Helicobacter spp are gram-negative, spiral-shaped bacteria. At least 13

CE 688 V Vol. 24, No. 9 September 2002 Article #3 (1.5 contact hours) Refereed Peer Review Comments? Questions? Email: compendium@medimedia.com Web: VetLearn.com Fax: 800-556-3288 KEY FACTS Peptic ulcers and gastric neoplasia secondary to Helicobacter infection are significant sequelae in humans but have not been reported in dogs and cats. Noninvasive diagnostic testing for Helicobacter infection is not readily available for dogs and cats. Treatment of Helicobacter infection consists of combination therapy with antimicrobial and antisecretory drugs. It is unknown whether Helicobacter infection in dogs and cats can be eradicated with treatment, and it is uncertain which drugs are best to use. Helicobacter Infection in Humans and Animals University of Georgia Bente Flatland, DVM, MS, DACVIM (Internal Medicine) ABSTRACT: Helicobacter are gram-negative, spiral-shaped bacteria. Infection is thought to occur via ingestion. The role of Helicobacter in the pathogenesis of canine and feline gastrointestinal disease is unknown. Many animals harboring the bacteria do not show signs. Diagnostic testing for Helicobacter can be conducted with invasive (gastric biopsy) and noninvasive methods. Many treatment protocols exist, and antibacterial drug resistance is an emerging problem in human medicine. This article provides a comparative review of Helicobacter pathogenesis, diagnostic testing, and treatment between human and veterinary medicine. Helicobacter spp are gram-negative, spiral-shaped bacteria. At least 13 species have been reported, and most are suspected or proven gastric or hepatic pathogens. 1 Helicobacter spp have been reported in humans (mainly Helicobacter pylori ), nonhuman primates (Helicobacter nemestrinae), cats and dogs (various species, including Helicobacter felis and Helicobacter bizzozeronii ), pigs (Helicobacter heilmannii), ferrets (Helicobacter mustelae), and cheetahs (Helicobacter acinonys). 2 In humans, gastric H. pylori infection has been associated with chronic gastritis, peptic ulcers, and gastric neoplasia (mucosa-associated lymphoid tissue type lymphoma and carcinoma). 3 6 Some humans with H. pylori infection develop only mild, asymptomatic gastritis. Whether more severe disease develops is thought to be influenced by individual host factors and pathogenicity of the bacteria involved. 6 The odds of developing symptomatic H. pylori infection vary with geographic location and age. 7 Different strains of H. pylori have recently been identified. Furthermore, certain H. pylori genes have been associated with increased incidence of peptic ulcer and gastric neoplasia formation. Therefore, H. pylori should be considered a population of closely related but genetically heterogenous bacteria of differing genotypes and virulence. 8 In humans, the reservoir for H. pylori is the stomach. Risk factors for H. pylori infection in humans include age and socioeconomic status, with children and those of low socioeconomic status at greater risk. 9 The role of Helicobacter spp in gastrointestinal (GI) disease in dogs and cats is uncertain. It has been known for years that spiral bacteria are commonly present in the stomachs of dogs. The relationship of these organisms to the presence and pathogenesis of gastric disease is not clear. H. pylori transmission is proposed to be fecal oral, oral oral, or gastro oral

Compendium September 2002 Helicobacter Infection 689 (via vomited fluids). 9 The exact details of transmission are still unclear. 10 A higher incidence of H. pylori infection has been reported in gastroenterologists, suggesting that transmission from patient to physician is possible. 11 It has been suggested that Helicobacter infection might be zoonotic because contact with dogs and cats has been correlated with human H. heilmannii infection. There is no correlation between pet ownership and human H. pylori infection. 9,12,13 PATHOGENESIS Helicobacter spp produce the enzyme urease, which breaks down urea into ammonia and bicarbonate ions. In the stomach, ammonia has a buffering effect that may help Helicobacter colonize mucosa in the normally acidic gastric environment. In addition, ammonia is directly toxic to gastric epithelial cells. 