Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Norwalk virus genome cloning and characterization.

Major epidemic outbreaks of acute gastroenteritis result from infections with Norwalk or Norwalk-like viruses. Virus purified from stool specimens of volunteers experimentally infected with Norwalk virus was used to construct recombinant complementary DNA (cDNA) and derive clones representing most of the viral genome. The specificity of the clones was shown by their hybridization with post- (but not pre-) infection stool samples from volunteers infected with Norwalk virus and with purified Norwalk virus. A correlation was observed between the appearance of hybridization signals in stool samples and clinical symptoms of acute gastroenteritis in volunteers. Hybridization assays between overlapping clones, restriction enzyme analyses, and partial nucleotide sequence information of the clones indicated that Norwalk virus contains a single-stranded RNA genome of positive sense, with a polyadenylated tail at the 3' end and a size of at least 7.5 kilobases. A consensus amino acid sequence motif typical of viral RNA-dependent RNA polymerases was identified in one of the Norwalk virus clones. The availability of Norwalk-specific cDNA and the new sequence information of the viral genome should permit the development of sensitive diagnostic assays and studies of the molecular biology of the virus.

Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines.

BACKGROUND: Helicobacter pylori remains a global health hazard, and vaccination would be ideal for its control. Natural infection appears not to induce protective immunity. Thus, the feasibility of a vaccine for humans is doubtful. METHODS: In two prospective, randomised, double-blind, controlled studies (Paul Ehrlich Institute application nos 0802/02 and 1097/01), live vaccines against H pylori were tested in human volunteers seronegative for, and without evidence of, active H pylori infection. Volunteers (n = 58) were immunised orally with Salmonella enterica serovar Typhi Ty21a expressing H pylori urease or HP0231, or solely with Ty21a, and then challenged with 2x10(5) cagPAI(-) H pylori. Adverse events, infection, humoral, cellular and mucosal immune response were monitored. Gastric biopsies were taken before and after vaccination, and postchallenge. Infection was terminated with antibiotics. RESULTS: Vaccines were well tolerated. Challenge infection induced transient, mild to moderate dyspeptic symptoms, and histological and transcriptional changes in the mucosa known from chronic infection. Vaccines did not show satisfactory protection. However, 13 of 58 volunteers, 8 vaccinees and 5 controls, became breath test negative and either cleared H pylori (5/13) completely or reduced the H pylori burden (8/13). H pylori-specific T helper cells were detected in 9 of these 13 (69%), but only in 6 of 45 (13%) breath test-positive volunteers (p = 0.0002; Fisher exact test). T cells were either vaccine induced or pre-existing, depending on the volunteer. CONCLUSION: Challenge infection offers a controlled model for vaccine testing. Importantly, it revealed evidence for T cell-mediated immunity against H pylori infection in humans.

Gastritis, dyspepsia and peptic ulcer disease.

Peptic ulcer disease remains a common problem and it most frequently due to the presence of an Helicobacter pylori infection or use of non-steroidal anti-inflammatory drugs (NSAIDs). Dyspepsia is neither sensitive or specific for diagnosing peptic ulcer disease. The approach to patients with dyspepsia is to arrive at a definitive diagnosis without unnecessary exposure to invasive or costly diagnostic procedures. Non-invasive testing is preferred with endoscopy being reserved for those with alarm markers or above a specified age (e.g., 55 years in Western countries). Patients negative for H. pylori infection should receive an empiric trial of acid suppression for 4 to 8 weeks and if beneficial it can be continued.

Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial.

AIM: To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. METHODS: This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. RESULTS: Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. CONCLUSIONS: Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids.

Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori.

