The significance of Helicobacter pylori in the approach of dyspepsia in primary care

Summary and conclusions In this thesis the management of dyspepsia in primary care in relation to Helicobacter pylori (H. pylori) infection was studied. In chapter two several important issues considering the approach of dyspepsia are discussed. It is clear that dyspepsia is not a disease but merely a cluster of symptoms believed to originate from the gastrointestinal tract. This is probably the main reason why a universal consensus regarding the approach of dyspepsia is still lacking. Although many studies have evaluated strategies for dyspepsia, considerable differences exist in the definitions of dyspepsia, hampering a reliable comparison between study results. The discovery of H. pylori has resulted in new strategies to approach dyspepsia in primary care, based on screening for H. pylori infection. Altogether, four main strategies for dyspepsia are currently considered: 1. Symptom guided empirical treatment, 2. Direct referral for endoscopy, 3. Non-invasive testing for H. pylori and subjecting the H. pylori-positive patients to endoscopy (“test-and-scope”), and 4. Noninvasive testing for H. pylori and treatment of the infection in H. pylori-positive patients (“test-and-treat”). Based on data derived from the literature, several key issues were identified which have a significant impact on the cost-effectiveness of these strategies, namely: cost of endoscopy,cost of therapy, cost of physician visit, prevalence of H. pylori in the dyspeptic population, prevalence of peptic ulcer disease (PUD) in H. pylori positive patients, prevalence of all underlying diseases in dyspepsia, benefit of H. pylori eradication in patients with functional dyspepsia, and recurrence of dyspeptic symptoms in patients with (functional) dyspepsia after treatment. After careful consideration of the literature with respect to the advantages and disadvantages of the various strategies and the key issues mentioned above, it is concluded that at this moment, a “test-and-treat” strategy is the most rational approach in the younger patient with uncomplicated dyspepsia. Chapter three reports the results of the SENSE study (Strategy: ENdoscopy versus SErolgy). Patients who visited their general practitioner (GP) for dyspepsia could participate in the study if the GP judged the symptoms severe enough to justify treatment with acid-suppressive drugs or an upper endoscopy. Two hundered seventy patients fulfilling this condition were randomised to either a serology based “test-and-treat” strategy or a prompt open-access endoscopy. The study was performed completely in a primary care setting in the northern part of the Netherlands. After a one year follow-up period, only 33% of the patients in the “test-and-treat” arm were eventually referred for endoscopy. In these patients, no H. pylori associated PUD was detected. Symptom resolution, change in quality of life, and patient satisfaction were comparable between the “testand-treat” patients and the patients in the prompt endoscopy arm. The “test-and-treat” patients, however, visited their GP more frequently and were more frequently prescribed prokinetic drugs. On the other hand, prompt endoscopy patients were more often prescribed PPI's. Altogether, the SENSE study proved that the “test-and-treat” strategy is a save and cost-effective approach in primary care. Before a “test-and-treat” strategy can be savely implemented in primary care, however, several conditions need to be fulfilled. Firstly, reliable non-invasive testing for H. pylori has to be possible and therefore, accurate tests are required. In chapter four, the accuracy of the recently introduced Helicobacter pylori Stool Antigen (HpSA) test, which is based on the detection of H. pylori antigens in faecal samples by antigen capture ELISA, was evaluated. This test showed accurate results for the detection of H. pylori infection in untreated patients (sensitivity and specificity of 96.3% and 81.8% respectively) when compared to a gold standard based on culture, histology, and rapid-urease testing of gastric biopsy specimens. Both one and four weeks after cessation of therapy, however, the test failed to detect persisting H. pylori infection (sensitivity 20.0%, specificity 95.0% (at one week), sensitivity 40.0% and specificity 95.0% (at four weeks)). These results are in contrast to the results published by others. No adequate explanation can be given for this discrepancy. It is concluded, however, that the HpSA test is not sufficiently reliable to monitor treatment success, at least in our hands. Secondly, as stated before in chapter two, the cost-effectiveness of strategies based on screening for H. pylori mainly depend on the number of patients who will clearly benefit from anti-H. pylori therapy. As these are patients suffering from H. pylori related PUD, a decrease inthe prevalence of H. pylori related PUD will result in a decreased cost-effectiveness of the “test-and-treat” strategy. Recently, it has been suggested that the significance of H. pylori in PUD has been overestimated and that the decrease in H. pylori prevalence will unmask idiopathic PUD (not related to NSAID use or H. pylori infection). In chapter five the results of all endoscopies performed over an eigth year period in a single hospital were studied. These data revealed a decreasing trend in the prevalence of H. pylori in PUD. The proportion of PUD ascribed to NSAID-use increased significantly, but the proportion ascribed to idiopathic PUD remained stable at about 10% during the study period. Thirdly, a “test-and-treat” strategy in primary care is only useful if patients can be effectively treated in the absence of information on antibiotic susceptibility. Numerous studies have shown that antibiotic resistance has a significant impact on the efficacy of anti-H. pylori regimens. In the Netherlands, the most frequently used anti-H. pylori regimens are the triple regimens PAM (protonpump inhibitor, amoxicillin, metronidazole), and PAC (protonpump inhibitor, amoxicillin, clarithromycin). In chapter six we showed that in the north-eastern part of the Netherlands the prevalence of metronidazole resistance decreased significantly from 1996 to 2001. The prevalence of clarithromycin resistance fluctuated over this period, but no significant trend could be observed. Interestingly, the decrease in prevalence of metronidazole resistance was accompanied by a concurrent decrease in the number of metronidazole prescriptions in the Netherlands (precriptions for other conditions than anti-H. pylori treatment were also included). Altogether both regimens (PAM and PAC) had a calculated efficacy of > 80%. The efficacy of the PAM regimen is likely to increase if the decrease in prevalence of metronidazole resistance continues, whereas the efficacy of the PAC regimen will