Breath testing for Helicobacter pylori infection in children: A breath of fresh air?
1997; Elsevier BV; Volume: 131; Issue: 6 Linguagem: Inglês
10.1016/s0022-3476(97)70020-9
ISSN1097-6833
AutoresNicola Jones, Billy Bourke, Philip M. Sherman,
Tópico(s)Gastric Cancer Management and Outcomes
ResumoDiscovered in 1983 by Drs. Barry Marshall and Robin Warren, the microaerophilic, gram-negative urease-producing bacterium Helicobacter pylori now fulfills each of Koch's postulates as the first gastric pathogen identified in human beings.1Blaser MJ Not all Helicobacter pylori strains are created equal: Should all be eliminated?.Lancet. 1997; 349: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 2Veldhuyzen van Zanten SJO Sherman PM Hunt RH Helicobacter pylori: new developments and new treatments.Can Med Assoc J. 1997; 156: 1565-1574Google Scholar Infection with H. pylori results in the development of gastritis in all infected human beings, including children and adolescents.3Bourke B Jones N Sherman P Helicobacter pylori infection and peptic ulcer disease in children.Pediatr Infect Dis J. 1996; 15: 1-13Crossref PubMed Scopus (62) Google Scholar The majority of these individuals will be free of symptoms throughout their lifetime, despite harboring the infection. A small minority of infected subjects will experience the complications of peptic ulcer disease (lifetime risk, 15%); an even smaller minority will have gastric cancers including lymphoma, mucosa-associated lymphoid tissue lymphoma, and adenocarcinoma (lifetime risk, 0.1%).4Fennerty MB Is the only good H. pylori a dead H. pylori?.Gastroenterology. 1996; 111: 1773-1774Abstract Full Text PDF PubMed Scopus (22) Google Scholar The combined results of several studies of children with peptic ulcer disease identify the presence of H. pylori infection in a median of 92% of children with duodenal ulcers and in a median of 25% of children with gastric ulcers.5Macarthur C Saunders N Feldman W Helicobacter pylori, gastroduodenal disease and recurrent abdominal pain in children.JAMA. 1995; 273: 729-734Crossref PubMed Scopus (229) Google Scholar Among those with H. pylori infection, eradication therapy alters the natural history of recurrences with attendant morbidity and death, which previously required lifelong maintenance therapy.2Veldhuyzen van Zanten SJO Sherman PM Hunt RH Helicobacter pylori: new developments and new treatments.Can Med Assoc J. 1997; 156: 1565-1574Google ScholarPerhaps the greatest concern with regard to infection with H. pylori is the increased risk for the development of gastric cancers in adulthood.6Parsonnet J Freidman GD Vandersteen DP Chang X Vogelman JH Orentreich N et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3580) Google Scholar This is particularly relevant because infection dating from childhood appears to enhance the risk of carcinogenesis.7Blaser MJ Chyou PH Nomura A Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer and duodenal ulcer risk.Cancer Res. 1995; 55: 562-565PubMed Google Scholar At present, precise details concerning the bacterial, host, and environmental factors that lead to the development of disease complications are lacking. Because H. pylori infection is contracted primarily during the childhood years, additional epidemiologic studies among pediatric populations are imperative. Therefore the validation of an inexpensive, easy-to-perform, sensitive, specific, and noninvasive diagnostic test for H. pylori infection in children and adolescents is of paramount importance to enhance our presently limited understanding of H. pylori– related diseases.Currently available noninvasive tests for H. pylori infection in children are not optimal tools for use in large-scale epidemiologic research. Serologic immunoassays based on H. pylori antigens require validation in the pediatric population under evaluation because cutoff values established in adult subjects are often higher than antibody levels present in infected children.8Crabtree JE Mahoney MJ Taylor JD Heatley RV Littlewood JM Tompkins DS Immune responses to Helicobacter pylori in children with recurrent abdominal pain.J Clin Pathol. 1991; 44: 768-771Crossref PubMed Scopus (92) Google Scholar In addition, commercially available serologic tests demonstrate lower accuracy compared with testing in the research setting.9Loy CT Irwig LM Katelaris PH Talley NJ Do commercial serologic kits for Helicobacter pylori infection differ in accuracy? A meta-analysis.Am J Gastroenterol. 