DISCLAIMER: This document was originally drafted in French by the Institut national d'excellence en santé et en services sociaux (INESSS), and that version can be consulted at http://www.inesss.qc.ca/fileadmin/doc/INESSS/Analyse_biomedicale/Decembre_2013/INESSS_Test_respir_uree_marquee_carb13_spectro_masse_ratios_isotopiques_Detec_Hpylori.pdf. It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS’s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation.

While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.

Carbon-13 Urea Breath Test by Isotope Ratio Mass Spectrometry for Detection of H. pylori

(Reference – 2013.02.003.1)

Notice of Assessment

December 2013

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1 GENERAL INFORMATION

1.1 Requestor: Hôpital Saint-Luc, CHUM

1.2 Application Submitted to MSSS: August 29, 2012

1.3 Application Received by INESSS: July 1, 2013

1.4 Notice Issued: October 31, 2013

Note

This notice is based on the scientific and commercial information [submitted by the requestor] and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS.

2 TECHNOLOGY, COMPANY, AND LICENCE

2.1 Name of the Technology

Detection of Helicobacter pylori (H. pylori) bacteria using the carbon-13 urea breath test (13C-UBT) analyzed by isotope ratio mass spectrometry (IRMS)

2.2 Brief Description of the Technology with Technical and Clinical Specifications

Of the carbon-1317 breath tests, the most widely used is the carbon-13 urea breath test (13C-UBT) [Mion, 2000]. The 13C-UBT for detection of H. pylori is based on the principle that, when this bacterium is present in the stomach of an individual who ingests urea labelled with 13C, the bacterium converts this urea into 13CO2 and ammonia (NH3), owing to its elevated urease activity. The enzymatic reaction takes place in the mucous layer where H. pylori is present, and the 13CO2 produced diffuses to the epithelial cells, then to the blood, and is eliminated through the lungs [Wang et al., 2013] (Figure 1). An initial sample of exhaled air is collected from the patient at baseline (T = 0), and a second one is collected a half-hour later (T = 30). The samples are then analyzed by means of IRMS or other technologies such as non-dispersive infrared spectroscopy (NDIRS) or laser-assisted ratio analysis (LARA) [Gisbert and Pajares, 2004]. The result of each sample’s analysis is the delta (δ), expressed in parts per thousand (‰), which represents the relative difference between the isotope ratio of the sample and that of a reference substance.18 The difference between the δ of a given patient’s samples (T = 30 and T = 0) represents the delta over baseline (DOB). The test endpoint is generally considered positive when the DOB is greater than 5‰ [Gisbert and Pajares, 2004].

17. An element of the periodic table may have atoms of different mass, called isotopes. For example, most of the carbon in nature has a mass of 12, but some of the carbon has a mass of 13 (carbon-13) and some carbon has a mass of 14 (carbon-14) [Eastmain1 web site. Available at http://www.eastmain1.org/files/pdf/fichespedagogiques/EN/HQ_04_en_GES_Isotopes_081006_FM.pdf]. 18. δ = 1,000(Rsample – Rref)/Rref Rsample is the 13C:12C ratio in the sample and Rref is the 13C:12C ratio in a reference substance [Wang et al., 2013; Verkouteren et al., 1995].

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Figure 1: Principle Underlying 13C-UBT for Detection of H. pylori

Source: Kajiwara et al., 1997.

IRMS is a specialization of mass spectrometry, the principle of which is to separate ions based on their mass and charge. As is shown in Figure 2, the test sample is introduced19 to an ionization source. The sample’s molecules are first ionized (by electron bombardment) and then accelerated. The detectors sort the ions by their mass (mass 44 for 12C16O2, mass 45 for 13C16O2, etc.). These different ions follow, in the magnetic field, different circular trajectories of which the radii are a function of the mass-to-charge ratio. The intensity of the signals is thus measured specifically to obtain the sample’s 13C:12C ratio [Elbast and Brazier, 1999; Brazier, 1997]. According to the information provided by the requestor, IRMS is a semi-quantitative test.

Figure 2: Isotope Ratio Mass Spectrometer Schematic

Source: Muccio, Z. and G. P. Jackson (2009). Isotope Ratio Mass Spectrometry. Analyst 134 (2): 213-222.

