I OriginalResearch

The prevalence of Campylobacterpylori

gastritis among asymptomatic adults

Daniel B. Gregson, MDDonald E. Low, MDMax M. Cohen, MDNoel B. Cooter, MBJoseph J. Connon, MDStephen L. Wolman, MDAndrew E. Simor, MD

To determine the prevalence of Campylobacterpylori colonization in the healthy populationwe studied 54 asymptomatic volunteers and 65patients referred because of gastrointestinalsymptoms. All subjects underwent gastroscopyand gastric biopsy. C. pylori was isolated from 6volunteers (11%) and 36 patients (55%). Histolog-ic evidence of inflammation was present in 98%of the culture-positive subjects. Linear regres-sion analysis revealed that the prevalence of C.pylori colonization increased with age. Therewas no difference in the isolation rate betweenthe two groups when adjusted for age. Four ofthe six culture-positive volunteers underwentrepeat endoscopy and gastric biopsy 1 year later;despite remaining asymptomatic, all still hadpositive culture results and histologic evidenceof gastritis. We conclude that the prevalence ofC. pylori-associated gastritis among symptomat-ic patients increases with age and that theorganism may be present in the gastrointestinaltract for prolonged periods without symptoms orevidence of disease progression.

Afin de connaitre le taux d'implantation gastri-que du Campylobacterpyloi dans la populationnormale, on procede a la biopsie par gastrosco-pie chez 54 volontaires bien portants et 65personnes adressees pour des symptomes gastro-

From the departments of Microbiology, Medicine, Surgery andPathology, Mount Sinai Hospital, and the departments ofMedicine, Toronto General Hospital and University of Toronto

Reprint requests to: Dr. Andrew E. Simor, Department ofMicrobiology, Mount Sinai Hospital, 600 University Ave.,Toronto, Ont. M5G 1X5

intestinaux. On isole le C. pylori chez 6 (11%)des volontaires et 36 (55%) des malades. Danstous ces cas positifs sauf un, on trouve del'inflammation i l'etude histologique. La regres-sion lineaire montre que la frequence de cetteimplantation augmente avec l'age. Si on tientcompte de celui-ci, le taux d'irnplantation nediffere pas d'un groupe k l'autre. A la reprise deces examens au bout de 1 an, pratiquee chezquatre des six volontaires dont la culture a etepositive, elle le sera encore, et l'Etude histologi-que montrera toujours une gastrite, bien qu'ilsdemeurent sans sympt6mes. On conclut que letaux de gastrite k C. pylori augmente avec l'&gechez les sujets qui accusent des sympt6mes etque ce germe peut se trouver dans le tractusdigestif pendant longtemps sans sympt6mes etsans dvolution.

The association between curved or spiralgram-negative organisms and gastric dis-ease was initially described at the turn of

the century.1 However, it was not until 1983 thatWarren2 and Marshall3 reported the isolation of anew organism, now referred to as Campylobacterpylon, from patients with gastritis. This organismhas since been better characterized and is thoughtto be distinct from other Campylobacter species onthe basis of its cell-wall components, its structureas seen under the electron microscope and itsribosomal RNA sequence.4'5

Over the last 5 years studies have shown thatC. pylon can be identified in most patients withnonulcerating dyspepsia, peptic ulcer or otherinflammatory lesions of the stomach and duode-num.6-9 Virtually all patients from whom C. pyloriis isolated have histologic evidence of gastritis.7-12

CMAJ, VOL. 140, JUNE 15, 1989 1449

Challenge experiments,"3'4 therapeutic trialsl"15'16and an animal model17'18 have supported the hy-pothesis that this organism may have an etiologicrole in the pathogenesis of gastritis. We studiedhealthy asymptomatic volunteers to determine theprevalence and natural history of C. pylori coloni-zation in this population. Symptomatic patientsreferred for endoscopy were also studied.