1996; 91: 1138-1144PubMed Google Scholar, 10Bodhidatta L Hoge CW Churnratanakul S Nirdnoy W Sampathanukul P Tungtaem C et al.Diagnosis of Helicobacter pylori infection in a developing country: comparison of two ELISA's and a seroprevalence study.J Infect Dis. 1993; 168: 1549-1553Crossref PubMed Scopus (73) Google Scholar H. pylori antibody testing in saliva was initially considered to be attractive for use in the pediatric population because it provides a noninvasive sampling technique. However, salivary tests detecting H. pylori–specific IgG antibodies lack sufficient accuracy.11Simor AE Lin E Saibil F Cohen L Louie M Pearan S et al.Evaluation of enzyme immunoassay for detection of salivary antibody to Helicobacter pylori.J Clin Microbiol. 1996; 34: 550-553PubMed Google Scholar, 12Christie JML McNulty CAM Shepherd NA Valori RM Is salivary serology useful for the diagnosis of Helicobacter pylori?.Gut. 1996; 39: 27-30Crossref PubMed Scopus (51) Google ScholarThe potent urease activity of H. pylori has been studied for its role as a microbial virulence factor and exploited for use as a diagnostic tool. All H. pylori isolates produce large quantities of the enzyme urease, a nickel-containing metalloenzyme comprised of two structural subunits, UreA and UreB.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar Urease hydrolyzes urea to bicarbonate and ammonia, resulting in a net increase in the ambient pH. Urease activity has been demonstrated as essential for colonization in animal models of Helicobacter infection.14Eaton KA Brooks CL Morgan DR Krakowka S Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets.Infect Immun. 1991; 59: 2470-2475Crossref PubMed Google Scholar Urease was originally considered to promote colonization of H. pylori by buffering acidic pH present in the lumen of the stomach. However, in gnotobiotic piglets rendered achlorhydric, urease is still required to establish infection.15Eaton KA Krakowka S Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori.Infect Immun. 1994; 62: 3604-3607Crossref PubMed Google Scholar Alternatively, urease was suggested to function as an adhesin, despite the fact that urease is an archetypal cytoplasmic protein.16Dunn BE Vakil NB Schneider BG Miller MM Zitzer JB Peutz T et al.Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.Infect Immun. 1997; 65: 1181-1188Crossref PubMed Google Scholar At least in a mouse model of Helicobacter infection, vaccines based on the structural subunits of urease as the antigen are effective in preventing infection.17Ferrero RL Thiberge JM Heurre M Labigne A Recombinant antigens prepared from the urease subunits of Helicobacter spp.: evidence of protection in a mouse model of gastric infection.Infect Immun. 1994; 62: 4981-4989Crossref PubMed Google Scholar This apparent conflict may be clarified by recent studies indicating that H. pylori urease is surface-associated both in vitro and in vivo.16Dunn BE Vakil NB Schneider BG Miller MM Zitzer JB Peutz T et al.Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.Infect Immun. 1997; 65: 1181-1188Crossref PubMed Google Scholar, 18Phadnis SH Parlow MH Levy M Ilver D Caulkins CM Connors JB et al.Surface localization of Helicobacter pylori urease and heat shock protein homologue requires bacterial autolysis.Infect Immun. 1996; 64: 905-912Crossref PubMed Google Scholar Bacterial autolysis releases cytoplasmic proteins including urease, which then allows nonspecific adsorption to the surface of intact, viable bacteria. The ability of urease to function as an adhesin was directly assessed by comparing adherence of an isogenic urease-deficient mutant with that of a wild-type strain.19Clyne M Drumm B The urease enzyme of Helicobacter pylori does not function as an adhesin.Infect Immun. 1996; 64: 2817-2820Crossref PubMed Google Scholar There was no difference in the ability of the two strains to adhere to gastric cell lines in vitro, bringing into question the role of urease as an adhesin. An additional role for urease in H. pylori virulence could be the induction of mucosal inflammation. Purified urease stimulates the release of a variety of inflammatory cytokines including IL-β, IL-6, tumor necrosis factor-α, and chemokines such as IL-8.20Harris PR Mobley HLT Perez-Perez GI Blaser MJ Smith PD Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production.Gastroenterology. 