André L. Blum

Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification

BACKGROUND Endoscopic oesophageal changes are diagnostically helpful and identify patients exposed to the risk of disease chronicity. However, there is a serious lack of agreement about how to describe and classify the appearance of reflux oesophagitis AIMS To examine the reliability of criteria that describe the circumferential extent of mucosal breaks and to evaluate the functional and clinical correlates of patients with reflux disease whose oesophagitis was graded according to the Los Angeles system. METHODS Forty six endoscopists from different countries used a detailed worksheet to evaluate endoscopic video recordings from 22 patients with the full range of severity of reflux oesophagitis. In separate studies, Los Angeles system gradings were correlated with 24 hour oesophageal pH monitoring (178 patients), and with clinical trials of omeprazole treatment (277 patients). RESULTS Evaluation of circumferential extent of oesophagitis by the criterion of whether mucosal breaks extended between the tops of mucosal folds, gave acceptable agreement (mean κ value 0.4) among observers. This approach is used in the Los Angeles system. An alternative approach of grouping the circumferential extent of mucosal breaks as occupying 0–25%, 26–50%, 51–75%, 76–99%, or 100% of the oesophageal circumference, gave unacceptably high interobserver variation (mean κ values 0–0.15) for all but the lowest category of extent (mean κ value 0.4). Severity of oesophageal acid exposure was significantly (p<0.001) related to the severity grade of oesophagitis. Preteatment oesophagitis grades A–C were related to heartburn severity (p<0.01), outcomes of omeprazole (10 mg daily) treatment (p<0.01), and the risk for symptom relapse off therapy over six months (p<0.05). CONCLUSIONS Results add further support to previous studies for the clinical utility of the Los Angeles system for endoscopic grading of oesophagitis.

Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis

BACKGROUND & AIMS We have shown previously that cure of Helicobacter pylori infection leads to the disappearance of acid-neutralizing substances. Also, patients with ulcer after cure may gain weight. The aim of this study was to investigate whether cure of the infection increases the risk of reflux esophagitis. METHODS Patients with duodenal ulcer without reflux esophagitis at the time of Helicobacter treatment were followed up prospectively after cure of the infection (n = 244) or after diagnosis of persisting infection (n = 216). All patients underwent endoscopy at 1-year intervals or when upper gastrointestinal symptoms recurred. H. pylori infection was assessed by rapid urease test and histology. RESULTS The estimated incidence of reflux esophagitis within 3 years was 25.8% after cure of the infection and 12.9% when the infection was ongoing (P < 0.001). Patients who developed reflux esophagitis after the cure had a more severe body gastritis before cure (odds ratio, 5.5; 95% confidence interval [CI], 2.8-13.6), gained weight more frequently after cure (odds ratio, 3.2; 95% CI, 1.2-9.4), and were predominantly men (odds ratio, 3.6; 95% CI, 1.1-10.6). CONCLUSIONS A considerable proportion of patients with duodenal ulcer treated for H. pylori will develop reflux esophagitis; risk factors are male sex, severity of corpus gastritis, and weight gain.

Lack of Effect of Treating Helicobacter pylori Infection in Patients with Nonulcer Dyspepsia

BACKGROUND It is uncertain whether treatment of Helicobacter pylori infection relieves symptoms in patients with nonulcer, or functional, dyspepsia. METHODS We conducted a double-blind, multicenter trial of patients with H. pylori infection and dyspeptic symptoms (moderate-to-very-severe pain and discomfort centered in the upper abdomen). Patients were excluded if they had a history of peptic ulcer disease or gastroesophageal reflux disease and had abnormal findings on upper endoscopy. Patients were randomly assigned to seven days of treatment with 20 mg of omeprazole twice daily, 1000 mg of amoxicillin twice daily, and 500 mg of clarithromycin twice daily or with omeprazole alone and then followed up for one year. Treatment success was defined as the absence of dyspeptic symptoms or the presence of minimal symptoms on any of the 7 days preceding the 12-month visit. RESULTS Twenty of the 348 patients were excluded after randomization because they were not infected with H. pylori, were not treated, or had no data available. For the remaining 328 patients (164 in each group), treatment was successful for 27.4 percent of those assigned to receive omeprazole and antibiotics and 20.7 percent of those assigned to receive omeprazole alone (P=0.17; absolute difference between groups, 6.7 percent; 95 percent confidence interval, -2.6 to 16.0). After 12 months, gastritis had healed in 75.0 percent of the patients in the group given omeprazole and antibiotics and in 3.0 percent of the patients in the omeprazole group (P<0.001); the respective rates of H. pylori eradication were 79 percent and 2 percent. In the group given omeprazole and antibiotics, the rate of treatment success among patients with persistent H. pylori infection was similar to that among patients in whom the infection was eradicated (26 percent vs. 31 percent). There were no significant differences between the groups in the quality of life after treatment. CONCLUSIONS In patients with nonulcer dyspepsia, the eradication of H. pylori infection is not likely to relieve symptoms.

Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.

BACKGROUND: Gastric and duodenal bacterial overgrowth frequently occurs in conditions where diminished acid secretion is present. Omeprazole inhibits acid secretion more effectively than cimetidine and might therefore more frequently cause bacterial overgrowth. AIM: This controlled prospective study compared the incidence of gastric and duodenal bacterial overgrowth in patients treated with omeprazole or cimetidine. METHODS: 47 outpatients with peptic disease were randomly assigned to a four week treatment regimen with omeprazole 20 mg or cimetidine 800 mg daily. Gastric and duodenal juice were obtained during upper gastrointestinal endoscopy and plated for anaerobic and aerobic organisms. RESULTS: Bacterial overgrowth (> or = 10(5) cfu/ml) was present in 53% of the patients receiving omeprazole and in 17% receiving cimetidine (p < 0.05). The mean (SEM) number of gastric and duodenal bacterial counts was 6.0 (0.2) and 5.0 (0.2) respectively in the omeprazole group and 4.0 (0.2) and 4.0 (0.1) in the cimetidine group (p < 0.001 and < 0.01; respectively). Faecal type bacteria were found in 30% of the patients with bacterial overgrowth. Basal gastric pH was higher in patients treated with omeprazole compared with cimetidine (4.2 (0.5) versus 2.0 (0.2); p < 0.001) and in patients with bacterial overgrowth compared with those without bacterial overgrowth (5.1 (0.6) versus 2.0 (0.1); p < 0.0001). The nitrate, nitrite, and nitrosamine values in gastric juice did not increase after treatment with either cimetidine or omeprazole. Serum concentrations of vitamin B12, beta carotene, and albumin were similar before and after treatment with both drugs. CONCLUSIONS: These results show that the incidence of gastric and duodenal bacterial overgrowth is considerably higher in patients treated with omeprazole compared with cimetidine. This can be explained by more pronounced inhibition of gastric acid secretion. No patient developed signs of malabsorption or an increase of N-nitroso compounds. The clinical significance of these findings needs to be assessed in studies with long-term treatment with omeprazole, in particular in patients belonging to high risk groups such as HIV infected and intensive care units patients.

Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori–infected adults☆☆☆

BACKGROUND & AIMS Oral immunization with Helicobacter pylori urease can cure Helicobacter infection in animals. As a step toward therapeutic immunization in humans, the safety and immunogenicity of oral immunization with recombinant H. pylori urease were tested in H. pylori-infected adults. METHODS Twenty-six H. pylori-infected volunteers were randomized in a double-blind study to four weekly oral doses of 180, 60, or 20 mg of urease with 5 microg heat-labile enterotoxin of Escherichia coli (LT), LT alone, or placebo. Side effects and immune responses were evaluated weekly after immunization, and gastric biopsy specimens were obtained after 1 month and 6 months for histology and quantitative cultures. RESULTS Diarrhea was noted in 16 of 24 (66%) of the volunteers who completed the study. Antiurease serum immunoglobulin A titers increased 1. 58-fold +/- 0.37-fold and 3.66-fold +/- 1.5-fold (mean +/- SEM) after immunization with 60 and 180 mg urease, respectively, whereas no change occurred in the placebo +/- LT groups (P = 0.005). Circulating antiurease immunoglobulin A-producing cells increased in volunteers exposed to urease compared with placebo (38.9 +/- 13. 6/10(6) vs. 5.4 +/- 3.1; P = 0.018). Eradication of H. pylori infection was not observed, but urease immunization induced a significant decrease in gastric H. pylori density. CONCLUSIONS H. pylori urease with LT is well tolerated and immunogenic in H. pylori-infected individuals. An improved vaccine formulation may induce curative immunity.

