Background

Until very recently, peptic ulcer disease was thought to be largely due to excess acid production within the stomach. Although this is certainly an important cause, a novel bacterial organism has established itself as the cause for many cases of peptic ulcers, stomach cancers, and even stomach lymphomas. Helicobacter pylori normally resides in the stomach and is acquired early in life. It is estimated that more than 50% of children worldwide harbor the bacteria by the age of 10 years. Although there is geographic variation, the majority of adults, especially in developing countries, also harbor the bacteria. Humans are the primary host for the bacteria. The organism can be cultured from vomit, saliva, and stool. Thus, the organism is potentially transmissible during episodes of gastrointestinal distress such as vomiting.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
AGE
CHILDREN
Histopathology of gastritis in Helicobacter pylori-infected children from populations at high and low gastric cancer risk. Bedoya A, Garay J, Sanzon F, Bravo LE, Bravo JC, Correa H, Craver R, Fontham E, Du JX, Correa P. Hospital Infantil, Pasto, Colombia.	Hum Pathol 2003 Mar;34(3):206-13 Abstract quote Infection with Helicobacter pylori has been recognized as a cause of gastric carcinoma. Although the neoplasia is always detected in adults, the infection starts in childhood. It has been reported that early age at first infection is a determinant of gastric cancer risk. In this study, we examined the histopathology of the gastric mucosa in infected children from a population at high risk for gastric cancer (Pasto, Colombia) and compared it with that of a lower-risk population (New Orleans, LA). Gastric biopsies obtained from antrum and corpus were stained with hematoxylin and eosin and Steiner's silver method. Immunohistochemical stains were used to identify B lymphocytes (CD20), T lymphocytes (CD3 and CD8), macrophages (CD68), and polymorphonuclear neutrophil myeloperoxidase. Morphometric techniques were used to evaluate the immunohistochemical stains. In both populations, the inflammatory lesions were seen predominantly in the antrum. Compared with children from the lower-risk populations, children from the higher-risk population exhibited more severe polymorphonuclear neutrophil infiltration, stromal and intraepithelial lymphocyte infiltration, mucus depletion, and H. pylori colonization density. Regenerative activity was significantly more marked in the lower-risk population. Morphometric analysis of immunohistochemical stains showed increased representation of T lymphocytes and macrophages in the higher-risk population. Most T lymphocytes stained positive for CD8, a marker of suppressor/cytotoxic cells. B lymphocytes were relatively more abundant in the lower-risk population. The possibility that the aforementioned characteristics of H. pylori infection in children are related to cancer risk in adults is discussed.
GEOGRAPHY
AFRICAN AMERICANS
H. pylori infection and genotyping in patients undergoing upper endoscopy at inner city hospitals. Straus EW, Patel H, Chang J, Gupta RM, Sottile V, Scirica J, Tarabay G, Iyer S, Samuel S, Raffaniello RD. SUNY-Downstate Medical College, Division of Digestive Diseases, Brooklyn, New York 11203, USA.	Dig Dis Sci 2002 Jul;47(7):1575-81 Abstract quote Kings County Hospital (KCH), and St. John's Episcopal Hospital (SJH) are inner-city hospitals in New York City serving predominantly minority populations. Staten Island University Hospital (SIUH) serves a predominantly middle-class Caucasian population. We examined H. pylori (HP) infection in patients undergoing upper endoscopy at these hospitals. Two gastric biopsies were obtained from each patient. One biopsy was examined by histology or the rapid urease test for the presence of HP. The other was subjected to analysis by PCR to detect HP DNA and to identify putative HP virulence factors. Of 200 subjects, 54% were African-American, 10% were Hispanic, and 36% were Caucasian. HP infection rates in African-American, Hispanic, and Caucasian patients were 43%, 20%, and 11%, respectively. Many of the African-American patients are recent immigrants from the Caribbean Islands. In these patients, an inverse relationship was observed between HP infection and the number of years living in the United States. Higher levels of HP infection were observed in patients with duodenitis and peptic ulcer disease. With respect to HP virulence factors, the vacA s1b and m1 alleles, as well as the iceA2 allele were the predominant alleles expressed in HP-positive samples obtained from African-Americans. The cagA gene was detected in 81% of HP-positive samples. However, CagA positivity was not related to any specific gastrointestinal disorder. Our findings indicate that among several ethnic groups served by three hospitals, African-American patients have the highest rate of HP infection. Moreover, in AfricanAmerican patients undergoing endoscopy: (1) HP infection was inversely related to the number of years the patients have been living in the USA; (2) HP infection rates were higher in patients diagnosed with duodenitis and peptic ulcer disease versus other disorders; (3) expression of the CagA gene was not associated with any specific gastroduodenal disorder; and (4) there was little allelic heterogeneity with respect to VacA and IceA subtypes. These findings suggest that inner-city African-Americans are more likely to be infected with HP and suffer from more serious gastroduodenal disorders than other ethnic groups.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
CIRRHOSIS
Helicobacter pylori is a risk factor for peptic ulcer disease in cirrhotic patients. A meta-analysis. Vergara M, Calvet X, Roque M. Unitat de Malalties Digestives, Corporacio Parc Tauli, Parc Tauli s/n, 08208 Sabadell, Barcelona, Spain.	Eur J Gastroenterol Hepatol 2002 Jul;14(7):717-22 Abstract quote BACKGROUND : Peptic ulcer disease is highly prevalent in cirrhosis, and ulcer complications are a major cause of morbidity in these patients. Helicobacter pylori infection is considered the chief aetiological factor of ulcer disease. However, in cirrhotic patients the role of H. pylori in the pathogenesis of peptic ulcer remains uncertain. AIM : To evaluate the evidence of the pathogenic role of H. pylori infection in peptic ulcer disease in patients with cirrhosis. MATERIALS AND METHODS : An extensive MEDLINE search of the literature was performed. Studies reporting the prevalence of H. pylori infection in cirrhotic patients with and without ulcers were selected. Meta-analysis was conducted using RevMan 4.0.3. Pooled odds ratios were calculated for each comparison, using a fixed model analysis. RESULTS : The search identified seven studies with a total of 976 patients with cirrhosis (275 cases with ulcer disease and 701 controls). The prevalence of H. pylori infection in patients with peptic ulcer disease was higher than in those without. The pooled odds ratio was 2.70 (95% CI, 1.91-3.82). H. pylori infection was associated more or less equally with duodenal and gastric ulcers. CONCLUSION: H. pylori infection increases the risk of peptic ulcer disease in patients with cirrhosis.
GASTRIC CANCER
Helicobacter pylori infection and the development of gastric cancer. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ. Department of Gastroenterology, Kure Kyosai Hospital, Kure City, Japan.	N Engl J Med 2001 Sep 13;345(11):784-9 Abstract quote BACKGROUND: Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain. METHODS: We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests. RESULTS: Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers. CONCLUSIONS: Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.
LYMPHOMA, STOMACH
. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group. Bayerdorffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt S, Stolte M. Medical Department II, Klinikum Grosshadern, University of Munich, Germany.	Lancet 1995 Jun 24;345(8965):1591-4 Abstract quote Lymphoma of gastric-mucosa-associated lymphatic tissue (MALT) type has been linked to infection with Helicobacter pylori. We investigated the effect on MALT lymphoma of eradicating H pylori infection. 33 patients with primary gastric low-grade MALT lymphoma associated with H pylori gastritis were treated with omeprazole (120 mg daily) and amoxycillin (2.25 g daily) for 14 days to eradicate H pylori. In addition to histology, PCR was used to examine proliferation of monoclonal B cells before treatment and during follow-up. All patients had at least two post-treatment examinations, and all became negative for H pylori, 2 after a second treatment course. On histology, 23 (70%) patients showed complete regression and 4 (12%) partial regression of lymphoma. 6 (18%) patients had no change after cure of H pylori infection. 1 was treated with chemotherapy. Of 5 treated surgically, 4 were found to have high-grade B-cell lymphoma on histology of the resected stomach and 1 a high-grade T-cell lymphoma. PCR showed complete disappearance of monoclonal B cells after cure of H pylori infection in 13 of 16 patients investigated. During median follow-up of 1 year no relapse of MALT lymphoma occurred. Low-grade primary gastric MALT lymphoma can completely regress after eradication of H pylori infection. However, longer follow-up is needed to clarify whether the remission is lasting.
Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Morgner A, Lehn N, Andersen LP, Thiede C, Bennedsen M, Trebesius K, Neubauer B, Neubauer A, Stolte M, Bayerdorffer E. Medical Department I, Technical University, Dresden, Germany.	Gastroenterology 2000 May;118(5):821-8 Abstract quote BACKGROUND & AIMS: Cure of Helicobacter pylori infection may lead to complete remission of associated low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in stage EI. This study investigated whether Helicobacter heilmannii infection-associated primary gastric MALT lymphoma will regress after cure of the infection. METHODS: H. heilmannii-induced gastritis was diagnosed histologically, by a new specific immunoglobulin G enzyme-linked immunosorbent assay, and with 16S ribosomal RNA amplification and sequencing in 5 consecutive patients with primary gastric MALT lymphoma clinical stage EI. Patients received 40 mg omeprazole and 750 mg amoxicillin 3 times per day for 14 days. Polymerase chain reaction (PCR) was used to detect rearrangement of immunoglobulin heavy-chain genes before treatment and during follow-up. RESULTS: Five patients (3 men, 2 women; mean age, 65 years; range, 42-79 years) were studied. H. pylori was not detected by culture, histology, serology, or PCR. Treatment resulted in the cure of H. heilmannii infection in each case and complete histological and endoscopic remission of the tumors. Three of 5 patients showed monoclonal B cells before treatment, 2 of whom remained PCR positive. Within a median follow-up period of 24 months, no relapse of the lymphoma or reinfection with H. heilmannii occurred. CONCLUSIONS: These data suggest that gastric MALT lymphoma may arise in patients with H. heilmannii infection. Cure of this infection may lead to complete remission of the MALT lymphoma.