1996; 111: 419-425Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Although the exact mechanism by which urease functions in disease pathogenesis remains unclear, it is likely that urease is important as a virulence factor in H. pylori infection in human beings.Detection of urease activity of H. pylori has been used for the diagnosis of H. pylori infection.3 A variety of commercial assays are available to rapidly detect the presence of urease activity in gastric biopsy specimens obtained during diagnostic upper endoscopy. Biopsy specimens are placed into medium containing urea as substrate and phenol red as a pH indicator dye. A positive test result is denoted by a color change of the medium in response to an elevation in the ambient pH as a result of urea hydrolysis by urease. Although these biopsy urease tests have a high degree of sensitivity in adults, false-negative results are common in children, possibly because of a smaller bacterial load.21Drumm B Sherman P Cutz E Karmali M Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children.N Engl J Med. 1987; 316: 1557-1561Crossref PubMed Scopus (317) Google ScholarThe urea breath test follows the same principle as other breath tests used as indirect diagnostic assays in patients. Carbon 13–labeled or carbon 14–labeled urea is ingested, and if H. pylori is present, urease will hydrolyze ingested urea into labeled bicarbonate and ammonia.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar After equilibration with body compartments, labeled bicarbonate is exhaled in breath as labeled carbon dioxide, which can be collected for evaluation.The 13C urea breath test has been extensively studied in adult populations in which it demonstrates high degrees of both sensitivity and specificity.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar In this issue of The Journal, Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar address the efficacy of the 13C UBT for use in the detection of H. pylori infection in children. Although studies in which the 13C UBT was used in the pediatric population have been reported previously,24Vandenplas Y Blecker U Devreker T Keppens E Nijs J Cadranel S et al.Contribution of the 13C-urea breath test to the detection of Helicobacter pylori gastritis in children.Pediatrics. 1992; 90: 608-611PubMed Google Scholar the study by Rowland et al. addresses several important issues not previously investigated in children. These include the efficacy of the test after Helicobacter eradication therapy and the effects of either fasting or the administration of a test meal on the accuracy of the findings. Results of 13C UBT were compared with the gold standard of culture or positive histologic findings and rapid urease testing of mucosal biopsy specimens obtained from the antrum of the stomach.In contrast to findings in adult patients in whom the administration of a test meal to delay gastric emptying enhances the accuracy of urea breath testing,25Atherton JC Washington N Blackshaw PE Greaves JL Perkins AC Hawkey CJ et al.Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.Gut. 1995; 36: 337-340Crossref PubMed Scopus (60) Google Scholar, 26Dominguez-Munoz JE Leodolter A Sauerbruch T Malfertheiner P A citric acid solution is an optimal test drink in the 13C-urea breath test for the diagnosis of Helicobacter pylori infection.Gut. 1997; 40: 459-462PubMed Google Scholar the findings in the study by Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar suggest that a test meal administered before the UBT decreases test sensitivity. The reasons underlying these apparently conflicting findings in children and adults are unclear. In a study of nine adult patients undergoing urea breath testing, administration of a test meal expanded the intragastric distribution of urea to include the gastric body and fundus compared with distribution to the antrum alone in the absence of a test meal.25Atherton JC Washington N Blackshaw PE Greaves JL Perkins AC Hawkey CJ et al.Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.Gut. 1995; 36: 337-340Crossref PubMed Scopus (60) Google Scholar Infection with H. pylori in children is not limited to the antrum, and the bacterial load during infection is considered to be lower than that found in adults.21Drumm B Sherman P Cutz E Karmali M Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children.N Engl J Med. 1987; 316: 1557-1561Crossref PubMed Scopus (317) Google Scholar, 27Mitchell HM Bohane TD Tobias V Bullpit P Daskalopoulos G Carrick J et al.Helicobacter pylori infection in children: potential clues to pathogenesis.J Pediatr Gastroenterol Nutr. 1993; 16: 120-125Crossref PubMed Scopus (134) Google Scholar Thus at least in theory, a test meal to delay gastric emptying and allow H. pylori urease to hydrolyze urea should also be important in children.The effect of oral hygiene on the UBT has not been directly assessed previously. However, in adult patients the timing of the UBT is critical to avoid false-positive test results caused by oral urease-producing organisms.