2.3 Company or Developer: No particular device is mentioned by the requestor.

2.4 Licence: Not applicable.

2.5 Patent, If Any: Not applicable.

2.6 Approval Status (Health Canada, FDA)

19. One of the most common devices for introducing a sample is a gas chromatograph, used for separating the chemicals of an admixture before analysis [Muccio and Jackson, 2009].

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For 13C-UBT, the Dia13-Helico Breath Test Kit manufactured by RAD Diagnostics is licensed by Health Canada (licence number 64105).20 However, no isotope ratio mass spectrometer has been licensed by Health Canada, probably because these devices are sold for general laboratory applications, which are outside the scope of Health Canada’s regulations on licensing medical devices.21

2.7 Weighted Value: 33.5.

3 CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES

3.1 Targeted Patient Group

The clinical indications for the test are the initial detection of an H. pylori infection and the confirmation of its eradication among adults with dyspepsia22 and without alarm symptoms.23

3.2 Targeted Disease

The infection H. pylori, a bacterium that infects only humans, is in most cases acquired during childhood and is usually asymptomatic [Neale and Logan, 1995].

This infection can lead to various disorders, such as inflammation of the stomach lining (gastritis), gastroduodenal ulcer (10%–20%), distal gastric adenocarcinoma (1%–2%) and gastric mucosa-associated lymphoid tissue lymphoma [Kusters et al., 2006; Parsonnet et al., 1994; Nomura et al., 1991; Parsonnet et al., 1991].

In Canada, the prevalence of H. pylori infection ranged from 21% to 41% in a sample of the population of Nova Scotia aged 20 to 59 years [Veldhuyzen van Zanten et al., 1994]. In Ontario, the overall prevalence among adults aged 50 to 80 years was 23% (29.4% among men and 14.9% among women) [Naja et al., 2007].

3.3 Number of Patients Targeted

According to the information provided by the requestor, the expected provincial volume for the next three years is 500 patients per year. However, the reported high prevalence of H. pylori infection suggests that the volume could be much larger.

3.4 Medical Specialties Involved

Gastroenterology, family medicine and pediatrics.

3.5 Testing Procedure

According to the information provided by the requestor, a 13C-UBT is performed using the RAD Diagnostics Dia13-Helico Breath Test Kit. The requestor’s institution provides the public with additional details on this test.24 First, after fasting for at least 3 hours, the patient must drink a citric acid solution and then blow through a straw into two glass tubes. Second, the patient must drink another citric acid solution in which the 13C-labelled urea has been dissolved and then wait 30 minutes. Lastly, the patient must again blow through a straw into two other glass tubes. Ingesting the solutions slows gastric emptying and maximizes distribution of the labelled urea in the stomach, while the acid pH of these

20. [Health Canada web site. Available at http://webprod5.hc-sc.gc.ca/mdll-limh/information.do?companyId_idCompanie=112087&lang=eng]. 21. Personal electronic communication with Christine Tabib of Health Canada (October 8, 2013). 22. Dyspepsia: chronic or recurrent pain or discomfort in the upper abdomen [Talley et al., 2005]. 23. Alarm symptoms: bleeding, anemia, unexplained weight loss (> 10 %), persistent vomiting, family history of gastrointestinal cancer, previous documented gastroduodenal ulcer, etc. [Talley et al., 2005]. 24. CHUM web site. Available in French only at http://www.chumontreal.qc.ca/sites/default/files//documents/Votre_sante/PDF/91_4005008_test_respiratoire_a_luree_2013-03-19.pdf.

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solutions fosters H. pylori urease activity [Wang et al., 2013]. In addition to fasting, the patient must prepare for the test by following instructions regarding the use of certain medications.25

Medical staff must also follow certain instructions on handling the samples.26 These instructions indicate that samples must be collected using the containers provided with the kit, that the containers must be hermetically sealed, and stored and forwarded at room temperature. Collected samples are then sent by mail to the institution for analysis by IRMS. Breath samples are effectively stable for long periods of time (5 weeks) [Jordaan and Laurens, 2008].