Early stage gastric MALT lymphoma with high-grade component cured by Helicobacter pylori eradication. Miki H, Kobayashi S, Harada H, Yamanoi Y, Uraoka T, Sotozono M, Ohmori M. Department of Pathology, Kagawa Medical University, Miki, Japan.	J Gastroenterol 2001 Feb;36(2):121-4 Related Articles, Links Early stage gastric MALT lymphoma with high-grade component cured by Helicobacter pylori eradication. Miki H, Kobayashi S, Harada H, Yamanoi Y, Uraoka T, Sotozono M, Ohmori M. Department of Pathology, Kagawa Medical University, Miki, Japan. A 68-year-old woman was diagnosed with gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type with a high-grade component. Surgical treatment was recommended because of the presence of the high-grade component, but she refused surgery. As an alternative, she received Helicobacter pylori eradication treatment, which successfully induced regression of the lymphoma. She shows no sign of recurrence endoscopically and histologically, as of 29 months after the eradication treatment. Moreover, the B-cell monoclonality and Helicobacter pylori infection demonstrated at diagnosis has disappeared. This is one of the rare cases of gastric lymphoma of the MALT type with a high-grade component cured by Helicobacter pylori eradication alone.
Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication. Montalban C, Santon A, Boixeda D, Bellas C. Department of Internal Medicine, Hospital Ramon y Cajal, Madrid, Spain.	Gut 2001 Oct;49(4):584-7 Abstract quote BACKGROUND: Most low grade gastric lymphomas arising from the mucosa associated lymphoid tissue (MALT) are related to Helicobacter pylori colonisation. Cases with disease limited to the stomach can be cured after H pylori eradication and remain in remission for years. In contrast, high grade lymphomas of the stomach, although also related to H pylori, do not usually respond to eradication treatment. CASE REPORT: A 36 year old patient was referred from another hospital with a diagnosis of a low grade gastric MALT lymphoma associated with H pylori. The patient was in stage I and while waiting for the biopsies to be reviewed H pylori eradication therapy was given as the first step of treatment. Review of the biopsies showed a high grade immunoblastic lymphoma with areas of low grade gastric MALT lymphoma (high grade gastric MALT lymphoma or diffuse large B cell lymphoma with areas of MALT type lymphoma of the WHO classification). The patient received no further treatment but has been closely followed up for 32 months with sequential endoscopies to obtain biopsies for histological studies, H pylori cultures, and polymerase chain reaction analysis of the IgH gene. RESULTS: After H pylori eradication the patient had a complete histological response that has been maintained for 32 months. Monoclonal IgH gene rearrangement persisted for 32 months. CONCLUSION: The response of this patient indicates the possibility that some cases of high grade gastric MALT lymphoma (possibly patients in stage I with a superficial or limited disease) may still be responsive to H pylori antigenic drive and may be cured with eradication therapy. Prospective studies should be performed to identify patients with high grade gastric MALT lymphomas that may respond to eradication therapy and be spared of other more aggressive treatments.
Regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori: possible association with p16 hypermethylation. Kim YS, Kim JS, Jung HC, Lee CH, Kim CW, Song IS, Kim CY. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea.	J Gastroenterol 2002 Jan;37(1):17-22 Abstract quote BACKGROUND: Many reports have stated that the cure of Helicobacter pylori infection can induce a complete remission of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although p16 hypermethylation was frequently found in MALT lymphoma, the association between this finding and the remission of MALT lymphoma has not been clarified. We performed a prospective study to evaluate the outcome of patients with low-grade gastric MALT lymphoma and the expression of p16 hypermethylation. METHODS: We prospectively enrolled 20 patients with H. pylori-positive low-grade gastric MALT lymphoma (stage I E1). After the eradication of H. pylori, the patients were regularly followed-up with endoscopic and histological assessment. The methylation-specific polymerase chain reaction (PCR) (MSP) method was used for the serial detection of p16 hypermethylation. RESULTS: Eighteen patients (90%) achieved complete remission, with a median duration of 15.7 months. The initial detection rate of p16 hypermethylation was 58% (7 of the 12 patients in whom p16 hypermethylation was evaluated successfully). In a serial investigation, 3 patients who were followed-up for a median 28 months showed that the p16 hypermethylation had disappeared. CONCLUSIONS: Complete remission of low-grade gastric MALT lymphoma after the eradication of H. pylori infection can be maintained for more than 1 year. Further studies are warranted to investigate the role of p16 hypermethylation in the pathogenesis of gastric MALT lymphoma.
PRURITIS

 

PATHOGENESIS	CHARACTERIZATION
GENERAL
Gene expression profiling in human gastric mucosa infected with Helicobacter pylori. Hofman VJ, Moreilhon C, Brest PD, Lassalle S, Le Brigand K, Sicard D, Raymond J, Lamarque D, Hébuterne XA, Mari B, Barbry PJ, Hofman PM. [1] 1Faculty of Medicine, INSERM ERI-21, Nice Cedex, France [2] 2Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France.	Mod Pathol. 2007 Sep;20(9):974-89. Abstract quote Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway.
CLONALITY
B-cell Monoclonality Is Associated With Lymphoid Follicles in Gastritis. Wundisch T, Neubauer A, Stolte M, Ritter M, Thiede C.	Am J Surg Pathol. 2003 Jul;27(7):882-7 Abstract quote The gold standard for diagnosis of gastric MALT lymphoma is histopathology. Polymerase chain reaction-based assays to detect the expansion of monoclonal B cells have also been used to corroborate the diagnosis. However, there are conflicting data on monoclonal B-cell expansion in gastritis. We asked about its frequency in graded gastritis cases. Lymphocytic infiltration in gastric biopsies was graded according to Wotherspoon in 129 cases. The histologic diagnosis ranged from normal gastric mucosa to suspicious for gastric MALT lymphoma. To search for a monoclonal B-cell population, a semi-nested polymerase chain reaction strategy was used for amplification of rearranged VDJ sequences of the immunoglobulin heavy chain gene. Of 106 evaluable samples, 18 were found to be monoclonal. The detection of a monoclonal B-cell population was strongly associated with the presence of lymphoid follicles. In cases with lymphoid follicles, detection of monoclonality was independent of Wotherspoon grading; there is no significant difference between cases being suspicious for lymphoma and those not. We found B-cell monoclonality to be a more frequent than expected finding in gastritis and to be strongly associated with the presence of lymphoid follicles; thus, its presence is of little significance in patient management.
LOCATION OF ORGANISMS
Infiltration of Helicobacter pylori in the gastric mucosa. Jhala NC, Siegal GP, Klemm K, Atkinson BF, Jhala DN. Department of Pathology, University of Alabama at Birmingham, 619, 6th Ave S, Birmingham, AL 35233, USA.	Am J Clin Pathol 2003 Jan;119(1):101-7 Abstract quote It is our hypothesis that if Helicobacter pylori could be demonstrated conclusively to have transgressed the mucosal surface into the lamina propria, this would help explain how H pylori recruits inflammatory cells. We report our immunohistochemical and electron microscopic findings that demonstrate that H pylori can be detected in the lamina propria of the stomach, offering evidence of its invasive potential. We stained 67 endoscopic gastric biopsy specimens with Warthin-Starry silver and immunoperoxidase stains for H pylori. In addition, transmission electron microscopy was performed on 1 case. The presence of surface H pylori was associated significantly with active (P < .0001) and chronic (P < .0001) inflammation. H pylori could not be identified in the lamina propria using the Warthin-Starry silver stain alone. Immunoreactivity for H pylori in the lamina propria was detected in 20 (30%) of 67 gastric biopsy specimens. Transmission electron microscopy confirmed the immunohistochemical findings. H pylori can infiltrate the lamina propria of the gastric mucosa, thereby proving morphologic evidence of its invasive capability.