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar In the study by Rowland et al.,23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar the optimal time for sampling was at baseline and once again at 30 minutes. Sampling at earlier time points decreases the sensitivity of the test, suggesting that oral urease-producing organisms need to be considered during urea breath testing in children.The results presented by Rowland et al. are promising. However, caution is warranted before urea breath testing in children is considered for use in either the clinical setting or in clinicoepidemiologic studies. The test is expensive, thereby prohibiting its more generalized use, particularly in developing countries.28Braden B Schafer F Caspary WF Lembcke B Nondispersive isotope-selective infrared spectroscopy: a new analytical method for 13C-urea breath tests.Scand J Gastroenterol. 1996; 31: 442-445Crossref PubMed Scopus (74) Google Scholar A less expensive method for the analysis of 13C-labeled carbon dioxide is nondispersive infrared spectrometry, which provides comparable results in terms of sensitivity and specificity.28Braden B Schafer F Caspary WF Lembcke B Nondispersive isotope-selective infrared spectroscopy: a new analytical method for 13C-urea breath tests.Scand J Gastroenterol. 1996; 31: 442-445Crossref PubMed Scopus (74) Google Scholar, 29Koletzko S Haisch M Seeboth I Braden B Hengels K Koletzko B et al.Isotope-selective non-dispersive infrared spectrometry for detection of Helicobacter pylori infection with 13C-urea breath test.Lancet. 1995; 345: 961-962Abstract PubMed Google Scholar However, nondispersive infrared spectrometry requires a larger volume of air for sampling, which makes use in small children and infants more difficult. In addition, shipping of large-volume samples is impractical, thus limiting the usefulness of this assay technique in large-scale epidemiologic studies. Alternatively, measurement of 14C-labeled carbon dioxide, performed by using a scintillation counter, is relatively inexpensive.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar Although the use of radioisotopes is not recommended currently for pregnant women, adolescents, and children, the level of radiation exposure with the 14C UBT is equivalent to the natural background radiation over 1 day. In the future, improvements in both the availability and techniques for analysis of stable isotopes should result in a reduction in the costs associated with the current stable isotope methods for urea breath testing.The accuracy of the UBT in adult populations is similar in most settings, suggesting that the level of expertise required to perform the test is limited.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar However, the UBT likely will prove technically more difficult to perform in small children or infants. In the study by Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar breath samples from approximately 10% of the children initially enrolled could not be analyzed because of insufficient material. Therefore particularly outside of the research setting, the accuracy of the results could be limited by the level of expertise required to carry out the test in children. Comparisons of the accuracy of urea breath testing in children performed in different centers are required to clarify both the ease of use and applicability in more generalized studies.At present, there is no scientific evidence to recommend noninvasive testing and treatment for H. pylori in the absence of an established diagnosis of peptic ulcer disease.30National Institutes of Health Consensus Conference Development Panel Helicobacter pylori in peptic ulcer disease.JAMA. 1994; 272: 65-69Crossref PubMed Scopus (1062) Google Scholar Therefore noninvasive testing cannot replace endoscopy in the initial diagnosis of H. pylori–related gastrointestinal diseases in children. However, current recommendations will undoubtedly evolve. Therefore noninvasive testing for H. pylori in the future could play a larger role in the investigation and management of this important gastric pathogen in the pediatric population.See related article.Division of Gastroenterology and Nutrition, Research Institute, The Hospital for Sick Children, Departments of Pediatrics and Microbiology, University of Toronto, Toronto, Ontario, M5G 1X8 Canada Discovered in 1983 by Drs. Barry Marshall and Robin Warren, the microaerophilic, gram-negative urease-producing bacterium Helicobacter pylori now fulfills each of Koch's postulates as the first gastric pathogen identified in human beings.1Blaser MJ Not all Helicobacter pylori strains are created equal: Should all be eliminated?.Lancet. 