According to the information provided by the requestor, IRMS analyses of samples will be performed once each week and the response time will be one week.

4 TECHNOLOGY BACKGROUND

4.1 Nature of the Diagnostic Technology

The test would complement the sampling for the 13C urea breath test for detection of Helicobacter pylori (Index code 70019). Also, the requestor indicated that the test would replace the carbon-14 urea breath test (14C-UBT) performed in nuclear medicine. 14C-UBT is not listed in the Index.

4.2 Brief Description of the Current Technological Context

In addition to breath and serological tests, H. pylori infection can be detected by a stool bacterial antigen test. For 13C-UBT samples, IRMS is the gold standard internationally [Jordaan and Laurens, 2008].

4.3 Brief Description of the Advantages Cited for the New Technology

Being a very sensitive technique, IRMS can detect minimal variations of isotopic enrichment in very small gas volumes. For example, a sample of about 100 microlitres (µL) is needed for analysis [Mion, 2000], and even 50 to 100 µL if gas chromatography is used [Mion et al., 2001]. Since each glass tube contains about 10 millilitres (mL) of breath, each sample can be retested up to 10 times [Elbast and Brazier, 1999], or even more. Moreover, a large number of glass tubes (> 200) can be analyzed at a time, which is ideal for a reference clinic [Gisbert and Pajares, 2004].

Furthermore, purchasing one device for use by several institutions allows for amortizing its costs [Gisbert and Pajares, 2004], especially if the same device can be used for other 13C tests (for example, for assaying gastric emptying) that, it may be noted, represent a future prospect for functional investigation of digestive and hepatic functions [Mion, 2000].

According to the information provided by the requestor, 13C-UBT and 14C-UBT generally have equivalent efficacy, but 14C-UBT involves radioactivity and must be performed in a nuclear medicine department (which is less accessible). Furthermore, it is not indicated for pregnant women or children, and there are restrictions on the frequency and transportation of samples [Lee et al., 1998]. In comparison, the 13C-UBT has the advantage of being non-invasive and of exploring the entire stomach, such that the detection problem associated with a biopsy (due to uneven colonization of the stomach by H. pylori) does not arise [Kato et al., 2002]. Lastly, serologic detection is an indirect test and cannot distinguish a

25. The patient must not have taken any antibiotics during the 4 weeks leading up to the test, any proton pump inhibitors during the 2 weeks leading up to the test, nor any antacids during the week leading up to the test [CHUM web site. Available in French only at http://www.chumontreal.com/laboratories/images/stories/documents/appendices/A7Bi_.pdf]. 26. CHUM web site. Available in French only at http://www.chumontreal.com/laboratoires/index.php?option=com_content&view=article&id=1233%3Ahelicobacter-pylori&catid=34%3Aanalysesbio&Itemid=58.

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previous infection from a current one [Kalach et al., 1998], whereas the 13C-UBT analyzed by IRMS is direct, as it detects only active H. pylori urease.

4.4 Cost of Technology and Options: Not assessed.

5 EVIDENCE

5.1 Clinical Relevance

The clinical relevance of the 13C-UBT is discussed the following sections, independent of the device used for sample analysis.

5.1.1 Other Tests Replaced

The 13C-UBT would replace the 14C-UBT (Section 4.1) because, unlike the latter, it is non-radioactive (Section 4.3). This test is not in the Index.

5.1.2 Diagnostic or Prognostic Value

The 13C-UBT is an established test for routine diagnosis of H. pylori infection [AÉTMIS, 2005; Braden et al., 1994].

5.1.3 Therapeutic Value

The 13C-UBT is a good post-treatment test for assessing eradication of H. pylori because it can avoid false negatives associated with biopsy (due to the uneven colonization of the stomach by H. pylori) and false positives associated with serology (due to the presence of anti-H. pylori antibodies) [Peng et al., 2004].