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Antacid, Ranitidine, or Sucralfate as Prophylaxis for Stress Ulcer A Randomized Controlled Trial

Intensive care patients are at risk for bleeding from stress ulcers of the upper gastrointestinal tract [1]. Despite the decline of this complication over the last two decades [2], certain patients, such as those requiring prolonged mechanical ventilation, remain at high risk and may benefit from stress ulcer prophylaxis [1, 3-5]. Over the last few years, studies have shown that agents that raise the gastric pH may promote proliferation of bacteria in the stomach, particularly gram-negative bacilli that may originate in the duodenum [6-10]. Passive esophageal reflux and microaspiration of the gastric content along the endotracheal tube may lead to the colonization of the trachea and then to pneumonia [6, 7, 10-18]. Thus, concerns have arisen that the risk for nosocomial pneumonia may outweigh the benefit of stress ulcer prophylaxis when agents raising the gastric pH are used. Sucralfate is a complex salt of sucrose sulfate and aluminum hydroxide that appears to be as effective as antacids or histamine-2 (H2) antagonists for stress ulcer prophylaxis [2, 19, 20] but by mechanisms of action that do not result in clinically relevant gastric pH modification. Several studies have documented that gastric colonization is less frequent and of a lesser magnitude in ventilated patients treated with this agent compared with antacids or H2-antagonists [8, 21-23]. However, whether this would result in a decreased risk for nosocomial pneumonia is controversial [18, 24] because a reduction was found in some [21-23, 25] but not all [17, 21-23, 25-29] comparative studies. Methodologic differences among these studies might explain these conflicting findings [18]. For example, small numbers of patients for analysis [17, 26], low risk for pneumonia in the study patients [27, 28], periods of observation that were too brief [28], insufficient dosages of the agents that raise pH [27, 29], and wide use of enteral feeding [17] might account for the absence of reduction in the incidence of pneumonia noted in some studies. On the other hand, differences in the distribution of the base-line characteristics among the patients [22, 23], the grouping of patients receiving antacids and H2-antagonists, and analysis of subgroups of patients not randomly assigned to a treatment group [21, 25] may have biased the studies in which sucralfate was associated with lower rates of pneumonia. In addition, in two of these latter studies, the reduction of pneumonia developing in patients treated with sucralfate compared with other treatment did not reach the usual 0.05 level of significance [21, 23]. Furthermore, previous studies did not distinguish between pneumonia occurring early or late after intubation. This may be important because it is likely that early-onset pneumonia may be related to the introduction of bacteria in the trachea at the time of intubation [30-32], a process that is not expected to be influenced by the type of anti-stress ulcer prophylaxis. Therefore, we compared three anti-stress ulcer prophylaxis regimens (antacid, ranitidine, and sucralfate) in a large group of ventilated patients for the occurrence of bacterial colonization, early and late-onset nosocomial pneumonia, and overt gastrointestinal bleeding. Methods Patients The Centre Hospitalier Universitaire Vaudois is a 1100-bed hospital serving both as a municipal facility and a tertiary referral center. During a 2-year period (January 1989 to January 1991), all patients admitted to the adult medical and surgical intensive care units who were receiving mechanical ventilation and had a nasogastric tube in place were eligible for the study. Exclusion criteria were as follows: active upper gastrointestinal bleeding; treatment with antacids, H2-blockers, or sucralfate during the preceding 48 hours; creatinine levels greater than 200 mol/L; esogastric surgery; cardiac surgery; or organ transplantations. Patients likely to be extubated within 24 hours were also excluded. At intubation, patients were stratified into five categories according to the following underlying conditions: trauma (surgical intensive care unit), intervention after surgery (surgical intensive care unit), cardiac disease (medical intensive care unit), pulmonary disease (medical intensive care unit), and other medical conditions [medical intensive care unit]. Randomization was done using a random permutable table to generate a random treatment list. Treatment regimens were included in opaque, sealed envelopes. The patients were assigned to one of the following anti-stress ulcer prophylactic regimens: 1) antacid, a hospital-made suspension containing 5.4% aluminum hydroxide and 1.5% magnesium hydroxide with a buffer capacity of 1.2 mEq/mL, administered every 2 hoursthe standard dose of 20 mL was doubled if the gastric pH (tested with pH-indicator strips [Merck and Co., Darmstadt, Germany] before each administration) was less than 4.0; 2) ranitidine (Zantac, Glaxo, Bern, Switzerland) administered as a continuous intravenous infusion of 150 mg/d [100 mg/d if the blood creatinine level was between 150 and 200 mol/L]; or 3) sucralfate (Ulcogant, Merck and Co., Zurich, Switzerland) administered every 4 hours as 1 gram of suspension diluted in 20 mL of sterile water. After antacid or sucralfate was administered, the nasogastric tube was flushed with 10 mL of sterile water and clamped for 30 minutes. Each prophylactic regimen was continued until extubation unless interrupted earlier for any of the following predetermined reasons: an increase of the blood creatinine level to more than 200 mol/L, removal of the nasogastric tube, moribund state, discharge from the intensive care units, or side effects likely to be related to the stress ulcer regimen. Data Collection and Definitions For all eligible patients, demographic characteristics, diagnosis, underlying diseases, physical signs, laboratory tests, and medications were recorded prospectively by one of the investigators. However, only patients eventually intubated for more than 24 hours were followed and included in the final analysis. Glasgow coma and Acute Physiology and Chronic Health Evaluation (APACHE II) scoring systems were used to assess the severity of the acute illness [33]. The adult respiratory distress syndrome was defined by the following criteria: acute bilateral diffuse pulmonary infiltrates and severe hypoxemia without evidence of cardiogenic edema [34]. Gastric aspirates were examined for the macroscopic presence of blood (coffee ground material or fresh blood). The severity of gastric hemorrhage was assessed by clinical criteria (physical signs, blood transfusion requirements, and outcome). Chest radiographs were obtained on a daily basis or more often if clinically indicated. They were interpreted by a pneumologist who had knowledge of all relevant data except for the patients stress ulcer prophylactic regimen, gastric pH, or colonization data. Criteria for the diagnosis of ventilator-associated pneumonia were predetermined and derived from those of Salata and colleagues [35]: presence of a new or progressive infiltrate on the chest radiograph consistent with pneumonia, without other obvious cause, and associated with conditions A or B or both, defined as follows. Condition A refers to any of the following findings: pleural fluid or blood culture positive for an organism also isolated in the tracheal aspirate, radiographic cavitation, or histopathologic evidence of pneumonia. Condition B includes at least two of the following: tracheal aspirates with more than 25 leukocytes per low-power field (x 100) on a Gram stain, new leukocytosis defined as a leukocyte count greater than 10 109/L with an increase of at least 25% over baseline, or body temperature greater than 38.5 C with an increase of at least 1 C above baseline. The latter two criteria were considered only when other causes for these findings were excluded. Pneumonia was considered to be caused by a pathogen when it was cultured in high counts as the sole or predominant microorganism in the tracheal aspirate culture. Using the criteria of Langer and colleagues [30], early-onset and late-onset pneumonia were diagnosed if they occurred during the first 4 days of or 4 days after the initiation of mechanical ventilation, respectively. Consequently, only patients observed for more than 4 days could be evaluated for the development of late-onset pneumonia. A second episode of pneumonia was diagnosed when it was clearly temporally distinct from the first episode and when it involved other areas of the lungs. Pneumonia was attributed to a given anti-stress ulcer prophylactic regimen if it developed during treatment or within 2 days after extubation or treatment interruption. Death was considered to be directly related to nosocomial pneumonia when it occurred during the episode and when no other major contributing cause was present. Bacteriologic Investigations and pH Measurements Gastric and tracheal aspirates and oropharyngeal swabs were obtained twice daily and cultured quantitatively (gastric juice) or semi-quantitatively in aerobic conditions. Aerobic bacteria were identified by standard microbiologic methods. Cultures for Chlamydia species, Legionella pneumophila, or Mycoplasma pneumoniae were not done. Blood or pleural fluid cultures were ordered by the primary care physician according to the clinical situation. Gastric pH was measured twice a day using a pH meter (except in 11 patients for whom values were derived only from pH-indicator strips [Merck and Co.]). A cut-off value of 4.0 for median pH was chosen for further analysis within the three treatment groups because it has been shown to be a critical value for the growth of gram-negative bacilli in the stomach [6, 7, 25]. Colonization was defined by the presence of one microorganism at a given site on at least two occasions. A patient was considered to have gastric colonization with high counts when quantitative culture of at least one speci

