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This year, the Nobel Prize in Physiology or Medicine was awarded to the Australian doctors Marshall and Warren for their discovery and further identification of the stomach bacterium Helicobacter pylori. Thanks to their confidence in their own observations, we are now able to cure people with peptic-ulcer disease and low-grade gastric lymphoma and are potentially able to prevent gastric cancer.

Background: In western European countries, most dyspeptic patients are initially managed by their general practitioners (GPs), who use a range of strategies to manage dyspepsia. We performed an economic analysis of a Helicobacter pylori test-and-treat strategy versus a prompt endoscopy approach in a primary care setting., Methods: Data were used from the Strategy: Endoscopy versus Serology (SENSE) study, performed in The Netherlands from 1998 to 2001. Patients were randomized to a prompt endoscopy (n = 105) or test-and-treat (n = 118) group. Follow-up lasted 1 year. Adverse events were not recorded in the SENSE study. Health care costs were based on the total amount of dyspepsia-related drugs used, the number of dyspepsia-related GP visits, the number of diagnostic tests, and the number of dyspepsia-related referrals to specialists. The use of medical resources was calculated as standardized costs for 1999, recorded as euros. (On December 31, 1999, 1.00 Euro = 1.00 US dollar.) Quality of life was measured at inclusion and 1 year later, using the RAND-36 questionnaire. To calculate quality-adjusted life-years (QALYs), we transformed the individual scores of the RAND-36 into 1 overall score, the Health Utilities Index Mark 2, which introduced a limitation to the study. An incremental cost-effectiveness ratio (ICER) was calculated. The 95% confidence limits were calculated using a parametric bootstrap method with angular transformation. All cost data were analyzed from a third-party payer perspective., Results: The total costs per patient were 511 Euros, with 0.037 QALY gained per patient, in the test-and-treat group, and 748 Euros, with 0.032 QALY gained per patient, in the endoscopy group (between groups, P < 0.001 and P = NS, respectively). The point estimate of the ICER indicated that the test-and-treat strategy yielded cost savings and QALYs gained. Parametric bootstrap confidence limits indicated cost savings per QALY gained in 75.7% of the bootstrap simulations., Conclusion: This analysis of data from the SENSE1026 study suggests that the H pylori test-and-treat strategy was more cost-effective than prompt endoscopy in the initial management of dyspepsia in general practice, from the perspective of a third-party payer.

Objectives: Recent studies have suggested that the prevalence of Helicobacter pylori infection in patients with ulcer disease who were not using non-steroidal anti-inflammatory drugs (NSAIDs) has been overestimated. The decreasing prevalence of H. pylori could lead to a relative increase in the number of patients with this idiopathic peptic ulcer disease (IPUD). This study aimed to investigate the prevalence of IPUD and any possible trends., Design and Methods: The reports of all upper gastro-intestinal endoscopies performed in a Dutch regional hospital over the period 1991 to 1998 were reviewed. If a gastric and/or duodenal ulcer had been diagnosed, data concerning possible H. pylori infection (culture, histology, rapid in-house urease test) were retrieved. If H. pylori tests were negative, hospital files were examined for possible use of NSAIDs or other rare causes of ulcer disease. When these were not found, stored biopsy specimens were tested for H. heilmanii by using the polymerase chain reaction technique., Results: Ulcer disease was diagnosed in 405 patients who had undergone endoscopy (159 with gastric ulcer, 235 with duodenal ulcer, and 11 with both gastric and duodenal ulcer). H. pylori infection was found in 349 of these patients (86.2%). Thirty-three of the 56 H. pylori negative patients used NSAIDs and three patients had Crohn's disease, leaving 20 patients with IPUD (4.9%, 12 gastric ulcer and eight duodenal ulcer). Time trends over the study period showed a decrease of H. pylori associated peptic ulcer disease (P <0.002) and an increase of NSAID associated peptic ulcer disease (P <0.0005). The prevalence of IPUD remained stable (P=0.978)., Conclusions: The prevalence of patients with H. pylori negative ulcer disease significantly decreased in our study population due to an increase in the number of patients with NSAID associated peptic ulcer disease. IPUD was rare and its prevalence did not increase over a period of 8 years.

