Volume 61 - 1998 - Fasc.3 - Symposium
CHU Brugmann ULB; **UZ St Raphaël KUL Leuven.
The 1998 national Belgian consensus meeting on HP-related diseases an extensive summary
"HP testing must be regarded as ONE of the important elements of the proper diagnostic work-up of a DISEASE, managed in close cooperation between GP's and specialists": that's the key message of the national consensus meeting held in CHU Brugmann on February 6th and 7th 1998. HP testing (usually by 2 direct methods : RUT-histology) and eradication treatment (ER), in infected patients, are strongly recommended in: 1. Past or current GDU (absolute indication), regardless of activity, complication(s), NSAID intake; 2. Low-grade MALT Lymphomas (Stage IE1) unequivocally diagnosed, managed and followed-up in specialised centers; 3. Post endoscopic resection of EGC. ER is advisable in HP carriers with a family history of gastric cancer. Chronic atrophic-, lymphocytic-, giant folds gastritis and hyperplastic polyps are acceptable indications for ER as well as scheduled long-term NSAID treatment in individuals with known HP status. Systematic ER in HP+ patients with fully investigated NUD is not indicated but could be considered in individual patients. Extra alimentary disorders and auto immune gastritis are no indication and there was no consensus for a "test and treat" policy in patients under 45 yrs old without alarm symptoms. Systematic screening of asymptomatic individuals is not recommended. A correct monitoring of eradication after treatment is recommended, mainly by UBT. In severe or refractory PUD, symptom recurrence and follow-up of EGC and Maltomas, endoscopic follow-up with HP testing is mandatory. The recommended first line treatment course (except known allergy or intolerance) is PPI full dose bid, Clarithromycin 500 mg bid Amoxycillin 1000 mg bid (7 days minimal 10 days maximal). RBC-based schemes must be locally validated and quadruple therapy is proposed when retreatment is needed. Culture, optional after the first treatment failure, is strongly recommended after a second failure. Overall, ER therapies are safe and neither the decreased efficacy of acid-lowering drugs, nor the possible increased risk of peptic oesophagitis are considered as contra-indications to eradicate. ER is cost-effective and costbeneficial in PUD and adjusted number of pihs delivered would cut costs. No clear economic data are currently available for a potential benefit of ER in GC prevention or NUD management. A national monitoring of HP resistance (Macrolides and Imidazoles) must be organized by specialised centers.
Gastro-duodenal ulcers. Who ? When to treat ?
Helicobacter pylori and gastric malignancies
Who ? When to treat ? Gastritis, particular histological lesions, NSAID therapy and extradigestive diseases
Indications of whom and when to treat Helicobacter pylori infection are reviewed in chronic atrophic gastritis, in particular types of gastritis (lymphocytic, giant fold, auto-immune gastritis), in hyperplastic polyps, before or during treatment with NSAIDs and in association with various extra-digestive diseases. Although there is no convincing evidence that Helicobacter pylori eradication may interrupt or reverse mucosal atrophy and intestinal metaplasia (potentially pre-cancerous lesions), indication for eradication could be considered in young patients if atrophic gastritis is considered as a consequence of chronic superficial gastritis which is reversible after Heficobacter pylori cure. The still evidence limited for a causal relationship between Heficobacter pylori and lympbocytic gastritis, giant folds gastritis and hyperplastic polyps suggests it is acceptable to eradicate Helicobacter pylori in infected patients presenting these special forms of gastritis. Despite the uncertainty on the interactions of Helicobacter pylon and NSAID in the genesis of peptic ulcer disease, it seems acceptable to prescribe eradication treatment in known Helicobacter pylori carriers before a long-term treatment with NSAID. The clinical evidence for an association between Helicob"ter pylori and extra-digestive diseases is at the present time too limited to advocate routine eradication in these conditions before large prospective trials are performed.