drop significantly after even a slight increase in the prevalence of clarithromycin resistance. The second part of the thesis focussed on genetic differences between H. pylori strains. These genetic differences have been hold responsible for the differences in clinical outcome. Several virulence factors have been identified in H. pylori, like the vacA gene which encodes for the vacuolating cytotoxin, the cagA gene responsible for the production of the CagA protein, and the iceA gene, which is expressed at contact with gastric epithelial cells. In chapter seven, we have studied the association between these virulence factors and various clinical outcomes (PUD, gastrooesophageal reflux disease (GERD) and gastritis only). The results of this study showed that many patients (over 20%) harboured a mixture of H. pylori strains. PUD patients were most frequently infected with an H. pylori strain of the s1 vacA genotype or a strain which carried the cagA gene. On the other hand, patients with GERD, were most frequently colonized by a strain lacking both the cagA and the iceA1 gene. This finding supports the hypothesis that more virulent H. pylori strains may protect against the development of GERD. It was concluded that virulence factors are indeed associated with specific clinical outcomes. Whether the detection of these virulence factors is significant in a clinical setting, however, needs further exploration. If so, a reliable non-invasive test to detect the presence of these virulence factors in dyspeptic patients would be essential. Chapter eight reports the results of a study evaluating the accuracy of the CagA rapid test (Orion). It has been claimed that this test enables the accurate detection of CagA-antibodies in serum samples by an easy to perform immunochromatographic test, showing results within 10 minutes. We compared the CagA rapid test (Orion) to a surrogate gold standard based on a combination of PCR based cagA gene detection in gastric biopsies and the OroVax recombinant based ELISA for the detection of serum antibodies. The gold standard was considered positive if both PCR and OroVax recombinant based ELISA were positive. In other cases, the gold standard was considered negative. This gold standard was chosen, as it is well known that the presence of the cagA gene does not always result in the transcription of this gene. Without transcription serological antibodies may be absent. On the other hand, persisting CagA-antibodies after a previously cleared H. pylori infection may result in a positive CagA rapid test (Orion), whereas the PCR results are negative. Compared to the surrogate gold standard, the CagA rapid test (Orion) showed a sensitivity and a specificity of 96.8% and 95.4% respectively. Finally, in chapter nine the results are reported of an extensive study performed on biopsy specimens of nine patients in whom both metronidazole susceptible and resistant H. pylori bacteria had been demonstrated. The question was whether these patients were colonized by two different H. pylori strains or by a single strain, part of which became resistant. The second hypothesis appeared to be true as eight patients harboured only a single H. pylori strain, part of which was sensitive and part of which was resistant to metronidazole. In one patient, the presence of two different strains could be demonstrated, but both strains were in part susceptible and resistent to metronidazole. Based on these data it is concluded that the occurence of metronidazole resistant and metronidazole susceptible bacteria within one single biopsy specimen does not imply the presence of a multiple strain infection with one resistant and one susceptible strain. General conclusions The discovery of the role of H. pylori in several diseases of the upper alimentary tract has resulted in new strategies to approach uncomplicated dyspepsia. Several authors have suggested that an approach based on screening for H. pylori may be more rational than the common strategy of empirical treatment with acid-suppressive drugs. This suggestion is supported by both decision analytic studies and clinical studies, among which the SENSE study described in this thesis. Moreover, most studies suggest that such an approach, especially the “test-and-treat” strategy, may be more cost-effective. In contrast to most other clinical studies, the SENSE study was completely performed in a primary care setting. It showed that in primary care a “test-and-treat” strategy is safe, is more cost-effective than a prompt endoscopy approach, and results in comparable symptom resolution. Implementation of the “test-and-treat” strategy in primary care is feasible, as accurate noninvasive tests to diagnose H. pylori infection are available. Moreover, given the current levels of antibiotic resistance, treatment of H. pylori infection with the usual PAC or PAM regimens should result in acceptable success rates (>80%), even in the abscence of information on antibiotic susceptibility. Monitoring of antibiotic resistance in H. pylori, however, remains mandatory, as even a slight increase in the prevalence of clarithromycin resistance will result in a sharp drop in cure rates if the PAC regimen is used. Any strategy for dyspepsia that is based on non-invasive detection of H. pylori is critically dependent on the prevalence of H. pylori in the dyspeptic population. At a low prevalence, the positive predicitive value of any test for H. pylori will drop below an acceptable level, prohibiting the implementation of a “test-and-treat” strategy. Moreover, if the prevalence of H. pylori in the dyspeptic population is to low, conditions unrelated to H. pylori infection (among which idiopathic PUD) are more likely to be the cause of dyspepsia. In our view, however, the current prevalence of H. pylori in the dyspeptic population (>30% in the SENSE study) still justifies a “test-and-treat” approach of uncomplicated dyspepsia in primary care. It is feasible, safe and cost-effective. The prevalence of H. pylori infection, however, is rapidly decreasing in the Western world, and it is likely that empirical treatment with acid suppression will eventually become more cost-effective than the “test-and-treat” strategy. As the prevalence of H. pylori is strongly associated with age this may already be true for the very young dyspeptic patient. The virulence of the infecting H. pylori strain is probably related to the clinical outcome of the infection. However, as the most virulent strains at the same time seem to cause PUD and protect against GERD, it is unlikely that the non-invasive detection of virulence factors will contribute to the clinical decision to treat or not to treat an infected patient, even though accurate tests are available. Finally, it should be stressed that prompt endoscopy is the only acceptable approach of any patient presenting with alarm symptoms.