1 Humans H. pylori infection is associated with increased gastric acid secretion (hyperacidity), which causes inflammation in the gastric antrum (antral gastritis) and duodenal ulceration. It has been proposed that hyperacidity is caused by hypergastrinemia resulting from the inhibition of somatostatin-secreting cells (somatostatin inhibits gastrin release). 14 Hypergastrinemia also increases parietal cell mass through a trophic effect on gastric mucosa. H. pylori infection can also be associated with lack of gastric acid (achlorhydria). This is thought to occur when H. pylori causes mucosal atrophy in the gastric fundus and body or inhibits functioning of the parietal cells. 2,15 Chronic gastric inflammation may progress to chronic atrophic gastritis and intestinal metaplasia, which are precancerous conditions. 7 Dogs and Cats It appears that Helicobacter infection does not significantly alter gastric acid secretion in dogs. Study of naturally infected dogs and cats has shown that Helicobacter predominantly colonizes the gastric fundus and cardia and is associated with mild to moderate mononuclear cell inflammation. 16 In a study of beagles infected with H. felis and H. bizzozeronii like organisms, Simpson et al. 16 concluded that acid secretion was not markedly perturbed by infection and that treatment temporarily suppressed but did not eradicate the bacteria. Infected dogs showed no signs and had mild gastritis histologically before and after treatment (mild gastric inflammation was also found in the uninfected control dogs of this study). No correlation was identified between the degree of inflammation and degree of bacterial colonization. 2 Happonen et al. 17 found that successful treatment of Helicobacter in pet dogs did not change gastric histology and that mild chronic gastritis persisted following treatment, even in dogs that tested negative to Helicobacter infection, based on repeat endoscopic biopsy, brush cytology, and urease testing. DIAGNOSIS Humans Diagnostic tests for Helicobacter can be divided into invasive (those requiring a gastric mucosal biopsy specimen) and noninvasive methods. H. pylori may exhibit a patchy distribution in gastric mucosa and may cause atrophic gastritis (with resultant low bacterial numbers in the gastric mucosa). Both factors may limit sensitivity of biopsy-based diagnostic tests. 8 Of the invasive methods, culture of a gastric biopsy specimen is considered the gold standard. 8 Unfortunately, organism characteristics make culture difficult, 18 and false-negative results can occur because of loss of bacterial viability if samples are not cultured quickly (within 6 to 24 hours, depending on storage temperature). 19 Culture is considered 100% specific, but sensitivity varies widely with laboratory expertise. 19 In experienced hands, sensitivity of culture is reportedly greater than 90%. 18 Other invasive tests include rapid urease testing, direct observation of Helicobacter organisms via histopathology or electron microscopy, and polymerase chain reaction (PCR) testing. Only culture, electron microscopy, and PCR can be used to identify the particular Helicobacter sp present. Rapid urease tests identify Helicobacter by detecting urease activity. 19 A gastric mucosal biopsy specimen should be embedded in urea containing gel medium. Urease from the Helicobacter (if present) hydrolyzes urea, increasing ph and changing the color of the medium. A positive result is a color change from orange red to bright pink. Rapid urease tests are commercially available and can be used with endoscopic biopsy samples. Urease testing should be conducted on biopsy specimens within 24 hours, or false-negative results may occur. 18 False-negative results may also occur following treatment because of low organism numbers in the biopsy sample 19 and following the use of antisecretory drugs. 20 False-positive results may occur with artificial ph increases because of contamination of the sample with blood or urease-producing bacteria from the oral cavity. 18 The sensitivity and specificity of rapid urease tests are reportedly very good (88% to 100%), 19,21 except in patients with bleeding duodenal ulcers. 22 Direct observation of Helicobacter organisms in biopsy specimens usually requires special stains (e.g., Giemsa, Warthin-Starry, Genta s, alcian yellow-tolui-

