Helicobacter pylori-related disease: guidelines for testing and treatment.

OBJECTIVE: To develop practical guidelines for the treatment of patients with suspected and documented Helicobacter pylori-related gastroduodenal diseases. METHODS: A panel of physicians with expertise in H. pylori reviewed, critically appraised, and synthesized the literature on assigned topics and presented their overviews to the panel. Consensus was obtained in controversial areas through discussion. RESULTS AND CONCLUSIONS: The panel recommended testing for H. pylori in patients with active ulcers, a history of ulcers, or gastric mucosa-associated lymphoid tissue lymphomas. Young, otherwise healthy patients with ulcerlike dyspepsia and those with a family history or fear of gastric cancer may also undergo H pylori testing. Non-endoscopic methods are preferred for H. pylori diagnosis. Dual medication regimens should not be used for therapy; twice-daily triple therapy with a proton pump inhibitor or ranitidine bismuth citrate, clarithromycin, and amoxicillin for 10 to 14 days is an appropriate therapy. Posttreatment assessment of H. pylori status using urea breath testing should be considered in patients with a documented history of ulcer disease or with persistent symptoms.

Helicobacter pylori and ulcerogenesis.

The dictum "no acid-no ulcer" had, in the past, summarized the thinking concerning the pathogenesis of peptic ulcer disease. It is now recognized that infection with Helicobacter pylori is the major causal factor leading to both duodenal and gastric ulceration. Infection is associated with many of the acid secretory abnormalities that have traditionally characterized peptic ulcer disease; indeed, acid secretory physiology returns to normal following bacterial eradication. Since not all individuals infected with H. pylori develop ulcers, host susceptibility, bacterial virulence, and/or specific environmental factors must determine the response to infection and the ultimate clinical outcome. The relative importance of these factors and their complex interactions remain to be determined. H. pylori infection produces tissue damage indirectly because the organism does not directly invade gastroduodenal tissue. A variety of bacterial enzymes, toxins, and inflammatory mediators produced in response to bacterial colonization challenge the integrity of host mucosal defenses. In a susceptible host, breached defenses render epithelium more vulnerable to acid injury and ulcer development. Eradication of H. pylori leads to rapid ulcer healing and reversal of tissue injury, thereby obviating ulcer recurrence.

Stress-related mucosal damage: an overview.

Stress-related mucosal damage of the upper gastrointestinal tract occurs in the majority of critically ill patients. The more severe the underlying disease, the greater the chance that mucosal damage and subsequent bleeding will develop. Clinical outcome is determined by the type and severity of the underlying illness; however, cases with severe gastric damage, as diagnosed by endoscopic examination or by bleeding, have the poorest prognoses. Endoscopy is the most sensitive method for diagnosing stress-related mucosal damage. Other indicators of stress-related mucosal damage are macroscopic evidence of bleeding, blood transfusion requirement, or measures of occult bleeding; these tests cannot diagnose nonbleeding lesions. Low gastric pH values may also indicate physiologic response to stress, but such values are not uniformly correlated with the presence of injury. Vigorous acid suppression with prolonged periods of pH control may be necessary to treat stress-related mucosal damage and to prevent bleeding. Treatment modalities in current use include antacids, cimetidine, and other histamine (H2)-receptor antagonists, and, more recently, sucralfate. Current evidence indicates that antacids, given hourly and titrated to a present pH goal, or primed continuous infusion of cimetidine are the most efficacious regimens in maintaining intragastric pH control.

Chairmen's summary: dichotomies and directions in acid-related disorders.