p27
Alterations in the proliferating compartment of gastric mucosa during Helicobacter pylori infection: the putative role of epithelial cells expressing p27(kip1). Sougioultzis S, Foukas PG, Tzivras M, Kourtessas D, Gorgoulis VG, Davaris P, Archimandritis AJ. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.	Mod Pathol. 2003 Nov;16(11):1076-85. Abstract quote   The proliferating zone contains stem cells that give rise to all epithelial cells of the gastric mucosa. In the present study, we investigated the turnover of gastric epithelial cells in the proliferating zone of Helicobacter pylori-infected mucosa, with or without intestinal metaplasia, before and after eradication of the microorganism. In addition, we studied the topographical distribution of the cyclin dependent kinase inhibitor p27(Kip1), which plays a critical role in cell cycle progression and differentiation programs. Twenty-eight patients (22 male), aged 32-78 years and with dyspeptic symptoms, were endoscoped, and gastric biopsies were obtained from antrum and corpus for histopathological examination and the Campylobacter-like organisms test; eradication therapy was given to infected patients, and all patients were re-endoscoped after 105 +/- 33 days (mean +/- SD). The kinetics of gastric epithelial cells and p27(Kip1) status was assessed by means of immunohistochemistry and TUNEL (Tdt-mediated dUTP-biotin nick end labeling) assay. Twenty-one (21) of 28 patients were H. pylori positive, and 7 were found H. pylori negative and served as controls. In antrum, intestinal metaplasia was detected in 7/21 (33.3%). In H. pylori gastritis, Ki67 expression was found increased in the proliferating zone, compared with normal (P =.03); analogous results were obtained with the other proliferation markers, namely retinoblastoma protein and topoisomerase IIalpha. An inverse relationship between proliferation index and atrophy was disclosed (P =.02). A reduction in the proliferation index was observed after eradication, albeit not significant. Apoptotic epithelial cells were found significantly increased (P <.01) in H. pylori gastritis, and a significant reduction was observed after eradication (P <.01). In addition, apoptotic index was found to correlate with H. pylori density. The topographical study of p27(Kip1) revealed a p27(kip1)-positive epithelial cell population that resided deep in the proliferating zone; these cells were considered to be stem cells and were found significantly increased in areas with intestinal metaplasia (P <.05); in H. pylori gastritis, there was also an increase that did not reach statistical significance. H. pylori infection induces apoptosis and increases proliferation in the proliferating zone. The increased cellular turnover, together with the increased number of putative p27(Kip1)-positive stem cells in the context of intestinal metaplasia, provides further evidence for the role of H. pylori infection in gastric carcinogenesis.

 

LABORATORY/ RADIOLOGIC/OTHER	CHARACTERIZATION
LABORATORY
GENERAL
Helicobacter pylori Pathology and Diagnostic Strategies James Versalovic, MD, PhD	Am J Clin Pathol 2003;119:403-412 Abstract quote Helicobacter pylori represents one of the most common and medically prominent infections worldwide. Infection with this microaerobic, gram-negative bacterium has been established as an etiologic factor in the development of peptic ulcer disease. In addition, H pylori infection has been associated firmly with the development of gastric neoplasia, including gastric adenocarcinomas and gastric mucosa-associated lymphoid tissue lymphomas. Effective antimicrobial treatment depends on sensitive and accurate diagnostic approaches. This review article discusses invasive and noninvasive strategies for diagnosis of H pylori infection. Invasive methods requiring endoscopic evaluation include bacteriologic culture and susceptibility testing, histopathologic studies, molecular diagnostics, and rapid urease testing. Noninvasive approaches include fecal antigen detection, serologic testing, and urea breath testing.
CLO Test, Urea breath test	May give false negative results in patients with mild infection
Helicobacter pylori stool antigen (HpSA) test--a simple, accurate and non-invasive test for detection of Helicobacter pylori infection. Chang MC, Wu MS, Wang HH, Wang HP, Lin JT. Department of Internal Medicine, National Taiwan University Hospital, Taipei, R.O.C.	Hepatogastroenterology 1999 Jan-Feb;46(25):299-302 Abstract quote BACKGROUND/AIMS: To access the reliability of a newly developed test, the Helicobacter pylori (H. pylori) stool antigen (HpSA) test was used for detection of H. pylori infection. METHODOLOGY: Stool specimens were collected from 33 consecutive patients (19 males and 14 females, age range: 16-73 years, mean: 49 years) who received upper gastrointestinal endoscopic examination for gastrointestinal symptoms. The H. pylori status was evaluated based on six different tests: culture, histology, biopsy urease test, 13C-urea breath test (13C-UBT), serology, and HpSA test. A commercial kit using an enzyme-linked immunosorbent assay examined HpSA in the stool. H. pylori status was defined as positive when the culture was positive or concordance of three of the other four tests (histology, biopsy urease test, 13C-UBT, and serology) was positive. RESULTS: Twenty patients were diagnosed as H. pylori-positive. The HpSA test was positive in 19 patients and negative in 14 patients. The sensitivity and specificity were 95.0% and 100%, respectively. The overall accuracy rate was 96.3%. CONCLUSIONS: The HpSA test is a new, simple, non-invasive method for accurate diagnosis of H. pylori infection.
Usefulness of a novel enzyme immunoassay for the detection of Helicobacter pylori in feces. Ohkura R, Miwa H, Murai T, Nagahara A, Ohta K, Sato K, Yamada T, Sato N. Dept. of Gastroenterology, Juntendo University, School of Medicine, Tokyo, Japan.	Scand J Gastroenterol 2000 Jan;35(1):49-53 Abstract quote BACKGROUND: In this study we assessed the reliability of a newly developed enzyme immunoassay (HpSA) kit for detecting Helicobacter pylori antigen in stool. METHODS: This study included 309 patients, 147 of whom were defined as positive and 162 as negative by the 13C-urea breath test, rapid urease test, and pathologic findings. From these patients fresh stool specimens were collected for HpSA. RESULTS: When 0.100 was adopted as the cut-off value, in accordance with the manufacturer's recommendations, the sensitivity, specificity, and accuracy of the HpSA were 98.0%, 87.0%, and 92.2%, respectively. However, these values were much improved when a cut-off value of 0.300 was adopted, which was obtained with our receiver-operator characteristics curve; with this value the sensitivity, specificity, and accuracy of HpSA were 93.9%, 95.7%, and 94.8%, respectively. CONCLUSION: These results indicate that HpSA is a highly reliable diagnostic method for H. pylori infection and is useful in confirming eradication.
Discrepancy between Helicobacter pylori stool antigen assay and urea breath test in the detection of Helicobacter pylori infection. Masoero G, Lombardo L, Della Monica P, Vicari S, Crocilla C, Duglio A, Pera A. Department of Gastroenterology, Mauriziano Hospital, Turin, Italy.	Dig Liver Dis 2000 May;32(4):285-90 Abstract quote BACKGROUND: The reference diagnostic methods available for detection of Helicobacter pylori infection are either invasive (histology) or expensive and highly sophisticated (Urea Breath Test). A new enzyme immunoassay, which can be easily performed in any laboratory, has been developed to detect Helicobacter pylori in stool specimens (HpSA-Meridian Diagnostics, Cincinnati, USA). Aim of the study was to compare HpSA to Urea Breath Test. PATIENTS AND METHODS: A total of 125 patients (52 never treated for Helicobacter pylori infection and 73 after Helicobacter pylori eradication therapy) referring to our Department, underwent both tests within two weeks. RESULTS: Contrasting results between the two tests were found in 30% of cases: in 19% of the untreated patients and in 37% of the treated patients (p<0.001). The main discrepancy consisted in positive HpSA associated with negative Urea Breath Test. Mean HpSA value in such conditions was 0.273 optical density, while in patients with both positive tests, it was 1.192 optical density. In untreated, but not in treated patients, raising the HpSA cut off value significantly decreased the percentage of conflicting results. CONCLUSIONS: Some disagreement was detected between HpSA and Urea Breath Test results, especially in treated patients. Possible explanations for our findings are a low HpSA cut off value together with the identification of Helicobacter pylori coccoid forms by the immunoassay but not by the urease based Urea Breath Test. The higher percentage of discrepancy detected in treated patients might support this hypothesis.
Limitations to carbon 13-labeled urea breath testing for Helicobacter pylori in infants. Imrie C, Rowland M, Bourke B, Drumm B Department of Paediatrics, The Conway Institute of Molecular and Biomedical Research, University College, and The Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.	J Pediatr 2001 Nov;139(5):734-7 Abstract quote We determined the validity of the carbon 13-labeled urea breath test in young children. We found that although the (13)C-labeled urea breath test had a specificity greater than 90%, borderline or false positive results occurred more frequently in children younger than 2 years compared with older children. False positive results may be caused by oral-urease-producing organisms because direct intragastric administration of (13)C urea reduced the excess delta (13)CO(2.) Care is urged in interpreting one positive (13)C-labeled urea breath test in children younger than 2 years.
A 13C-urea breath test in children with helicobacter pylori infection: assessment of eradication therapy and follow-up after treatment. Yoshimura N, Tajiri H, Sawada A, Kozaiwa K, Ida S, Fujisawa T, Konno M, Kato S. Osaka Medical Center and Research Institute for Maternal and Child Health, Japan	J Gastroenterol 2001 Sep;36(9):606-11 Abstract quote PURPOSE: Our aim was to evaluate the usefulness of the 13C-urea breath test (UBT) for the diagnosis of Helicobacter pylori infection, for assessment of the efficacy of eradication therapy, and for post-treatment follow-up in children. METHODS: Seventy-two patients who underwent endoscopy for symptoms related to the upper gastrointestinal tract were examined by rapid urease test, histology, and culture. The patients were also studied with serology and UBT. RESULTS: Forty-seven of the 72 patients were diagnosed with H. pylori infection, based on the results of biopsy-based tests and serology. As an initial diagnostic test to detect H. pylori infection, the sensitivity of the UBT was 95%, which was comparable with that of histology (94%), rapid urease test (96%), and serology (91%) and was greater than that of culture (79%). The specificity of the UBT was 100%, which was comparable with that of the other four tests. The efficacy of eradication therapy was assessed by biopsy-based tests and the UBT in 24 H. pylori-positive patients. For this purpose, the sensitivities of UBT and histology were 100%, while the sensitivities of culture and the rapid urease test were 88%. The specificity was 100% for all of these tests. Eleven patients were assessed by biopsy-based tests and UBT after more than 6 months of post-treatment follow-up. There were no discordances between the results of the UBT and those of the biopsy-based tests in any of the patients. CONCLUSIONS: The UBT may be useful for detecting H. pylori infection in children with upper gastrointestinal tract symptoms, for assessment of the efficacy of eradication therapy, and for the follow-up evaluation of patients after the therapy.