Patients and methods

This study was carried out in accordance withthe Helsinki Declaration and approved by theUniversity of Toronto Review Committee on theUse of Human Subjects. Informed consent wasobtained from all participants before enrolment.

Healthy asymptomatic volunteers without ahistory of gastrointestinal disease or surgery wererecruited. Patients referred for endoscopy becauseof gastrointestinal symptoms were also included.The following demographic and clinical data wereobtained: age, sex, smoking history, alcohol con-sumption, use of analgesic agents, current use ofdrugs (including antiulcer drugs and antibiotics)and symptoms. A complete physical examinationwas done. Endoscopy was performed with anOlympus GIF Q10 fibreoptic endoscope (OlympusOptical, Mississauga, Ont.). At endoscopy twobiopsies each were obtained from the gastric body,the gastric antrum and the first part of the duode-num for culture and histopathologic study. A thirdbiopsy from the antrum was also obtained forrapid urease testing. The endoscope and the biopsyforceps were disinfected in 2%o glutaraldehydeafter each procedure.

Formalin-fixed specimens were processed andstained with hematoxylin and eosin. The slideswere assessed by one of us (N.B.C.) in a blindedmanner, independent of the endoscopic and cul-ture results. A modification of the criteria ofWhitehead, Truelove and Gear19 was used to assessinflammation. Each biopsy specimen was exam-ined for the presence, localization, type and degreeof inflammatory cell infiltrate. The degree of plas-ma cell and neutrophil infiltration in the superficialand deep lamina propria and in the intraepithelialportion of the gastric pits and tubules was gradedas none, mild, moderate or severe. The presence ofglandular depletion, superficial erosion and ulcer-ation was also noted.

Specimens for culture were transported direct-ly to the microbiology laboratory in 5 ml of 20%odextrose and were processed within 2 hours ofprocurement. Gram's staining of a touch prepara-tion of an antral biopsy specimen was done todetect curved gram-negative bacilli compatiblewith C. pylon. The specimens were minced andinoculated onto 5% sheep blood agar, modifiedThayer-Martin agar (containing LCAT antibioticsupplement; Oxoid Ltd., Basingstoke, England) andmodified Skirrow medium (Oxoid Ltd.). The plateswere incubated at 37°C in a microaerophilic envi-

ronment (Gas Generating Kit for Campylobacters,Oxoid Ltd.) and examined daily for 7 days. C.pylozi was identified with the use of acceptedcriteria.7'10,20

The antral specimen used for rapid ureasetesting was inoculated onto a urea agar slant (BactoUrea Agar Base Concentrate, Difco Laboratories,Detroit) and incubated at 37°C. The urea slant wasexamined for colour change at 10 minutes and at 1,2, 4 and 24 hours.

Attempts were made to repeat the investiga-tions 1 year later on all of the culture-positivevolunteers and 10 randomly selected culture-nega-tive volunteers.

Continuous variables were compared withStudent's t-test, and proportions were comparedwith either a chi-squared test with Yates's continu-ity correction or Fisher's exact test. Odds ratioswere estimated to determine the association ofsymptoms with culture positivity, and logistic re-gression analysis was used to adjust for age.1

Results

Fifty-four asymptomatic volunteers (27 men)and 65 symptomatic patients (28 men) were re-cruited. Most of the volunteers were universitystudents. None of the volunteers drank more thanone alcoholic beverage daily, were receiving long-term drug therapy or had been taking any medica-tion within 4 weeks before endoscopy. The meanage of the volunteers was 28 (extremes 20 and 56)years and of the symptomatic patients 50 (extremes22 and 86) years (p < 0.001) (Table I). Nine of thevolunteers and 14 of the patients were smokers.

Of the symptomatic patients 44 (68%) weretaking one or more of the following antiulcerdrugs: H2-receptor antagonists (26 patients), ant-acids (13), sucralfate (9) and bismuth subsalicyl-ate (4); 16 were also taking nonsteroidal anti-in-

Table Endoscopic findings anc histopatholoqi.features of gastric biopsy specimens taKur-asymptomatic volunteers and symptomatifor the detection of Carnpylobacter pylor.,

Grou-1

di--. q.tearui

u Iture-oosItIv.

