Search

The aim of the study is to determine the proportion of patients who have esophageal biopsy specimens taken for an endoscopic diagnosis of reflux esophagitis in which an endoscopic grade of esophagitis (Los Angeles [LA] or Savary-Miller [SM]) is communicated to the pathologist, and to evaluate the correlation between those endoscopic grades and histopathologic findings. We searched the database of Caris Diagnostics (a large, gastrointestinal pathology practice that receives specimens from community-based endoscopy centers), and extracted data from all patients who had an endoscopy with esophageal biopsies submitted in a 12-month period. There were esophageal biopsy specimens from 49,480 patients obtained during 58,986 endoscopies. The LA grade was provided in 5513 cases (27.9% of 19,778 with endoscopic esophagitis); the SM grade was stated in only 2416 cases (12.2%). A histopathologic diagnosis of erosive or ulcerative esophagitis was made significantly less often in LA grade A patients (3.2%) than in those with LA grades C (20.0%) and D (23.3%); erosive or ulcerative esophagitis was found in only 1.4% of patients with SM grade I and in 35.5% of cases with grade IV. Endoscopists who biopsy the esophagus of patients with reflux esophagitis usually do not communicate the grade of esophagitis to the pathologist. Although both the LA and SM grading systems are based on the presence of esophageal mucosal breaks (erosions or ulcers), in practice such breaks are documented in only a minority of esophageal biopsy specimens taken from patients with reflux esophagitis of any grade.

Gastric cancer remains the second most frequent and lethal malignancy worldwide, with a wide range of incidence rates in different populations. Reducing its incidence is a priority in many high-risk countries, and screening programmes are often advocated as an option. An effective screening programme should have the following characteristics: (i) the disease should be common in the population, otherwise the individual benefit will not offset the risk, cost and inconvenience of screening of the rest of the population; (ii) the diagnostic test(s) used should be safe, simple, inexpensive and reliable; and (iii) effective treatment should be available. With respect to gastric cancer, these conditions are not fulfilled completely in any population and therefore population-based screening does not appear to be a viable approach to the prevention of this neoplasia. In contrast, gastroscopic screening in selected high-risk subjects would seem appropriate. A more effective strategy, particularly in high-incidence populations, could be the widespread screening and treatment for Helicobacter pylori infection. This could result in the virtually complete elimination of chronic gastritis and its associated conditions, including most peptic ulcers, primary gastric B-cell lymphomas and a major portion of gastric epithelial tumours.

Rebamipide stimulates the generation of endogenous prostaglandins in the gastric mucosa and is reported to accelerate ulcer healing. This review discusses whether rebamipide can prevent Helicobacter pylori infection, reduce inflammation, accelerate healing after eradication, promote ulcer healing, and prevent progression of preneoplastic lesions. Furthermore, we evaluate its usefulness in other inflammatory conditions of the gastrointestinal tract. We conclude that rebamipide is an important candidate for long-term suppression of gastro-intestinal inflammation, particularly if reducing the complications of H. pylori infection without eradicating the organism becomes accepted. If its ability to accelerate mucosal normalization is confirmed, rebamipide could be added to eradication regimens. Little information exists on whether such therapy could help limit the development of pre-neoplastic lesions. In light of the dearth of effective drugs to control inflammation in idiopathic inflammatory bowel disease, the potential of any promising new and safe compound deserves to be fully explored. The next step is to devise a targeted plan of translational research, so that results from the bench may be used to design rigorously controlled international clinical trials.

This article explores the consequences of the world-wide trend that may result--at different times for different populations--in the disappearance of Helicobacter pylori and gastritis. After a brief historical introduction, some of the factors that contribute to the decrease in the prevalence of H. pylori are presented. The most apparent results of this trend in the industrialized world have been a decrease in the incidence of peptic ulcer and distal gastric adenocarcinoma. However, some other conditions of the upper digestive tract, such as acid reflux disease and adenocarcinoma of the cardio-oesophageal junction have been increasing. This simultaneous increase has led to the speculation that it may be causally related to the decreased prevalence of gastritis, and currents of thought supporting a laissez faire attitude with regards to H. pylori infection have developed. If these trends continue, future research aimed at understanding the pathogenesis of H. pylori-related conditions, including gastric carcinogenesis, will hinge on access to populations in which H. pylori is still highly prevalent, and on further refinement of the recently introduced Mongolian gerbil model.

The sequence leading to gastric cancer can be schematically reduced to Helicobacter pylori infection-chronic gastritis-atrophy-intestinal metaplasia-dysplasia-neoplasia. Although clinicians have not yet developed a uniform approach to the treatment of gastritis (when should H. pylori infection be treated?), the entity itself is not the subject of controversy. All other lesions are still the focus of debate. There are no guidelines for the management of patients with intestinal metaplasia; pathologists are still searching for universal diagnostic criteria for atrophic gastritis; dysplasia and early neoplasia have elicited scientific diatribes between Japanese and Western pathologists. Amidst such controversies and in the absence of guidelines to regulate the management of gastric lesions, the responsibility to provide sensible clinical advice is often bestowed upon pathologists. This review discusses whether pathologists have access to sufficient evidence to provide the requested advice, and whether a consensus on the management of gastric "pre-neoplastic" states is within reach. We conclude that, although many sensible and useful definitions, criteria and classifications are being generated, the final decision on how to manage the individual patient with gastric lesions will continue to be based on the communication between pathologist and clinician.