Evaluation of Two Commercial Enzyme Immunoassays, Testing Immunoglobulin G (IgG) and IgA Responses, for Diagnosis of Helicobacter pylori Infection in Children. Kindermann A, Konstantopoulos N, Lehn N, Demmelmair H, Koletzko S. University Children's Hospital, Munich, Germany.	J Clin Microbiol 2001 Oct;39(10):3591-6 Abstract quote Serological testing to diagnose Helicobacter pylori infection in children is still controversial, although commonly used in clinical practice. We compared the immunoglobulin G (IgG) and IgA results of two commercially available enzyme immunoassays (EIAs) (Pyloriset IgG and IgA and Enzygnost II IgG and IgA) for 175 children with abdominal symptoms divided into three age groups (0 to 6 to 12 years, n = 51). A child was considered H. pylori infected if at least two of three tests (histology, rapid urease test, (13)C-urea breath test) or culture were positive and noninfected if all results were concordantly negative. Of 175 children, 93 (53%) were H. pylori negative and 82 were H. pylori positive. With the recommended cutoff values, the overall specificity was excellent for all four EIAs (95.7 to 97.8%) regardless of age. Sensitivity varied markedly between tests and was 92.7, 70.7, 47.5, and 24.4% for Enzygnost II IgG, Pyloriset IgG, Enzygnost II IgA, and Pyloriset IgA, respectively. Sensitivity was low in the youngest age group (25 to 33.3%), except for Enzygnost II IgG (91.6%). Receiver-operating curve analyses revealed that lower cutoff values would improve the accuracy of all of the tests except Enzygnost II IgG. Measurement of specific IgA, in addition to IgG, antibodies hardly improved the sensitivity. The specificity of commercial serological tests is high in children when the cutoff values obtained from adults are used. In contrast, sensitivity is variable, with a strong age dependence in some, but not all, tests. We speculate that young children may have a different immune response to H. pylori, with preferable responses to certain antigens, as well as lower titers than adults. The Pyloriset test may fail to recognize these specific antibodies.
POLYMERASE CHAIN REACTION (PCR)
Increased Rate of Helicobacter pylori Infection Detected by PCR in Biopsies With Chronic Gastritis. Zsikla V, Hailemariam S, Baumann M, Mund MT, Schaub N, Meier R, Cathomas G. From the *Laboratory for Pathology of Infectious Diseases, Cantonal Institute of Pathology, Liestal; and daggerDepartment of Gastroenterology, Cantonal Liestal Hospital; and daggerDepartment of Gastroenterology, Cantonal Hospital, Bruderholz, Switzerland.	Am J Surg Pathol. 2006 Feb;30(2):242-248. Abstract quote   Histology is considered a sensitive method for detection of Helicobacter pylori, in gastric biopsies. We investigated the diagnostic potential of qualitative nested (nPCR) and quantitative PCR (qPCR) for detection of H. pylori using different primers on 126 archived gastric biopsies with inflammation and correlated the inflammatory changes with the presence and density of bacteria. H. pylori was detected in 42.8% biopsies by histology and PCR, an additional 15 samples were positive exclusively by PCR: nPCR was positive in all histologically positive samples, but qPCR failed to detect H. pylori in 10 biopsies. The inflammatory score was significantly higher in biopsies positive for H. pylori only by PCR showed a significant higher inflammatory score compared with negative biopsies (mean of neutrophils score, 1.60 vs. 0.90, P < 0.01; mean of mononuclear cells score, 2.27 vs. 1.67, P < 0.01), whereas the inflammatory score was similar compared with biopsies positive for H. pylori by histology (mean of neutrophils score, 1.60 vs. 1.56, not significant; mean of mononuclear cells score, 2.27 vs. 2.20, not significant). A weak correlation between inflammatory score and the density of H. pylori detected by histology was observed. The mean values of H. pylori DNA were significantly higher in histologic-positive than in histologic negative biopsies. We have shown that PCR can detect H. pylori in about 20% of histologic-negative gastric biopsies, indicating the clinical relevance of H. pylori detection by PCR in biopsies with characteristic inflammatory changes.
SEROLOGY
Disparity between mucosal and serum IgA and IgG in Helicobacter pylori infection. Schmausser B, Eck M, Greiner A, Luhrs H, Vollmers HP, Muller-Hermelink HK. Institut fur Pathologie, Universitat Wurzburg, Josef-Schneider-Strasse 2, 97080 Wurzburg, Germany.	Virchows Arch 2002 Aug;441(2):143-7 Abstract quote Mucosal IgA and IgG are involved in the immune defense against Helicobacter pylori in infected patients. In contrast to IgG, IgA is transported into the gastric lumen and is responsible for the first-line defense. Therefore antigens recognized by mucosal IgA are possible candidates for vaccination. This study compared the IgA and IgG immune response to H. pylori in the gastric mucosa and that in the serum of 21 patients with H. pylori gastritis by the immunoblotting technique. In particular, mucosal IgA immune response against the urease antigen of H. pylori was studied in detail, as vaccination with this antigen was not curative in men. The results show that mucosal IgA was not represented by serum IgA and IgG, and that the H. pylori specific mucosal IgA and IgG immune responses differ in antigen-recognition pattern. This disparity may reflect the different transport ways and functions of these two immunoglobulin isotypes. Furthermore, mucosal IgA specific for urease was found inconsistently in patients with H. pylori gastritis. As vaccination antigens should induce an appropriate mucosal IgA immune response against H. pylori, our findings may have important implications for the selection of antigens for vaccination against H. pylori.

 

CLINICAL VARIANTS	CHARACTERIZATION
CHILDREN
Distribution of Helicobacter pylori organisms in the stomachs of children with H. pylori infection. Elitsur Y, Lawrence Z, Triest WE. Department of Pediatrics, Gastroenterology Division, and Department of Pathology, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV.	Hum Pathol 2002 Nov;33(11):1133-5 Abstract quote Histology has been recognized as the gold standard for the diagnosis of Helicobacter pylori (Hp) infection in children. For ethical reasons, the number of mucosal biopsies obtained during endoscopic procedures is limited in the pediatric population. The aim of this study was to identify the optimal location where Hp organisms are colonized. Children who were scheduled for upper endoscopic procedures were prospectively recruited for the study. At least 2 mucosal biopsy samples were obtained from the following anatomic locations: greater curvature (mid-fundus [B3], mid-body [B1], and mid-antrum [A1] and lesser curvature mid-body [B2], incisura angularis [A3], and mid-antrum [A2]). In addition, a biopsy sample for a rapid urease test was obtained. The biopsy samples were stained with hematoxylin and eosin and Giemsa for the detection of inflammation and Hp colonization. The degree of mucosal inflammation and Hp colonization was assessed. The study group comprised 206 children, of whom 16 (8%) were positive for Hp infection. Hp colonization was significantly greater in the antral locations (A1, A2, and A3) than the body locations (B1, B2, and B3) (P <.001). The degree of mucosal inflammation correlated with the presence of Hp organisms, Hp density, and antral location. The mid-antrum location (A2) was superior for the detection of Hp organisms. The antrum, especially mid-antrum, at the lesser curvature is the best location in which to detect Hp organisms in children who have not recently used antibiotics or proton pump inhibitor medications.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Diagnostic yield of gastric biopsy specimens when screening for preneoplastic lesions. Guarner J, Herrera-Goepfert R, Mohar A, Smith C, Schofield A, Halperin D, Sanchez L, Parsonnet J. Infectious Disease Pathology Activity, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.	Hum Pathol 2003 Jan;34(1):28-31 Abstract quote The Sydney system recommends sites and numbers of stomach biopsies (mapping) for evaluation of Helicobacter pylori-associated lesions. The diagnostic yield of the recommended mapping technique in populations at high risk for gastric preneoplastic lesions has not been established. We evaluated pathology data from 733 endoscopies performed as part of an intervention study that assessed the effects of H. pylori treatment on preneoplastic conditions. Two pathologists assessed whether the mapping sequence of the 7 biopsy specimens obtained during each endoscopy was correctly followed and graded the specimens using the Sydney classification for gastritis. If the mapping sequence was followed, then we evaluated whether the amount of information obtained from 3 biopsy samples approximated that obtained from 5 and 7 biopsy samples. The mapping sequence was followed in only 239 (33%) endoscopies, indicating that experienced endoscopists can inadvertently misidentify sites in the stomach when obtaining specimens. When data from 7 specimens were used, H. pylori was found in 205 endoscopies, atrophy in 152, metaplasia in 135, and dysplasia in 22. When data from 3 specimens were used, the sensitivity was 99% for presence of H. pylori, 82% for atrophy and metaplasia, and 81% for dysplasia. When data from 5 specimens were used, the sensitivity was 100% for H. pylori, 96% for atrophy, and 95% for metaplasia and dysplasia. Although site-specific biopsy mapping is difficult in practice, the recommendations of the Sydney system as to the location and number of gastric biopsy specimens can adequately identify significant gastric histopathology.