690 Small Animal/Exotics Compendium September 2002 dine blue). H. pylori is typically not visualized with the commonly used hematoxylin and eosin stain. 19 Current standards in human medicine dictate that an estimate of H. pylori density, activity and grade of gastritis, and comments on the presence of atrophic gastritis or intestinal metaplasia should be provided when histopathologic examination is made. 18 The specificity of histopathology is 100%, and sensitivities of greater than 90% have been reported. 19,21 Immunohistochemical staining 8,19 and electron microscopy may also be used to evaluate gastric biopsy specimens. PCR allows identification of the particular Helicobacter sp or strain present and can be conducted using gastric biopsies, gastric juice, dental plaque, or feces. Sensitivity varies with the primer used but is considered high. 8,19,21 In addition, PCR allows identification of specific H. pylori genes associated with an increased incidence of peptic ulcer or cancer (so-called virulence factors). 8 Noninvasive diagnostic methods include urea breath testing, a stool antigen test, and serum antibody testing. Although consensus exists among gastroenterologists that noninvasive testing should be conducted first in patients suspected of H. pylori infection, agreement is lacking regarding which noninvasive test is best. 23 Urea breath testing (which detects urease activity) and the stool antigen test (which measures H. pylori antigen) are direct tests that detect active infection. Serum antibody tests are indirect and cannot distinguish between actively infected patients and those that were previously infected. Direct testing is thus preferred. However, serum antibody testing is currently the most commonly used screening method because of convenience, availability, and low cost. 23 Like the rapid urease test, urea breath testing finds Helicobacter by identifying urease activity. The patient swallows labeled (with nonradioactive carbon 13 or radioactive carbon 14) urea. If Helicobacter is present, urease hydrolyzes the labeled urea and the marker (carbon-labeled bicarbonate) is detected in the breath after 30 to 60 minutes. 24,25 A test meal is given to delay gastric emptying. 19 Antisecretory drugs increase gastric ph and decrease urease activity 20,25 ; thus test results may be false-negative immediately after treatment and must be interpreted in relation to treatment. The current recommendation in human medicine is to wait 4 weeks following cessation of therapy before conducting a follow-up urea breath test, 26 although research has demonstrated that the effect of antisecretory drugs on the urea breath test can resolve as early as 5 days after cessation of treatment. 20 Sensitivity and specificity of urea breath testing are high (greater than 95%), 19 and the urea breath test is considered a reliable, noninvasive way of documenting eradication after treatment. 26 Carbonlabeled bicarbonate can also be detected in serum, but FDA approval of this as a diagnostic test for Helicobacter is pending. 26 The stool antigen test, an enzyme immunoassay test for detecting H. pylori antigen, is the newest noninvasive technique for diagnosing Helicobacter infection in humans. Initial test kits employed polyclonal antibodies to H. pylori, but a newer test using monoclonal antibodies has been developed. Based on a review of 44 studies encompassing 4769 untreated patients, Gisbert and Pajares 27 found that sensitivity and specificity for H. pylori stool antigen testing were high (greater than 92%). The optimal time for using stool antigen testing after treatment to check for eradication is uncertain. The accuracy of this test in patients with GI bleeding is uncertain. 27 It is also uncertain whether cross-reactivity with other Helicobacter spp exists. 