Age

ndsoir.. tndrA.ge v ,

4 o r f .n

-j-bnrmal-istopathoiogac teaturezN ormal4-'bri rria

6 15^.

0.1 4.6 DV

1 L= , ,

|S

1450 CMAJ, VOL. 140, JUNE 15, 1989

flammatory drugs or salicylates, and 1 was takingprednisone. Only six drank more than one alcohol-ic beverage daily. Nineteen patients had a historyof endoscopically or surgically documented pepticulcer disease, eight had undergone gastrointestinalsurgery, and five had a history of symptomaticbiliary tract disease. At the time of endoscopythree of the patients were taking cloxacillin, ceph-alexin or tetracycline.

C. pyloA was isolated from 6 volunteers (11%)and 36 patients (55%) (p < 0.001) (Table I),including the patient taking cloxacillin. Endoscopyrevealed visible abnormalities in 42 (65%) of thepatients; C. pylori was isolated from the 3 withduodenal ulcer, 9 (82Y%) of the 11 with gastric ulcerand 16 (577%) of the 28 with gastroduodenalmucosal erythema or erosions without ulceration.Four volunteers were also thought to have local-ized areas of erythema of the gastric mucosa atendoscopy. Culture of the gastric biopsy specimensfrom 1 (25%) of the volunteers and 28 (67%) of thepatients with abnormal endoscopic findings yield-ed C. pyloA. The organism was also detected in 9(39%) of the 23 patients with normal findings.

C. pyloA was recovered from 6 (54%) of the11 volunteers and 35 (74%) of the 47 patients withabnormal histologic findings, consisting of an an-tral inflammatory cell infiltrate or ulceration orboth (Table I). Histologic evidence of antral gastri-tis was present in 41 (98%) of the 42 culture-posi-tive subjects but in only 17 (22%) of the 77culture-negative ones (p < 0.001). Eight of the 17had other conditions that may have predisposed tothe development of gastritis, such as ingestion ofalcohol, salicylates or NSAIDs. Two other culture-negative patients with gastritis had been takingbismuth subsalicylate.

The antrum was the source of C. pylori in 40(95%) of the 42 culture-positive subjects, as com-pared with the gastric body in 31 (74%) and theduodenum in 7 (17%). Gram's staining confirmedthe results for 26 specimens (62%), all of whichwere from culture-positive patients. The rapidurease test results were also positive for 26 speci-mens, 24 of which reacted within the first 4 hours.C. pylori was not isolated, and no organisms wereseen with Gram's staining in 1 of the 2 specimensthat reacted between 4 and 24 hours; this repre-sented the only false-positive result. The sensitivityand specificity of the rapid urease test were 62%and 100% respectively at 4 hours and 64% and99% respectively at 24 hours.

The culture-positive patients were older thanthe culture-negative patients (mean ages 56 and 43years respectively) (p < 0.01). The odds ratio forthe association of symptoms with the presence ofC. pylon, unadjusted for age, was 8.1 (95% confi-dence limits 3.0 and 22.1, p < 0.001). The age-adjusted odds ratio, however, was only 2.5 (95%confidence limits 0.7 and 8.6, p = 0.14). Amongthe patients the prevalence of C. pylon-associatedgastritis was independently related to age (p =0.001) (Table I). The number of volunteers over 35

years was too small to determine the associationwith age in this group.

Four of the 6 culture-positive volunteers and 8of the 10 randomly selected culture-negative vol-unteers consented to undergo repeat endoscopy 1year later. All had remained asymptomatic andhad not taken any antimicrobial or antiulcer drugs.The appearance of the gastric mucosa was normalin all the subjects. C. pyloi was isolated againfrom the four people who had had positive cultureresults, and the antral biopsy specimens againshowed histologic evidence of gastritis. The cultureresults and histopathologic findings were normalin the eight volunteers who had had negativeculture results.