As part of a multinational effort to reach a consensus in the definition and evaluation of atrophic gastritis, we applied morphometric techniques to 22 antral biopsy specimens examined visually by 12 experienced gastrointestinal pathologists.Atrophy was defined as loss of glands. Each pathologist graded atrophy with both non-standardized and standardized approaches. Discriminant function analyses of morphometric measurements were conducted to validate and grade atrophy. Kappa statistics were used to compare the performance of each pathologist against the group mode and against the discriminant functions' grading of atrophy. Three morphometric indexes showed significant differences among categories of atrophy utilizing non-standardized as well as standardized visual atrophy grades: (i) the ratio of glandular length to total mucosal thickness; (ii) the proportion of the secretory compartment area occupied by glands; and (iii) the number of glandular cross sections per 40x microscopic field. The discriminant function analyses verified all cases classified visually as either non-atrophic, or moderately/severely atrophic; it verified as mildly atrophic 40% of the cases classified visually as mildly atrophic; and classified the remaining 60% as moderately or severely atrophic. The kappa statistics were good or excellent for the majority of pathologists.The evaluation of antral atrophy, simply defined as loss of glands, can be reliable and reproducible. The visual grading of atrophy as absent, moderate and severe is entirely consistent with objective morphometric observations.

Helicobacter pylori is the major cause of chronic gastritis worldwide. With an estimated rate of infection of over one half of the world's population, it is responsible for extensive morbidity and mortality. Infection with this organism does not appear to spontaneously resolve. Instead it reaches a chronic stage from which a number of outcomes are possible. This article reviews those outcomes that have been linked to H. pylori and explores the pathogenesis while attempting to resolve the discrepant paths infection can take. The associations include duodenal and gastric ulcers and the majority of gastric lymphomas of B-cell type derived from the mucosa-associated lymphoid tissue (MALT). Chronic gastritis has also been shown to evolve into atrophy with intestinal metaplasia in certain populations. This change in the gastric epithelium has been linked with an increased risk of gastric adenocarcinoma. Microsc. Res. Tech. 48:313-320, 2000. Published 2000 Wiley-Liss, Inc.

Autoimmune gastritis is defined as a chronic atrophic gastritis of the corpus-fundus mucosa, which is associated with diffuse atrophy of the oxyntic mucosa and thus accompanying achlorhydria1. The presence of serum antibodies directed against parietal cell antigens and intrinsic factor is a specific feature of the disease. The advanced phases of this immunopathological spectrum are often associated with pernicious anaemia, a condition resulting from the impaired absorption of vitamin B12 caused by the unavailability of intrinsic factor2.

In preparing this review we have maintained the title originally assigned but shall not, however, defend such a radical position, particularly in light of evidence slowly percolating into the literature that seems to suggest that not all changes believed to lead to gastric malignancy are irreversible. Therefore, we will discuss the topic from the more moderate viewpoint that, as of today, there is insufficient evidence that cure of Helicobacter pylori infection results in the regression or disappearance of the lesions that are commonly referred to as ‘pre-malignant changes.’

No question involving atrophic gastritis can ignore the continuing saga of the consensus agreement or disagreement among pathologists on the recognition and assessment of the histological features that define atrophy. One would expect these apparently tedious debates to have taken their just toll on clinicians’ interest. Yet gastroenterologists, whose understanding and management of gastric disorders relies heavily on their pathologists’ opinions, continue to follow closely the atrophy debate and to give pathologists space in their journals.

The condensed article reports the results of the histopathologic evaluation of the colorectal biopsy specimens from 14 patients who developed abdominal pain and bloody stools or diarrhea while receiving nonsteroidal anti-inflammatory drugs (NSAIDs). All patients had a mixed inflammatory infiltrate (predominantly neutrophilic in four patients and lymphocytic in two) and about one-half also had minimal crypt disarray. The intestinal symptoms resolved in all patients after NSAIDs were discontinued, but there was no histopathologic verification that the inflammatory changes had subsided. Nonspecific changes ("focal colitis"), similar to those described in this group, are present in most patients who undergo a colonoscopy for the investigation of diarrhea. This article calls attention on one of the possible and neglected causes for nonspecific colitis. However, larger controlled studies are needed to firmly establish a cause-and-effect relationship with NSAID intake.

The eradication of Helicobacter pylori results in the decrease and eventual disappearance of inflammation in the gastric mucosa. An important question with practical implications is whether treatment of H. pylori can promote the resolution of atrophy and intestinal metaplasia. If this happens, then one could infer that even in the presence of established multifocal atrophic gastritis the cure of Helicobacter pylori could reduce the risk of developing gastric cancer. Several investigators have addressed the issue, but the cumulative results remain inconclusive. The great latitude that there exists in the interpretation of the concept of atrophy and the patchy distribution of both atrophic changes and intestinal metaplasia (with resulting inevitable sampling error) are important reasons for the wide discrepancy in the conclusions reached by different authors. Controlled, long-term prospective studies conducted in different ethnic and geographic settings are needed to provide sound evidence-based answers to the question of reversibility of atrophy, intestinal metaplasia, and epithelial dysplasia.

An international workshop to evaluate the concepts of atrophy and atrophic gastritis was held in Houston in 1998. A consensus emerged that: 1) there is a phenotype of Helicobacter pylori-associated gastritis characterized by progressive loss of glands and intestinalization; 2) this phenotype is associated with increased risk of gastric ulcer and adenocarcinoma. This pattern must be consistently recognized are reproducibly diagnosed by histopathologists. The mucosal biopsy sampling suggested in the updated Sydney System were considered adequate to evaluate a patient for atrophic gastritis. Histopathologists were advised to refrain from making a diagnosis of "atrophic gastritis" unless moderate or severe unequivocal loss of gastric glands and/or moderate or severe metaplasia is found in at least 50% of the total gastric mucosa evaluated in the biopsy specimens. When atrophic or metaplastic changes appear to be more limited, "chronic gastritis with focal atrophy or metaplasia" should be diagnosed, and more extensive sampling should be obtained before the entity "atrophic gastritis" can be diagnosed. Particular attention was devoted to the issue of "unequivocal loss of gastric glands." In general, it was felt that it is difficult to be certain about loss of glands in the presence of moderate or severe inflammation, when one cannot be sure whether the glands have actually disappeared of have been displaced by the inflammatory infiltrate. In these circumstances, the term "indefinite for atrophy" can be used and the patient should be re-evaluated several months after the eradication of Helicobacter pylori infection.