1997; 349: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 2Veldhuyzen van Zanten SJO Sherman PM Hunt RH Helicobacter pylori: new developments and new treatments.Can Med Assoc J. 1997; 156: 1565-1574Google Scholar Infection with H. pylori results in the development of gastritis in all infected human beings, including children and adolescents.3Bourke B Jones N Sherman P Helicobacter pylori infection and peptic ulcer disease in children.Pediatr Infect Dis J. 1996; 15: 1-13Crossref PubMed Scopus (62) Google Scholar The majority of these individuals will be free of symptoms throughout their lifetime, despite harboring the infection. A small minority of infected subjects will experience the complications of peptic ulcer disease (lifetime risk, 15%); an even smaller minority will have gastric cancers including lymphoma, mucosa-associated lymphoid tissue lymphoma, and adenocarcinoma (lifetime risk, 0.1%).4Fennerty MB Is the only good H. pylori a dead H. pylori?.Gastroenterology. 1996; 111: 1773-1774Abstract Full Text PDF PubMed Scopus (22) Google Scholar The combined results of several studies of children with peptic ulcer disease identify the presence of H. pylori infection in a median of 92% of children with duodenal ulcers and in a median of 25% of children with gastric ulcers.5Macarthur C Saunders N Feldman W Helicobacter pylori, gastroduodenal disease and recurrent abdominal pain in children.JAMA. 1995; 273: 729-734Crossref PubMed Scopus (229) Google Scholar Among those with H. pylori infection, eradication therapy alters the natural history of recurrences with attendant morbidity and death, which previously required lifelong maintenance therapy.2Veldhuyzen van Zanten SJO Sherman PM Hunt RH Helicobacter pylori: new developments and new treatments.Can Med Assoc J. 1997; 156: 1565-1574Google Scholar Perhaps the greatest concern with regard to infection with H. pylori is the increased risk for the development of gastric cancers in adulthood.6Parsonnet J Freidman GD Vandersteen DP Chang X Vogelman JH Orentreich N et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3580) Google Scholar This is particularly relevant because infection dating from childhood appears to enhance the risk of carcinogenesis.7Blaser MJ Chyou PH Nomura A Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer and duodenal ulcer risk.Cancer Res. 1995; 55: 562-565PubMed Google Scholar At present, precise details concerning the bacterial, host, and environmental factors that lead to the development of disease complications are lacking. Because H. pylori infection is contracted primarily during the childhood years, additional epidemiologic studies among pediatric populations are imperative. Therefore the validation of an inexpensive, easy-to-perform, sensitive, specific, and noninvasive diagnostic test for H. pylori infection in children and adolescents is of paramount importance to enhance our presently limited understanding of H. pylori– related diseases. Currently available noninvasive tests for H. pylori infection in children are not optimal tools for use in large-scale epidemiologic research. Serologic immunoassays based on H. pylori antigens require validation in the pediatric population under evaluation because cutoff values established in adult subjects are often higher than antibody levels present in infected children.8Crabtree JE Mahoney MJ Taylor JD Heatley RV Littlewood JM Tompkins DS Immune responses to Helicobacter pylori in children with recurrent abdominal pain.J Clin Pathol. 1991; 44: 768-771Crossref PubMed Scopus (92) Google Scholar In addition, commercially available serologic tests demonstrate lower accuracy compared with testing in the research setting.9Loy CT Irwig LM Katelaris PH Talley NJ Do commercial serologic kits for Helicobacter pylori infection differ in accuracy? A meta-analysis.Am J Gastroenterol. 1996; 91: 1138-1144PubMed Google Scholar, 10Bodhidatta L Hoge CW Churnratanakul S Nirdnoy W Sampathanukul P Tungtaem C et al.Diagnosis of Helicobacter pylori infection in a developing country: comparison of two ELISA's and a seroprevalence study.J Infect Dis. 1993; 168: 1549-1553Crossref PubMed Scopus (73) Google Scholar H. pylori antibody testing in saliva was initially considered to be attractive for use in the pediatric population because it provides a noninvasive sampling technique. However, salivary tests detecting H. pylori–specific IgG antibodies lack sufficient accuracy.11Simor AE Lin E Saibil F Cohen L Louie M Pearan S et al.Evaluation of enzyme immunoassay for detection of salivary antibody to Helicobacter pylori.J Clin Microbiol. 