Discussion

Although isolation of C. pylori has beenassociated with inflammatory disease of the stom-ach and duodenum,6-12 the role of this organism inthe pathogenesis of gastritis and peptic ulcer iscontroversial. C. pylori has been isolated from 50%to 80% of symptomatic patients referred for uppergastrointestinal endoscopy6'7'9 and has now beendetected in asymptomatic volunteers in associationwith antral inflammation.","22 Barthel and col-leagues22 found histologic evidence of C. pyloricolonization in gastric biopsy specimens from 4(20%) of 20 asymptomatic subjects; culture yieldedthe organism in only 1 person. In a study from theNetherlands11 7 (20%) of 34 asymptomatic volun-teers had positive culture results. We isolated C.pylon from 6 (11%) of 54 asymptomatic people.The isolation of this organism from symptomaticand asymptomatic people has been consistentlyassociated with histologic evidence of antral in-flammation, regardless of the endoscopic ap-pearance.8-12'22,23

The significance of antral inflammation orgastritis in the absence of symptoms is uncertain. Ithas been known for several years that the occur-rence of chronic antral gastritis is extremely com-mon among asymptomatic subjects and that theprevalence increases with age.24 Our study hasbeen the first to document, through culture, anincrease in the prevalence of both C. pyloi coloni-zation and the associated gastritis with age, verify-ing observations made in previous studies thatused nonculture techniques.25-27 Jones and collabo-rators25 found that antibodies to C. pylori werepresent in only 5% of those less than 10 years ofage, as compared with 50% of those over 50 years.Similarly, Perez-Perez and coworkers26 reportedthat the prevalence of such antibodies increasedwith age, reaching 50% among patients more than60 years old. Using a carbon-13 urea breath test todetect C. pylori, Graham and associates27 foundthat 25%Y of those aged 20 to 35 years and 82% ofthose aged 60 to 84 years had positive results.Although in our study the rate of C. pyloniisolation was significantly higher among symptom-

CMAJ, VOL. 140, JUNE 15, 1989 1451

atic patients than among asymptomatic volunteers,comparison between these two groups is not validbecause of the age differences.

The association between age and C. pylongastric colonization suggests that contact with thisorganism is common and widespread. An environ-mental reservoir has not yet been identified, butperhaps age-related changes in the gastric lumenor mucosa promote colonization after exposure.

The results of our follow-up study add to theexperience gained from three similar cases22 andshow that C. pylozi can be present with histologicevidence of gastritis for at least 1 year withoutchanges in symptoms, endoscopic findings or de-gree of histologic inflammation. This persistence ofC. pyloA and the associated inflammation has alsobeen noted in symptomatic patients,"",5"2 amongwhom eradication of the organism and resolutionof the symptoms occurred only after appropriateantimicrobial therapy.

Evidence to support the hypothesis that C.pyloA is involved in the pathogenesis of gastricmucosal inflammation includes the strong associa-tion of this organism with histologic evidence ofgastritis,8-1" the serologic and mucosal antibodyresponse to its presence,'2'25'26 the presence ofinfection in a gnotobiotic pig model'7"8 and theresults of uncontrolled human inoculation experi-ments.'3,4 Data from in-vitro studies have indicat-ed that C. pylonz may produce a cytotoxin orsubstances that degrade the protective mucouslayer of the stomach.2829 In addition, it has beenpostulated that the strong urease production of thisorganism may initiate mucosal injury.30 However,the persistence of C. pylozi in such a large segmentof the asymptomatic population suggests that thepresence of this organism alone cannot account forthe pathogenesis of gastritis or peptic ulcer disease.Prolonged colonization, accentuated host inflam-matory responses or other factors may be requiredbefore symptoms develop. Alternatively, pre-exist-ing changes in the gastric mucosa may simplyprovide this organism with an appropriate envi-ronment for growth. C. pylori cannot survive inthe absence of urea at the normally acidic gastricpH,3' and in both human challenge experimentsand the gnotobiotic pig model the stomach mustbe rendered achlorhydric through pretreatmentwith H2-receptor antagonists before colonizationcan be induced.'3"14"18