VARIANTS
DUODENUM
Metaplasia of the duodenum shows a Helicobacter pylori-correlated differentiation into gastric-type protein expression. Van De Bovenkamp JH, Korteland-Van Male AM, Buller HA, Einerhand AW, Dekker J. Laboratory of Pediatrics, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.	Hum Pathol 2003 Feb;34(2):156-65 Abstract quote The origin of gastric metaplasia of the duodenum (GMD) remains enigmatic. We studied expression of mucins and trefoil peptides in GMD to gain insight into its phenotype and origin. We examined duodenal tissue of 95 patients (0 to 83 years old, 26 with gastric Helicobacter pylori infection) for the presence of GMD. Expression was examined immunohistochemically of secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), trefoil peptides (TFF1, TFF2, and TFF3), and sucrase-isomaltase (SI). GMD, found in 37 patients, correlated positively to gastric H. pylori infection, age, and villus atrophy. MUC2 and TFF3, expressed in normal goblet cells, were absent from 100% and 87% of GMD, respectively. GMD ubiquitously expressed MUC5AC, whereas MUC5AC expression in adjacent goblet cells was closely correlated with the extent of GMD. TFF1, TFF2, and MUC6 were found in 84%, 92%, and 65% of GMD, respectively. MUC5B was absent from epithelium and GMD. SI, expressed by villus enterocytes, was absent from GMD. Brunner's glands ubiquitously expressed MUC5B, MUC6, and TFF2. GMD was characterized by the expression of gastric-type proteins MUC5AC, MUC6, TFF1, and TFF2 and the absence of intestinal markers MUC2, TFF3, and SI. In terms of the location of metaplastic cells, our results suggest that epithelial cells migrating toward villus tips switch to gastric-type secretory cells. Positive correlation with infection suggests an inductive role H. pylori in the development of GMD.
GASTRITIS
Prevalence of intestinal metaplasia in Helicobacter pylori gastritis. Eidt S, Stolte M. Institute of Pathology, University of Cologne, Germany.	Scand J Gastroenterol 1994 Jul;29(7):607-10 Abstract quote BACKGROUND: The prevalence of intestinal metaplasia (IM) in underlying Helicobacter pylori gastritis was studied in 1446 patients. METHODS: Antral and body mucosa biopsy specimens (stains: hematoxylin and eosin, Warthin-Starry) were taken from five groups of patients: gastritis with no lesions, gastritis with duodenal, pyloric, or gastric ulcers or with chronic antral erosions. RESULTS: The prevalence of IM was higher in the antral than in the body mucosa (22.9% versus 2.8%; p < 0.001). Patients with IM had a higher mean age than those without IM in the overall group (p < 0.01). IM could be detected with the highest frequency in patients with gastric ulcers (p < 0.001). CONCLUSIONS: The higher prevalence of IM in the antral mucosa--the preferred location of gastric carcinomas--further supports the postulated association of H. pylori and gastric carcinoma. The various prevalences of IM might contribute to explaining the different probabilities of gastric carcinoma developing in the groups investigated.
Helicobacter pylori-associated gastritis. Evolution of histologic changes over 10 years. Niemela S, Karttunen T, Kerola T. Dept. of Internal Medicine, Oulu University Hospital, Finland.	Scand J Gastroenterol 1995 Jun;30(6):542-9 Abstract quote BACKGROUND: Helicobacter pylori seems to be the commonest cause of chronic gastritis, but the natural course of H. pylori-associated gastritis is largely obscure. METHODS: We present a histologic follow-up of 39 patients with H. pylori-positive gastritis. Gastroscopies with stepwise biopsies were performed in all the patients at an interval of 10 years. RESULTS: Of the patients 87% (34/39) had a persistent infection and showed a significant decrease in the grades of antral gastritis, eosinophilic granulocytes, corpus eosinophilic granulocytes, and foveolar hyperplasia and a significant increase in the grade of corpus neutrophilic granulocytes. The quantities of H. pylori as estimated histologically did not change significantly during the follow-up period in patients with a persistent infection. In the five other patients (13%) the H. pylori infection had apparently disappeared spontaneously, and this was accompanied by decreases in the amount of inflammatory cells in the gastric mucosa. CONCLUSIONS: H. pylori infection in the gastric mucosa is chronic and may be associated with both regressive and progressive histologic changes. Spontaneous healing of H. pylori infection is possible and is associated with partial resolution of the inflammatory changes in the gastric mucosa.
Numbers of inflammatory cells different in infected children versus adults	Ann Diagn Pathol 2000;4:279-285 Children had marked amounts of H. pylori organisms, mild degree of neutrophils, plasma cells, and eosinophils when compared to adults Utilized the Updated Sydney Classification
Quantitative assessment of gastric corpus atrophy in subjects using omeprazole: a randomized follow-up study. van Grieken NC, Meijer GA, Weiss MM, Bloemena E, Lindeman J, Baak JP, Meuwissen SG, Kuipers EJ. Department of Gastroenterology, Free University Hospital, Amsterdam, The Netherlands.	Am J Gastroenterol 2001 Oct;96(10):2882-6 Abstract quote OBJECTIVES: Atrophy of the gastric mucosa most frequently results from chronic Helicobacter pylori infection and is a risk factor for the development of gastric cancer. Profound acid suppression has been suggested to accelerate the onset of gastric mucosal atrophy. The aim of the present study was to evaluate the effects of H. pylori eradication and acid inhibition by omeprazole on gastric atrophy by means of quantitative analysis of tissue morphology. METHODS: Corpus biopsy specimens were obtained during endoscopy in 71 gastroesophageal reflux disease (GERD) patients at baseline and after 3 and 12 months. A total of 48 subjects were H. pylori positive and 23 were H. pylori negative. All subjects received omeprazole 40 mg once daily after the first endoscopy for 12 months. After randomization, 27 of the 48 H. pylori-positive patients also received eradication therapy. In hematoxylin and eosin-stained slides the volume percentages of glands (VPGL), volume percentages of stroma (VPS), and volume percentages of infiltrate (VPI) were measured in the glandular zone of the mucosa. The results were evaluated by computerized morphometric analysis. RESULTS: In the eradication group, the mean VPGL increased from 63.0% to 67.7% and 71.5% after 3 and 12 months (p < 0.001), respectively. The mean VPS and VPI decreased from 33.1% and 4.0% to 29.3% and 3.0% and to 26.4% and 2.1% (p < 0.001 and p = 0.04), respectively. Patients with the lowest VPGL at baseline showed the largest increases of VPGL after eradication treatment as compared to patients with high a VPGL at baseline. In the H. pylori-persistent group the VPI showed a significant increase (p = 0.01), and in the H. pylori-negative group VPGL increased significantly from 71.9% to 75.2% (p = 0.03) after 12 months. CONCLUSIONS: Eradication of H. pylori leads to restitution of the volume percentage of glandular epithelium to normal levels, even during treatment with proton pump inhibitors. Whether this effect can also be seen in patients with marked atrophy needs further investigation.
GASTRITIS, GRANULOMATOUS
Granulomatous Gastritis: A Clinicopathologic Analysis of 18 Biopsy Cases. Maeng L, Lee A, Choi K, Kang CS, Kim KM. Departments of *Pathology and daggerInternal Medicine, College of Medicine, The Catholic University of Korea, Bupyung-gu, Inchon, Korea.	Am J Surg Pathol. 2004 Jul;28(7):941-945. Abstract quote   Granulomas in gastric biopsy specimens are extremely rare, and in Western countries, more than half are associated with Crohn's disease. To evaluate the incidence and their etiology in a gastric carcinoma (and Helicobater pylori infection)-prevalent area, gastric mucosal biopsies were reviewed and their clinicopathologic findings were analyzed. The clinicopathologic diagnoses of the 18 patients with granulomatous gastritis were as follows: chronic gastritis with (n = 14) and without (n = 1) H. pylori infection; gastric adenocarcinomas (n = 2); and Crohn's disease (n = 1). Almost all cases of granulomatous gastritis in this study showed small erosions or ulcers on the endoscopic examinations. H. pylori were found to be one of the most common causes of granulomatous gastritis after excluding all other causes for the granulomas in this study. The granulomas were more frequently found in the antrum, superficially located, and were related to damage within a pit in which the H. pylori were commonly observed. These findings suggest that H. pylori can be causal in the pathogenesis of granulomatous gastritis.
LYMPHOMA
The role of Helicobacter pylori in primary gastric MALT lymphoma. Bouzourene H, Haefliger T, Delacretaz F, Saraga E. Institute of Pathology, Lausanne, Switzerland.	Histopathology 1999 Feb;34(2):118-23 Abstract quote AIMS: Helicobacter pylori has been claimed to be an important aetiological factor which raises the risk of mucosa-associated tissue lymphoid (MALT) lymphoma. However, some studies on gastric MALT lymphoma revealed a low rate of H. pylori infection suggesting that not all gastric lymphomas are related to H. pylori infection. The aim of this study was to verify the H. pylori infection frequency in a series of patients with primary gastric MALT lymphomas and to examine the relationship between H. pylori and the pathological features of those lymphomas. METHODS AND RESULTS: Thirty-one cases of resected gastric lymphoma were analysed: 10 cases (32%) were low-grade MALT lymphomas and 21 cases (68%) were high-grade MALT lymphomas. Helicobacter pylori was found in only 18 of 31 (58%) cases. Helicobacter pylori infection was significantly correlated with the grade and depth of invasion of MALT lymphoma since 63% of superficial low-grade MALT lymphomas were positive for H. pylori compared with 38% of advanced high-grade MALT lymphomas (P = 0.02). CONCLUSION: We confirmed the relationship between H. pylori infection and a subset of gastric MALT lymphoma. Our results also showed that not all low- and high-grade gastric MALT lymphomas are H. pylori-dependent. This suggests that H. pylori infection may play a promoter role in the development of MALT lymphoma, but its presence is not mandatory for the progression of the lymphoma in view of its low frequency in advanced high-grade MALT lymphoma.