21 Serology identifies antibodies to H. pylori, which can be detectable for more than 1 year following infection. Three types of antibody tests are available: quantitative serum ELISA, Western blot test using serum, and qualitative rapid whole blood tests (in-office, rapid latex agglutination or flow-through, membrane-based enzyme immunoassays). Serum ELISA testing is the most commonly used method and can detect IgG and IgA. The serum IgG ELISA is considered most sensitive, although sensitivity depends on characteristics of the population tested and the particular H. pylori antigen preparation used to make the test kit. Herbrink and van Doorn 8 reported that sensitivity and specificity of commercial ELISA assays vary 60% to 100%, and most had values over 85%. Western blot testing of serum permits more detailed analysis of the patient antibody profile but has limited usefulness because of labor-intensive methodology. Variable sensitivity has been reported for in-office, rapid, whole blood tests designed for use in primary care clinics. 8 Antibodies (IgG) to H. pylori can also be detected in saliva, but this method had lower sensitivity and specificity (81% and 73%, respectively) than serum antibody testing (90% sensitivity, 78% specificity) in a recent multicenter study of 213 dyspeptic patients. 28 IgG against H. pylori has also been detected in urine, and a urine-based ELISA test recently validated in Japan had an accuracy comparable to that of the serum ELISA test. 18 Dogs and Cats Noninvasive test methods for detecting Helicobacter (e.g., urea breath testing, antibody testing, stool antigen testing) are not routinely available for dogs and cats. Urease testing (breath and blood) has been inves-

Compendium September 2002 Helicobacter Infection 691 Figure 1 H. pylori organisms (arrow) in the lumen of a gastric gland of a cat. (Warthin-Starry silver stain, original magnification, 100) Figure 2 H. felis organisms (arrows) in the lumen and cytoplasm of parietal cells in the fundic mucosa of a cat. (Triple stained with Warthin-Starry, hematoxylin and eosin, and alcian blue, original magnification, 100) Figure 3 Numerous long H. heilmannii-like organisms (arrows) in the lumen and cytoplasm of parietal cells in the fundic mucosa of a cat. (Van Orden silver stain, original magnification, 100) tigated in dogs but is not widely available. 25,29 Antibody testing in dogs and cats is potentially more difficult than in humans because of the variety of Helicobacter spp infecting dogs and cats. Nonetheless, antibody testing is being investigated, and infected animals are known to develop antibodies. 30,31 Theoretically, stool antigen testing could be useful in H. pylori infected cats (or in animals infected with Helicobacter spp that have antigenic homology and thus cross-reactivity with H. pylori ). This has not been investigated. The only way to confirm the presence of Helicobacter in dogs and cats is with the invasive methods already discussed. Endoscopically obtained gastric mucosal biopsies are commonly used, and direct observation of organisms (via histologic examination of biopsies or cytologic examination of brush cytology specimens) and rapid urease testing are common methods of identifying Helicobacter. Because Helicobacter distribution in the stomach may be patchy, evaluation of multiple biopsies and anatomic locations (i.e., cardia, fundus, antrum) is recommended. 24 Figures 1 through 3 show photomicrographs of Helicobacter spp in feline gastric mucosae. Unfortunately, the lack of noninvasive diagnostic testing for Helicobacter in veterinary medicine makes response to treatment difficult to assess. Repeat endoscopy or biopsy is required, which is expensive and unappealing to many pet owners. However, an advantage of followup endoscopy over noninvasive testing is the opportunity to reassess gastric morphologic changes. TREATMENT Humans Eradication therapy for Helicobacter is recommended for humans with symptomatic H. pylori infection. Treatment guidelines exist for the various subcategories of GI disease caused by H. pylori in humans. 7 In general, eradication therapy consists of antibiotic drugs in conjunction with antisecretory drugs. Some gastroprotective drugs have also been reported to have antimicrobial activity against H. pylori. 32 Experience in humans has revealed that multiple drugs are needed to cure H. pylori infection. The most successful treatment regimens consist of at least two antibiotics combined with bismuth and/or an antisecretory drug. Many combination drug regimens exist in human medicine. Treatment duration is 1 to 2 weeks; 10- and 14-day treatment regimens have better cure rates and are considered superior to 7-day regimens. Currently recommended antimicrobials include amoxicillin, tetracycline, metronidazole, clarithromycin, and bismuth (Table 1). Antisecretory therapy accompanies antibiotic therapy because eradication rates increase