Usual methods for detecting C. pylori includemicroscopic examination, culture and rapid ureasetesting. In our study C. pylori was isolated fromthe antral biopsy specimen in 40 (95%) of the 42subjects, with positive culture results. Thus, werecommend that only biopsy of the antrum isneeded for isolating C. pylozi. Although we foundGram's staining and rapid urease testing to bespecific for the presence of C. pyloni, the sensitivityof each method was only 62%. The observationthat Gram's staining and urease test results wereusually positive in the same patients suggests thatthese tests probably depend on the quantity of

organisms present. The lower sensitivity of therapid urease test in our study than in others32'33may have been due to our use of smaller biopsyspecimens or of solid urea-containing media ratherthan a broth or gel.

In summary, C. pylori was isolated in associa-tion with histologic evidence of inflammation from11% of the asymptomatic volunteers. The isolationrate increased with age among the symptomaticpatients; there were too few volunteers over 35years of age to demonstrate a similar association inthis group. In several of the volunteers the organ-ism persisted for at least 1 year without causingsymptoms. Only prospective long-term follow-upstudies will determine the significance of C. pyloricolonization in asymptomatic subjects with histo-logic evidence of antral gastritis.

We thank Dr. Shelley Bull for her help with thestatistical analysis, the nurses in the endoscopy units atthe Mount Sinai and Toronto General hospitals for theircooperation, Elizabeth Gesicki, Craig Porter and Chris-tine Moore for their technical assistance, and MymaApanay for her secretarial assistance.

This work was supported in part by Norwich EatonPharmaceuticals Inc., Norwich, New York.

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thophysiology. Ann Intern Med 1988; 108: 865-87925. Jones DM, Eldridge J, Fox AJ et al: Antibody to gastric

Campylobacter-like organism ("Campylobacter pyloridis")- clinical correlations and distribution in the normalpopulation. JMed Microbiol 1986; 22: 57-62

26. Perez-Perez GI, Dworkin BM, Chodos JE et al: Cam-pylobacter pylor antibodies in humans. Ann Intern Med1988; 109: 11-17

27. Graham DY, Klein PD, Opekun AR et al: Effect of age onthe frequency of active Campylobacter pylor infectiondiagnosed by the (13C)urea breath test in normal subjectsand patients with peptic ulcer disease. J Infect Dis 1988;157: 777-780

28. Leunk RD, Johnson PT, David BC et al: Cytotoxic activityin broth-culture filtrates of Campylobacter pylori. J MedMicrobiol 1988; 26: 93-99

29. Sarosiek J, Slomiany A, Slomiany BL: Evidence for weaken-ing of gastric mucus integrity by Campylobacter pylozi.ScandJ Gastroenterol 1988; 23: 585-590

30. Hazell SL, Lee A: Campylobacter pyloridis, urease, hydro-gen ion back diffusion, and gastric ulcers. Lancet 1986; 2:15-17

31. Barrett Li, Marshall BJ, Prakash C et al: Protection ofCampylobacter pylon but not Campylobacter jejuni againstacid susceptibility by urea [abstr]. In Abstracts of the 27thInterscience Conference on Antimicrobial Agents and Che-motherapy, New York, Oct. 5-7, 1987: 302

32. Czinn Si, Carr H: Rapid diagnosis of Campylobacterpyloridis-associated gastritis. J Pediatr 1987; 110: 569-570

33. Marshall BJ, Warren JR, Francis GJ et al: Rapid urease testin the management of Campylobacter pyloridis-associatedgastritis. AmJ Gastroenterol 1987; 82: 200-210

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