Epidemiological and biological evidence indicates that atrophic gastritis represents an important risk factor for gastric adenocarcinoma of the intestinal type. To estimate an individual subject's risk of gastric cancer, pathologists should be able to diagnose correctly and reliably assess gastric atrophy. However, both anecdotal evidence and recent studies suggest that pathologists have a low level of agreement on gastric atrophy. Moreover, the terms 'gastric atrophy' and 'atrophic gastritis' remain imprecisely defined, further adding confusion to the histopathological imprecision. The use of visual analogue scales proposed in the recently updated Sydney System for the classification and grading of gastritis may eventually help pathologists achieve a greater degree of interobserver agreement on the histopathological features of gastritis. However, this cannot be achieved in the absence of a stringent and widely accepted definition of atrophy. The purpose of this article is to review briefly the possible pathogenetic pathways leading to the development of atrophic changes in the gastric mucosa, explore the issue of its reversibility, and propose a working definition that could contribute to improved diagnostic reproducibility.

To compare the Giemsa, Diff-Quik, and Genta stains for detection of Helicobacter pylori in gastric biopsy specimens, we stained, coded, and randomized slides, which were then independently reviewed by two pathologists and one trainee. H. pylori was graded from 0 (absent) to 5 (maximal intensity). Negative cases were from recently cured patients to ensure that a background of chronic inflammation was present. The time required to complete the evaluation was tabulated. The pathologists interpreted 72 H. pylori-negative slides, of which 1 (1.3%), 2 (3%), and 3 (4%) were scored positive (each with the score of 1) with Diff-Quik, Genta, and Giemsa stains, respectively (P = ns). Of the 128 H. pylori-positive slides, 5 (4%) had false-negative results with Diff-Quik, 8 with Genta (6%), and 14 with Giemsa stains( 11%). No Grade 2 slides were missed by Genta or Diff-Quik stains, but 3 of 20 were missed by Giemsa stain. The combination of hematoxylin and eosin and Diff-Quik provides accuracy similar to that of the Genta stain but requires more processing time. No stain was excellent after therapy for detecting one or two bacteria per slide; this finding emphasizes the need for obtaining multiple biopsy specimen to exclude failure of H. pylori therapy.

Pathologists and gastroenterologists have attempted to devise a useful classification of gastritis since the advent of the endoscopic biopsy technique1–7. However, the aetiology of chronic gastritis was unknown and, consequently, the clinical usefulness of any classification remained very limited. It was only after 1983, when Helicobacter pylori was discovered and its role in the aetiology of most cases of chronic gastritis became apparent, that it was possible to work towards an aetiology-based classification with potential therapeutic implications. The first comprehensive and systematic attempt to reach a classification that would consider the aetiological, morphological, and topographical features of gastritis resulted from the efforts of a group of gastroenterologists and pathologists who proposed a new classification at the Ninth World Congress of Gastroenterology in Sydney, Australia, in 1990. Named the Sydney System8–10 this classification had both endoscopic and histological divisions, but the former has not gained wide acceptance. In contrast, the histological arm was found valuable because it presented a way to combine topographical, morphological, and aetiological information into a schema that would help generate reproducible and clinically useful diagnoses.

Rapid urease tests (RUTs) are used commonly as a convenient method to detect Helicobacter pylori infection. New rapid tests have been commercially available with promotional literature suggesting enhanced utility. We compared CLOtest to a new reagent strip RUT, PyloriTek.Gastric antral mucosal biopsy specimens were obtained from 102 patients for comparison between CLOtest and PyloriTek (204 specimens). Biopsy specimens obtained from a nearby area were stained using the Genta stain for determination of H. pylori status. The RUT to be used first was selected randomly.Sixty-five of the 102 patients had peptic ulcer disease, two had gastric cancer, and 35 had dyspepsia; 61 patients had active H. pylori infection. There were one false-negative and three false-positive CLOtest results, compared with one false-negative and 13 false-positive PyloriTek results (p0.02 for incorrect categorization with PyloriTek). Sensitivity and specificity were 98 and 92% compared with 98 and 68% for CLOtest and PyloriTek, respectively. An erroneous categorization of H. pylori status occurred in 3.9% (95% confidence interval [CI]: 1-9.7%) with CLOtest compared with 13.7% (95% CI: 7.7 -22%) with PyloriTek. When the PyloriTek was scored at 1 h (0-1 h) after obtaining the specimen, the accuracy improved; erroneous categorization of H. pylori status occurred in only 2.9% (95% CI: 0.6-8.3%).Used according to manufacturer instructions, the new reagent strip RUT PyloriTek has too many false-positive results for use in a clinical situation. In contrast, when the test was interpreted within 1 h, accuracy was comparable to that of CLOtest.