Compendium September 2002 Helicobacter Infection 693 when both are used together. Furthermore, the antimicrobial activity of amoxicillin and clarithromycin is better at a higher ph. Both H 2 -receptor antagonists and proton-pump inhibitors can be used for antisecretory therapy, but proton-pump inhibitors are preferred because they suppress acid production more reliably, provide more rapid ulcer healing, and have anti H. pylori activity in vitro. Classic triple therapy in humans consists of bismuth, metronidazole, and tetracycline. New triple therapies refers to combinations of antibiotics and a proton-pump inhibitor. Quadruple therapy refers to classic triple therapy that has been modified by increasing the dose of metronidazole and adding a proton-pump inhibitor. 32 Antibiotic resistance of H. pylori is a problem in human medicine and has been reported for clarithromycin, metronidazole, amoxicillin, and tetracycline. Interestingly, combination therapies involving metronidazole have been used successfully despite apparent metronidazole resistance in vitro. Treatment failure in humans is caused by antibiotic resistance or insufficient suppression of gastric acid production. 32 Dogs and Cats Treating Helicobacter infection in dogs and cats is controversial. Whether treatment is needed in all cases and which drugs are preferred is not clear. Efficacy of treatment is also unclear, and it is unknown whether drug resistance is a problem in veterinary patients. Recent studies suggest that treatment might only suppress infection but not eradicate it. 2,17,25 More reports of posttreatment follow-up assessing bacterial status and GI Table 1. Drugs Used To Treat H. pylori Infection in Humans 32,a Recommended Drug Class Drug(s) Mechanism Resistance Penicillins Amoxicillin Inhibits bacterial wall synthesis Not common; does produce crossresistance to other penicillins Tetracyclines a Tetracycline Inhibits bacterial protein synthesis Not common Oxytetracycline by binding the 30S ribosomal subunit Nitroimidazoles Metronidazole Damages bacterial DNA Common in countries where it is used for diarrhea, amoebiasis, or trichomoniasis Macrolides Clarithromycin Inhibits bacterial protein synthesis Increasing; may limit usefulness by binding the 50S ribosomal in the future subunit Bismuth salts Bismuth subsalicylate Disrupts bacterial cell walls Not reported Bismuth subcitrate Ranitidine bismuth Combination of bismuth and the Not reported citrate H 2 antagonist ranitidine; an advantage is that bismuth is soluble in acid Proton-pump Omeprazole Suppresses gastric acid production Does not apply inhibitors Lansoprazole via inhibition of the sodium- Pantoprazole potassium-atpase pump Rabeprazole H 2 -receptor Cimetidine Suppresses gastric acid production by Does not apply antagonists Famotidine competitively inhibiting histamine Nizatidine Ranitidine Roxatidine a Doxycycline is reportedly ineffective for treating H. pylori. 24

694 Small Animal/Exotics Compendium September 2002 changes are needed for naturally acquired clinical cases. Treating Helicobacter infection in a dog or cat should be considered if all of the following are true: The animal has clinical signs of gastritis. The animal has histologic evidence of gastritis. Helicobacter is identified. There is no other apparent cause of the gastritis. Table 2. Drugs Used to Treat Helicobacter Infection in Dogs and Cats Drug Dosage a,b Study Antimicrobial Amoxicillin 15 20 mg/kg PO q8h Fox 13,33 Clarithromycin 7.5 mg/kg PO q12h Fox 13 Metronidazole 10 20 mg/kg PO q12h Fox 13,33 Tetracycline 20 mg/kg PO q8 12h Fox 13, Happonen et al. 17 Antisecretory Cimetidine 5 10 mg/kg PO or IV q8h Fox 13 Famotidine 0.5 mg/kg PO q12h Simpson et al. 2, Cornetta et al. 25 Ranitidine 1 2 mg/kg PO or IV q12h; Fox 13 2.5 mg/kg IV or 3.5 mg/kg PO q8h (cats) Omeprazole 0.5 1 mg/kg/day PO Fox 13,3 (maximum dose in dogs, 20 mg) 3 Other Misoprostol 1 5 µg/kg PO q8h (dogs) Fox 13 Bismuth subsalicylate c 0.5 2 ml/kg (dogs) or 0.5 1 Fox 13,33 ml/kg (cats) PO q6h Bismuth subcitrate 6 mg/kg PO q12h Fox 13,33 Sucralfate 0.5 1 g PO q2 4h Hall 1 a Treatment duration is