that the presence of mutations detected by molecular tests correlates well with culture-based susceptibility testing 5, with local data showing a correlation of 85% 66. Molecular methods should be considered a useful approach for monitoring the prevalence of H. pylori clarithromycin resistance nationally as well as a means for tailoring individual patient therapy.

Domain 3: H. pylori rescue therapy

Statement 12: second-line therapy depends on the first-line treatment and should not be the same treatment. The options are (a) 14 days of levofloxacin-based therapy with high-dose proton pump inhibitor, (b) 14 days of clarithromycin-based triple therapy with high-dose proton pump inhibitor or (c) bismuth quadruple therapy for 14 days

Recommendation: strong. Quality of evidence: moderate.

After the completion of first-line therapy, follow-up H. pylori testing must be performed. In cases where clarithromycin-based triple therapy has failed to eradicate the bacteria, clarithromycin resistance should be assumed 3 and repetition of the same treatment regimen should be avoided. Levofloxacin-based triple therapy represents a valid second-line therapy 87–89, unless local levofloxacin resistance data indicate otherwise. The rate of levofloxacin resistance in Ireland tested between 2008 and 2009 was 11.7% 90 and these rates have not increased since 91. Similar to first-line treatments, studies have shown that increasing the treatment duration of levofloxacin-based triple therapy enhances eradication success 87,88. A recent meta-analysis supports the use of either levofloxacin triple therapy or a bismuth-containing quadruple therapy following failure of standard clarithromycin-based triple therapy 92. High H. pylori eradication rates with bismuth therapy have been described in patients who did not respond to previous therapies, including those with metronidazole resistance 93,94. Second-line treatment regimens are described in Table 1 and Fig. 1.

Statement 13: culture and antimicrobial susceptibility testing should be performed following two treatment failures

Recommendation: weak. Quality of evidence: low or very low.

If possible, culture and antimicrobial susceptibility testing should be performed following two treatment failures (Fig. 1) to tailor therapy and increase the likelihood of eradication success. Although tailoring first-line treatment on the basis of antimicrobial susceptibility testing has indicated improved eradication rates over standard therapies 81–84, tailoring second and subsequent therapies has been explored less. Data from the limited number of studies performed to date are encouraging 44,95. Culture and antimicrobial susceptibility testing should be performed at least 4 weeks following the completion of any treatment.

Statement 14: rifabutin should be reserved for third or subsequent treatments

Recommendation: weak. Quality of evidence: low or very low.

Primary H. pylori rifabutin resistance is low 96 and rifabutin is effective in patients with dual metronidazole and clarithromycin resistance 97. Rifabutin-based therapy has been reported as a valid rescue strategy following multiple eradication failures 98. However, there is some concern over the adverse events associated with its use. Myelotoxicity is the most significant adverse event associated with rifabutin use for H. pylori therapy, although this complication is rare. Meta-analysis has shown that most patients recover from leucopenia within a few days 96. The widespread use of rifabutin should be avoided to prevent resistance selection pressure on Mycobacterium tuberculosis. We therefore recommend reserving its use for third-line and subsequent H. pylori eradication attempts. A description of rifabutin-based triple therapy is outlined in Table 1.

Statement 15: sequential therapy cannot be recommended for rescue therapy

Recommendation: strong. Quality of evidence: moderate.

There are limited data available on the use of sequential therapy as a rescue strategy for H. pylori infection 95,99. However, local data indicate suboptimal efficacy of sequential therapy as a first-line therapy 60. Moreover, studies have shown that the efficacy of sequential therapy is impacted by clarithromycin resistance and by dual metronidazole and clarithromycin resistance 80,100. Following the failure of clarithromycin-based triple therapy, clarithromycin resistance should be assumed. Similarly, data on the use of concomitant and hybrid therapy as a rescue strategy are limited and have not been investigated in Ireland to date. Thus, sequential, concomitant or hybrid therapies cannot be recommended for rescue therapy.


The resulting recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adult patients in Ireland, with a view to improving eradication rates and preventing the progression of H. pylori-associated disease. The success of these guidelines will require evaluation following implementation. On the basis of the relatively low-prevalence of H. pylori infection in Ireland, local validation of noninvasive H. pylori diagnostic tests should be performed. As antibiotic resistance is a constantly evolving process, an on-going effort to monitor antibiotic resistance rates, using both culture and molecular-based methods, should be made at a national level with centralized data collection established to accurately monitor the prevalence of resistance.


The authors would like to thank all of the Working Group members for their invaluable input into the project, especially Professor Peter Malfertheiner and Professor Francis Megraud, for travelling to Ireland to participate in the IHPWG Workshop. They also thank Associate Professor Tamasine Grimes, School of Pharmacy and Pharmaceutical Sciences, TCD, for advice on the national availability of medicinal products.

This work was supported by a Health Research Board Knowledge Exchange and Dissemination Scheme award (HEB-KEDS-2015-1616).

Conflicts of interest

There are no conflicts of interest.


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amoxicillin; antibiotic resistance; bismuth; clarithromycin; Helicobacter pylori; levofloxacin; metronidazole; proton pump inhibitor; quadruple therapy; triple therapy

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