Favourable effect of an acidified milk (LC-1) on Helicobacter pylori gastritis in man

Objective The supernatant of Lactobacillus johnsonii La1 culture was shown to be bactericidal and to have a partial, acid-independent suppressive effect on Helicobacter pylori in humans. The aim of the present study was to investigate the effect of L. johnsonii La1-acidified milk (LC-1) on H. pylori infection. Design and methods Fifty-three volunteers infected with H. pylori as determined by positive 13C-urea breath test and positive serology were randomized to receive either LC-1 or a placebo 180 ml twice a day for 3 weeks. All subjects also received clarithromycin 500 mg bid during the last two weeks of acidified milk therapy. Oesophagogastroduodenoscopy and biopsies were performed at inclusion and repeated 4–8 weeks after the end of the treatment. H. pylori infection was confirmed by urease test and histology. H. pylori density and inflammation were scored using a modified Sydney classification. Results LC-1 ingestion induced a decrease in H. pylori density in the antrum (P = 0.02) and the corpus (P = 0.04). LC-1 also reduced inflammation and gastritis activity in the antrum (P = 0.02 and P = 0.01, respectively) and of activity in the corpus (P = 0.02). Clarithromycin eradicated H. pylori in 26% of the subjects; LC-1 did not improve the antibiotic effect. Conclusion These results suggest that H. pylori infection and gastritis can be down-regulated by LC-1.