typically 2 to 4 weeks. b Dosages can be used in both dogs and cats unless specified otherwise. c Bismuth subsalicylate (Pepto-Bismol, Procter & Gamble). Use with caution in cats because of their sensitivity to salicylate. Suggested Drug Combinations for Treatment of Helicobacter Infection Triple therapy (amoxicillin + metronidazole + bismuth) Fox 13,33 Tetracycline + metronidazole + bismuth Fox 13 Clarithromycin + metronidazole + bismuth Fox 13 Amoxicillin + metronidazole + one of the following: Fox 13, Cornetta cimetidine, famotidine, ranitidine, omeprazole, et al. 25 or misoprostol Amoxicillin + metronidazole + sucralfate Hall 1 Tetracycline + omeprazole Happonen et al. 17 Amoxicillin + clarithromycin + omeprazole Hall 1 A thorough investigation to rule out underlying GI disease (e.g., food intolerance/hypersensitivity, parasitism, inflammatory bowel disease, neoplasia) should be undertaken before treating Helicobacter infection. Even with such a workup, it may be difficult to know whether all GI inflammation is caused by Helicobacter infection alone or whether underlying inflammatory disease is present. This is especially true for patients in which inflammation persists following treatment and apparent Helicobacter eradication. Treatment protocols in dogs and cats have been adapted from human medicine and include various combinations of antibiotic and antisecretory therapy. Traditional veterinary triple therapy consists of metronidazole, amoxicillin, and bismuth subsalicylate and has been used as initial treatment for Helicobacter infection in dogs and cats. 33 Other antimicrobial drugs that have been used in animals in which traditional triple therapy fails include tetracycline and clarithromycin. Antisecretory drugs that have been used include H 2 antagonists (e.g., cimetidine, ranitidine, famotidine) and proton-pump inhibitors (omeprazole). The synthetic prostaglandin analogue misoprostol has also been used. 13 Veterinary drug protocols and dosages are summarized on this page (see box and Table 2). Treatment is typically administered for 2 to 4 weeks, 1,13 but the optimal duration of treatment is unknown. 13 Bismuth subsalicylate should be administered cautiously or not at all in cats because of their innate salicylate sensitivity. I have seen clinical gastritis resolve following 4 weeks of treatment with traditional veterinary triple therapy (in dogs) or a combination of amoxicillin, metronidazole, and famotidine (in dogs and cats).

Compendium September 2002 Helicobacter Infection 695 Current Knowledge of the Role of Helicobacter in Dogs and Cats What We Do Know Many dogs and cats, healthy and sick, are infected with Helicobacter-like organisms. Most infected animals are asymptomatic. Gastric acid secretion may not be significantly affected. 2 Helicobacter infection can be associated with lymphocytic-plasmacytic gastritis and proliferation of lymphoid follicles. 1 Degeneration of gastric glands may occur. Infected animals can develop antibodies (seroconvert). 16 Peptic ulcers and gastric neoplasia as a result of Helicobacter infection have not been reported in dogs and cats. 16 Treatment may not eradicate the bacteria, and subclinical gastritis may persist following treatment. 2,25,35 What We Do Not Know What are the factors that control the interaction between host and Helicobacter and the development of clinical gastritis in dogs and cats? Recent studies have not found a correlation between the degree of colonization and the degree of gastric inflammation in dogs. 2,34 Is there a difference between the young, otherwise healthy laboratory animals used in many studies and the pet population? 6 Is treatment always indicated when Helicobacter is identified? Based on what is known, the answer may be no for many dogs and cats. 6 When should infection be considered significant? Are all Helicobacter spp equally significant in the pathogenesis of canine and feline GI disease? Can treatment eradicate the bacteria in dogs and cats? Does it merely suppress infection, rendering Helicobacter undetectable? 