Indications for HP eradication : gastro-esophageal reflux disease
HP infection of the stomach is not a risk factor for reflux oesophagitis, and may even protect against reflux oesophagitis. HP eradication may lead to an accelerated development of GERD in duodenal ulcer disease patients. It is unknown whether this is also true for HP positive patients who do not suffer from duodenal ulcer disease. HP eradication may decrease the efficacy of acid secretion lowering drugs such as Proton Pump Inhibitors and H2-Receptor Antagonists. It is unclear whether this has any practical consequences, but it cannot be excluded that some patient may need an increased dose of acid secretion lowering drugs after HP eradication for control of symptoms and lesions of GERD. There are conflicting data on the possibility that long-term proton pump inhibitor treatment may accelerate the development of atrophic gastritis in Heficobacter pylori positive patients. The possible acceleration of atrophic gastritis development in HP positive patients using strong acid secretion inhibitors is the strongest argument in favour of eradicating HP in patients receiving long term potent acid inhibition, especially GERD patients. In view of the uncertainty concerning these data, both eradicating and non eradicating HP in patients with GERD can be defended.
Consensus for the management of Helicobacter pylori infection in children: still searching for a paradigm
Microbiological and serological diagnostic tests for Helicobacter pylori: an overview
Different invasive and non-invasive diagnostic tests are available for the diagnosis of H. pylori in the individual patient. In practice, endoscopic tests are best for a primary diagnosis of H. pylori infection because endoscopy allows assessment of treatment indications. The new rapid urease tests may help the clinician in treatment decisionmaking. Culture is currently not recommended for routine evaluation, but it is becoming increasingly important in certain populations with higher prevalence of drug resistance, since it allows to test for susceptibility to antibiotics. Serological testing has been recommended for initial pre-endoscopy or pre-treatment screening in dyspeptic patients. However, several current "in-office" tests appear insufficiently accurate or would need further validation before being recommended for use in clinical management strategies at a primary care level. The urea breath tests are best suited to confirm eradication early after treatment while laboratory serology tests are of limited use since 6 months are required before a result can be obtained. The serological office tests cannot be used for post-treatment assessment of H. pylori status.
Histological detection of Helicobacter pylori
Detection of Helicobacter pylon infection by biopsy urease test
Urea breath test : a diagnostic tool in the management of Helicobacter pylori-related gastrointestinal diseases
The urea breath test (UBT) is generally considered as a simple, non-invasive and accurate test to demonstrate Helicobacter pylori (H. pylori) infection. The principle of the test is simple. The orally given urea, isotopically labelled with 14C or 13C, is hydrolysed by the enzyme urease of H. pylori and *CO2 is expired in breath. Although the radiation exposure is negligible (3*10-6 Sv), the test with the stable isotope 13C should be preferred. Since the first description of the test in 1987 many refinements have been described. Most studies reported sensitivity and specificity figures between 95-100% for both. A uniform test protocol with regard to the test meal, the appropriate 13C-urea dose, the number of breath samples to be taken, ... would be ideal. But today, it is better to strive for a validation and a deternitination of cut off values for each protocol as such. The main indication for UBT is the confirmation of successful eradication. To avoid false negative results, testing should be performed 4 to 6 weeks after the end of treatment and 5 days after the end of acid suppressive drugs. The test is also an ideal tool to check for infection when an ulcer is found at endoscopy, but biopsy specimens can't be taken because of anticoagulant treatment. Mostly serology is the first choice to perform epidemiological studies, but UBT is a good alternative and moreover it gives an idea of the presence of active infection. The role of non-invasive tests, i.e. UBT and serology, in primary diagnosis of H. pylori is more controversial. Questions such as who will perform the test (general practitioner or gastroenterologist), what is the age limit, how to organise the follow up, what is the costbenefit, ... still remain. All these questions need a further evaluation in terms of its influence upon clinical decision making not only in general, but also more specific for the Belgian situation. In conclusion : 1. The 13C-urea breath test is a very accurate, non-invasive test to diagnose gastric H. pylori colonisation in adults and children. 2. If local protocols are validated and appropriate cut off values are determined, general standardisation of methodology isn't necessary. 3. The 13C-urea breath test is the ideal diagnostic tool to monitor eradication therapy in patients with complicated duodenal ulcers, gastric ulcers, Malt lymphomas, poor compliance and to perform large epidemiological studies. 4. The role of the 13C-urea breath test in the clinical decision making prior endoseopy remains controversial.