Presentations by international experts from old and new worlds bordering the Atlantic Ocean revealed surprising similarities with respect to the diagnosis and management of patients with upper gastrointestinal disorders. It was agreed that Helicobacter pylori infection continues to play a key role in gastroduodenal disease and has a great impact on clinical management. However, testing and treatment strategies vary in patients affected by functional dyspepsia and those receiving nonsteroidal anti-inflammatory drug (NSAID) therapy including aspirin. Among patients with gastro-oesophageal reflux disease (GERD), it was clear that we need to re-evaluate the validity of the classical concept of GERD as a progressive spectrum and instead focus on the pathophysiologic mechanisms responsible for producing the common symptom of heartburn and complications that occur in the three principle subsets of GERD patients: those with endoscopic negative reflux disease, erosive oesophagitis and Barrett's oesophagus. In addition, we need to be increasingly aware of the concept of extra-oesophageal manifestations of gastro-oesophageal reflux and the fact that GERD in adults often originates in childhood. In all these gastrointestinal disorders, proton pump inhibitor therapy has become the common thread either as a diagnostic tool or an effective short-term or long-term management strategy.

Rapid diagnosis of Campylobacter pylori by Gram's stain.

Campylobacter pylori (CP) is implicated as a probable pathogen in gastritis and peptic ulcer disease. A blinded prospective study of 112 subjects evaluated how Gram's-stained touch preparations of mucosal biopsies compared with culture, routinely processed hematoxylin and eosin (H and E) and Warthin-Starry (WS) staining in confirming the presence of CP. At endoscopic examination, two mucosal biopsies were taken from the gastric antrum and two from the fundus of each subject. One biopsy from each site was Gram's stained and cultured and the other submitted for H and E and WS. Fifty of the 112 subjects had positive results for CP by at least two of the tests (44.6%). Histologically, 48 (96%) of the CP-positive subjects showed the presence of gastritis. Of 55 subjects who had gastritis, 50 had CP (91%). If both sites in the stomach were taken into account, the sensitivity and specificity of Gram's staining in detecting CP were 92% and 100%, respectively. These results are comparable to H and E and WS and slightly better than culture. The diagnosis of CP can be made accurately, rapidly, and inexpensively by Gram's stained touch preparations of mucosal biopsies.

Stress-related mucosal damage.

Stress-related mucosal damage (SRMD) of the upper gastrointestinal tract is being increasingly recognized in critically ill patients. Its precise pathogenesis is unknown. Acid is a prerequisite for the development of mucosal injury. However, mucosal defense factors that maintain the integrity of the gastric mucosal barrier are equally important. Therapy is directed toward reducing the intraluminal acid concentration. Since histamine H2-receptor antagonists became available in 1977, they have been used for the prevention and treatment of SRMD. They offer the potential for use as an effective parenteral as well as oral agent that could obviate the need for frequent antacid administration and eliminate some of the troublesome side effects that accompany an intensive antacid regimen. Although the beneficial effects of H2 blockers are probably related to their ability to inhibit acid secretion, recent evidence suggests that they may also act by mechanisms independent of their antisecretory effect. Numerous controlled studies have confirmed that cimetidine, being superior to placebo and equivalent to antacids, is effective therapy for SRMD. Sucralfate, a basic aluminum salt of sucrose octasulfate, has been shown to protect animal and human gastric mucosa from a variety of injurious agents. However, few clinical trials have evaluated the efficacy of sucralfate in SRMD. Exogenous prostaglandins also have been shown to protect gastric mucosa from a variety of insults. Although exogenous prostaglandins may work by augmenting mucosal defense mechanisms, most clinical studies have used antisecretory doses of prostaglandin drugs, making it difficult to discount the antisecretory component as being responsible for efficacy.

Recognizing, setting therapeutic goals, and selecting therapy for the prevention and treatment of stress-related mucosal damage.