Background: The value of the "test-and-treat" strategy in the approach to dyspepsia has been evaluated only in a few secondary care studies. Most patients with dyspepsia, however, are treated by their primary care physician. This study evaluated the test-and-treat strategy in primary care., Methods: Patients consulting their general practitioners for dyspepsia were randomized to either direct open-access endoscopy with Helicobacter pylori testing or a test-and-treat strategy by H pylori serology. In the 12-month follow-up period, any additional treatment or referral for investigations was left at the discretion of the general practitioner. At the end of the study, data were collected concerning the number of endoscopies, changes in symptom severity and quality of life, patient satisfaction, and the use of medical resources., Results: Two hundred seventy patients were enrolled (129 who received endoscopy and 141 in the test-and-treat group). The prevalence of H pylori infection was 38.3% and 37.2% in the test-and-treat and endoscopy groups, respectively. In the test-and-treat group, 46 patients (33%) were referred for endoscopy during follow-up. Improvement in symptom severity, quality of life, and patient satisfaction was comparable in both groups. Patients in the test-and-treat group paid more dyspepsia-related visits to their general practitioner (P =.005). Patients in the endoscopy group were more often prescribed proton pump inhibitors (P =.007), whereas patients in the test-and-treat group were more often prescribed prokinetic drugs (P =.005)., Conclusions: The test-and-treat strategy proved to be as effective and safe as prompt endoscopy. Only a minority of patients were referred for endoscopy after the test-and-treat approach.

In this paper the rationale and limitations of the four most important approach strategies to dyspepsia in primary care (empiric treatment, prompt endoscopy, "test-and-scope", and "test-and-treat") are analysed. It is concluded that in the absence of alarm symptoms, a "test-and-treat" approach is currently the most rational approach provided that three conditions are met: (1) a highly accurate test should be used, (2) the prevalence of Helicobacter pylori in the population should not be too low, and (3) an effective anti-H pylori regimen should be prescribed taking sufficient time to instruct and motivate the patient.

Objective: To study the relationship between the presence of H. pylori virulence factors and clinical outcome in H. pylori infected patients., Methods: DNA was isolated from an antral biopsy sample and vacA, cagA, and iceA genotype were determined by PCR and a reverse hybridization technique in 183 patients with culture-proven H. pylori infection: 51 with peptic ulcer disease (PUD), 62 with gastroesophageal reflux disease (GERD), and 70 with a normal endoscopy (gastritis only; GO)., Results: Forty-four samples (24%) showed more than one allelic variant in the vacA s- or in-region and/or both iceA1 and iceA2 genotypes, indicating multiple strain infection. These were excluded from statistical analysis. vacA s1 and cagA were significantly more common in PUD than in GERD and GO. Logistic regression analysis showed that GERD patients were more often infected with strains lacking both cagA and iceA than GO patients (OR = 0.36; CI = 0.15-0.89). Trend analysis showed that GERD patients were most often infected with less virulent strains (p < 0.002)., Conclusion: Multiple strain infection is common. H. pylori strains possessing the vacA s1 genotype and/or cagA are associated with PUD. GERD patients, infected with H. pylori, mostly carry less virulent strains possessing neither cagA nor iceA1. Our findings support the hypothesis that virulent strains protect against the development of GERD.

Objective and Design: To evaluate the performance of the Helicobacter pylori stool antigen test (HpSA test) in detecting H. pylori infection and monitoring the effect of treatment. This was done in two separate studies using either a biopsy or the 13C-urea breath test based 'gold standard' (in untreated and treated patients, respectively)., Setting: Endoscopy units of two general hospitals., Patients: One hundred and twenty-eight dyspeptic patients undergoing endoscopy in the first study. Sixty-five patients receiving anti-H. pylori treatment in the second study., Results: Sensitivity and specificity in untreated patients were 96.3% and 81.8%, respectively. Seven days after treatment, these figures were 20% and 95%, and 4 weeks after treatment they were 40% and 95%., Conclusion: The HpSA test is accurate in untreated patients but fails in monitoring treatment success.