POST ERADICATION THERAPY
Chronic Inactive Gastritis and Coccoid Helicobacter pylori in Patients Treated for Gastroesophageal Reflux Disease or With H pylori Eradication Therapy Neal S. Goldstein, MD	Am J Clin Pathol 2002;118:719-726 Abstract quote Gastric biopsy specimens from 105 consecutive adults with persistent dyspepsia who did not have changes due to esophageal reflux disease changes or gastric or duodenal ulcers at endoscopy were scored using the updated Sydney gastritis classification system. The medication history of proton pump inhibitors (PPIs) or Helicobacter pylori eradication therapy during the month before endoscopy was retrieved. Of the patients, 72 (68.6%) had chronic inactive gastritis, and 7 (6.7%) had antral-predominant, chronic mild active gastritis. H pylori infection was present in 36 patients (34.3%), of whom 29 had chronic inactive gastritis. Forty-six patients (43.8%) had a positive medication history, including 40 (56%) of 72 with chronic inactive gastritis. The most common morphologic feature associated with H pylori infection was moderate chronic inactive gastritis, which was found most often in patients who had received recent PPIs or H pylori eradication therapy. Pathologists should be aware of the extensive use of these medications, their association with chronic inactive gastritis, and rare H pylori that frequently are coccoid shaped. Modified Giemsa stain may not be the optimal method to detect H pylori in this group of patients.

 

SPECIAL STAINS/ IMMUNOPEROXIDASE	CHARACTERIZATION
Special stains	Giemsa, Gram Modified Steiner stain
The use of routine special stains for upper gastrointestinal biopsies. Wright CL, Kelly JK. Department of Anatomic Pathology, Royal Jubilee Hospital, Victoria, British Columbia, Canada.	Am J Surg Pathol. 2006 Mar;30(3):357-61. Abstract quote   Helicobacter pylori and intestinal metaplasia (IM) are readily seen in hematoxylin and eosin-stained slides of gastric and/or esophageal biopsies, yet many pathology laboratories perform routine special stains on all of these biopsies. We wished to determine if special stains are necessary for every single gastric and/or esophageal biopsy. We prospectively studied 613 gastric and/or esophageal biopsies from 494 consecutive patients. The slides were stained with hematoxylin and eosin, toluidine blue (TB) for H. pylori, and Alcian blue (AB) for IM. The hematoxylin and eosin slide was classed as positive or negative for H. pylori and IM. Then it was determined if the case needed a TB or AB stain. A total of 436 cases (71.1%) were identified as H. pylori-negative and not needing a TB stain, and none was TB+. A total of 126 (20.6%) of hematoxylin and eosin slides were inconclusive for H. pylori and were regarded as needing a TB stain. Twenty of these (15.9%) were TB+. Fifty-one biopsies (8.3%) were regarded as H. pylori+ on hematoxylin and eosin; the TB stain was also positive in 49. IM was present in 113 (18.4%) hematoxylin and eosin biopsies. Hematoxylin and eosin slides were IM-negative in 498 cases (81.2%). The AB stain revealed rare goblet cells in 3 of 498 cases (0.6%). Only one of those biopsies was esophageal, and that had one goblet cell that was missed on hematoxylin and eosin. Only 2 (0.3%) were regarded as needing an AB stain. We conclude that routine special stains for all gastric and/or esophageal biopsies are not required, and hematoxylin and eosin assessment combined with selective ordering of these stains will identify virtually all cases of H. pylori gastritis and intestinal metaplasia.
FISH
Reliable detection of macrolide-resistant Helicobacter pylori via fluorescence in situ hybridization in formalin-fixed tissue. Juttner S, Vieth M, Miehlke S, Schneider-Brachert W, Kirsch C, Pfeuffer T, Lehn N, Stolte M. 1Institute for Pathology, Klinikum Bayreuth, Bayreuth, Germany	Mod Pathol. 2004 Jun;17(6):684-9. Abstract quote   Macrolide-resistant Helicobacter (H.) pylori represent an increasing therapeutic problem. Macrolide resistance is usually determined phenotypically in vitro with methods such as E-test or agar dilution test. A prerequisite for those tests, however, is bacterial culture that is not routinely set up in the course of gastroscopy. In contrast, formalin-fixed, paraffin-embedded biopsies are regularly available from patients who have undergone gastroscopy. In such biopsies macrolide-resistant H. pylori can be detected by the genotype-based technique of fluorescence in situ hybridization (FISH). Experience gained by this new method, however, is still extremely limited, especially in formalin-fixed tissue. Therefore, we retrospectively investigated formalin-fixed, paraffin-embedded biopsy specimens by FISH in 104 patients suffering from therapy-resistant H. pylori gastritis. To test the accuracy of FISH, we initially examined specimens from 53 patients for whom results of the E-test were available. Next we analyzed biopsies from another 51 patients that had been selected since phenotypical resistance testing had failed despite documented culturing attempts. In all 104 patients, H. pylori was detected by FISH and could thus be investigated for macrolide resistance. Overall, macrolide-resistant bacteria were found in 71 patients (68.3%). In 49 of 53 patients (92.4%), FISH and E-test returned identical results (no significant discordance according to McNemar's chi(2)-test). Taken together, our study demonstrates that FISH is a highly sensitive and reliable method for detecting macrolide-resistant H. pylori in formalin-fixed, paraffin-embedded biopsy specimens, which represents the routine method of processing tissue obtained upon gastroscopy.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Helicobacter heilmanni	0.3-0.7% prevalence in developed countries Probably from household pets
Helicobacter heilmannii gastritis: a case study with review of literature. Singhal AV, Sepulveda AR. From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.	Am J Surg Pathol. 2005 Nov;29(11):1537-9. Abstract quote   H. heilmannii belongs to the Helicobacter family and is found in a small number of gastric biopsies. This bacterium is generally found in primates, cats, pigs, and carnivorous mammals. About 0.5% to 6% of human gastric infections have been attributed to H. heilmannii. The bacterium usually induces mild chronic gastritis but may be associated with peptic ulceration, and rare cases were reported in association with gastric carcinoma and mucosa-associated lymphoid tissue lymphoma. We report a case of H. heilmannii chronic gastritis in a 44-year-old man with a history of chronic heartburn, found to have erythema and granularity in the antrum. Antral biopsy showed mild chronic gastritis with prominent lymphoid aggregates, and rare long, thin, spiral bacilli were present adjacent to the surface epithelium. The long tightly coiled morphology suggestive of H. heilmannii was obvious at 1000 x magnification. The lack of information in the literature regarding cross-reactivity of H. heilmannii to commercially available antibodies used for immunohistochemical detection of H. pylori prompted us to evaluate whether commercially available polyclonal anti-H. pylori antibodies show cross-reactivity between the two organisms. The H. pylori immunostain highlighted H. heilmannii organisms and their characteristic morphology, confirming cross-reactivity with the anti-H. pylori polyclonal antibody. This case illustrates the potential contribution of commercially available polyclonal antibodies against H. pylori to help confirm a diagnosis of H. heilmannii gastritis. The use of immunohistochemical stain to identify H. heilmannii may be useful in cases with a paucity of organisms, with suggestive but not diagnostic forms on routine hematoxylin and eosin stain.
Helicobacter felis	Probably from household pets Associated with more acute gastritis and more severe chronic active gastritis

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors
A 12-year follow-up study of chronic gastritis and Helicobacter pylori in a population-based random sample. Villako K, Kekki M, Maaroos HI, Sipponen P, Tammur R, Tamm A, Keevallik R. Faculty of Medicine, University of Tartu, Estonia.	Scand J Gastroenterol 1995 Oct;30(10):964-7 Abstract quote BACKGROUND: The study is a 12-year endoscopic follow-up investigation on the course of chronic gastritis and Helicobacter pylori infection in a sample of 81 Estonian people. METHODS: The series is a subset from a random sample of 227 subjects in whom a gastroduodenal endoscopy had been done. The grade of superficial gastritis (SG), atrophy, and colonization of the mucosa by H. pylori was evaluated in biopsy specimens from both antrum and corpus in accordance with the principles of the Sydney System. RESULTS: The healing rate of the H. pylori and gastritis was 0.3% (3 of 81); H. pylori colonization with gastritis developed in 5 of 81 during the follow-up. The mean prevalence of atrophic gastritis (AG) was three times more common in the corpus than in the antrum on the average. The formation of new cases of AG and the disappearance of AG were quite equal during the follow-up, and the overall changes in the grade of SG and atrophy were slow. The mean life span of corpus AG was nearly three times as long as that of antrum AG. In the antrum the grade of chronic inflammation correlated positively with the grade of H. pylori colonization. In cases of SG a low grade of colonization of H. pylori in the antral mucosa in connection with moderate inflammation predicted a reduction or even a healing of gastritis in the long term. CONCLUSIONS: New H. pylori infections with subsequent gastritis may occur in adulthood; a healing of gastritis occurs but is a quite rare event in the course of the 12-year follow-up. Further, in the present random sample of Estonian people atrophic corpus gastritis did not show an overall progression, in contrast to our earlier findings.