Advances in the care of critically ill patients and in diagnostic techniques, such as fiberoptic endoscopy, have enabled greater recognition of stress-related mucosal damage (SRMD). This condition is distinguished from chronic peptic ulcer disease by its greater number of lesions, proximal location in the acid-producing portion of the stomach, and superficial bleeding. Endoscopy is considered the best method for detecting and monitoring mucosal damage. The onset of SRMD occurs early, within hours of the traumatic insult. Pharmacologic treatment has been oriented toward suppressing intraluminal acid and enhancing mucosal defense mechanisms. Antacid therapy is considered the best method for treatment of SRMD, although extensive experience has been gained with the H2-receptor antagonists. The vast majority of experience with the H2-receptor antagonists has been with cimetidine, which is as effective as antacids, as shown by endoscopy. Investigations of alternative forms of therapy (e.g., prostaglandins) are in progress.

Stress-related mucosal damage. What to do or not to do.

SRMD and associated bleeding continue to challenge physicians caring for critically ill patients; however, the incidence of clinically significant bleeding appears to be decreasing. The reason for this decrease is multifactorial. Improved ICU support and early attention to patients' nutritional and metabolic needs have attenuated the pathogenic mechanisms leading to gastrointestinal mucosal injury. It remains to be seen whether future advances in critical care medicine, especially in the area of nutritional support and control of nosocomial infection, will completely obviate gastrointestinal complications. Until that time it is probably unwise entirely to abandon traditional SRMD prophylactic practices. For the present, clinicians should target treatment toward those individuals at highest risk for bleeding. Such a selective strategy is cost effective and provides the greatest clinical benefit.

Scope and consequences of peptic ulcer disease. How important is asymptomatic Helicobacter pylori infection?

H pylori infection is so common as to seem ubiquitous in many areas of the world. Transmission is believed to be primarily person to person. The pathogen invariably damages the gastric mucosa, resulting in both structural and functional abnormalities. It causes histologic gastritis and is critical in the pathogenesis of the gastritis-associated diseases, namely, gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and primary gastric lymphoma. Elimination of the infection results in healing of gastritis and cure of peptic ulcer disease.

Recognizing peptic ulcer disease. Keys to clinical and laboratory diagnosis.

An algorithmic approach to evaluation of dyspepsia or abdominal discomfort begins with differentiation between peptic ulcer disease and gastroesophageal reflux disease as well as recognition of alarm signs and symptoms for gastric cancer, which are indications for early endoscopy. In the absence of alarm symptoms, most patients should undergo noninvasive testing for H pylori infection with a serologic, urea breath, or stool antigen test. Factors to consider in selection of appropriate testing include reliability, specificity, sensitivity, cost, and local access and expertise. As a general rule, physicians should choose a test that has the best accuracy for the level of testing expertise available. The basic principle underlying testing for H pylori is that patients should not undergo testing unless the physician is willing to treat on the basis of a positive test result. In patients who receive treatment, confirmation of cure is important for preventing further morbidity and reducing risk of transmission of infection.

Practical advice on eradicating Helicobacter pylori infection.

Peptic ulcer disease associated with H pylori infection is curable. The important factors in selecting therapy are efficacy of eradication, prevention of resistance, avoidance or minimization of adverse effects, patient compliance, and cost. The most effective regimens include a bismuth preparation or antisecretory drug (proton pump inhibitor or H2 receptor antagonist) plus two antibiotics administered for 14 days. Dual-drug therapies are not recommended. Triple-drug regimens are more likely to eradicate H pylori and less likely to generate resistant strains among surviving organisms. In general, cure of the infection should be confirmed 4 weeks after completion of the treatment. Antibiotic resistance is an important consideration in choosing therapy, and patients should be taught the importance of compliance. When treatment fails, antibiotic combinations should not be repeated. Considerations for anti-H pylori treatment in a managed care environment mirror those for good medical practice in general, with special attention to stringent cost-control or outcomes-driven measures.

Mucolytic effects of Helicobacter pylori.