The Sydney System for the classification of gastritis emphasized the importance of combining topographical, morphological, and etiological information into a schema that would help to generate reproducible and clinically useful diagnoses. To reappraise the Sydney System 4 years after its introduction, a group of gastrointestinal pathologists from various parts of the world met in Houston, Texas, in September 1994. The aims of the workshop were (a) to establish an agreed terminology of gastritis; (b) to identify, define, and attempt to resolve some of the problems associated with the Sydney System. This article introduces the Sydney System as it was revised at the Houston Gastritis Workshop and represents the consensus of the participants. Overall, the principles and grading of the Sydney System were only slightly modified, the grading being aided by the provision of a visual analogue scale. The terminology of the final classification has been improved to emphasize the distinction between the atrophic and nonatrophic stomach; the names used for each entity were selected because they are generally acceptable to both pathologists and gastroenterologists. In addition to the main categories and atrophic and nonatrophic gastritis, the special or distinctive forms are described and their respective diagnostic criteria are provided. The article includes practical guidelines for optimal biopsy sampling of the stomach, for the use of the visual analogue scales for grading the histopathologic features, and for the formulation of a comprehensive standardized diagnosis. A glossary of gastritis-related terms as used in this article is provided.

A recent study from Italy reported a high prevalence of ulcer disease in asymptomatic Helicobacter pylori infection. Such results are at variance with previous endoscopy screening studies. Our study was performed to obtain data on ulcer prevalence in normal H. pylori-infected subjects in the United States.One hundred and ninety healthy individuals of either gender, over the age of 18, were studied. After completion of a detailed questionnaire and a urea breath test for H. pylori status, endoscopy was performed. Ulcer was defined as a mucosal ulceration5 mm in diameter and with apparent depth.There were 108 (57%) women and 82 (43%) men. The mean (+/-SD) age was 38.9 (+/-10.7) yr, range 21-79 yr. Careful history obtained after enrollment revealed presence of dyspeptic symptoms in 35 subjects (18%); the remaining 155 individuals were completely symptom-free. Infection with H. pylori was present in 102 subjects (54%). The infection rate was highest in Hispanics (70%), followed by African-Americans (58%), Caucasians (38%), and Asians (17%). The prevalence increased with age. Only two (1%) of 190 subjects, both with H.pylori infection, had peptic ulcer. In the H. pylori-infected group, the prevalence of peptic ulcer was 2%.In the United States, significant unrecognized and asymptomatic gastroduodenal disease is uncommon in H. pylori-infected individuals. These findings do not support the need for a mass screening program for H. pylori infection or for the use of antimicrobial treatment of asymptomatic subjects with this infection.

To validate the 13C urea breath test for the detection of Helicobacter pylori infection both before and after treatment.13C urea breath tests with 125-mg and 250-mg doses were carried out on each of 60 infected and 60 noninfected subjects. Results were compared with histological examination of gastric biopsies to establish detection limits. The best cut-off point was used in a clinical trial of the efficacy of the breath test in duodenal ulcer patients before and after antimicrobial therapy. The incremental increase (percentage, delta over baseline in U of delta/mil) in respiratory 13CO2 abundance was associated with histological evidence of H.pylori. Outpatient, tertiary care medical center, and secondary and primary care facilities were included. One hundred twenty healthy asymptomatic subjects and 465 patients with duodenal ulcer disease were studied. The test kit assessed repeatability of breath sample collection and storage and stability of stored samples. Test performance was analyzed by comparison of 125-mg and 250-mg 13C urea with measurements at 30 and 40 min postdose. The test was used to diagnose active H.pylori infection and gauge success of antimicrobial therapy.The test kit results were highly reproducible. The cut-off values were higher with 250-mg compared with 125-mg doses of 13C urea and 40 min compared with 30 min. Using a 125-mg 13C urea and test detection limit of 2.4% at 30 min, the accuracy was 94.8 (95% confidence interval = 92-97%) before antimicrobial therapy and 95.4% (95% confidence interval = 91-98%) after. An increase of 2.4% in the abundance of breath 13CO2 measured 30 min after a 125-mg dose of 13C urea reliably indicated the presence of active H.pylori infection either before or after antimicrobial therapy. The 13C urea breath test provides a simple and reliable and noninvasive method of assessing H.pylori status.

Helicobacter pylori infection causes gastritis which is typically asymptomatic, but is a condition that underlies gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. These different diseases may be the result of differences in the host, the bacterial strain infecting the host, environmental factors interacting with the bacteria or the host, or a combination of these factors1–3. This review is concerned with the relationship between H. pylori infection and duodenal ulcer disease.

Although a number of tests have been described to detect the presence of Helicobacter pylori in biopsy specimens, studies of positive and negative value have largely been performed on untreated patients; testing the reliability of posttherapy has not been done.We examined the value of the number and site of biopsies performed and the method used for specimen evaluation posttherapy. For postantimicrobial therapy of 141 patients with previously confirmed H. pylori infection, three biopsies were taken, two from the antrum and one from the corpus. Individual slides were coded, randomized, and interpreted blindly by two pathologists. Furthermore, in 143 patients, a biopsy specimen was taken from the antrum and was immediately inserted into the gel of the rapid urease test, and the results were compared with those obtained from histopathology obtained at the same time.In 71 patients, H. pylori therapy was unsuccessful; in 61 (86%), all three sites were positive. The highest yield with a single large cup biopsy specimen was 94%; the lowest was 91%. Two antral biopsies were negative in 4% [95% confidence interval (CI) = 1-12%]. The combination of a biopsy from the angulus incisura and one from the greater curvature of the corpus correctly identified all treatment failures (95% CI = 95-100%). The rapid urease test was false-negative in 5% (95% CI = 1-13%); there were no false-positives.Use of either the rapid urease test or two antral biopsies for evaluation of success of antimicrobial therapy for H. pylori infection will result in a false declaration of cure in at least 5% of cases. Three large cup gastric mucosal biopsies for histology are recommended for evaluation of the success of anti-H. pylori therapy.