Metronidazole was introduced in 1959 for the treatment of Trichomonas vaginalis, but was subsequently shown to be active against anaerobic and some micro-aerophilic bacteria as well. In anaerobic microorganisms with their low redox potential, metronidazole is reduced to its active metabolite by a one-electron transfer step. Metronidazole is often used in treatment regimens for Helicobacter pylori, a microaerophilic bacterium, but resistance to this drug is frequently encountered. The metabolism of metronidazole in H. pylori must differ from that in anaerobic bacteria as metabolites formed by a one-electron transfer are readily re-oxidized in the micro-aerophilic environment of H. pylori. This process is called 'futile cycling' and is accompanied by the formation of toxic oxygen radicals that are neutralized by an active scavenger system. Recently, it has been shown that in H. pylori, in contrast to the situation in anaerobes, an oxygen-insensitive nitroreductase. encoded by the rdxA gene, is responsible for the activation of metronidazole. Activation by this enzyme is by a two-electron transfer step, preventing futile cycling' and thereby enabling the activation of metronidazole in a micro-aerophilic environment. Metronidazole resistance has been shown to be associated with null mutations in the rdxA gene in most clinical isolates. However, there may be some 'background metronidazole susceptibility' in metronidazole-resistant strains caused by other (oxygen-sensitive) nitroreductases. Recently, three meta-analyses of the impact of metronidazole resistance on treatment efficacy have all shown a significant reduction in efficacy of metronidazole containing regimens in patients infected with a resistant strain. The impact of resistance proved to be dependent on the other components of the regimen and on treatment duration.

The efficacy of a nitroimidazole-containing regimen for the treatment of Helicobacter pylori infection is decreased by nitroimidazole resistance. Nitroimidazoles are meta- bolized by H. pylori by several nitro-reductases of which an oxygen-insensitive NADPH nitroreductase encoded by the rdxA gene is the most important. Null mutations in this gene are associated with resistance. Susceptibility testing to nitroimidazoles may give variable results. This is not only related to the slow growth under specific conditions, but also to variability in the activity of the other nitroreductases and the ability to deactivate toxic metabolites of an NI and to repair DNA damage. Moreover, co-infections with resistant and susceptible bacteria are frequently found. The presence of nitroimidazole resistance is related to the previous use of this drug. The prevalence of resistance is rising and nowadays 10-50% of the isolates are resistant. Resistance reduces the efficacy of a treatment regimen to a variable degree. This is related to efficacy of the other components of the regimen and the treatment duration. Whether a nitroimidazole is still effective in resistant strains remains unresolved. When nitroimidazole resistance is present, a nitro-imidazole-containing regimen should be avoided or a regimen with other highly effective components should be used.

Objective: Recurrence of Heliobacter pylori after apparently successful treatment mostly represents resurgence of the infection, rather than a new one. Therefore, the reliability of biopsy-based tests after treatment was investigated., Methods: Four weeks or more after treatment, antral biopsy samples were taken for culture, histology, urease test and polymerase chain reaction (PCR), and a corpus specimen for culture. Treatment failure was defined as > or = 2 tests positive. If one test was positive, a 13C-urea breath test was performed and considered conclusive., Results: One hundred and ninety-seven patients were evaluated. Endoscopy was performed 53 days (27-92 days) after treatment. Twenty-one patients with missing test results and 19 patients on acid-suppressive drugs were excluded. In 140 of 156 patients (89.7%), H. pylori was eradicated. Sensitivity and specificity of culture of antrum were, respectively, 100% and 100%; culture of corpus, 100% and 100%; rapid urease test, 87% and 99%; haematoxylin/eosin stain, 94% and 95%; Giemsa stain, 81% and 99%; and PCR, 88% and 100%., Conclusion: Although all biopsy-based tests are reliable after treatment, culture is the biopsy-based test of first choice as it is the most accurate and gives additional information on antibiotic resistance.