1996; 34: 550-553PubMed Google Scholar, 12Christie JML McNulty CAM Shepherd NA Valori RM Is salivary serology useful for the diagnosis of Helicobacter pylori?.Gut. 1996; 39: 27-30Crossref PubMed Scopus (51) Google Scholar The potent urease activity of H. pylori has been studied for its role as a microbial virulence factor and exploited for use as a diagnostic tool. All H. pylori isolates produce large quantities of the enzyme urease, a nickel-containing metalloenzyme comprised of two structural subunits, UreA and UreB.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar Urease hydrolyzes urea to bicarbonate and ammonia, resulting in a net increase in the ambient pH. Urease activity has been demonstrated as essential for colonization in animal models of Helicobacter infection.14Eaton KA Brooks CL Morgan DR Krakowka S Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets.Infect Immun. 1991; 59: 2470-2475Crossref PubMed Google Scholar Urease was originally considered to promote colonization of H. pylori by buffering acidic pH present in the lumen of the stomach. However, in gnotobiotic piglets rendered achlorhydric, urease is still required to establish infection.15Eaton KA Krakowka S Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori.Infect Immun. 1994; 62: 3604-3607Crossref PubMed Google Scholar Alternatively, urease was suggested to function as an adhesin, despite the fact that urease is an archetypal cytoplasmic protein.16Dunn BE Vakil NB Schneider BG Miller MM Zitzer JB Peutz T et al.Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.Infect Immun. 1997; 65: 1181-1188Crossref PubMed Google Scholar At least in a mouse model of Helicobacter infection, vaccines based on the structural subunits of urease as the antigen are effective in preventing infection.17Ferrero RL Thiberge JM Heurre M Labigne A Recombinant antigens prepared from the urease subunits of Helicobacter spp.: evidence of protection in a mouse model of gastric infection.Infect Immun. 1994; 62: 4981-4989Crossref PubMed Google Scholar This apparent conflict may be clarified by recent studies indicating that H. pylori urease is surface-associated both in vitro and in vivo.16Dunn BE Vakil NB Schneider BG Miller MM Zitzer JB Peutz T et al.Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.Infect Immun. 1997; 65: 1181-1188Crossref PubMed Google Scholar, 18Phadnis SH Parlow MH Levy M Ilver D Caulkins CM Connors JB et al.Surface localization of Helicobacter pylori urease and heat shock protein homologue requires bacterial autolysis.Infect Immun. 1996; 64: 905-912Crossref PubMed Google Scholar Bacterial autolysis releases cytoplasmic proteins including urease, which then allows nonspecific adsorption to the surface of intact, viable bacteria. The ability of urease to function as an adhesin was directly assessed by comparing adherence of an isogenic urease-deficient mutant with that of a wild-type strain.19Clyne M Drumm B The urease enzyme of Helicobacter pylori does not function as an adhesin.Infect Immun. 1996; 64: 2817-2820Crossref PubMed Google Scholar There was no difference in the ability of the two strains to adhere to gastric cell lines in vitro, bringing into question the role of urease as an adhesin. An additional role for urease in H. pylori virulence could be the induction of mucosal inflammation. Purified urease stimulates the release of a variety of inflammatory cytokines including IL-β, IL-6, tumor necrosis factor-α, and chemokines such as IL-8.20Harris PR Mobley HLT Perez-Perez GI Blaser MJ Smith PD Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production.Gastroenterology. 