Determine sensitivity and specificity of a new urease reagent strip (URS) test for detection of Helicobacter pylori in gastric biopsy specimens.Six paired biopsy specimens were obtained from the greater curvature of the distal antrum, the lesser curvature near the incisura, and the corpus along the greater curvature during 66 procedures on 59 patients with endoscopic findings of gastric antral mucosal erythema or erosions, or gastric or duodenal ulcers. One biopsy from each site was tested with the URS. The second was evaluated with histology. A final antral biopsy was evaluated with a urea/gel test.Twenty-eight of the 66 cases were histologically positive, with H. pylori observed in at least one of the three biopsy sites. The URS test correctly identified all 28. Of 193 individual biopsy specimens, 78 were positive for H. pylori. The URS correctly identified 77. Sensitivity was 0.99, specificity 0.95, positive predictive value 0.93, negative predictive value 0.99, and kappa 0.92. Average time to positive was 20 min. Twenty-seven antral biopsies were histologically positive for H. pylori. The URS test correctly identified all 27, whereas the urea/gel test correctly identified 21. For antral sites, URS sensitivity was 1.00 and specificity 0.95 versus urea/gel test sensitivity of 0.75 and specificity of 1.00.In this sample, the URS test is as accurate as histology in diagnosing H. pylori infections, and it provides results in less time and at a lower cost than histology.

Accurate preoperative diagnosis of tumors of the ampulla of Vater is difficult because ampullary biopsies have a high false-negative rate. Recently, it has been suggested that p53 mutations in tumors of the ampulla of Vater are associated with the transformation of adenomas and low grade carcinomas to high grade carcinomas. The purpose of this study was to determine the extent of p53 protein accumulation in tumors of the ampulla of Vater, and to determine whether p53 accumulation can be detected in false-negative biopsies.Using a monoclonal anti-p53 antibody, sections of 4 normal ampullas, 5 adenomas, 17 carcinomas, and 9 initial biopsies of 9 of the tumors of the ampulla of Vater that had no morphologic evidence of carcinoma were immunostained.None of the 4 normal ampullas (0%), 2 of 5 adenomas (40%), and 16 of 17 carcinomas (94%) were positive for p53. This p53 positivity was present through all stages of ampullary carcinoma. Of the nine initial biopsies negative for carcinoma, seven were positive for p53 and, of these, six (86%) were found to be carcinomas upon resection.1) The molecular events leading to p53 accumulation in tumors of the ampulla of Vater occur early in the neoplastic process. 2) Tumors of the ampulla of Vater with biopsies negative for malignancy but positive for p53 are very likely to be carcinomas.

Simpler, effective therapies to treat Helicobacter pylori infection are greatly needed. Omeprazole co-therapy apparently enhances effectiveness of some antimicrobials. Our objective in this study was to determine whether the apparent additional benefit provided by omeprazole to amoxicillin therapy could be equaled by a high dose of ranitidine plus sodium bicarbonate.In a prospective randomized trial, we tested 1 g amoxicillin b.i.d. with either omeprazole 20 mg b.i.d., or high dose ranitidine (900 and 1800 mg) plus sodium bicarbonate tablets 650 t.i.d. (with meals) for 14 day.Fifty-two patients with documented H. pylori infection and peptic ulcer completed therapy. The cure rate with omeprazole and amoxicillin was poor (46%), with the 95% confidence interval (CI) = 25-67%. Ranitidine plus sodium bicarbonate was also poor (39% cure) with the 95% CI = 21.5-59% (p0.57). Average compliance was more than 92% for all three groups. Side effects were experienced in only two patients (stomatitis and mild diarrhea).Neither the omeprazole nor ranitidine plus bicarbonate plus amoxicillin therapies used here can be recommended for treatment of H. pylori infection.

Azithromycin is new acid-stable macrolide that achieves 10- to 40-fold higher tissue levels than erythromycin after oral dosing. Important to note, the tissue half-life of azithromycin is measured in days instead of hours.We evaluated two new triple therapies for Helicobacter pylori infection in which azithromycin was substituted for metronidazole either as 250 mg b.i.d. or t.i.d. along with tetracycline 500 mg q.i.d. and bismuth subsalicylate 2 tablets q.i.d. for 14 days. H. pylori status was determined by histology before and 6 wk or more after therapy.Thirty men with documented H. pylori peptic ulcers completed therapy. Twenty-one also received ranitidine (300 mg in the evening) along with the antimicrobial therapy. H. pylori infection was successfully treated in 15 (50%) (95% CI = 31-69%). The cure rate was significantly higher with the 250-mg-t.i.d.-azithromycin dosage regime (83%) (95% CI = 52-98%) compared to the 250-mg-b.i.d.-dosage regime (28%) (95% CI = 10-53%) (p0.01). Troublesome side effects were experienced by the majority of those receiving azithromycin t.i.d.We conclude that although 750 mg or more of azithromycin might eventually be able to replace metronidazole or clarithromycin in standard triple therapy, additional studies are required to identify a regime that is both effective and tolerable.

Metronidazole resistance has become an increasing problem that has limited the usefulness of the original triple therapy. Our objective was to evaluate clarithromycin, a new macrolide compound active against Helicobacter pylori.We evaluated a new clarithromycin triple therapy for H. pylori infection consisting of the combination of clarithromycin (500 mg t.i.d.), tetracycline (500 mg q.i.d.), and bismuth subsalicylate tablets (2 q.i.d.) for 14 days. Patients with ulcer also received concomitant ranitidine, 300 mg after the evening meal, for 6 wk.Thirty men with documented H. pylori infection were studied; 29 had peptic ulcer disease. Seven had previously failed antimicrobial therapy, including three with metronidazole-based triple therapy. H. pylori status was determined by histology. H. pylori status and ulcer status were evaluated 4 wk after the end of antimicrobial therapy. The ulcer was healed in 90%. The H. pylori infection was cured in 93%, including all three patients who previously failed metronidazole-based triple therapy.We conclude that the combination of clarithromycin, tetracycline, and bismuth is an effective new therapy for treatment of H. pylori infection.

