Dino Vaira

Diagnosis of Helicobacter pylori infection with a new non-in vasive antigen-based assay

Summary Background Helicobacter pylori is a common human pathogen implicated in certain gastrointestinal diseases. In the search for new non-invasive techniques to diagnose H pylori infection, we evaluated an EIA for H pylori antigen in stool (HpSA). Methods In a prospective multicentre study, stool specimens from 501 patients (276 men, 225 women; age range 17–88 years, mean 52) undergoing gastroscopy in 11 centres throughout Europe were tested with HpSA and the carbon-13-urea breath test. At endoscopy, four biopsy samples were taken for histology (haematoxylin and eosin) and H pylori detection (giemsa in both antrum and corpus, culture and rapid urease test). Patients were defined as positive for H pylori if histology (antrum, corpus, or both) and urease test were positive, or if culture was positive. Patients classified as having H pylori infection received an eradication regimen; 107 were reassessed 4 weeks after therapy. Findings Of 272 patients with H pylori infection by the predefined criteria, 256 were positive by HpSA (sensitivity 94·1% [95% CI 90·6–96·6]). Of 219 patients without infection, 201 were negative by HpSA (specificity 91·8% [87·3–95·1]). Interpretation The stool assay was a reliable and easy-to-use tool for diagnosis of H pylori infection. The test was accurate even shortly after treatment.

Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: A Randomized Trial

Context Eradication rates for Helicobacter pylori infection are decreasing worldwide because of increasing antimicro-bial resistance. Contribution This double-blind trial randomly assigned 300 adults with dyspepsia or peptic ulcers to a 10-day sequential regimen (pantoprazole, amoxicillin, and placebo taken for 5 days followed by pantoprazole, clarithromycin, and tinidazole taken for 5 days) or standard 10-day therapy (pantoprazole, clarithromycin, and amoxicillin). The eradication rate of H. pylori infection was greater with the sequential regimen (89%) than with the standard treatment (77%). Approximately 5% of patients in each group had epigastric pain and 3% to 5% had mild diarrhea. Implication Sequential therapy eradicates H. pylori infection more often than does standard therapy. The Editors Helicobacter pylori infection causes peptic ulcers, gastric mucosaassociated lymphoid tissue lymphoma, and gastric cancer (1). Standard treatments for H. pylori infection that have been endorsed by U.S. and European authorities rely on clarithromycin or metronidazole in conjunction with other antibiotics and acid inhibitors (2, 3). The prevalence of clarithromycin and metronidazole resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection (4). Eradication rates in most western countries have declined to unacceptable levels. Eradication therapy fails in approximately 1 in 5 patients (5). A simple, short treatment regimen that would return eradication levels to those seen at the advent of H. pylori treatment is urgently needed (5). Such a regimen should have high efficacy against clarithromycin-resistant and metronidazole-resistant strains of H. pylori because these strains are increasingly encountered in routine clinical practice. Novel 10-day sequential therapy consisting of 5-day dual therapy (proton-pump inhibitor plus amoxicillin) followed by 5-day triple therapy (proton-pump inhibitor, clarithromycin, and tinidazole) has had good eradication success in unblinded trials in elderly and pediatric patients (68). However, no double-blind, controlled trials using conventional therapy have been reported, and the effect of clarithromycin and metronidazole resistance on the outcome of sequential therapy has not been studied prospectively. The aim of this study was to compare a 10-day sequential treatment regimen for H. pylori infection with standard 10-day triple therapy in a randomized, controlled trial. Secondary objectives were to determine the efficacy of the treatment regimen in patients with resistant strains of H. pylori, to assess treatment adherence, and to evaluate side effects. Methods Design Overview This was a prospective, double-blind, controlled study with a parallel-group design. At baseline, patients were evaluated for inclusion and exclusion criteria and provided written informed consent. Patients were then randomly assigned to a treatment group and had follow-up evaluations to assess the eradication rate of H. pylori infection, treatment adherence, and side effects. The study was performed according to good clinical practice and the Declaration of Helsinki. The ethics committees at the 2 participating centers approved the study. The consent form indicated that patients would be randomly assigned to treatment that was the current standard or a new therapy that might have higher eradication rates. Patients were told that eradication failure was possible with any therapy regimen. All patients with eradication failure were offered a rescue therapy on the basis of the results of sensitivity testing. Setting and Participants Between September 2003 and April 2006, consecutive patients with dyspepsia who were at least 18 years of age, who had never received treatment for H. pylori infection, and who had been referred to our hospitals (Bologna, Italy, and Rome, Italy) for a gastroenterology consultation were asked to participate in the study. No special recruitment techniques (such as advertisements or letters sent to primary care physicians) were used. Exclusion criteria were previous treatment for H. pylori infection; use of proton-pump inhibitors, H2-receptor antagonists, bismuth preparations, or antibiotics in the previous 2 weeks; concomitant use of anticoagulants or ketoconazole (because of potential interaction with the nonsteroidal anti-inflammatory drugs) and glucocorticoids (because of association with ulcer disease); the ZollingerEllison syndrome; previous surgery of the esophagus or upper gastrointestinal tract (except appendectomy, polypectomy, or cholecystectomy); severe or unstable cardiovascular, pulmonary, or endocrine disease; clinically significant renal or hepatic disease or dysfunction; hematologic disorders; any other clinically significant medical condition that could increase risk; malignant disease of any kind except for successfully treated skin cancer (basal- or squamous-cell carcinoma) during the previous 5 years; Barrett esophagus or high-grade dysplasia; drug, alcohol, or medication abuse within the past year; severe psychiatric or neurologic disorders; and pregnancy or lactation, as well as sexually active women of child-bearing years who were not willing to practice medically acceptable contraception (oral or injectable contraceptives, implantable or mechanical intrauterine or vaginal devices, or vasectomy for the partner) for the study duration. Randomization and Interventions Patient allocation was determined with a random-number chart that was concealed from investigators and patients by using numbered blister packs of the study medication that corresponded to the random-number chart. A computer-generated randomization chart was used to determine allocation, which was stratified according to center by using a block design and a block size of 4. Allocation was concealed with an opaque envelope, which contained a number that corresponded to the numbered blister packs. The envelope was opened when the patient met the inclusion criteria and provided informed consent. Patients and investigators were blinded to treatment group. Patients were randomly allocated to receive a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, and placebo, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days); or standard therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily for 10 days). Medications were contained in individual blisters in the package. A placebo that was identical in color and shape to the clarithromycin capsule was administered during the first 5 days of sequential therapy to maintain blinding. This ensured that all patients took 3 medications twice a day for 10 days. Measurements and Outcomes The primary outcome of the study was eradication of H. pylori infection. Secondary outcomes were to determine the efficacy of sequential treatment against clarithromycin-resistant strains of H. pylori, to assess adherence to therapy, and to determine the frequency of self-reported side effects. 13C-Urea Breath Test Urea breath tests were done after an overnight fast. A baseline breath sample was obtained, and 75 mg of 13C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 minutes after the test solution was administered. The results of the test were considered positive if the difference between the baseline sample and the 30-minute sample exceeded 4.5 parts per 1000 of 13CO2. All breath samples were analyzed in Bologna by using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany). The accuracy of the urea breath test was previously validated in our laboratory. We reported sensitivity and specificity values of 94.7% and 95.7%, respectively (9). Endoscopy All patients with positive results on the urea breath test had upper endoscopy, and 5 biopsy specimens were obtained during the procedure. Two specimens were taken from the antrum and 2 were taken from the corpus for histologic evaluation. The specimens were stained with hematoxylin and eosin and Giemsa stains, and gastritis was scored by using the updated Sydney System (10). The pathologist who performed the histologic examination was blinded to the results of all other tests. One biopsy specimen was obtained from the antrum for the rapid urease test (Campylobacter pylori test, Yamanouchi Pharma S.p.A, Corrugate, Milan, Italy). Two additional biopsy samples from the antrum were collected for bacterial culture and susceptibility testing. We performed cultures without knowing the other test results. For this purpose, biopsy specimens were sent to a single microbiological laboratory in Bologna within 24 hours and were stored at 70C. Isolated strains were tested for primary clarithromycin and metronidazole resistance by using an agar dilution method, which was defined as a minimal inhibitory concentration greater than 1 mg/L and greater than 8 mg/L for clarithromycin and metronidazole, respectively (11). Strains were classified as having isolated resistance to clarithromycin or metronidazole if the organisms were only resistant to 1 antibiotic. Dual resistance was defined as resistance to clarithromycin and metronidazole. At baseline, patients were classified as having H. pylori infection if the results on the urea breath test were positive and if the results on at least 2 of the following 3 tests were positive: rapid urease test, histologic examination, and culture. An expert panel recommended these criteria for use in clinical trials of H. pylori infection (12). Follow-up Procedures Treatment Adherence and Side Effects Patients were asked to return at the completion of therapy for a physical evaluation and to assess adherence to therapy and side effects. We first aske

Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children.