1996; 111: 419-425Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Although the exact mechanism by which urease functions in disease pathogenesis remains unclear, it is likely that urease is important as a virulence factor in H. pylori infection in human beings. Detection of urease activity of H. pylori has been used for the diagnosis of H. pylori infection.3 A variety of commercial assays are available to rapidly detect the presence of urease activity in gastric biopsy specimens obtained during diagnostic upper endoscopy. Biopsy specimens are placed into medium containing urea as substrate and phenol red as a pH indicator dye. A positive test result is denoted by a color change of the medium in response to an elevation in the ambient pH as a result of urea hydrolysis by urease. Although these biopsy urease tests have a high degree of sensitivity in adults, false-negative results are common in children, possibly because of a smaller bacterial load.21Drumm B Sherman P Cutz E Karmali M Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children.N Engl J Med. 1987; 316: 1557-1561Crossref PubMed Scopus (317) Google Scholar The urea breath test follows the same principle as other breath tests used as indirect diagnostic assays in patients. Carbon 13–labeled or carbon 14–labeled urea is ingested, and if H. pylori is present, urease will hydrolyze ingested urea into labeled bicarbonate and ammonia.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar After equilibration with body compartments, labeled bicarbonate is exhaled in breath as labeled carbon dioxide, which can be collected for evaluation. The 13C urea breath test has been extensively studied in adult populations in which it demonstrates high degrees of both sensitivity and specificity.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar In this issue of The Journal, Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar address the efficacy of the 13C UBT for use in the detection of H. pylori infection in children. Although studies in which the 13C UBT was used in the pediatric population have been reported previously,24Vandenplas Y Blecker U Devreker T Keppens E Nijs J Cadranel S et al.Contribution of the 13C-urea breath test to the detection of Helicobacter pylori gastritis in children.Pediatrics. 1992; 90: 608-611PubMed Google Scholar the study by Rowland et al. addresses several important issues not previously investigated in children. These include the efficacy of the test after Helicobacter eradication therapy and the effects of either fasting or the administration of a test meal on the accuracy of the findings. Results of 13C UBT were compared with the gold standard of culture or positive histologic findings and rapid urease testing of mucosal biopsy specimens obtained from the antrum of the stomach. In contrast to findings in adult patients in whom the administration of a test meal to delay gastric emptying enhances the accuracy of urea breath testing,25Atherton JC Washington N Blackshaw PE Greaves JL Perkins AC Hawkey CJ et al.Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.Gut. 1995; 36: 337-340Crossref PubMed Scopus (60) Google Scholar, 26Dominguez-Munoz JE Leodolter A Sauerbruch T Malfertheiner P A citric acid solution is an optimal test drink in the 13C-urea breath test for the diagnosis of Helicobacter pylori infection.Gut. 1997; 40: 459-462PubMed Google Scholar the findings in the study by Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar suggest that a test meal administered before the UBT decreases test sensitivity. The reasons underlying these apparently conflicting findings in children and adults are unclear. In a study of nine adult patients undergoing urea breath testing, administration of a test meal expanded the intragastric distribution of urea to include the gastric body and fundus compared with distribution to the antrum alone in the absence of a test meal.25Atherton JC Washington N Blackshaw PE Greaves JL Perkins AC Hawkey CJ et al.Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.Gut. 1995; 36: 337-340Crossref PubMed Scopus (60) Google Scholar Infection with H. pylori in children is not limited to the antrum, and the bacterial load during infection is considered to be lower than that found in adults.21Drumm B Sherman P Cutz E Karmali M Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children.N Engl J Med. 1987; 316: 1557-1561Crossref PubMed Scopus (317) Google Scholar, 27Mitchell HM Bohane TD Tobias V Bullpit P Daskalopoulos G Carrick J et al.Helicobacter pylori infection in children: potential clues to pathogenesis.J Pediatr Gastroenterol Nutr. 1993; 16: 120-125Crossref PubMed Scopus (134) Google Scholar Thus at least in theory, a test meal to delay gastric emptying and allow H. pylori urease to hydrolyze urea should also be important in children. The effect of oral hygiene on the UBT has not been directly assessed previously. However, in adult patients the timing of the UBT is critical to avoid false-positive test results caused by oral urease-producing organisms.13Graham DY Klein PD What you should know about the methods, problems, interpretations, and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar In the study by Rowland et