Lymphoid follicles are a common feature of Helicobacter pylori-associated gastritis. Recently, by using gastric mapping, we demonstrated lymphoid follicles in all of 62 patients with H pylori infection. This study was designed to address (1) the prevalence of lymphoid follicles in routine gastric biopsy specimens, (2) their correlation with chronic active gastritis, and (3) their predictive value with respect to H pylori infection. Slides from 174 patients whose gastric biopsy findings carried a nonneoplastic diagnosis were evaluated for the presence of (1) chronic active gastritis, (2) lymphoid follicles, and (3) H pylori. When either follicles or active gastritis was found, but H pylori could not be identified by the hematoxylin-eosin stain, additional slides were prepared with a newly developed silver-hematoxylin-eosin-alcian blue stain. Active gastritis was present in 153 patients (88%). Helicobacter pylori was identified on hematoxylin-eosin-stained slides in 123 patients and by the modified Steiner stain in 11 additional patients. Thus, 87% of the patients with chronic active gastritis had histologically detectable H pylori infection. One or more lymphoid aggregates were present in 110 patients (82% of patients with H pylori and 72% of those with chronic active gastritis). Of these, 101 (92%) had H pylori infection. In six of the nine H pylori-negative patients with lymphoid aggregates, biopsy specimens were taken from the edges of an ulcer. In summary, except when biopsy specimens are obtained from the immediate vicinity of a gastric ulcer, lymphoid aggregates in a gastric biopsy specimen are virtually always associated with chronic active gastritis and provide a useful marker for H pylori infection.

The activation of the complement system by living Strongyloides stercoralis filariform larvae and their antigenic preparation was demonstrated in vitro through both classical and alternative pathways. This activation does not require the presence of specific antibodies but promotes the adhesion of peripheral blood monocytes (MNC) and polymorphonuclear cells (PMNC) to the larval surface. Larvae, totally coated by PMNC, showed a visible loss of motility after 2 hr incubation. Ethylenediamine tetraacetic acid, in contrast to ethylene glycol-bis beta-aminoethylether N,N,N,N-tetraacetic acid, abolished the adherence activity, suggesting the involvement of the alternative pathway in this process. Deposition of complement components C1q, C3, C4, C8, and properdin on the larval surface was demonstrated by immunofluorescence assays. In addition, complement activation by the larvae was demonstrated through C3 conversion and C4 cleavage assays, both depending on the number of larvae. On the other hand, complement activation by S. stercoralis antigen was determined by factor B and C4 cleavage, as well as C3 conversion assays. Our results suggest that the complement system as a first line of defense, in association with the effector cells, plays an important role in the nonspecific immune response of the host to S. stercoralis infection, especially considering the constant parasite recycling through the host tissues.

Helicobacter pylori therapy can either succeed (cure the infection) or fail. Failure is demonstrated by return of the original infecting organism soon after ending antimicrobial therapy (recrudescence of the infection). Cure of the infection does not guarantee that the individual will not be re-exposed to the bacterium and become reinfected with either the same or a new strain of H. pylori. Discovery of return of infection after a course or courses of antimicrobial therapy can be the result of either reinfection or recrudescence. It is not always easy to distinguish between them.

To gain new insights into the pathogenesis of hepatitis B virus-induced chronic liver disease, we have used nonisotopic in situ detection methods for the simultaneous analysis of hepatitis B virus DNA and antigens at the single-cell level. Paraffin-embedded liver specimens from 23 cirrhotic patients (12 HBsAg positive and 11 HBsAg negative) who underwent liver transplantation were evaluated by in situ hybridization with a digoxigenin-labeled DNA probe and digoxigenin detection system and by immunohistochemistry with an enhanced biotin-streptavidin technique. DNAs extracted from liver and serum specimens were analyzed by Southern- and slot-blot hybridization, respectively. Using the in situ techniques, we detected hepatitis B virus-specific DNA and antigens in 11 of 12 HBsAg-positive patients and in none of the 11 HBsAg-negative individuals. Replicative intermediates of hepatitis B virus DNA were detected by Southern-blot analysis in the same 11 HBsAg-positive patients, 6 of whom had no serological markers of hepatitis B virus replication. Therefore a good correlation was found between the results obtained by the in situ and Southern-blot hybridization analyses of tissue specimens. However, a lack of correlation was found between serum- and tissue-associated markers of viral replication. In addition, the simultaneous in situ detection analyses revealed that some hepatocytes containing high levels of viral DNA were devoid of detectable HBcAg, suggesting a mechanism by which the virus may escape immunological surveillance.(ABSTRACT TRUNCATED AT 250 WORDS)

Current regimens to eradicate Helicobacter pylori usually consist of metronidazole plus a bismuth compound, as well as a third agent such as tetracycline. Such regimens are not ideal because organisms may be metronidazole-resistant, side-effects occur, and compliance is often poor. This randomized, double-blind study was designed to assess the ability of clarithromycin, a new macrolide antimicrobial, as monotherapy to eradicate H. pylori. Thirty-seven healthy volunteers who were H. pylori positive by 13C-urea breath test plus histology and/or culture completed 14 days of oral therapy with clarithromycin in one of three dosages. Eradication, defined as all three tests negative at 4-6 wk after the end of therapy, was achieved in 2/13 (15%) with clarithromycin 500 mg bid, 4/11 (36%) with 1000 mg bid, and 7/13 (54%) with 500 mg qid. Isolates of H. pylori were resistant to clarithromycin prior to therapy in 12% of subjects, and became resistant during therapy in 21% of subjects. Taste perversion, the most common side effect, resulted in one subject terminating therapy.Whereas clarithromycin is a promising antimicrobial in the eradication of H. pylori, it is not sufficient to be used as monotherapy.

