J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.385 on 1 November 1997. Downloaded from

ORIGINAL ARTICLES Breath Test Diagnosis of in : A Noninvasive Primary Care Option

Michael W Felz, MD, George] Burke, MD, and Bernard M. Schuman, MD

Background: Hellcobacter pylori is implicated as the causative agent for most duodenal and gastric ulcers. Invasive ( and ) and noninvasive (serology, breath test) methods are currently available for definitive diagnosis of infectious peptic ulcer disease. Methods: Twenty-six patients with chronic symptoms underwent upper endoscopy, biopsy, rapid test, and [14C] breath test for the detection of H pylori. Results: Twenty of 26 patients (77 percent) had biopsy-proved H pylori . All 20 (100 percent) with definite H pylori proved by invasive diagnosis had strongly positive results on . Six patients with absence of H pylori on biopsy had negative urea breath test results. The urea breath test displayed 100 percent sensitivity, specificity, and predictive value compared with endoscopy and biopsy. Conclusions: [14C]Urea breath testing is comparable to endoscopy and biopsy in the diagnosis of H pylori infection and could become useful in primary care settings for noninvasive evaluation of peptic ulcer disease. (J Am Board Fam Pract 1997;10:385-9.)

A dramatic transformation in the understanding diagnosis of H pylori infection. This procedure, and treatment of peptic ulcer disease occurred however, is invasive, expensive, and often depen­ during the past decade with discovery of the piv­ dent on referral to a specialist. Recent studies have otal contribution of Helicobacter pylori to antral emphasized the emerging role of the [14C]urea gastritis, gastric ulceration, duodenal ulceration, breath test as a safe, precise, cost-effective, and eas­ and ulcer recurrence. 1 The methods of diagnos­ ily performed outpatient diagnostic test.7-12 ing H pylori infection are numerous, as indicated Marshall and WarrenJ3 were the first investiga­ by several recent clinical reviews.2-6 Endoscopy is tors to associate gastritis and peptic ulceration

a central diagnostic method in all studies. With with a curved urease-producing organism identi­ http://www.jabfm.org/ the introduction of a new nuclear medicine test fied as Campylobacter pyloridis. This organism, suitable for the primary care setting, the noninva­ later reclassified as H pylori, is histologically de­ sive diagnosis and management of peptic ulcer tectable in most patients with active chronic gas­ disease might soon undergo considerable change tritis. Moreover, H pylori is found in gastric antral as well. in 90 to 95 percent of patients with visi­ A novel diagnostic radiopharmaceutical, urea la­ ble duodenal ulcer and 65 to 80 percent of those beled with radioactive carbon (14C), shows promise with gastric ulcer.14-16 Eradication of H pylori is on 23 September 2021 by guest. Protected copyright. as a noninvasive tool for detecting H pylori in hu­ also strongly linked to ulcer healing and preven­ mans. Previously, endoscopy was a frequent initial tion of ulcer recurrence. 17,18 Although gastric step in the detection of peptic ulcer disease and, acid has long been recognized as one of many fac­ coupled with biopsy, was considered essential for tors in the pathogenesis of ulcers, the causative evidence linking H pylori to ulceration is now compelling enough to regard duodenal and gas­ Submitted, revised, 21 April 1997. tric ulcers as infectious diseases in the vast ma­ From the Department of Family Practice (M\VF), Depart­ 19 ment of Radiology (Nuclear Medicine) (G]B), and the Depart­ jority of cases. Notable exceptions are patients ment of Medicine (Gastroenterology) (BMS), Medical College of with nonsteroidal anti-inflammatory drug Georgia, Augusta. Address reprint requests to Michael W. Felz, (NSAID)-induced ulceration or Zollinger-Elli­ MD, Department of Family Practice, Medical College of Geor­ son syndrome. gia - HB 4032, Augusta, GA 30912. The authors have no affiliation whatsoever with the urea A particular biochemical property of H pylori breath test manufacturer, Tri-Med Specialties. facilitates the use of the [14C]urea breath test to