Duodenal bacterial overgrowth during treatment in outpatients with omeprazole.

The extent of duodenal bacterial overgrowth during the pronounced inhibition of acid secretion that occurs with omeprazole treatment is unknown. The bacterial content of duodenal juice of patients treated with omeprazole was therefore examined in a controlled prospective study. Duodenal juice was obtained under sterile conditions during diagnostic upper endoscopy. Aspirates were plated quantitatively for anaerobic and aerobic organisms. Twenty five outpatients with peptic ulcer disease were investigated after a 5.7 (0.5) weeks (mean (SEM)) treatment course with 20 mg (nine patients) or 40 mg (16 patients). The control group consisted of 15 outpatients referred for diagnostic endoscopy without prior antisecretory treatment. No patient in the control group had duodenal bacterial overgrowth. In the omeprazole group bacterial overgrowth (> or = 10(5) cfu/ml) was found in 14 (56%) patients (p = 0.0003). The number of bacteria (log10) in duodenal juice in patients treated with omeprazole was distinctly higher (median 5.7; range < 2-8.7) when compared with the control group (median < 2; range < 2-5.0; p = 0.0004). As well as orally derived bacteria, faecal type bacteria were found in seven of 14 and anaerobic bacteria in three of 14 patients. Bacterial overgrowth was similar with the two doses of omeprazole. These results indicate that duodenal bacterial overgrowth of both oral and faecal type bacteria occurs often in ambulatory patients treated with omeprazole. Further studies are needed to determine the clinical significance of these findings, particularly in high risk groups during long term treatment with omeprazole.

Differential expression of laminin-5 subunits and integrin receptors in human colorectal neoplasia

Cell‐matrix interactions contribute to regulating the adhesion, growth, migration, and differentiation of epithelial intestinal cells. Alterations in matrix components and their cellular receptors have been found in tumours but their specific roles remain unclear. The tissue patterns of laminin‐5 and α3, β3 and γ2 subunits, as well as those of the α3, α6, β1, and β4 integrin chains, were determined by immunofluorescence on frozen sections of 12 colorectal mucosal samples from four patients, 15 adenomas, 29 adenocarcinomas, and eight metastases. Distinct patterns of laminin‐5 and integrin expression were found along the mucosa–adenoma and adenoma–carcinoma transitions. Expression of basement membrane laminin‐5 and subunits was continuous and gradient‐like in normal mucosa, enhanced at the periphery of adenomas, and discontinuous in places in carcinomas and metastases. Decrease of the α3 integrin chain was found in adenomas, together with that of α6 and β4 chains in carcinomas. A subpopulation of carcinoma cells dissociating (budding) from neoplastic tubules was found to accumulate the laminin‐5 β3γ2 heterodimer in the cytoplasm, with progressive loss of surface integrin expression. These results suggest that in colorectal cancer, an abnormal expression of laminin‐5 subunits and integrin chains may identify a subset of carcinoma cells prone to invade focally and to contribute to disease aggressiveness.

Predictors of Duodenal Ulcer Healing and Relapse

Predictors of duodenal ulcer healing and relapse were examined in a population known to have a high healing incidence. Two double-blind prospective studies were performed in 134 patients over 4 wk and in 66 patients over 1 yr, respectively. Short-term treatment consisted either of cimetidine 1 g/day, pirenzepine 75 mg/day, or placebo. In a multiple stepwise linear regression analysis the following factors proved to increase healing incidence in decreasing order of importance: female sex, moderate alcohol consumption, abstinence from smoking, young age, and cimetidine treatment. The following factors had no influence on duodenal ulcer healing: number and total area of peptic lesions, concomitant disease, relatives with duodenal ulcer, duration of duodenal ulcer disease, and status as a migrant worker. In the long-term study, treatment consisted either of cimetidine 400 mg at bedtime, pirenzepine 30 mg at bedtime, or placebo. Cimetidine prevented ulcer relapse. Smoking favored duodenal ulcer relapse in the placebo group, but not in the cimetidine and pirenzepine group. For all the other factors no statistically significant effect was found. It is concluded that in a population with high spontaneous healing incidence (a) factors other than drug treatment such as sex, alcohol intake, smoking, and age are at least as important predictors of the outcome of short-term treatment as the drug treatment itself; (b) moderate alcohol intake might favor ulcer healing; (c) the unfavorable effect of smoking on ulcer relapse is overcome by low-dose, long-term, antisecretory treatment.