The mechanisms associated with colonization of human gastroduodenal mucosa by Helicobacter pylori remain unclear. To colonize gastric-type epithelium H. pylori must enter the gastric lumen, resist damage by all bactericidal factors operating within the acidic gastric milieu, penetrate the mucus gel despite highly viscous and hydrophobic properties of the mucus layer, and, finally, secure optimal conditions for its further multiplication. Since the H. pylori microorganism has been seen freely spread throughout the entire mucus layer thickness as well as in intimate contact with surface epithelium, the interrelationship between this spiral microorganism and the mucus seems to be of paramount importance. H. pylori has been shown to affect adversely the chemical and physical properties of the mucus layer. Therefore, the mucus layer compromised by the presence of this microorganism may become an easy target for acid and peptic damage, which ultimately leads to mucosal pathology, inflammation and/or peptic ulcer disease.

Distinguishing the impact of dexlansoprazole on heartburn vs. regurgitation in patients with gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is characterised by symptomatic heartburn and regurgitation. Treatment with proton pump inhibitors (PPI) effectively decreases heartburn symptoms, but their effects on symptomatic regurgitation are less clear. AIM: To determine the impact of PPI therapy on heartburn and regurgitation severity in patients with either non-erosive GERD (NERD) or erosive oesophagitis (EE). METHODS: Endoscopically-confirmed NERD patients received dexlansoprazole 30 or 60 mg or placebo in a randomised, blinded, 4-week study. Endoscopically-confirmed EE patients received dexlansoprazole 60 mg or lansoprazole 30 mg in two 8-week, randomised, blinded healing studies. The Patient Assessment of Upper Gastrointestinal Symptom Severity questionnaire, which includes a heartburn/regurgitation subscale, was administered to assess symptom severity at baseline, and at weeks 2 and 4 of the NERD study and at weeks 4 and 8 during the EE trials. We defined separate subscales for heartburn and regurgitation for this post-hoc analysis. Among patients with both symptoms at baseline, improvements in individual heartburn and regurgitation subscales along with the original combined heartburn/regurgitation subscale were determined. RESULTS: In the NERD and EE studies, 661 and 1909 patients, respectively, had both heartburn and regurgitation at baseline. NERD patients receiving dexlansoprazole 30 and 60 mg experienced significantly greater improvements in symptom severity for both heartburn and regurgitation compared with placebo. EE patients receiving dexlansoprazole 60 mg had significantly greater improvements in heartburn/regurgitation and heartburn-only subscales at week 4 compared with those receiving lansoprazole. CONCLUSIONS: Dexlansoprazole appears to be effective in improving both heartburn and regurgitation, and this improvement is maintained for the duration of treatment.

The effects of increasing body mass index on heartburn severity, frequency and response to treatment with dexlansoprazole or lansoprazole.

BACKGROUND: Higher body mass index (BMI) is a recognised risk factor for gastro-oesophageal reflux disease (GERD). Data regarding the impact of BMI on proton pump inhibitor (PPI) therapy are conflicting. AIM: To assess the impact of BMI on baseline heartburn symptom severity and frequency and response to PPI therapy in patients with non-erosive GERD (NERD) or erosive oesophagitis (EO). METHODS: In post hoc analyses of phase 3 trial data, 621 NERD and 2692 EO patients were stratified by BMI (<25, 25 to <30 and ≥30 kg/m(2) ). NERD patients received either dexlansoprazole MR 30 mg or placebo daily for 4 weeks. EO patients received either dexlansoprazole MR 60 mg or lansoprazole 30 mg for 8 weeks. Symptom frequency and severity were assessed at baseline and subsequently by daily diary. RESULTS: In both the NERD and EO cohorts, baseline heartburn severity increased with increasing BMI. The impact of PPI therapy on the reduction in heartburn symptom frequency and severity in both NERD and EO patients was similar across BMI categories. EO healing rates in patients treated with dexlansoprazole but not lansoprazole were higher in obese patients compared with those with a BMI <30 kg/m(2) . Differences between the PPIs were small. CONCLUSIONS: The PPIs evaluated in this study reduced the frequency and severity of 24-h heartburn regardless of baseline BMI. In addition, because patients with higher BMI have more severe symptoms at baseline, they may experience greater therapeutic gain with dexlansoprazole (NERD and erosive oesophagitis) and possibly lansoprazole (erosive oesophagitis) treatment.