BACKGROUND: Up-to-date information regarding the recurrence rate of Helicobacter pylori (H. pylori) after eradication therapy is not available. AIM: To evaluate the global recurrence rate following H. pylori eradication therapy and confirm its association with socioeconomic and sanitary conditions. METHODS: A systematic search of PubMed, EMBASE and the Cochrane library was performed to identify potentially relevant publications using the following keywords: "Helicobacter pylori" or "H. pylori" or "Hp" and "recurrence" or "recrudescence" or "reinfection" or "recurrent" or "recurred" or "re-infect*" or "relapse*." RESULTS: A total of 132 studies (53 934 patient-years) were analysed. Each study was weighted according to the duration of patient-years. The global annual recurrence, reinfection and recrudescence rate of H. pylori were 4.3% (95% CI, 4-5), 3.1% (95% CI, 2-5) and 2.2% (95% CI, 1-3), respectively. The H. pylori recurrence rate was inversely related to the human development index (HDI) (ie, 3.1% [95% CI, 2-4], 6.2% [95% CI, 4-8] and 10.9% [95% CI, 6-18] in countries with a very high, high and medium or low HDI) (P <.01) and directly related to H. pylori prevalence (10.9% [95% CI, 7-16], 3.7% [95% CI, 3-5], 3.4% [95% CI, 2-5] and 1.6% [95% CI, 0.5-3] in countries with a very high, high, medium or low local H. pylori prevalence) (P <.01). Global recurrence rates remained relatively stable between 1990s, 2000s and 2010s but varied across different regions (P <.05). CONCLUSIONS: H. pylori recurrence remains a problem closely associated with socioeconomic and sanitary conditions. Methods to reduce recurrence in developing countries are needed.

Sequential therapy using high-dose esomeprazole-amoxicillin followed by gatifloxacin for Helicobacter pylori infection.

BACKGROUND: The success rate of current anti-Helicobacter pylori triple therapies in now generally 80% or less. Sequential therapy has proved superior. AIM: To test a new sequential therapy for H. pylori eradication. METHODS: This was a pilot study of a sequential therapy consisting of 40 mg of esomeprazole and 1 g amoxicillin t.d.s., for 12 days. On days 6 through 12 gatifloxacin (400 mg in the morning) was added. Outcome was accessed 4 or more weeks after ending antibiotic therapy. Both naive and treatment failures were eligible. RESULTS: Thirty patients were entered in the study. One was lost to follow-up and one stopped early because of side effects. The success rate intention-to-treat was 80% (95% CI: 61-92%). The per-protocol eradication rate was 85.7% (95% CI: 67-95%); two of the four failures had pre-treatment gatifloxacin-resistant H. pylori. Side effects were reported by 13 patients (46%) and were generally mild with diarrhoea being most common (n = 6). Only one patient stopped medicine because of side effects of dizziness (severe) and diarrhoea (mild). CONCLUSIONS: Sequential therapy using the combination of a high dose of proton-pump inhibitor and amoxicillin followed gatifloxacin was effective, but pre-treatment susceptibility testing may become necessary as fluoroquinolone resistance increases.

Rabeprazole containing triple therapy to eradicate Helicobacter pylori infection on the Texas-Mexican border.

BACKGROUND: Antibiotic resistance and duration of therapy influence the success of proton-pump inhibitor-containing Helicobacter pylori eradication therapy. Clarithromycin resistance is associated with treatment failure. AIM: To examine the success of a 7-day rabeprazole-clarithromycin-amoxicillin therapy in the study population. METHODS: Adults from Ciudad Juarez with H. pylori infections identified by culture or histology received rabeprazole 20 mg, clarithromycin 0.5 g and amoxicillin 1 g, each b.d. for 7 days. Outcome was assessed by 13C-urea breath test carried out 4+ weeks after treatment. RESULTS: A total of 111 patients were enrolled and evaluated by urea breath test; 102 completed the full 7 days therapy. Two deviated from protocol, and five stopped because of adverse events. The cure rate (intention-to-treat) was 85% (95% CI: 78-91%); the per-protocol cure rate was 85% (95% CI: 78-91%). Side-effects were not serious and only 6.6% of those with adverse events stopped medication. Only three isolates were clarithromycin-resistant and none was cured. Compliance explained most of the successes. CONCLUSIONS: In the study population a 7-day rabeprazole triple eradication therapy was both effective and well-tolerated. Clarithromycin resistance was uncommon. We observed a slightly better outcome but consistent with results from recent large studies in US populations.

Current understandings of Helicobacter pylori, peptic ulcer and gastroesophageal reflux disease.