OBJECTIVES:Eradication rates with triple therapy (TT) for Helicobacter pylori infection have declined to unacceptable levels. Sequential therapy (ST) is a novel treatment that has shown promise in several controlled trials. Our aim was to assess the efficacy of ST in adults and children compared with that of TT by performing a systematic review and meta-analysis.METHODS:We performed an electronic search of the following: Cochrane Trial Register (until Issue 4, 2008), MEDLINE (1966 to 21 October 2008), EMBASE (1980 to 21 October 2008), and abstracts from the major US, European, and Asian gastroenterology conferences. Randomized controlled trials (RCTs) and controlled clinical trials with a parallel group design comparing the ST with a TT lasting at least 7 days were used.RESULTS:Ten RCTs enrolled 3,006 adult patients and the odds ratio (OR) for eradication of H. pylori with ST compared with TT was 2.99 (95% confidence interval (CI): 2.47–3.62), giving a number needed to treat (NNT) of 6 (95% CI: 5–7) favoring ST. There was no publication bias. The OR for eradication with ST compared with 10-day TT was 2.92 (95% CI: 1.95–4.38), yielding an NNT of 8 (95% CI: 6–12), favoring ST. In patients with clarithromycin resistance, the OR for eradication with ST was 10.21 (95% CI: 3.01–34.58) compared with TT, but the numbers studied are small. Three RCTs enrolled 260 children and adolescents, and the OR for eradication was 1.98 (95% CI: 0.96–4.07). There was no difference in the rate of side effects between the ST and the TT (OR, 1.01; 95% CI: 0.78–1.30).CONCLUSIONS:ST appears to be better than TT in the eradication of H. pylori. This is a promising therapy, but further trials are needed in other European countries and North America before it can be recommended as a first-line treatment.

Endoscopic Biliary Therapy Using the Combined Percutaneous and Endoscopic Technique

Between September 1985 and December 1987, 74 patients underwent attempted endoscopic biliary therapy using a combined percutaneous transhepatic and endoscopic transpapillary approach (combined procedure). All patients had had failed endoscopy-alone procedures and had contraindications to surgery. The indication was palliation of malignant biliary obstruction in 66 cases (41 common bile duct, 25 hilar), assistance with sphincterotomy for the removal of common bile duct stones in 6 cases, and management of benign biliary stenosis in 2 cases. The initial procedure was percutaneous transhepatic access to the biliary tree, which was successful in all but 1 case (99%). The bile duct was drained externally for an average of 3.4 days before the combined procedure. One patient died during this period from hemorrhage associated with liver puncture. Combined procedure was performed in 72 cases and was successful in 60 [53 malignant stricture (53/66 = 80%), five common duct stone (5/6 = 83%), two benign stricture (2/2 = 100%)]. Procedure-related morbidity and mortality, respectively, were 12.5% and 0% for benign disease and 36% and 3% for malignant disease. The total (initial endoscopy included) morbidity and 30-day mortality were 33% and 0%, respectively, for benign disease and 62% and 27% for malignant disease. Subsequently, stent change has been required on 16 occasions, with endoscopy-only successful in 13 (81%) and repeat combined procedure being required in three (19%). The combined procedure improves the ability of endoscopy to offer nonsurgical therapy to poor risk patients with both malignant and benign biliary disease but is associated with significant morbidity and disease-related mortality.

High eradication rates of Helicobacter pylori with a new sequential treatment

Background : Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance.

ENDOSCOPIC SPHINCTEROTOMY IN 1000 CONSECUTIVE PATIENTS

Between 1983 and 1988, endoscopic sphincterotomy was attempted on 1000 consecutive patients with a clinical diagnosis of bileduct stones in a centre with a policy to establish immediate bileduct drainage for retained stones. Endoscopic cholangiography was successful in 985 patients, of whom 782 had visible stones and 203 had a dilated bileduct but no visible stones. Endoscopic sphincterotomy was successful in 975 of these patients, with eventual bileduct clearance in 674 of 772 patients (87.3%) with visible stones; immediate bileduct drainage was achieved in 160 of the 161 patients (99%) in whom bileduct clearance failed at the first attempt. Overall, 771 of 797 patients (96.7%) with visible bileduct stones had successful bileduct clearance or drainage. Complications occurred in 6.9%, with a 30-day mortality rate of 1.2%, but procedure-related mortality was only 0.6%.