How (who ?) and when to test or retest for H. pylori
Several direct/invasive and indirect/non-invasive diagnostic tests are available for the diagnosis of H. pylori infection. Invasive tests require biopsy sampling of the gastric mucosa and include rapid urease test, histology, bacteria] culture and polymerase chain reaction technique. Non-invasive tests include the urea breath test and serological assays. This review gives a critical comparative analysis of accuracy, advantages and limitations of the different diagnostic tests including current cost and availability in Belgium. Rapid urease testing (RUT) of gastric biopsy specimens is probably the initial test of choice in patients undergoing endoscopy because of its low cost, rapid availability of results, simplicity and accuracy. Histological examination of gastric biopsy samples should be mandatory at the initial presentation of the patient because it also gives insight on the status of the gastric mucosa (initammation & premahgnant changes). Although not mandatory for primary diagnosis, a biopsy for culture and sensitivity testing should always be obtained when it is available and when endoscopy is undertaken as part of the patient's management. Among the non-invasive tests, the place of serology remains questionable for other than epidemiological purposes. How is H. pylori infection best diagnosed ? How many tests are needed in routine clinical practice ? The answer will depends on the clinical setting and local availability of the tests. For primary diagnosis in dyspeptic patients - where endoscopy is an important tool - a biopsy-based detection system is appropriate an we recommend the use of at least two diagnostic tests based on different principles, like RUT (with 1 or 2 biopsy specimen/test) and histology (including antrum & corpus biopsies) which are widely available. Alternatively a urea breath test may also be recommended when endoscopy is not required. Post-treatment monitoring seems to be justified in most cases and must always be performed at least 4-6 weeks after completion of therapy. The urea breath test is probably the method of choice for non-invasive testing in this clinical setting. When endoscopy is required, mutiple biopsy specimens both from the antrum and the corpus and the use of at least two different diagnostic methods must be performed. Whenever possible, culture should always be done as it is very specific and allows testing of antimicrobial susceptibility which is mandatory in case of treatment failures. Neither the "Test and Treat' nor the "Test and Scope" strategies have been investigated in terms of effectiveness of symptoms relief and cost in Belgium and cannot therefore be recontirnended at this time.
The search for optimal Helicobacter pylori eradication regimen: a mid 1997 update
Short-term side effects during H. pylori eradication therapy
Adverse events of HP eradication: long term negative consequences of HP eradication
Two problems can be identified as possible long term negative consequences of HP eradication : diminished efficacy of acid-lowering drugs, and an accelerated development of GERD. It was shown that omeprazole produces a greater decrease in gastric acidity in subjects with H. pylori infection than in those who are H. pylori negative, and that omeprazole produces a smaller decrease in gastric acidity after cure of H. pylori. This effect persisted for at least one year after HP eradication. It is not limited to omeprazole, but can also be seen with the H2 receptor antagonist ranitidine. At least one proven mechanism involved in this phenomenon is the disappearance of the alkamzing effect of ammonia generated from urea by HPs urease, after eradication of the bacteri a , other mechanisms may also be involved. HP eradication may therefore potentially hamper acid inhibitory treatment. It is unknown to what extent this is clinically relevant. Although one study did not observe' a relation between H. pylori status and efficacy of omeprazole maintenance therapy for GERD, it cannot be excluded that some patients may need more potent or higher doses of acidlowering medication after HP eradication. Three studies suggest that duodenal ulcer patients who were successfully treated with H. pylori eradication therapy, may be at increased risk to develop GERD. Labenzs study finds that the incidence of GERD may be double 3 years after eradication. The life-table analysis suggested that cure of the infection was associated with an increased risk of reflux oesophagitis during the first year after treatment, whereas later the incidence of reflux oesophagitis was similar in both groups. Patients who developed reflux oesophagitis after the cure had a more severe body gastritis before cure, gained weight more frequently after cure, and were predominantly men. There are no data on the fate of the oesophagus after HP eradication in patients with reflux oesopbagitis. The data thus strongly suggest that there is a risk for developing reflux oesophagitis after HP eradication in patients with duodenal ulcer. It is unknown whether HP eradication in patients without duodenal ulcer also increases the risk for developing reflux oesophagitis.