Breath lest Diagnosis of H pylori 385 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.385 on 1 November 1997. Downloaded from

diagnose the presence of the organism in gastric Under a study protocol approved by our institl/­ or duodenal mucos,l. This microbe produces rela­ tional review board, 26 patients with symptoms tively high concentrations of urease, an underwent upper gastrointestinal endoscopy and that hydrolyzes urea into the alkaline buffers am­ biopsy in a nonblinded study of presumed peptic monium and bicarbonate. ulcer disease during a 20-month period. The group consisted of 14 men and 12 women; their Urease mean age was 49.8 years (range, 24 to 82 years). CO(NH2h + IV) + IT' -) 2NH-++ + IICO;- Most were referred by primary care clinicians. Urea Ammonium Bicarbonate Symptoms included postprandial epigastric pain, failure of acid suppression therapy, hematemesis, Bicarbonate generated in gastric mucosa enters melena, and iron deficiency anemia determined by the blood stream, is transported to the lungs, and testing. Each patient underwent is rapidly excreted from the lungs as volatile car­ endoscopic inspection, photography and biopsy of bon dioxide. In the [HC]urea breath test, a cap­ gastroduodenal mucosa, and the Campylobactel·­ sule of urea tagged with radioactive carbon is like organism (CLO) test of gastric antral tissue administered orally to a patient; the patient's ex­ specimens for bacterial urease. Hematoxylin and haled is then collected in airtight eosin and Giemsa stains of gastric antral mucosa balloons. Detection of elevated quantities of ex­ were processed in the Medical College of Georgia haled carbon dioxide tagged with carbon 14 Department of and reviewed by faculty ([l4C]02) indicates marked bacterial urease activ­ pathologists. CLO tests were interpreted within ity in the patient's . Production of ammo­ 24 hours by the endoscopist who performed the nium and bicarbonate could allow local buffering biopsies. Serologic tests, while sensitive for H py­ of highly acidic (pH 1.5) gastric secretions and lori infection, were not available for all patients confer on H pylori its unique microbiologic ability and thus were not analyzed in this protocol. Pa­ to survive in the hostile gastric lumen.2o Vigorous tients were excluded from the study if they had in­ urease activity, then, might be vital to the organ­ gested antibiotics or bismuth-containing drugs ism's ecologic niche, and the elevated [14C]02 during the previous 28 days. measurements of exhaled carbon dioxide labeled The [14C]urea breath test was performed in our with carbon 14 from intense urea is a nuclear medicine outpatient clinic within 5 days biologically plausible indirect measure of H pylori of upper gastrointestinal endoscopy. We used http://www.jabfm.org/ presence. specifications established by the manufacturer (Tri-Med Specialties, Charlottesville, Va) to in­ Methods terpret all breath samples. Samples were inter­ Carbon-14-labeled urea is supplied in a gelatin preted as negative if they contained fewer than 49 capsule containing 1 pCi (37 kBq) of the radio­ disintegrations per minute (dpm); indeterminate pharmaceutical. Before the breath test is adminis­ if 50 to 99 dpm; and positive if more than 100 tered, the patient must fast for 6 hours and refrain dpm. Patients who had positive test results for H on 23 September 2021 by guest. Protected copyright. from ingesting antibiotics or bismuth salts for at pylori were defined as those in whom characteris­ least 4 weeks. The capsule, coated to prevent hy­ tic curved were detected in the gastric drolysis by oral flora, is swallowed with 30 mL of mucus layer on Giemsa-stainecl antral histologic warm water to promote its dissolution in the sections or who had a definite biochemical color stomach and release of [14C]urea, a process that reaction on the CLO . takes approximately 3 minutes. Radioactive car­ bon dioxide is usually detectable in the breath Results within 5 minutes, with peak excretion occurring Seventeen (65 percent) of the 26 patients had en­ between 10 and 15 minutes after capsule adminis­ doscopic evidence of discrete ulceration: 11 with tration. Breath samples are obtained at 10, 15, duodenal, 3 with gastric, and 3 with both gastric and 20 minutes by having the patient exhale and duodenal ulcers. Fourteen with discrete ulcers through a straw into a 1.5-L aluminized balloon. had histologic evidence of H pylor-i on antral Carbon radioactivity is then counted in a liquid biopsy; in the other three cases, histologic ex­ scintillation counter. amination was deferred as a result of a strongly