Risk factors associated with a decrease ≥2 g/dL in haemoglobin and/or ≥10% haematocrit in osteoarthritis patients taking celecoxib or a nonselective NSAID plus a PPI in a large randomised controlled trial (CONDOR).

BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with gastrointestinal (GI) damage. The Celecoxib vs. Omeprazole and Diclofenac for At-Risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) trial showed that a haemoglobin drop ≥2 g/dL adjudicated as either of defined or presumed GI origin was the most frequent component/event for the composite GI primary end point. This adverse event is potentially clinically relevant in long-term NSAID treatment. AIM: To define potential risk factors associated with a decrease in haemoglobin/haematocrit. METHODS: Post hoc analysis of the CONDOR trial was conducted in the intention-to-treat population. Clinically significant blood loss was defined as: (i) a haemoglobin drop ≥2 g/dL and/or a haematocrit drop ≥10%; and (ii) blood loss adjudicated as either of defined or presumed GI origin. Fifteen risk factors were evaluated by stepwise logistic regression. Each factor had to be significant at <0.20 α to be included in the model. RESULTS: A total of 64/3774 (1.7%) osteoarthritis (OA) patients had decreased haemoglobin/haematocrit and were adjudicated to the GI endpoint. Significant risk factors, at the 0.20 α level found to be associated with clinically significant blood loss in OA patients included [odds ratio (80% CI)] baseline C-reactive protein (CRP) levels [2.27 (1.46-3.53)], history of gastritis and history of GI intolerance [1.55 (1.06-2.28)], positive Helicobacter pylori at screening [1.54 (1.07-2.22)], increasing age [1.17 (1.04-1.32)] and body mass index [BMI; 1.03 (1.00-1.06)]. CONCLUSIONS: Monitoring for decreases in haemoglobin should be considered for all OA patients and especially those with an increased age, BMI, history of gastritis and GI intolerance, CRP levels >1 mg/dL and/or positive H. pylori status, as this may affect their clinical management.

The 12-month safety profile of dexlansoprazole, a proton pump inhibitor with a dual delayed release formulation, in patients with gastro-oesophageal reflux disease.

BACKGROUND: Dexlansoprazole MR is a Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. AIM: To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). METHODS: In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). RESULTS: Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. CONCLUSIONS: Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).

Changes of gastric histology in patients with erosive oesophagitis receiving long-term lansoprazole maintenance therapy.

BACKGROUND: Changes in gastric histology associated with long-term maintenance therapy with lansoprazole for erosive oesophagitis have not been well described. AIM: To evaluate the effect on gastric histology of long-term dose-titrated lansoprazole administered as maintenance therapy for up to 82 months in patients with erosive oesophagitis. METHODS: Sequential gastric biopsy specimens were obtained for evaluation of histological changes and Helicobacter pylori infection status. RESULTS: Active and chronic inflammation improved from baseline to final visit in a majority of patients receiving long-term therapy with lansoprazole, irrespective of baseline H. pylori infection status. Reductions in active inflammation in the gastric body and antrum were seen in 53% (17/32) and 67% (20/30) of H. pylori-positive patients, respectively, and in 88% (7/8) and 86% (12/14) of H. pylori-negative patients, respectively. Reductions in chronic inflammation in the gastric body and antrum were seen in 38% (12/32) and 47% (15/32) of H. pylori-positive patients, respectively, and in 58% (70/121) and 57% (68/120) of H. pylori-negative patients, respectively. No clinically meaningful increases in hyperplasia, dysplasia, neoplasia, intestinal metaplasia or atrophy were observed during the follow-up period. CONCLUSIONS: Lansoprazole administered as maintenance therapy for up to 6 years in patients with erosive oesophagitis demonstrated gastric mucosal safety and was well tolerated.