H. pylori infection is a major pathogen inducing gastric mucosal inflammation and causing dysregulation of normal acid inhibitory regulatory mechanisms. The overall effect on gastric acid secretion is dependent on the location and severity of inflammation. Eradication results in healing of gastric mucosal inflammation, healing of peptic ulcers, prevention of new peptic ulcers, prevention or reduction in gastric cancer risk and in transmission of the infection. Neither H. pylori infection nor H. pylori eradication causes gastroesophageal reflux disease (GERD). H. pylori eradication also does not impede anti-secretory drug therapy of GERD. Misunderstandings of the negative association between H. pylori infection and GERD and/or Barrett's esophagus and misuse of the epidemiologic concept of ''protection'' led to considerable confusion and likely resulted in some patients receiving poor care. Current evidence is consistent with the notion that H. pylori should be eliminated whenever the organism is found. However, H. pylori infection has become increasing difficult to cure in part due to the emergence of antimicrobial resistance. In Western countries, triple therapy consisting of a proton pump inhibitor, amoxicillin and clarithromycin no longer achieves adequate eradication rates and will soon need to be abandoned. When used, legacy triple therapy should be given for 14 days. Fluorquinolones may temporarily be useful: 10-14 day duration is superior to 7 days. However, worldwide resistance is rapidly increasing. Other potential replacement therapies and strategies are discussed including sequential therapies, high-dose proton pump inhibitor plus amoxicillin, and new quadruple therapies.

Etiology of Crohn's disease: the role of Mycobacterium avium paratuberculosis.

Crohn's disease is a chronic inflammatory bowel disease characterized by transmural inflammation and granuloma formation. Several theories regarding the etiology of Crohn's disease have been proposed, one of which is infection with Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis), which causes a similar disease in animals, and is present in the human food chain. Considerable evidence supports the presence of M. paratuberculosis in the intestinal tissues of many patients with Crohn's disease including culture, detection of homologous mycobacterial DNA, detection of the mycobacterial insertion sequence IS900 by both PCR and in situ hybridization in tissues, and a serologic immune response to recombinant M. paratuberculosis antigens. Despite this evidence, and our personal belief that M. paratuberculosis is a cause of Crohn's disease, widespread acceptance of this hypothesis will require evidence that specific anti-mycobacterial chemotherapy will cure the disease.

Effect of different organic acids (citric, malic and ascorbic) on intragastric urease activity.

BACKGROUND: The mechanism of citric acid-enhanced Helicobacter pylori urease activity remains unclear. AIM: To compare ascorbic, citric and malic acid given at the same concentration and pH on intragastric urease activity. METHODS: Volunteers received 40 mg of famotidine the evening prior to breath testing. After an overnight fast volunteers were randomized to receive 100 mL of water or 100 mm citric, malic, or ascorbic acid, pH 2.3 containing 75 mg of 13C-urea. At 15 min a second 100 mL solution of one of the test solutions was taken without added urea. RESULTS: Twelve volunteers were studied (eight men, four women, age 19-57, median 50.7) in a randomized-crossover study. The mean breath test result at 30 min with ascorbic (17.5 +/- 5), malic (25.8 +/- 5) and citric acid (29.5 +/- 5) were all significantly greater than with water (9.5 +/- 3). Citric and malic acid were similar (P = 0.699) and significantly greater than ascorbic acid (P < 0.02). When the ascorbic acid was followed by citric acid, the result was similar to that with citrate alone (25.8 +/- 4) and greater than with ascorbic then ascorbic (P = 0.026). CONCLUSIONS: Enhancement of H. pylori urease activity is not strictly a function of the pH. We propose the effect is related to differential effects of the availability of nickel, which is required for urease activity. Citric acid and malic acid were essentially equivalent such that malic acid could substitute for citric acid in the UBT; ascorbic acid would be a poor choice.

Novel bismuth-metronidazole-tetracycline triple-layer tablet for treatment of Helicobacter pylori.

BACKGROUND: Current anti-Helicobacter pylori treatment regimens are costly and because of the increasing antibiotic resistance, are becoming ineffective. AIM: To evaluate a triple-layer tablet containing 100 mg bismuth subcitrate, 250 mg metronidazole, and 250 mg tetracycline in a single triple-layer tablet. METHODS: H. pylori-infected adult patients received bismuth-metronidazole-tetracycline (two tablets, t.d.s.) and ranitidine (300 mg) once daily for 14 days. Efficacy was determined using 13C-urea breath testing. RESULTS: Thirty-three of 35 enrolled patients were available for evaluation; using the protocol-specified modified intention-to-treat analysis, five failed treatment, two were lost to follow-up (cure rate per-protocol = 85.7%, intention-to-treat = 78.7%). The cure rate among metronidazole-susceptible strains was 100% (22 of 22) (95% confidence interval 84-100%) compared with 55% (five of nine intention-to-treat) (95% confidence interval 21-86%) among metronidazole-resistant strains. In four cases, therapy was truncated at 4-7 days because of side-effects; yet the treatment was effective in three. The three metronidazole-susceptible but clarithromycin-resistant infections were cured. CONCLUSION: This novel triple-layer tablet combination therapy was effective in all patients with metronidazole-susceptible H. pylori and many of those with resistant organisms. A greater degree of acid suppression may further improve effectiveness.