Objective: The aim of this study was to determine the influence of nitroimidazole resistance (NIR) on the efficacy of treatment for Helicobacter pylori (H. pylori) infections by meta-analysis of the world literature., Methods: A MEDLINE search, a manual search of all major gastroenterological journals from 1993 to 1997, and abstracts of gastroenterological and H. pylori meetings from 1993 to 1997 were performed. All treatment studies using a nitroimidazole and providing data about the medication used, dose frequency, total daily dose, duration of treatment, and eradication results in relation to NIR were included. Eradication had to be assessed by two biopsy-based tests or a urea breath test > or = 4 wk after treatment. Individual studies were pooled into groups according to the medication used and the duration of treatment. The pooled estimate of the odds ratio (OR) of NIR for treatment failure and its 95% confidence interval (95% CI) were calculated for each group using the logit method. To detect any possible bias, funnel plots (plots of effect estimates against sample size) were constructed., Results: A total of 91 treatment arms, including a total of 4823 patients, were evaluated. The pooled ORs of NIR for treatment failure (95% CI) of proton pump inhibitors, bismuth, and quadruple regimens were 5.2 (3.8-7.1), 5.9 (4.1-8.3), and 7.0 (3.1-16.0), respectively. Eradication rates were 90% in susceptible strains but <75% in resistant strains. In susceptible strains, neither treatment duration nor the choice of the second antibiotic influenced efficacy. In resistant strains, tetracycline was more effective than amoxicillin (bismuth regimens), and the longer the duration of regimens (bismuth-amoxicillin regimens) the more effective they were. Only quadruple regimens given for > or = 1 wk were effective in resistant strains., Conclusions: NIR decreases treatment efficacy. Treatment duration and choice of other drugs influence the impact of NIR on treatment efficacy. If NIR is present, a nitroimidazole-containing regimen should be avoided or a quadruple regimen should be given for > 1 wk.

Background: Helicobacter pylori exaggerates the effect of acid suppressive drugs on intragastric pH. It is unknown whether this is relevant for the treatment of GERD., Aim: To compare oesophageal acid exposure and symptoms in H. pylori-negative and H. pylori-positive GERD patients during low and profound acid suppression., Methods: Barrett's oesophagus patients with gastro- oesophageal acid reflux were studied by 24-h oesophageal pH-metry at baseline and during randomized treatment with omeprazole 40 mg b.d. or ranitidine 150 mg b.d. H. pylori status was determined by a serum IgG ELISA. Symptoms were scored on a four-graded scale., Results: Of 58 patients, 26 (14 H. pylori-negative, 12 H. pylori-positive) were randomized to omeprazole, 32 (16 H. pylori-negative, 16 H. pylori-positive) to ranitidine. At baseline, oesophageal acid exposure and symptoms did not differ between H. pylori-negative and H. pylori-positive: mean time proportion pH < 4 per 24 h was 16.1% (95% CI 11.5-23.2) in H. pylori-negative, and 15.8% (11.3-21.4) in H. pylori-positive patients. Omeprazole treatment resulted in a decrease of acid reflux per 24 h from 23.4% (7.9-39.3) to 0.0% (0.0-2.9) in H. pylori-negative, and from 17.3% (8.9-38.8) to 0.1% (0.0-1.7) in H. pylori-positive patients; ranitidine resulted in a decrease from 14.4% (10.5-18.5) to 9.3% (5.6-12.8) in H. pylori-negative, and from 15.1% (9.8-21.0) to 9.0% (3.1-20.1) in H. pylori-positive patients, the difference between H. pylori-negative and H. pylori-positive patients being N.S. There was no significant difference between H. pylori-negative and H. pylori-positive patients with respect to erect and supine acid reflux, or symptom scores in both treatment groups., Conclusions: H. pylori infection does not influence oesophageal acid reflux and symptoms in patients with Barrett's oesophagus, either at baseline or during low as well as profound acid suppressive therapy. We conclude that the dose of acid suppression does not have to be titrated upon H. pylori status in GERD.