386 JABFP Nov.-Dec.1997 Vol. 10 No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.385 on 1 November 1997. Downloaded from positive CLO test. Three additional patients (12 sensitivity of 20 of 20 (100 percent; 95 percent percent) had no visible ulceration but did have his­ confidence interval[CI]: 83.2 to 100.0) and speci­ tologic evidence of active chronic gastritis on ficity of 6 of 6 (100 percent; 95 percent CI: 54.1 to antral biopsy, H pylori organisms on , 100.0). The [14C]urea breath test showed no diag­ and positive CLO test results. Of the 20 patients nostic errors in this sample; thus, both positive determined to have H pylori infection, 19 had pos­ and negative predictive values are 100 percent. itive CLO test results for rapid urease activity. One patient had duodenal ulceration and visible H Discussion pylori organisms on biopsy, but that patient's CLO In our series of patients with chronic gastritis test results were negative. In all 20 patients with symptoms and definite H pylori infection, the evidence of H pylori infection, the [l4C]urea breath [14C]urea breath test proved a simple and reliable test had strongly positive results (more than 100 method for documenting the presence of the or­ dpm), with counts in IS-minute exhaled samples ganism in association with frank ulceration (17 averaging 1868 dpm (range: 345 to 2976 dpm). patients) and active chronic gastritis (3 patients). Six (23 percent) of the 26 patients had no ulcer Assuming that the reference standard of en­ on endoscopy, normal antral histologic findings, doscopy and biopsy is 100 percent sensitive, then absence of H pylori on Giemsa-stained sections, the [14C]urea breath test, at least in our cohort, and negative CLO test results. Five had negative was 100 percent sensitive as well. Conversely, in (fewer than 49 dpm) [14C]urea breath test results. the 6 patients who had no endoscopic ulceration One case was indeterminate with 66, 97, and 93 and no evidence of gastritis or H pylori infection dpm at 10, 15, and 20 minutes, respectively, and on biopsy, [l4C]urea breath test results were neg­ was regarded not to have H pylori infection. For the ative in all six cases. Specificity, then, would be 6 patients who did not have H pylori infection, the 100 percent. Both positive and negative predic­ average [14C]urea breath test reading was 33 dpm. tive values are likewise quite high in our cohort. All patients with evidence of H pylori infection Such high sensitivity, specificity, and predictive were given prescriptions for a combination of an­ values for a single test are unusual in clinical set­ tibiotics and bismuth subsalicylate, according to tings and might, at first glance, seem too good to published recommendations, for at least 10 be true. Yet H pylori status was carefully charac­ days.21 Proton-pump inhibitors and histamine-2 terized clinically and by tissue diagnosis for all blockers were prescribed infrequently and at the our cases. [l4C]Urea breath test performance pro­

discretion of personal physicians. Of the 20 pa­ cedures were meticulously observed. Patients http://www.jabfm.org/ tients found to have positive breath test results whose test results were positive for H pylori had before treatment, 7 underwent repeat testing 2 breath samples that had 60-fold higher average months after treatment was concluded. All 7 had disintegrations per minute than those with neg­ negative (fewer than 49 dpm) breath test results ative results (1868 vs 33 dpm, respectively). on follow-up examination, and their ulcer symp­ Other investigators have also found extremely toms were in remission. To date, no ulcer relapse high (90 to 100 percent) sensitivity and speci­ on 23 September 2021 by guest. Protected copyright. has been documented by symptoms or esopha­ ficity of the [l4C]urea breath test in larger series gogastroduodenoscopy in these 7 patients for a of patients at other institutions. 11.12.22.23 We be­ mean follow-up time of approximately 17 months lieve the [l4C]urea breath test has an accuracy per patient. The other 13 patients with initially equal to endoscopy and biopsy in detection of positive [14C]urea breath test results had sympto­ symptomatic H pylori infection. The main limita­ matic improvement with antibiotic therapy and tion of our study is its small sample size; there­ were not referred for retesting by their personal fore, high predictive values might not apply to all physicians. Serologic follow-up was not systemat­ ulcer patients seen in a diverse primary care set­ ically obtained in any of our cohort. ting or among dyspeptic primary care patients We observed a disease prevalence of 77 percent less rigorously selected than our cohort. (20 of 26) in our series. The [l4C]urea breath test In the 7 patients undergoing a repeated is strongly associated with the reference standard [l4C]urea breath test after treatment for definite for H pylori diagnosis by biopsy or the CLO test (P H pylori infection, the reversion to negative re­ < 0.0001, Fisher exact test), showing an estimated sults in all 7 breath tests suggests successful eradi-