5.2 Clinical Validity

PARAMETER PRESENCE ABSENCE NOT APPLICABLE

Sensitivity X

Specificity X

Positive predictive value (PPV) X

Negative predictive value (NPV) X

Likelihood ratio (RV) x

ROC curve x

Accuracy X

For each of the following parameters, between 4 and 6 studies were identified. It is shown that: clinical sensitivity ranges from 93.1% to 100%; clinical specificity ranges from 55.0% to 98.9%; positive predictive value (PPV) ranges from 63.0% to 98.7%; negative predictive value (NPV) ranges from 88.2% to 99.0%; and accuracy ranges from 74.4% to 98.0% (Table 1 in the appendix).

The studies used as evidence show differences in the cut-off value and in sampling for the 13C-UBT, most notably regarding the volume of labelled urea ingested, ingestion with or without a meal, with or without prior mouthwash, etc. These differences, like other factors (number and age of populations, comparator, etc.), can contribute to the variability observed in the results of the studies.

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5.3 Analytical (or Technical) Validity

PARAMETER PRESENCE ABSENCE NOT APPLICABLE

Repeatability x

Reproducibility x

Analytical sensitivity x

Analytical specificity x

Matrix effect x

Concordance x

Correlation between test and comparator x

For each of the following parameters, only one study is available. In this case, repeatability (expressed as a coefficient of variation) ranges from 0.30% to 2.89% and reproducibility (expressed as a coefficient of variation) is 21.6% (Table 2 in the appendix). Concordance with histological findings is 83%.

Once again, the studies used as evidence were heterogeneous, which explains the variability observed in the results of the studies.

5.4 Recommendations From Other Organizations

The following conclusions and recommendations are for the 13C-UBT, regardless of the technique used for sample analysis.

The guidelines published in 2004 by the National Institute for Health and Care Excellence (NICE) and the North of England Dyspepsia Guideline Development Group, which deal specifically with primary care for adults with dyspepsia,27 recommend 13C-UBT, stool antigen tests and serology (when validated by a laboratory) for the initial detection of H. pylori. For eradication, only 13C-UBT is recommended; the guidelines indicate that there is insufficient evidence to recommend stool antigen testing [CHSR, 2004]. These guidelines are currently being updated and a publication date has not been confirmed.

In a 2005 technical note on the potential applications in Quebec of the 13C-UBT for detection of H. pylori, the Agence d’évaluation des technologies et des modes d’intervention en santé (AETMIS) “recommends that the 13C-urea breath test be made available in all regions of Quebec…” while making a number of proposals to ensure its optimal use [AÉTMIS, 2005].

In 2011, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommended the 13C-UBT as a reliable, non-invasive test for determining whether H. pylori has been eradicated in children [Koletzko et al., 2011].

More recently, the Maastricht IV/ Florence Consensus Report28 noted that the urea breath test is an acceptable non-invasive test for H. pylori infection in young patients with no alarm symptoms29 or signs associated with an increased risk of gastric cancer. In addition, the urea breath test is recommended as a non-invasive test for determining the success of eradication treatment [Malfertheiner et al., 2012].

27. Dyspepsia: chronic or recurrent pain or discomfort in the upper abdomen [Talley et al., 2005]. 28. Consensus was defined as support by 70% or more of the 44 experts from 24 countries who took an active part in the conference [Malfertheiner et al., 2012]. 29. Alarm symptoms: bleeding, anemia, unexplained weight loss (> 10 %), persistent vomiting, family history of gastrointestinal cancer, previous documented gastroduodenal ulcer, etc.) [Talley et al., 2005].

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Lastly, in 2013, after reviewing the evidence (pertaining to adults with uninvestigated dyspepsia with no alarm symptoms and for whom endoscopy was not indicated), the government agency Health Quality Ontario concluded specifically that the 13C-UBT has high sensitivity and specificity for both diagnosis of H. pylori and treatment follow-up [Ling, 2013].

6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST

6.1 Impact on Material and Human Resources: Not assessed.

6.2 Economic Consequences of Introduction Into Quebec’s Health Care and Social Services System: Not assessed.

6.3 Main Organizational, Ethical, and Other (Social, Legal, Political) Issues: Not assessed.

7 IN BRIEF

7.1 Clinical Relevance 13C-UBT is an internationally established test for diagnosis of H. pylori infection, and it is recommended for determining the success of eradication treatment for the infection. However, other effective tests, such as the stool antigen test, are available.