Atrophic gastritis in young children and adolescents.

BACKGROUND: Helicobacter pylori associated gastric cancer arises via a multistage process, with atrophic gastritis being the precursor lesion. Helicobacter pylori is typically acquired in childhood, yet little is known of the prevalence of atrophic gastritis in childhood. AIM: To study atrophic gastritis among children from countries with high gastric cancer incidence. METHODS: Sections from topographically mapped gastric biopsy specimens from children undergoing clinically indicated endoscopy in Korea and Colombia were evaluated using visual analogue scales. Atrophy was defined as loss of normal glandular components, including replacement with fibrosis, intestinal metaplasia (IM), and/or pseudopyloric metaplasia of the corpus (identified by the presence of pepsinogen I in mucosa that was topographically corpus but phenotypically antrum). RESULTS: One hundred and seventy three children, 58 from Korea (median age, 14 years) and 115 from Colombia (median age, 13 years), were studied. Helicobacter pylori was present in 85% of Colombian children versus 17% of Korean children (p<0.01). Atrophic mucosa near the antrum-corpus border was present in 16% of children, primarily as pseudopyloric metaplasia (31%, IM; 63%, pseudopyloric metaplasia; 6%, both). The median age of children with corpus atrophy was 15 (range, 7-17) years. CONCLUSION: Gastric atrophy occurs in H pylori infected children living in countries with high gastric cancer incidence. Identification and characterisation of the natural history of H pylori gastritis requires targeted biopsies to include the lesser and greater curve of the corpus, starting just proximal to the anatomical antrum-corpus junction, in addition to biopsies targeting the antrum and cardia.

CagA in Barrett's oesophagus in Colombia, a country with a high prevalence of gastric cancer.

BACKGROUND: In the USA, atrophic gastritis and gastric cancer are rare, whereas gastro-oesophageal reflux disease (GERD) is common. Infection with Helicobacter pylori, especially a CagA positive strain, is unusual in patients with GERD/Barrett's oesophagus in the USA. AIM: To examine the relation between Barrett's oesophagus and CagA positive H pylori in Colombia, a country with a high prevalence of CagA positive H pylori associated atrophic gastritis and gastric cancer. METHODS: Helicobacter pylori and CagA status was determined among Colombian patients with long segment Barrett's oesophagus and a control group with simple H pylori gastritis. Helicobacter pylori status was determined using a triple stain and CagA status was determined by immunohistochemistry using a specific rabbit anti-CagA serum. RESULTS: Gastric and oesophageal mucosal biopsies were obtained from 51 patients--39 men (mean age, 57.8 years; SD, 13.1) and 12 women (mean age, 51.8 years; SD, 14.4)--with documented long segment Barrett's oesophagus. The results were compared with 24 Colombian patients with H pylori gastritis without oesophageal disease. Thirty two patients with Barrett's oesophagus had active H pylori infection. CagA status was evaluated in a subset of 23 H pylori infected patients with Barrett's oesophagus, and was positive in eight of these patients compared with 19 of 24 controls (p = 0.01). CONCLUSIONS: Although most Colombian patients with Barrett's oesophagus had H pylori infection, CagA positive infections were unusual. These data illustrate how consistent corpus inflammation reduces acid secretion, which prevents Barrett's oesophagus among those with abnormal gastro-oesophageal reflux barriers.

Alendronate and naproxen are synergistic for development of gastric ulcers.

BACKGROUND: Both alendronate sodium use and nonsteroidal anti-inflammatory drug use are associated with gastric ulcers. The aim of this study was to investigate whether alendronate and naproxen are synergistic as causes of gastric ulcers. METHODS: We performed an endoscopist-blind, randomized, crossover, single-center comparison of 10 mg/d of alendronate sodium, 500 mg of naproxen sodium twice daily, or the combination taken orally for 10 days in volunteers aged 30 years or older. Videoendoscopy was used to evaluate the presence and degree of mucosal damage to the esophagus, stomach, or duodenal bulb before and after each treatment. There was a 1- to 4-week washout between evaluations. RESULTS: Twenty-six healthy volunteers participated (18 women and 8 men), aged 30 to 50 years. Gastric ulcers were present in 2 subjects receiving alendronate (8%), in 3 receiving naproxen (12%), and in 10 receiving both (38%) (P<.05 for the combination vs either drug alone). CONCLUSIONS: Both alendronate and naproxen can cause gastric ulcers. The combination appears synergistic. Alendronate should be used with caution in those who simultaneously require nonsteroidal anti-inflammatory drugs.