al.,23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar the optimal time for sampling was at baseline and once again at 30 minutes. Sampling at earlier time points decreases the sensitivity of the test, suggesting that oral urease-producing organisms need to be considered during urea breath testing in children. The results presented by Rowland et al. are promising. However, caution is warranted before urea breath testing in children is considered for use in either the clinical setting or in clinicoepidemiologic studies. The test is expensive, thereby prohibiting its more generalized use, particularly in developing countries.28Braden B Schafer F Caspary WF Lembcke B Nondispersive isotope-selective infrared spectroscopy: a new analytical method for 13C-urea breath tests.Scand J Gastroenterol. 1996; 31: 442-445Crossref PubMed Scopus (74) Google Scholar A less expensive method for the analysis of 13C-labeled carbon dioxide is nondispersive infrared spectrometry, which provides comparable results in terms of sensitivity and specificity.28Braden B Schafer F Caspary WF Lembcke B Nondispersive isotope-selective infrared spectroscopy: a new analytical method for 13C-urea breath tests.Scand J Gastroenterol. 1996; 31: 442-445Crossref PubMed Scopus (74) Google Scholar, 29Koletzko S Haisch M Seeboth I Braden B Hengels K Koletzko B et al.Isotope-selective non-dispersive infrared spectrometry for detection of Helicobacter pylori infection with 13C-urea breath test.Lancet. 1995; 345: 961-962Abstract PubMed Google Scholar However, nondispersive infrared spectrometry requires a larger volume of air for sampling, which makes use in small children and infants more difficult. In addition, shipping of large-volume samples is impractical, thus limiting the usefulness of this assay technique in large-scale epidemiologic studies. Alternatively, measurement of 14C-labeled carbon dioxide, performed by using a scintillation counter, is relatively inexpensive.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar Although the use of radioisotopes is not recommended currently for pregnant women, adolescents, and children, the level of radiation exposure with the 14C UBT is equivalent to the natural background radiation over 1 day. In the future, improvements in both the availability and techniques for analysis of stable isotopes should result in a reduction in the costs associated with the current stable isotope methods for urea breath testing. The accuracy of the UBT in adult populations is similar in most settings, suggesting that the level of expertise required to perform the test is limited.22Atherton JC Spiller RC The urea breath test for Helicobacter pylori.Gut. 1994; 35: 723-725Crossref PubMed Scopus (197) Google Scholar However, the UBT likely will prove technically more difficult to perform in small children or infants. In the study by Rowland et al.23Rowland M Lambert I Gormally S Daly LE Thomas JE Hetherington C et al.Carbon 13–labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 1131: 815-820Abstract Full Text Full Text PDF Scopus (156) Google Scholar breath samples from approximately 10% of the children initially enrolled could not be analyzed because of insufficient material. Therefore particularly outside of the research setting, the accuracy of the results could be limited by the level of expertise required to carry out the test in children. Comparisons of the accuracy of urea breath testing in children performed in different centers are required to clarify both the ease of use and applicability in more generalized studies. At present, there is no scientific evidence to recommend noninvasive testing and treatment for H. pylori in the absence of an established diagnosis of peptic ulcer disease.30National Institutes of Health Consensus Conference Development Panel Helicobacter pylori in peptic ulcer disease.JAMA. 1994; 272: 65-69Crossref PubMed Scopus (1062) Google Scholar Therefore noninvasive testing cannot replace endoscopy in the initial diagnosis of H. pylori–related gastrointestinal diseases in children. However, current recommendations will undoubtedly evolve. Therefore noninvasive testing for H. pylori in the future could play a larger role in the investigation and management of this important gastric pathogen in the pediatric population. See related article. Division of Gastroenterology and Nutrition, Research Institute, The Hospital for Sick Children, Departments of Pediatrics and Microbiology, University of Toronto, Toronto, Ontario, M5G 1X8 Canada
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