17 How long should treatment last? What causes recurrence of infection? Reinfection? Recrudescence of suppressed infection? Is Helicobacter drug resistance a problem in veterinary medicine? LOOKING TO THE FUTURE Much is yet to be learned regarding the role of Helicobacter infection in dogs and cats (see box above). Further research is desperately needed. A systematic approach to diagnosis and treatment, including posttreatment assessment, is vital to furthering our understanding of this infection in the pathogenesis of canine and feline GI disease. PCR may prove helpful in determining the particular Helicobacter sp present and whether treatment truly eradicates or merely suppresses infection. Without such information, it is impossible to know whether apparent treatment failures and relapses are caused by persistence of Helicobacter infection, reinfection, or the presence of underlying GI disease. Development of noninvasive diagnostic tests appropriate for veterinary patients would also help improve our understanding of Helicobacter infection in dogs and cats. ACKNOWLEDGMENT The author thanks Elizabeth Howerth, DVM, PhD, for contributing the figures in this article. REFERENCES 1. Hall JA: Diseases of the stomach, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders Co, 2000, pp 1154 1181. 2. Simpson KW, Strauss-Ayali D, McDonough PL, et al: Gastric function in dogs with naturally acquired gastric Helicobacter spp infection. J Vet Intern Med 13:507 515, 1999. 3. Solte M, Bayerdorffer E, Morgner A, et al: Helicobacter and gastric MALT lymphoma. Gut 50(Suppl 3):III19 III24, 2002. 4. Uemura N, Okamoto S, Yamamoto S, et al: Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345(11):784 789, 2001. 5. Fox JG, Wang TC: Helicobacter pylori: Not a good bug after all. N Engl J Med 345(11):829 832, 2001. 6. Eaton KA: Man bites dog: Helicobacter in the new millennium [editorial]. J Vet Intern Med 13:505 506, 1999. 7. Nakajima S, Graham DY, Hattori T, Bamba T: Strategy for treatment of Helicobacter pylori infection in adults. I. Updated indications for test and eradication therapy suggested in 2000. Curr Pharm Design 6(15):1503 1514, 2000. 8. Herbrink P, van Doorn LJ: Serological methods for diagnosis of Helicobacter pylori infection and monitoring of eradication therapy. Eur J Clin Microbiol Infect Dis 19:164 173, 2000. 9. Deltenre M, de Koster E: How come I ve got it? (A review of Helicobacter pylori transmission). Eur J Gastroenterol Hepatol 12:479 482, 2000. 10. Blanchard JF, Czinn SJ: Helicobacter pylori acquisition and transmission: Where does it all begin? [editorial]. Gastroenterology 121:483 490, 2001. 11. Lin SK, Lambert JR, Schembri MA, et al: Helicobacter pylori prevalence in endoscopy and medical staff. J Gastroenterol Hepatol 9:319 324, 1994. 12. Meining A, Kroher G, Stolte M: Animal reservoirs in the transmission of Helicobacter heilmannii: Results of a questionnairebased study. Scand J Gastroenterol 33:795 798, 1998.

696 Small Animal/Exotics Compendium September 2002 13. Fox JG: Gastric helicobacters, in Greene CE (ed): Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders Co, 1998, pp 229 233. 14. Moss SF, Legon S, Bishop AE, et al: Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 340(8825):930 932, 1992. 15. El-Omar EM, Oien K, El-Nujumi A, et al: Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 113:15 24, 1997. 16. Simpson KW, Neiger R, DeNovo R, Sherding RG: The relationship of Helicobacter spp infection to gastric disease in dogs and cats. J Vet Intern Med 14:223 227, 2000. 17. Happonen I, Linden J, Estermarck E: Effect of triple therapy on eradication of canine gastric helicobacters and gastric disease. J Small Anim Pract 41:1 6, 2000. 18. Leodolter A, Wolle K, Malfertheiner P: Current standards in the diagnosis of Helicobacter pylori infection. Dig Dis 19:116 122, 2001. 19. Vaira D, Holton J, Menegatti M, et al: Review article: Invasive and noninvasive tests for Helicobacter pylori infection. Aliment Pharmacol Ther 14(Suppl 3):13 22, 2000. 20. Chey W, Woods M, Scheiman JM, et al: Lansoprazole and ranitidine affect the accuracy of the 14C-urea breath test by a phdependent mechanism. Am J Gastroenterol 92:446 450, 1997. 21. Montiero L, de Mascarel A, Sarrasqueta AM, et al: Diagnosis of Helicobacter pylori infection: Noninvasive methods compared to invasive methods and evaluation of two new tests. Am J Gastroenterol 96:353 357, 2001. 22. Lee JM, Breslin NP, Fallon C, O Morain CA: Rapid urease tests lack sensitivity in Helicobacter pylori diagnosis when peptic ulcer disease presents with bleeding. Am J Gastroenterol 95:1166 1170, 2000. 