Long-term course and consequences of Helicobacter pylori gastritis. Results of a 32-year follow-up study. Valle J, Kekki M, Sipponen P, Ihamaki T, Siurala M. Dept. of Pathology, University of Helsinki, Finland.	Scand J Gastroenterol 1996 Jun;31(6):546-50 Abstract quote BACKGROUND: The long-term course of Helicobacter pylori gastritis is not well known because there are few follow-up studies available, and the follow-up time has been short. METHODS: The progression of H. pylori infection and chronic gastritis was retrospectively examined in 102 patients followed up for 32 years. In all patients a blind suction biopsy from the corpus mucosa was taken in 1952, and an endoscopic re-examination with biopsy specimens from the antrum and corpus was performed in 1983. RESULTS: In the first examination 85 patients (83%) were H. pylori-positive as assessed from Giemsa-stained corpus mucosa specimens as compared with 70 H. pylori-positive patients (69%) at the end of the follow-up (1983). Two of the 17 patients who were initially H. pylori-negative became positive in 1983, implying an infection rate of 0.4% per patient-year. On the other hand, 17 of the 85 patients who were initially H. pylori-positive became negative in 1983, representing a disappearance rate of 0.6%. However, the stomach became completely normal in only eight cases, which represents a healing rate of 0.3% per patient-year. All patients with duodenal ulcer disease were H. pylori-positive at the first examination and remained so during the follow-up. In these patients chronic gastritis affected predominantly the antral mucosa, and corpus atrophy did not develop. Parietal cell antibodies appeared during the follow-up in six cases, and five of them were H. pylori-positive at the first examination. In most of these cases gastritis progressed into severe grades of corpus atrophy accompanied by the disappearance of H. pylori infection and normalization of the antral mucosa. CONCLUSIONS: New H. pylori infection and complete healing of infected mucosa may occur in adult life, but this is rare. Duodenal ulcer disease is associated with persistent H. pylori infection and absence of corpus atrophy. The appearance of parietal cell antibodies leads to progression of corpus atrophy and disappearance of H. pylori.
Helicobacter pylori Eradication Does Not Exacerbate Reflux Symptoms in Gastroesophageal Reflux Disease. Moayyedi P, Bardhan C, Young L, Dixon MF, Brown L, Axon AT.	Gastroenterology 2001 Nov;121(5):1120-6 Abstract quote Background & Aims: Observational studies have suggested that Helicobacter pylori may protect against gastrointestinal reflux disease (GERD), but these results could be due to bias or confounding factors. We addressed this in a prospective, double blind, randomized, controlled trial. Methods: H. pylori-positive patients with at least a 1-year history of heartburn with a normal endoscopy or grade A esophagitis were recruited. Patients were randomized to 20 mg omeprazole, 250 mg clarithromycin, and 500 mg tinidazole twice a day for 1 week or 20 mg omeprazole twice a day and identical placebos. A second concurrently recruited control group of H. pylori-negative patients were given open label 20 mg omeprazole twice a day for 1 week. All patients received 20 mg omeprazole twice a day for the following 3 weeks and 20 mg omeprazole once daily for a further 4 weeks. Omeprazole was discontinued at 8 weeks and patients were followed up for a further 10 months. A relapse was defined as moderate or severe reflux symptoms. H. pylori eradication was determined by (13)C-urea breath test. Results: The H. pylori-positive cases were randomized to antibiotics (n = 93) or placebo (n = 97). Relapse of GERD occurred in 83% of each of the antibiotic, placebo, and H. pylori-negative groups during the 12-month study period. Life tables revealed no statistical difference between the 2 H. pylori-positive groups (log rank test, P = 0.84) or between the 3 groups (log rank test, P = 0.94) in the time to first relapse. Two patients in each group developed grade B esophagitis at 12 months. Conclusions: H. pylori eradication therapy does not seem to influence relapse rates in GERD patients.
TREATMENT
Omeprazole combined with amoxicillin and clarithromycin in the eradication of Helicobacter pylori in children with gastritis: A prospective randomized double-blind trial. Gottrand F, Kalach N, Spyckerelle C, Guimber D, Mougenot JF, Tounian P, Lenaerts C, Roquelaure B, Lachaux A, Morali A, Dupont C, Maurage C, Husson MO, Barthelemy P. Departments of Paediatrics, Jeanne de Flandre Hospital, Saint Antoine Hospital, and the Department of Microbiology, Calmette Hospital, Lille, France.	J Pediatr 2001 Nov;139(5):664-8 Abstract quote OBJECTIVES: The aim of this multicenter prospective, randomized, double-blind study was to assess the efficacy of the combination of omeprazole, amoxicillin, and clarithromycin (OAC) for the treatment of Helicobacter pylori gastritis in children. Study design: Seventy-three children with dyspeptic symptoms were included in the trial (mean age 10.8 years; range, 3.3 to 15.4). Patients were randomized to receive OAC or amoxicillin and clarithromycin (AC) for 7 days. H pylori status was assessed before and 4 weeks after eradication treatment, by use of the carbon 13-labeled urea breath test. RESULTS: In intent-to-treat analysis (n = 63), eradication rates were 74.2% (95% CI, 58.7 to 89.6) in the OAC group and 9.4% (95% CI, 0 to 19.5) in the AC group. In per-protocol analysis (n = 53), the eradication rate increased to 80% (95% CI, 64.3 to 95.7), remaining significantly higher than in AC group (10.7%; 95% CI, 0 to 22.2). Resistance of strains to clarithromycin was rare (3/39 = 7.7%) and was not associated with failure of treatment. Adverse events were reported in 24.6% of patients and remained mild. CONCLUSION: This study shows that 1-week OAC triple therapy results in successful eradication of H pylori in 75% of children with gastritis.
Six-year follow-up after successful triple therapy for Helicobacter pylori infection in patients with peptic ulcer disease. Wouden EJ, Thijs JC, Zwet AA, Kleibeuker JH. aDepartment of Internal Medicine, Isala Klinieken, Zwolle, Departments of bInternal Medicine and cClinical Microbiology, Bethesda Hospital, Hoogeveen and dDepartment of Gastroenterology, University Hospital, Groningen, The Netherlands.	Eur J Gastroenterol Hepatol 2001 Oct;13(10):1235-9 Abstract quote OBJECTIVE & DESIGN: We question whether Helicobacter pylori eradication in peptic ulcer disease patients leads to a decrease in symptoms and reduced use of anti-dyspeptic drugs. Therefore, the recurrence rate of H. pylori, upper abdominal symptoms and the use of acid-suppressive drugs were determined 6 years after successful triple therapy. METHODS: Peptic ulcer disease patients successfully treated in 1990-1993 with 'classic' triple therapy were eligible. Patients were asked about symptoms and invited for a 13C-urea breath test or endoscopy in 1997-1998. Data on the use of anti-dyspeptic drugs were obtained from the pharmacy or general practitioner. RESULTS: Of the 113 eligible patients, 90 could be included in the study. The mean follow-up time was 6 years (range 4.6-7.6 years). H. pylori infection recurred in one patient (recurrence rate: 0.19% per patient-year; 95% confidence interval: 0.01-1.1%). Moderate or severe symptoms were experienced before therapy by 79% of the patients and after therapy by 18% of the patients (P< 10-7). Before triple therapy, 98% of the patients used H2-receptor antagonists and 54% were on maintenance treatment. After treatment, 30% used anti-dyspeptic medication and only 13% were on maintenance treatment (P < 10-7). CONCLUSIONS: Six years after successful triple therapy in peptic ulcer disease patients, the recurrence rate of H. pylori infection is low and both symptoms and the use of anti-dyspeptic drugs have decreased significantly.
Helicobacter pylori eradication therapy is more effective in peptic ulcer than in non-ulcer dyspepsia. Gisbert JP, Marcos S, Gisbert JL, Pajares JM. Department of Gastroenterology, University Hospital of 'La Princesa', Madrid, Spain.	Eur J Gastroenterol Hepatol 2001 Nov;13(11):1303-7 Abstract quote AIM : To evaluate whether eradication therapy is more effective in peptic ulcer disease (PUD) than in non-ulcer dyspepsia (NUD). METHODS : We retrospectively studied 481 patients with NUD (183 patients) or PUD (298 patients) infected with Helicobacter pylori included in several prospective clinical trials. Three eradication regimens were given: (1) proton pump inhibitor (PPI) plus clarithromycin, plus either amoxycillin or metronidazole for 7 days (297 patients); (2) ranitidine bismuth citrate (RBC) plus clarithromycin plus amoxycillin for 7 days (79 patients); and (3) RBC plus clarithromycin plus amoxycillin plus metronidazole for 5 days (105 patients). H. pylori eradication was defined as a negative 13C-urea breath test 4 weeks after completing treatment. RESULTS : H. pylori eradication rates were 82% (95% CI 78-87%) with PPI plus two antibiotics for 7 days, 85% (95% CI 75-91%) with RBC plus two antibiotics for 7 days, and 91% (95% CI 86-97%) with RBC plus three antibiotics for 5 days (P < 0.05 compared with the first regimen). Overall, the H. pylori eradication rate in patients with NUD was 78% (95% CI 71-84%), while in patients with PUD it was 89% (95% CI 86-93%) (P < 0.001). Both the combination of PPI plus two antibiotics for 7 days and the combination of RBC plus three antibiotics for 5 days were more effective in PUD than in NUD patients. However, RBC plus clarithromycin plus amoxycillin for 7 days was equally effective in both diseases. RBC plus two antibiotics for 7 days achieved better results than the same therapy with PPI only in NUD patients (84% v. 59%, P < 0.01), but both regimens were similar when prescribed in PUD patients (86% v. 88%). In the multivariate analysis, the type of therapy, the diagnosis (NUD v. PUD), and the product variable of therapy (with RBC plus 2 antibiotics for 7 days) and diagnosis (interaction variable) were the only variables that influenced H. pylori eradication. The odds ratio (OR) for the effect of RBC versus PPI plus two antibiotics for 7 days in patients with NUD was 4 (95% CI 1.7-9.7; P < 0.01), whereas in patients with PUD no statistical significance was achieved (OR 0.79; 95% CI 0.2-3.9). CONCLUSION : Overall, H. pylori eradication therapy is more effective in PUD than in NUD patients. This advantage of eradication therapies in PUD patients seems to be observed with 7-day PPI-based triple regimens, and with 5-day RBC-based quadruple therapy, while the 7-day RBC-based triple regimen seems to be equally effective in both diseases.