Blood, urine, stool, breath, money, and Helicobacter pylori

Helicobacter pylori infection can be diagnosed by invasive (that is, endoscopy and biopsy) and non-invasive techniques. The choice of a diagnostic test should depend on the clinical circumstances, the pre-test probability of infection, sensitivity and specificity of the test (or more correctly the likelihood ratio of a positive and negative test), the cost effectiveness of the testing strategy, and the availability of the test. Some clinical circumstances warrant invasive studies: patients who have failed eradication therapy may need culture and antimicrobial sensitivity testing to help determine an appropriate regimen, older patients with new onset dyspepsia, and those with “alarm” symptoms (bleeding, weight loss, etc) that raise the concern of malignancy. Non-invasive studies are preferable in epidemiological studies and in young children. Recent studies have also demonstrated that a strategy to test and treat H pylori in uninvestigated young (<50 years) dyspeptic patients in primary care is safe and reduces the need for endoscopy.1 Until recently, only two non-invasive methods of testing for H pylori have been available: (1) the13C or 14C labelled urea breath test (UBT), which is based on detection of 13C or 14C labelled CO2 in expired air as a result of H pylori urease activity2-4and (2) serology (which is based on detection of a specific anti- H pylori IgG antibody in the patients serum.5 6 Several new methods of detecting H pylori have recently been described and include detection of antibodies in saliva7 and urine,8 and detection of antigens in stool. ### SEROLOGY There are a number of different techniques for antibody detection in serum, including enzyme linked immunosorbant assay (ELISA), agglutination tests, and western blotting but ELISA is the most widely used clinically. Antibody levels persist in the blood for long periods of time. Not surprisingly, …

Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy

Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide. Design Systematic review and meta-analysis. Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings. Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy. Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin. Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.

Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma

BACKGROUND & AIMS Different remission rates of gastric low-grade, B-cell, mucosa-associated lymphoid tissue (MALT) lymphoma have been reported after Helicobacter pylori eradication. We assessed the long-term remission and relapse rates of early stage MALT lymphoma in patients treated only by H pylori eradication and identified factors that might predict outcome. METHODS This systematic review analyzed data from 32 studies, including 1408 patients. RESULTS The MALT lymphoma remission rate was 77.5% (95% confidence interval, 75.3-79.7), and was significantly higher in patients with stage I than stage II(1) lymphoma (78.4% vs 55.6%; P = .0003) and in Asian than in Western groups (84.1% vs 73.8%; P = .0001). Neoplasia confined to the submucosa regressed more frequently than that with deeper invasion (82.2% vs 54.5%; P = .0001); patients with lymphoma localized to the distal stomach experienced regression more frequently than those with lymphoma of the proximal stomach (91.8% vs 75.7%; P = .0037). The remission rate was higher among patients without the API2-MALT1 translocation than in those with this translocation (78% vs 22.2%; P = .0001). In an analysis of data from 994 patients, 7.2% experienced lymphoma relapse during 3253 patient-years of follow-up evaluation, with a yearly recurrence rate of 2.2%. Infection and lymphoma were cured by additional eradication therapy in all patients with H pylori recurrence (16.7%). Five (0.05%) of the patients initially cured of lymphoma developed high-grade lymphoma within 6 to 25 months of therapy. CONCLUSIONS H pylori eradication is effective in treating approximately 75% of patients with early stage gastric lymphoma. Long-term follow-up evaluation of these patients is needed to detect early lymphoma relapse or progression.

AMOXYCILLIN PLUS TINIDAZOLE FOR CAMPYLOBACTER PYLORI GASTRITIS IN CHILDREN: ASSESSMENT BY SERUM IgG ANTIBODY, PEPSINOGEN I, AND GASTRIN LEVELS

32 children (mean age 12 years, range 6-18) with non-specific abdominal pain and Campylobacter pylori positive gastritis received a six week course of daily oral amoxycillin (50 mg/kg) and tinidazole (20 mg/kg). Before treatment and one month after stopping treatment, endoscopic biopsy samples were taken from the antral mucosa and serum C pylori IgG antibody, pepsinogen I, and gastrin levels were measured in fasting blood samples. One month after treatment 30 children (94%) were cleared of C pylori and gastritis had resolved in 27 (84%) and was improved in the remaining 5. Serum IgG, pepsinogen I, and gastrin levels were significantly decreased after treatment. Of 12 children assessed at six months, 9 remained free of C pylori. Increases or decreases in IgG level indicated clearance or recurrence, respectively, of C pylori.