Pharmacoeconomics in HP-related diseases : more questions than answers
The infection of gastric mucosa by Helicobacter pylori (HP) is the commonest infection in human beings. The huge financial burden of HP infection's complications (direct and indirect costs of peptic ulcer disease and gastric malignancies, medical fees and cost of drugs in functional dyspepsia) is very difficult to evaluate. Pharmacoeconomics is at its very beginning in that field. In developing countries, many data are lacking to approach cost/benefit ratio in HP infection. The very high prevalence of HP infection is established but the true incidence of HP-associated diseases, peptic ulcer disease (PUD) and gastric cancer (GC) is not known. There is just no idea of the current (and affordable) fees for management. In developed countries, the necessity of pharmaecononidc approaches is bom because of the rapid increase of longevity and costs of medical investigations and therapies, along with economic recession and growing unemployment. Besides some real-time studies, economic models are built on historical data: prevalence and incidence of PUD and GC, direct-indirect costs and impact of HP eradication on the evolution 3
Antimicrobial resistance in Helicobacter pylori : a global overview
Helicobacter pylori resistance to antimicrobial agents is of particular concern because it is a major determinant in the failure of eradication regimens. Antimicrobial drug resistance has been reported to occur for nitroiniidazoles, macrolides, fluoroquinolones, rifampin and tetracyclines. Resistance to nitroimidazoles is the most common, in the range of 30-40% on the average in Europe while the overall prevalence rate of resistance to macrolides is lower, probably ranging between 2-10% in most countries. Development of secondary (acquired) resistance to nitroiniidazoles and to the macrolides usually occurs as a rule (> 70-100%) in case of failed eradication therapy. Data available from several centres seems however to indicate that a significant shift towards increasing resistance to metronidazole and to the mactoiides might have possibly occurred in many countries over the last years. Resistances to both metronidazole and to clarithromycin are the most significant ones because they influence the success of the treatments although this seems to be less marked and more dependent on the treatment regimens considered in the case of metronidazole resistance than in the setting of clarithromycin resistance. These differences may in part relate to methodological variations and to the inherent difficulties in assessing the susceptibility of H. pytori to metronidazole. It is possible that different resistance cut-off might also have to be considered for metronidazole depending on the treatment regimens administered. The mechanisms of resistance have been well defined for the macrolides and are beginning to be unraveled for the nitroiniidazoles. In all cases, resistance of H. pylon to antimicrobial agent seems to be due to the development of single mutational events in chromosomal genes rather than to the acquisition of exogeneous resistance genes. Owing to the restricted ability of microbiology laboratories with expertise in H. pylori culture and the lack of standardised methodology for susceptibility testing, H. pylori culture is not often performed routinely. It should however be considered after documented treatment failure or in patients from a geographic area or of an ethnic origin with higher likelihood of antimicrobial drug resistance. Likewise it is deemed very important to institute national and regional surveillance programs to follow the evolution of H. pylori resistance and to better adapt treatment regimens to changes in resistance patterns.
Helicobacter pylori - screening prospect