The hydrophobic properties of the gastric mucosa are reduced by NSAIDs and by Helicobacter pylori infection. Our investigation was to determine whether this abnormality was due to the bacteria or to the inflammatory response. Contact angle measurements were made on gastric antral and corpus biopsies taken from 10 H. pylori-infected volunteers before eradication therapy, after 2 and 14 days of therapy, and 4 weeks after therapy. The contact angle improved steadily and statistically throughout the 2 weeks of therapy (for day 0, 3, 14, respectively) antral mucosa 54.2 +/- 2, 59.3 +/- 2, and 63.2 +/- 2; corpus mucosa 55 +/- 1, 57.8 +/- 3, and 66.6 +/- 1. After 2 days of therapy, H. pylori bacteria were no longer evident, and yet the contact angle continued to improve, suggesting that bacteria and bacterial products (e.g., lipases) may not be critical factors. H. pylori was eradicated in five and failed in five. One month after ending therapy, the contact angles of those with recrudescence of infection and those with eradication were similar and higher (p0.05) than before therapy (antrum: 69.8 +/- 1 vs. 71.1 +/- 2, corpus: 66.4 +/- 4 vs. 70.8 +/- 2) (p0.25 for both). We conclude that gastric surface hydrophobicity abnormalities do not appear to be directly related to the presence of H. pylori organisms or the histologic features of acute inflammation, but are responsive to antimicrobial therapy.

Although most studies reporting on the examination of Helicobacter pylori infection have focused on the clearance of the bacteria and the rapid disappearance of the neutrophil infiltrates, the evolution of inflammatory and architectural changes in the antral and corporal mucosa following the eradication of H. pylori has not been addressed systematically. This study examines in detail the histopathologic appearance of the antral and corporal mucosa in a group of patients infected with H. pylori and follows the spectrum of morphologic changes in each of them after the eradication of the infection. At least 11 biopsies ("gastric mapping") were obtained from the antrum and body of each of 15 patients with H. pylori. Complete mapping was then repeated 1, 4, and 10 to 12 mo after the eradication of H. pylori by a course of "triple therapy." Each biopsy was assessed in a semi-quantitative fashion for presence of H. pylori, neutrophils, eosinophils, lymphocytes, lymphoid follicles, and intestinal metaplasia. Other features (integrity of surface epithelium, architecture, fibrosis) were evaluated descriptively. Results were compared with those obtained from a control group of 16 uninfected, healthy adult volunteers. H. pylori infection was eradicated in 11 subjects. The disappearance of neutrophils and the normalization of the surface epithelium closely paralleled that of H. pylori. Persistence of even small numbers of neutrophils was a predictor of relapse. Eosinophils and lymphocytes decreased slowly and did not return to normal levels within 1 yr. Lymphoid follicles decreased very slowly in all patients but were still present in all gastric locations at one year after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten patients with the acquired immunodeficiency syndrome and an endoscopic erosive/ulcerative lesion in esophagus (4), stomach (3), or colon (3) were prospectively studied with multiple biopsies (244 biopsies from 33 sites) to determine: 1) the frequency of positive tests for cytomegalovirus (CMV) in the lesions versus normal mucosa, 2) the influence of number of biopsies on the rate of positivity. As seen on histology, five out of 10 lesions had cytomegalic cells, but only six of 45 (13%) of the biopsies taken from lesions that were positive showed the diagnostic changes. Immunoperoxidase was positive in two of the lesions with cytomegalic cells, but the positive staining occurred in only three of 35 (9%) biopsies from the histologically positive lesions. Culture was positive in one of 10 lesions, and the rate of positivity did not depend on number of cultures sent or number of biopsies per culture. Polymerase chain reaction was positive in six of 10 lesions, including all lesions positive by either histology (5), immunoperoxidase stain (2), or culture (1). The frequency of a biopsy being positive for CMV in normal mucosa was found to be 4%, 0%, 17%, and 28% by histology, immunoperoxidase stain, culture, and polymerase chain reaction, respectively. In AIDS patients at high risk for CMV, histologic evidence of CMV infection is uncommon in normal mucosa but is frequent in suspicious lesions. However, the frequency of diagnostic histology is highly dependent on the number of biopsies taken and the diligence of the pathologist. Polymerase chain reaction has the potential to become a rapid test to rule out CMV infection in gastrointestinal tissue.

Sections of tubular adenomas (n = 40), ulcertive colitis (n = 97) and hyperplastic polyps (n = 31) were examined by immunoperoxidase staining to carcinoembryonic antigen (CEA) in order to assess its potential diagnostic value in predicting malignant potential of these lesions. We compared the degree of epithelial abnormality in these mucosal specimens with the extent of immunoperoxidase staining for CEA. We found that CEA staining correlated with the degree of epithelial alteration in tubular adenoma and ulcerative colitis groups. Scattered weakly positive staining was found in eight of 31 hyperplastic polyps. High tissue expression of CEA, when combined with histologic dysplasia, may prove to be an additional factor in the evaluation of malignant potential in ulcerative colitis specimens and adenomas.