A randomized comparison of four omeprazole-based triple therapy regimens for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Laurent J, Megraud F, Flejou JF, Caekaert A, Barthelemy P. 127 rue Saint Dizier, Nancy, FranceHopital Pellegrin, Bordeaux, FranceHopital Saint Antoine, Paris, France Laboratoires AstraZeneca France, Rueil-Malmaison Cedex, France.	Aliment Pharmacol Ther 2001 Nov;15(11):1787-93 Abstract quote BACKGROUND: Helicobacter pylori eradication rates in France after therapy with omeprazole, amoxicillin and clarithromycin are among the lowest in Europe. This study evaluated alternative eradication regimens. METHODS: Helicobacter pylori-positive patients (n=323) with non-ulcer dyspepsia were randomized to receive one of four 1-week regimens consisting of omeprazole, 20 mg b.d., plus either: amoxicillin, 1000 mg b.d., and clarithromycin, 500 mg b.d. (OAC); bacampicillin, 1200 mg b.d., and clarithromycin, 500 mg b.d. (OBC); clarithromycin, 250 mg b.d., and metronidazole, 500 mg b.d. (OCM); or amoxicillin, 1000 mg b.d, and azithromycin, 500 mg on day 1 and 250 mg on days 2-5 (OAAz). Eradication was confirmed by urea breath test 4-6 weeks after treatment. Susceptibility testing was performed in the case of eradication failure. RESULTS: The eradication rate with OAAz was 38% (95% CI, 25.6-49.4) on intention-to-treat analysis, which was lower (P < 0.05) than with the other regimens [OCM, 61% (50.0-72.8); OBC, 65% (54.0-76.5); OAC, 72% (61.8-81.8)]. Of the strains isolated following treatment failure with OAC, OBC or OCM, 84% were clarithromycin resistant. CONCLUSIONS: OAC remains the reference treatment for H. pylori eradication in France, although bacampicillin offers a useful alternative to amoxicillin. Susceptibility testing should be considered after unsuccessful eradication therapy.
Are twelve days of omeprazole, amoxicillin and clarithromycin better than six days for treating H. pylori infection in peptic ulcer and in non-ulcer dyspepsia? Gisbert JP, Hermida C, Pajares JM. Department of Gastroenterology, University Hospital of La Princesa, Madrid, Spain.	Hepatogastroenterology 2001 Sep-Oct;48(41):1383-8 Abstract quote BACKGROUND/AIMS: To evaluate whether omeprazole, amoxicillin and clarithromycin for 12 days is more effective for Helicobacter pylori eradication than the same regimen for only 6 days; and to verify whether these eradication regimens are more effective in peptic ulcer disease than in non-ulcer dyspepsia. METHODOLOGY: We studied 411 patients in whom a gastroscopy was carried out due to symptoms related to the upper gastrointestinal tract and who were diagnosed with duodenal ulcer (175 patients, 43%), gastric ulcer (42 patients, 10%), or non-ulcer dyspepsia (194 patients, 47%), and concomitant infection by H. pylori. At endoscopy, biopsies were obtained for rapid urease test, and a 13C-urea breath test was carried out. Urea breath test was repeated four weeks after completing eradication treatment with 1) omeprazole (20 mg b.i.d.), amoxicillin (1 g b.i.d.) and clarithromycin (500 mg b.i.d.) for six days (239 patients), or 2) the same regimen for 12 days (172 patients). RESULTS: H. pylori eradication was achieved in 73.6% (95% CI, 68-79%) of the patients treated during 6 days, and in 84.3% (79-90%) of those receiving 12 days of therapy (P < 0.01). The overall eradication rate with both regimens (6 plus 12 days), respectively in patients with duodenal ulcer, gastric ulcer and non-ulcer dyspepsia, was 84.6% (79-90%), 75.6% (61-86%), and 72.8% (67-79%) (P Ž 0.01 when comparing duodenal ulcer vs. non-ulcer dyspepsia). Twelve-day regimen was more effective than 6-day regimen only in non-ulcer dyspepsia (62% vs. 83%, P < 0.01), but not in duodenal or gastric ulcer. In the multivariate analysis the duration (6 vs. 12 days) of eradication therapy (odds ratio: 2.2; 1.3-3.7) and the type of disease (duodenal ulcer vs. non-ulcer dyspepsia; odds ratio: 2.3; 1.3-3.8) were the only variables which influenced on H. pylori eradication efficacy (chi 2 model, 17; P < 0.001). CONCLUSIONS: Efficacy with omeprazole-amoxicillin-clarithromycin regimen in patients with duodenal ulcer is higher than in those patients with non-ulcer dyspepsia. The increase of H. pylori eradication rate by 21% in our non-ulcer dyspepsia patients justifies the prolongation from 6 to 12 days of omeprazole-amoxicillin-clarithromycin therapy, whilst the increase of cure rates in duodenal or gastric ulcer patients with a 12-day therapy would not be cost-effective.
ANTIBIOTIC RESISTANCE
Prevalence of resistant Helicobacter pylori isolates in Bulgarian children. Boyanova L, Koumanova R, Gergova G, Popova M, Mitov I, Kovacheva Y, Derejian S, Katsarov N, Nikolov R, Krastev Z. Department of Microbiology, Medical University of Sofia, Bulgaria	J Med Microbiol 2002 Sep;51(9):786-90 Abstract quote The aim of this study was to assess the primary and combined resistances of Helicobacter pylori isolates obtained from paediatric patients in 2000-2001 to seven antimicrobial agents. Resistance rates of pre-treatment isolates from 115 children were investigated by the limited agar dilution method alone and by the E-test. The cut-off concentrations for resistance were: metronidazole >8 mg/L, clarithromycin and azithromycin >1 mg/L, clindamycin >4 mg/L, amoxicillin >0.5 mg/L, tetracycline >4 mg/L and ciprofloxacin >1 mg/L. Primary resistance rates were: metronidazole 15.8%, clarithromycin 12.4%, azithromycin 14.6%, clindamycin 20.0%, amoxicillin 0%, metronidazole + clarithromycin 4.5%, ciprofloxacin 6.0%, metronidazole + clarithromycin + ciprofloxacin 1.2%, tetracycline 3.1% and metronidazole + ciprofloxacin 1.2%. There were no significant age (1-9 years versus 10-18 years) or gender differences. Prevalence of both macrolide-resistant and intermediately susceptible strains was 21.9% for azithromycin and 15.9% for clarithromycin. Of 18 metronidazole-resistant isolates, 77.8% exhibited a metronidazole MIC > or = 32 mg/L. H. pylori resistance rates to metronidazole, clarithromycin and both agents were relatively low in Bulgarian children. However, resistance was found to all drugs tested except for amoxicillin. The consumption of newer macrolides and tetracyclines could be related to the prevalence of resistance to the corresponding agents. There were no significant differences in primary resistance rates of H. pylori to antimicrobial agents between children and adults except for metronidazole. Multi-drug resistance to newer macrolides, metronidazole and ciprofloxacin in association with a slightly elevated amoxicillin MIC (0.38 mg/L) was detected in one strain.
Molecular Resistance Testing of Helicobacter pylori in Gastric Biopsies Jeremy Andrew Peńa, etal.	Arch Pathol Lab Med 2001;125:493–497 Abstract quote Objective.—To evaluate simultaneous diagnosis of infection and molecular resistance testing of Helicobacter pylori. Methods.—Gastric biopsies were obtained from 26 rapid urease-positive and 51 rapid urease-negative test kits used to diagnose H pylori infection. Following glass bead–assisted DNA isolation, amplification of H pylori 16S ribosomal DNA (rDNA), glmM, and 23S rDNA target genes was performed. Results.—Helicobacter pylori DNA was successfully amplified from 100% (26/26) of urease-positive and 3.9% (2/51) of urease-negative gastric biopsies. Subsequent restriction enzyme–mediated digestion of 23S rDNA amplification products revealed that 17% (4/24) of urease-positive and H pylori DNA–positive biopsy specimens contained point mutations (A2142G or A2143G) associated with clarithromycin resistance. Helicobacter pylori DNA from gastric biopsies was successfully amplified 8 weeks following rapid urease testing. Conclusion.—Helicobacter pylori genotyping may be used to detect macrolide-resistant H pylori in individuals prior to initiation of therapy or in patients refractory to anti-H pylori therapy. Two urease-negative specimens yielded Helicobacter DNA distinct from that of H pylori and indicated the need for further investigations of Helicobacter species present in the human stomach.

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