Breath Test Diagnosis of H pylori 387 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.385 on 1 November 1997. Downloaded from

cation of the organism and predicts long-term re­ 3. Document H pylori infection in episodes of mission. We observed no ulcer relapse for an av­ gastric or duodenal ulcer recurrence erage follow-up period of 17 months in this co­ 4. Prove H pylori eradication after antibiotic hort. Longer periods of follow-up will he regimens and therefore predict long-term ul­ required to determine whether the predictive val­ cer remiSSion ues of once-positive, now-negative rl4C]urea 5. Evaluate for the presence of H pylori in dys­ breath test results are significant or durable in our peptic patients refractory to histamine-2 subset of patients. 17 blockers but without discrete ulceration by Carbon 14 is a naturally occurring isotope that upper examination or is continuously formed in the earth's atmosphere. endoscopy The I-rCi dose administered in the [14C]urea 6. Estimate quantitative activity of H pylori in­ breath test is similar to the whole body dose re­ fection in patients with seropositivity of un­ ceived from natural background sources during certain clinical importance or duration. an II-hour period (0.3 mrem).24 This low radia­ tion dose is far less than the exposure received Mark Litaker, MS, provided assistance in biostatistical analysis. from mammography, intravenous pyelogram, computed tomography scanning, and upper gas­ References trointestinal tract series and is not likely to confer 1. NIH Consensus Conference. Helicobacter pylori in any serious risk to patients with peptic ulcer dis­ peptic ulcer disease. NIH Consensus Development Panel on llelicobacter pylori in Peptic Ulcer Disease. ease. The usefulness of the [14C]urea breath test ]AMA 1994;272:65-9. in children and pregnant women needs further 2. Peterson WL. HelicobaLter pylo1'i and peptic ulcer dis­ evaluation. ease. N EnglJ Med 1991;324:1043-8. Our results show that a new noninvasive 3. Brown KE, Peura DA. Diagnosis of Helicobacter py­ modality using [l4CJurea appears to be reliable lori infection. Gastroenterol Clin North Am 1993; for diagnosis of H pylori infection in symptomatic 22:105-15. 4. Graham DY, Go MF. Helicobacter pylori: current sta­ patients who have duodenal or gastric ulceration tus. Gastroenterology 1993; 105 :279-82. and have active chronic gastritis. The breath test 5. Marshall BJ. Helicobacter pylori. Am] Gastroenterol is quick, simple, easily tolerated by a wide age 1994;89(8 Suppl):SI16-28. range of patients, and highly sensitive and spe­ 6. Peura DA. Helicobacter pylori: a diagnostic dilemma cific. This noninvasive modality can also docu­ and a dilemma of diagnosis. Gastroenterology 1995; ment eradication of H pylori infection, thus pre­ 109:313-5. http://www.jabfm.org/ 7. Marshall B], Surveyor 1. Carbon-14 urea breath test dicting long-term remission from gastroduodenal for the diagnosis of Campylobacter pylori associated ulceration and precise evaluation of curative out­ gastritis.] Nucl Med 1988;29: 11-6. patient treatment regimens in patients with pep­ 8. Debongnie] C, Pauwels S, Raat A, de Meeus Y, Haot tic ulcer disease. This investigational radiophar­ ], Mainguet P. Quantification of Helicobacter pylori maceutical was recently released for widespread infection in gastritis and ulcer disease using a simple and rapid carbon-14-urea breath test.] Nucl Med outpatient use in the United States and Canada. on 23 September 2021 by guest. Protected copyright. 1991;32:1192-8. Estimated cost will be less than $200. Primary 9. Marshall B], Plankey MW, Hoffman SR, Boyd CL, care clinicians will occupy a pivotal role in the ef­ Dye KR, Frierson HF ]r, et al. A 20-minute breath ficient utilization and precise interpretation of test for Helicobacter pylori. Am) Gastroenterol 1991; [l4C]urea breath tests for patients who have a va­ 86:438-45. riety of upper gastrointestinal tract syndromes. 10. Raju GS, Smith M), Morton D, Bardhan KD. Mini­ In conclusion, our data and discussion suggest dose (I pCi)I4C-urea breath test for the detection of llelicobacter pylori. Am ] Gastroenterol 1994;89: these potential uses for [l4C]urea breath test: 1027-31. 1. Provide a reliable primary care alternative to 11. Peura DA, Pambianco D], Dye KR, Lind C, Frier­ endoscopy for the initial diagnosis of H pylori son HF, Hoffman SR, et a1. Microdose 14C-urea infection in patients with peptic ulcer breath test offers diagnosis of Helicobacter pylo1'i in 10 2. Document H pylori infection in patients minutes. Am] GastroenteroI1996;91:233-8. known to have duodenal or gastric ulcers as 12. Faigel DO, Childs M, Furth EE, Alavi A, Metz DC. New noninvasive tests for Helicobacter pylori gastritis. shown by a noninvasive barium upper gas­ Comparison with tissue-based gold standard. Dig trointestinal tract series Dis Sci 1996;41: 740-8.

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Breath Test Diagnosis of H pylori 389