Diagnosis and course of nephrogenic ascites.

Nephrogenic ascites is a complex diagnostic problem with poorly understood pathophysiology. Morbidity and eventual mortality from this ongoing problem are significant. The diagnosis of nephrogenic ascites must be established by exclusion. We report the cases of nine patients investigated between 1978 and 1985. Laparoscopy, which was utilized in all nine patients, led to a specific diagnosis in two. We believe that a vigorous diagnostic evaluation, including laparoscopy, is essential in patients with chronic renal failure who develop persistent ascites.

Are genetic influences on peptic ulcer dependent or independent of genetic influences for Helicobacter pylori infection?

BACKGROUND: Genetic factors play a role or roles in the etiology of peptic ulcer disease and the acquisition of Helicobacter pylori infection. OBJECTIVE: To evaluate the relative importance of genetic and environmental influences as well as the importance of H. pylori on peptic ulcer disease. DESIGN: Cross-sectional study on monozygotic (MZ) and dizygotic (DZ) twins, reared apart or together. PARTICIPANTS: Twins of the subregistry of the Swedish Twin Registry included in the Swedish Adoption/Twin Study of Aging. MEASUREMENTS: Peptic ulcer disease and H. pylori status were assessed in MZ and DZ twin pairs reared apart or together. A total of 258 twin pairs had information regarding H. pylori status and history of peptic ulcer. Helicobacter pylori status was assessed as the presence of anti-H. pylori IgG. RESULTS: The intraclass correlations for peptic ulcer disease for MZ twins reared apart and together and DZ twins reared apart and together were 0.67, 0.65, 0.22, and 0.35, respectively, which indicates that genetic effects are important for liability to peptic ulcer. The correlation coefficient for MZ twins reared apart (0.67) provides the best single estimate of the relative importance of genetic effects (heritability) for variation in liability to peptic ulcer disease, and structural model fitting analyses confirmed this result (heritability, 62%). The cross-twin cross-trait correlations for MZ and DZ twins were examined to determine whether genetic effects for peptic ulcer were shared with or independent of genetic influences for H. pylori. The cross-correlations for MZ and DZ twins were almost identical (0.25 and 0.29, respectively), suggesting that familial environmental rather than genetic influences mediate the association between peptic ulcer disease and H. pylori infection. CONCLUSIONS: Genetic influences are of moderate importance for liability to peptic ulcer disease. Genetic influences for peptic ulcer are independent of genetic influences important for acquiring H. pylori infection.

Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States.

BACKGROUND: Therapy for Helicobacter pylori is generally empiric despite the fact that resistance to metronidazole and clarithromycin compromise therapeutic efficacy. The aim of this study was to aid clinicians in choosing a course of therapy for H pylori infection in the United States. METHODS: The frequency of primary clarithromycin and metronidazole resistance among H pylori isolated from patients enrolled in US-based clinical trials between 1993 and 1999 was reviewed in relation to patient age, sex, region of the United States, and test method (Etest and 2 agar dilution procedures). RESULTS: Clarithromycin and metronidazole resistance rates were based on the results of 3439 pretreatment Etest determinations and 3193 agar dilution determinations. Sex and age were available on 900 and 823 individuals, respectively. Metronidazole resistance was 39% by Etest and 21.6% by agar dilution (P<.001). Clarithromycin resistance was 12% by Etest and 10.6% by agar dilution. Amoxicillin or tetracycline resistance was rare. Metronidazole and clarithromycin resistance was more common in women than men (eg, 34.7% vs 22.6% for metronidazole and 14.1% vs 9.7% for clarithromycin (P =.01 and P =.06, respectively). Antibiotic resistance increased gradually up to age 70 years, then declined significantly (P<.05) regardless of test method. Regional differences in antimicrobial resistance did not occur. CONCLUSIONS: While age and sex had significant effects on resistance rates, regional differences were not present. The high prevalence of resistance to metronidazole and clarithromycin may soon require the performance of antimicrobial susceptibility testing of H pylori isolates prior to initiating treatment.