Strongyloides stercoralis is a small intestinal nematode that has the ability to multiply within the human host. Because of the potential opportunistic behavior of this parasite, immunocompromised patients may develop fatal disseminated infections. Chronic strongyloidiasis may last decades and give rise to various dermatologic lesions, the most characteristic of which is larva currens, a serpiginous creeping urticarial eruption caused by the intradermal migration of the infective filariform larvae. Rarely recognized is the presence of widespread petechiae and purpura that may develop in patients with disseminated infections. A 64-year-old immunosuppressed man developed fatal extraintestinal S stercoralis infection with extensive purpura associated with massive invasion of the skin by migrating larvae.

Parasite-specific humoral and cellular immune responses were evaluated in seven Erythrocebus patas monkeys experimentally infected with a Southeast Asian strain of Strongyloides stercoralis. Most animals developed high titers of anti-larval surface IgG antibody (as evaluated by the indirect immunofluorescence test), and all animals tested developed specific IgE antibody (as shown by the in vitro histamine release test). Modest lymphoproliferative responses to S. stercoralis antigens were demonstrated in most animals during the early phase of the infection (days 20-40), but disappeared later. Steroid treatment (prednisone, 12.5 mg/kg on alternate days) was given to three animals, but did not appear to significantly affect the immune parameters tested. The degree of the immune responses to S. stercoralis larval antigens did not correlate well with the course of the infection, and several animals died of disseminated disease in spite of demonstrable humoral and cellular responses to these antigens. We suggest therefore that other factors, such as local intestinal immune and nonimmune mechanisms may be of importance in protection against disseminated strongyloidiasis.

Antibodies to intact rhabditiform and filariform larvae of Strongyloides stercoralis were measured by indirect immunofluorescence using quantitative fluorescence microscopy. Forty-four of 48 sera from infected patients (92 per cent) were positive for IgG antibodies specific for surface antigens of filariform larvae. None of 30 North American adult control sera were positive. All sera from patients with Schistosoma mansoni, Loa loa, or hookworm infections or with idiopathic hypereosinophilia were negative. Three of nine sera from patients with Bancroftian filariasis were weakly positive. Pre- and posttreatment sera from seven patients were tested, and there was a marked decrease in antibody titers in all posttreatment sera. Twelve sera from infected patients were also tested for the presence of IgA and IgM antibodies specific for surface antigens of filariform larvae; all sera were negative for specific IgA, and only one exhibited a weak positivity for specific IgM. Nine of the IgG-positive sera were tested for the presence of IgA and IgG antibodies directed against surface antigens of S. stercoralis rhabditiform larvae. No parasite-specific IgA was detected in any of the sera, but most sera contained small amounts of parasite-specific IgG. We conclude that the majority of patients with chronic uncomplicated strongyloidiasis develop specific IgG antibodies directed against the surface of filariform larvae, the invasive stage of the parasite. such antibodies may be involved in host defenses that prevent fatal hyperinfection in immunocompetent individuals. In addition, our results confirm that the indirect immunofluorescence employing filariform larvae as antigen is a sensitive and specific test that may be a useful adjunct to stool examination in the diagnosis of strongyloidiasis.

Strongyloides stercoralis causes a usually silent infection that, under certain conditions of altered host-parasite balance, may become a severe, often fatal, disseminated disease. Patients, as well as experimental animals, develop specific humoral and cellular responses to the tissue-invading stage of the parasite, the filariform larvae. These responses, however, while potentially useful for diagnostic purposes, appear to be of little importance in determining the course of the disease. It is suggested that local intestinal factors may play a central role in the control of autoinfection. Until these questions are resolved and more accurate diagnostic methods are devised, preventive therapy in all patients from endemic areas that must undergo immunosuppressive therapy is advised.

Reaginic antibodies to antigens from the human parasite Strongyloides stercoralis were studied by histamine release from basophils in 15 patients with chronic uncomplicated strongyloidiasis and in 12 controls (six North Americans with no evidence of parasitic diseases, two patients with Schistosoma mansoni, two with hookworm, one with Ascaris lumbricoides, and one with Onchocerca volvulus). All of the patients had antibodies to the somatic larval antigens, and 14 of 15 patients also had antibodies to the excretory/secretory products of S. stercoralis larvae. None of the controls had a positive response to any of the antigens tested. These findings indicate that patients with chronic strongyloidiasis have parasite-specific IgE antibodies and that S. stercoralis larval allergens may have a potential role in the immunodiagnosis of strongyloidiasis.

Eighty-eight residents of Curitiba, Brazil, with parasitologically proven Strongyloides stercoralis infection were assessed clinically and evaluated for their specific and non-specific responses to the parasite. A control group of 73 patients with other intestinal parasites, but with negative stools for S. stercoralis were also evaluated. Abdominal symptoms and/or weight loss were present in 24% of the patients with strongyloidiasis and in 25% of the patients with other parasites only. Elevated peripheral eosinophilia (greater than 5%) was present in 68% of the patients with strongyloidiasis (mean = 10.6%) and in 73% of the individuals with other parasites only (mean = 8.8%). Total serum IgE were elevated (greater than IU/ml) in 84% of the patients with strongyloidiasis (mean = 2872 IU/ml), and in 79% of the patients with other parasites only. Over 90% of the patients with proven strongyloidiasis had detectable levels of parasite specific IgG and IgE antibodies, as detected by the ELISA and the RAST, respectively. These antibodies were present in 23% of the individuals in whom fecal examinations had failed to reveal S. stercoralis. We conclude that in an endemic area, gastrointestinal manifestations and non-specific indicators of parasitic infections, such as elevated peripheral eosinophilia and total IgE, are not useful indexes of the presence of strongyloidiasis. Immunoserologic tests, such as the ELISA and the RAST may represent sensitive and specific tools for the screening of candidates for immunosuppression and for gathering needed epidemiological information about this increasingly important opportunistic nematode.