Metronidazole susceptibility testing by E test was compared to that by disk diffusion for 263 Helicobacter pylori isolates and to that by breakpoint agar dilution for 90 H. pylori isolates. In 5% and 6% of the cases, respectively, results were discrepant. For each of 52 clinical isolates an E test was performed on 10 separate colonies. Subpopulations of resistant and susceptible bacteria were found in five cases. From three isolates, each colony was subcultured and tested up to 10 times. All but 1 of 292 tests showed the same result. We conclude that the E test is reliable and that subpopulations are responsible for discordant results.

Aim: To assess the influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate-based triple therapy regimens in two consecutive studies., Methods: In the first study, patients with a culture-proven Helicobacter pylori infection were treated with ranitidine bismuth citrate 400 mg, metronidazole 500 mg, and clarithromycin 500 mg, all twice daily for 1 week (RMC). In the second study, amoxycillin 1000 mg was substituted for clarithromycin (RMA). Susceptibility testing for metronidazole was performed with the E-test. Follow-up endoscopy was performed after >/= 4 weeks. Antral biopsy samples were taken for histology and urease test, and culture and corpus samples for histology and culture., Results: 112 patients, 53 males, age 55 +/- 14 years (39 duodenal ulcer, 7 gastric ulcer and 66 gastritis) were treated with RMC, and 89 patients, 52 males, age 58 +/- 15 years (23 duodenal ulcer, 7 gastric ulcer and 59 gastritis) were treated with RMA. For RMC, intention-to-treat eradication results were 98% (59/60, 95% CI: 91-100%) and 95% (20/21, 95% CI: 76-100%) for metronidazole susceptible and resistant strains, respectively (P = 0.45). For RMA these figures were 87% (53/61, 95% CI: 76-94%) for metronidazole susceptible strains and 22% (2/9, 95% CI: 3-60%) for resistant strains (P = 0.0001)., Conclusion: Both regimens are effective in metronidazole susceptible strains. However, in contrast to the amoxycillin-containing regimen, that containing clarithromycin is also effective in resistant strains.

Objective: The aim of this study was to compare the efficacy and side effects of 1-wk triple therapy with ranitidine bismuth citrate (RBC) 400 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg b.i.d., to 2-wk dual therapy with RBC 400 mg b.i.d. and clarithromycin 500 mg b.i.d. for H. pylori infection in a randomized, clinical trial., Methods: Patients (18-80 yr) with a culture proven H. pylori infection were randomized to one of these regimens. Side effects were scored on a semiquantitative scale. Endoscopy was performed > or = 4 wk after treatment. Antral biopsy samples were taken for hematoxylin-eosin stain (HE), rapid urease test, and culture and corpus samples for culture and HE. Two weeks after the endoscopy, a 13C-urea breath test was performed. Eradication failure was defined as detection of H. pylori by culture or by at least two other tests., Results: A total of 104 patients, 54 men, age 54+/-14 yr, (36 duodenal ulcer, 16 gastric ulcer, and 52 functional dyspepsia) were included. Gender, age, and diagnosis were comparable in both groups. Fourteen of 52 patients in both triple and dual therapy, respectively, had significant side effects, but all patients completed the course. Eradication results were 49 of 52 (94%; 95% CI: 84-99%) and 50 of 52 (96%; 95% CI: 87-100%) on intention to treat analysis and 44 of 46 (96%; 95% CI: 85-99%) and 48 of 49 (98%; 95% CI: 89-100%) on per protocol analysis for triple and dual therapy respectively., Conclusion: Both regimens are very effective and well tolerated in the treatment of H. pylori infection. The triple regimen has the advantage of being shorter.

The prevalence of primary metronidazole resistance of Helicobacter pylori was studied in one Dutch hospital from 1993 to 1996 and in two additional Dutch hospitals in 1993 and 1996. All cultures of antral biopsy specimens yielding H. pylori in the study period were evaluated, except those from patients who had received anti-H. pylori treatment; 1,037 H. pylori strains, all from different patients were included. Metronidazole resistance was determined by disk diffusion in 1993 and by Epilipsometer-test in 1994 to 1996. Metronidazole resistance increased from 7% (18/245) in 1993 to 32% (161/509) in 1996. More patients with nonulcer dyspepsia and more non-Western European patients were seen in 1996 than in 1993, but age and sex differences were not observed. A comparable increase in metronidazole resistance was observed in both nonulcer dyspepsia patients and peptic ulcer patients, and the prevalence of metronidazole resistance in Western Europeans increased from 5% in 1993 to 28% in 1996.