23. Chey W, Fendrick AM: Noninvasive Helicobacter pylori testing for the test and treat strategy. Arch Intern Med 161:2129 2132, 2001. 24. Neiger R, Simpson KW: Helicobacter infection in dogs and cats: Facts and fiction. J Vet Intern Med 14:125 133, 2000. 25. Cornetta AM, Simpson KW, Strauss-Ayali D, et al: Use of a [13C]urea breath test for detection of gastric infection with Helicobacter spp in dogs. Am J Vet Res 59(11):1364 1369, 1998. 26. Metz DC: Stool testing for Helicobacter pylori infection: Yet another noninvasive alternative. Am J Gastroenterol 95:546 548, 2000. 27. Gisbert JP, Pajares JM: Diagnosis of Helicobacter pylori infection by stool antigen determination: A systematic review. Am J Gastroenterol 96(10):2829 2838, 2001. 28. Luzza F, Imeneo M, Marasco A, et al: Evaluation of a commercial serological kit for detection of salivary immunoglobulin G to Helicobacter pylori: A multicenter study. Eur J Gastroenterol Hepatol 12:1117 1120, 2000. 29. Neiger R: Helicobacter-Infektion bei Hund und Katze. Teil 2: Diagnose und Therapie. Kleintierpraxis 43(12):875 883, 1998. 30. Strauss-Ayali D, Simpson KW, Schein AH, et al: Serologic discrimination of dogs infected with gastric Helicobacter spp and uninfected dogs. J Clin Microbiol 37:1280 1287, 1999. 31. Seidel KE, Stolte M, Lehn N, Bauer J: Antibodies against Helicobacter felis in sera of cats and dogs. Zentralblatt fur Veterinarmedizin Reihe B46:181 188, 1999. 32. Nakajima S, Graham DY, Hattori T, Bamba T: Strategy for

698 Small Animal/Exotics Compendium September 2002 treatment of Helicobacter pylori infection in adults, II. Practical policy in 2000. Curr Pharm Design 6(15):1515 1529, 2000. 33. Fox JG: Helicobacter-associated gastric disease in ferrets, dogs, and cats, in Bonagura JD (ed): Kirk s Current Veterinary Therapy XII. Philadelphia, WB Saunders Co, 1995, pp 720 723. 34. Happonen I, Linden J, Saari S, et al: Detection and effects of helicobacters in healthy dogs and dogs with signs of gastritis. JAVMA 213(12):1767 1774, 1998. 35. Hall E, Simpson KW: Diseases of the small intestine, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders Co, 2000, pp 1182 1233. ARTICLE #3 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 1. In humans, the reservoir for H. pylori is, and transmission is thought to be. a. dental tartar; oral oral or fecal oral b. saliva; oral oral or gastro oral c. the stomach; oral oral, fecal oral, or gastro oral d. the proximal small intestine; fecal oral or gastro oral 6. Rapid urease tests work by detecting a. labeled bicarbonate. b. anti H. pylori antibodies. c. an increase in ph due to urease activity. d. H. pylori antigen. 7. Detecting spiral bacteria in gastric biopsy specimens is not possible without a. full-thickness biopsies. b. electron microscopy. c. special staining. d. immunohistochemistry. 8. Treatment failure of Helicobacter infection can be due to a. antimicrobial resistance. b. inadequate suppression of gastric acid secretion. c. recrudescence of infection. d. all of the above 9. Bismuth is effective for treating Helicobacter infection because a. it reduces gastric acid. b. it disrupts bacterial cell walls, killing the bacteria. c. it comes combined with ranitidine. d. the salicylate component is antiinflammatory. 10. Which antibiotic(s) is useful for treating H. pylori? a. amoxicillin c. clarithromycin b. metronidazole d. all of the above 2. H. pylori causes gastric disease by a. producing urease, which causes ammonia formation. b. causing gastric hyperacidity. c. causing gastric mucosal atrophy. d. all of the above 3. In dogs and cats, Helicobacter infection may be associated with a. lymphocytic-plasmacytic gastritis. b. prominent lymphoid follicles. c. gastric lymphoma. d. a and b 4. The gold standard diagnostic test for Helicobacter is, but it is often not conducted because of. a. culture; the difficulty in culturing the organism b. urease testing; the need for gastric biopsy c. the stool antigen test; limited availability d. endoscopic biopsy; the expense 5. Which diagnostic test can be used to identify particular species of Helicobacter? a. urease testing b. PCR c. stool antigen test d. direct examination of organisms (biopsy)