Eight commercial enzyme-linked immunosorbent assays (ELISAs) were used to test sera taken from 102 patients in whom Helicobacter pylori infection status had been determined by means of biopsy culture, PCR, histology, and urease production and by 13C urea breath test. By those means, 61 patients had been found to be infected. Assays were compared by receiver operating characteristic analysis. Sensitivities ranged from 86 to 98%; specificities ranged from 83 to 98%. In a group consisting of the assays by Bio-Whittaker, Meddens Biotech, Orion (Pyloriset EIA G, new version), and Enteric Products, Inc. (HM Cap), differences in performance were not statistically significant. Sensitivities in this group ranged from 93 to 98%; specificities ranged from 95 to 98%. Assays from this group may be useful in addition to biopsy-based methods in diagnosing H. pylori infection.

Objective: To assess the accuracy of six commonly used diagnostic tests for Helicobacter pylori in a prospective study without using any specific test as the gold standard (the patient was regarded as H. pylori-infected if two or more tests, whatever their nature, were positive)., Methods: In 105 outpatients undergoing upper GI endoscopy, 62 without significant abnormalities, 28 with gastroesophageal reflux disease, 19 with peptic ulcer, one with erosive gastritis, and one with atrophic gastritis (some patients had more than one diagnosis), antral biopsy specimens were taken for culture, polymerase chain reaction, histological examination (hematoxylineosin and Giemsa stains), and rapid urease test. Corpus biopsy specimens were taken for histological examination. Serology (ELISA) and a 13C-urea breath test were also performed. Consistency of diagnosis between two pathologists was assessed by kappa statistics., Results: Sensitivity and specificity, respectively, were as follows: culture, 98.4 and 100%; polymerase chain reaction, 96.7 and 100%; histological examination (antrum), 96 and 98.8%; histological examination (antrum + corpus), 98.4 and 98.8%; rapid urease test, 90.2 and 100%; 13C-urea breath test, 100 and 100%; and serological examination, 98.4 and 88.4% (95% in those who had not been previously treated for H. pylori). All H. pylori-positive cases were detected by culture and rapid urease test. In 86.4% of these cases all antral biopsy-based tests were positive. Agreement between pathologists was good, with a kappa coefficient around 0.90 for antral biopsy specimens., Conclusions: All antral biopsy-based tests, as well as the 13C-urea breath test, are accurate for the diagnosis of H. pylori infection. Sampling error is a problem of minor importance. The lower specificity of serological tests may be largely explained by previous treatment of H. pylori.

Objective: This study analyses the 13C-urea breath test with the aim of determining the optimal time interval between dosing and breath sampling and examines the feasibility of having patients perform the test without supervision at home., Design: Prospective study comparing the 13C-urea breath test with four antral biopsy-based tests in a random population undergoing upper gastrointestinal endoscopy., Setting: One university hospital and one general hospital., Patients: One hundred and four patients were included; 61 were Helicobacter pylori-positive and 43 H. pylori-negative according to biopsy-based tests., Interventions: The 13C-urea breath test was performed at home by collecting a baseline and two post-dosing samples; the next day it was performed clinically by collecting a baseline and six post-dosing samples. A 100 mg dose of 13C-urea and a test meal were used., Outcome Measures: The breath samples collected were analysed. Excess delta 13CO2/12CO2 values above five per million were considered positive., Results: The specificity of the clinical test was 100% whereas that of the home-based test was 95.1%. The sensitivity of the clinical test depended on the time interval between dosing and collection of the evaluated sample. Sensitivity was 100% if the sample was taken 50 min or more after dosing. The home-based test had a sensitivity of 94.8%., Conclusion: To obtain maximum sensitivity (100%) using the single-sample technique the sample has to be collected at least 50 min after dosing. It is feasible to have the test performed at home. Patient selection and thorough instruction are necessary.