7.2 Clinical Validity

Specifically when analyzed with IRMS, the sensitivity of 13C-UBT is greater than 93% and the specificity is generally greater than 85%.

7.3 Analytical Validity

The 13C-UBT analyzed with IRMS has an inter-assay variability of 21.6% and a concordance of 83% with histological results.

7.4 Recommendations From Other Authorities

Several guidelines for the diagnosis and treatment of dyspepsia and one assessment report recommend 13C-UBT without specifying the method of analysis.

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8 INESSS NOTICE IN BRIEF

Carbon-13 Urea Breath Test by Isotope Ratio Mass Spectrometry for Detection of H. pylori

Status of the Diagnostic Technology

Established

Innovative

Experimental (for research purposes only)

Replacement for technology which becomes obsolete

INESSS Recommendation

Introduce test to Index

Do not introduce test to Index

Reassess test

Two analysis techniques for the 13C-urea breath test were assessed and found to be equivalent. The utility and the clinical and technical validity of the 13C urea breath test are demonstrated. However, the weighted value must be recalculated to reflect the different analysis techniques used and the fact that code 70019 (13C-urea breath test for detection of Helicobacter pylori) is already in the Index with a weighted value of 23.0. It would be helpful to have an uptake algorithm for Quebec that includes the serology test, the stool antigen test and 14C-UBT in order to produce a comprehensive view of how these tests are used in various clinical situations, for adults and for children.

Additional Recommendation

Draw connection with listing of drugs, if companion test

Production of an optimal use guide

Production of indicators, when monitoring is required

Note

If the test is added to the Index in future, a single code should be used for 13C-UBT, regardless of the technique.

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REFERENCES Agence d’évaluation des technologies et des modes d’intervention en santé et en services sociaux (AÉTMIS). Le test respiratoire à l’urée marquée au 13C pour la détection de Helicobacter pylori: possibilités d’application au Québec. Technical note written by par Lonny Erickson. Montréal, Qc ׃ AÉTMIS; 2005.

Bilal R, Khaar B, Qureshi TZ, Mirza SA, Ahmad T, Latif Z, et al. Accuracy of non-invasive 13C-Urea Breath Test compared to invasive tests for Helicobacter pylori detection. J Coll Physicians Surg Pak 2007;17(2):84-8.

Braden B, Haisch M, Duan LP, Lembcke B, Caspary WF, Hering P. Clinically feasible stable isotope technique at a reasonable price: analysis of 13CO2/

12CO2-abundance in breath samples with a new isotope selective-nondispersive infrared spectrometer. Z Gastroenterol 1994;32(12):675-8.

Brazier JL. Chapter 21. Breath test: drug metabolism studies. In: Browne TR, ed. Stable isotopes in pharmaceutical research. Amsterdam, Pays-Bas ׃ Elsevier Science B.V.; 1997.

Centre for health services research (CHSR). Dyspepsia: managing dyspepsia in adults in primary care. Evidence-based clinical practice guideline, no 112. Newcastle upon Tyne, Royaume-Uni ׃ North of England dyspepsia guideline development group; 2004.

Elbast W and Brazier JL. La spectroscopie infrarouge non dispersive, une alternative à la spectrométrie de masse isotopique, cas du test respiratoire à l’urée 13C. Analusis 1999;27(3):228-31.

Gisbert JP and Pajares JM. Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection - A critical review. Aliment Pharmacol Ther 2004;20(10):1001-17.

Jordaan M and Laurens JB. Diagnosis of Helicobacter pylori infection with the 13C-urea breath test by means of GC-MS analysis. J Sep Sci 2008;31(2):329-35.

Kalach N, Briet F, Raymond J, Benhamou PH, Barbet P, Bergeret M, et al. The 13carbon urea breath test for the noninvasive detection of Helicobacter pylori in children: comparison with culture and determination of minimum analysis requirements. J Pediatr Gastroenterol Nutr 1998;26(3):291-6.

Kato S, Ozawa K, Konno M, Tajiri H, Yoshimura N, Shimizu T, et al. Diagnostic accuracy of the 13C-urea breath test for childhood Helicobacter pylori infection: a multicenter Japanese study. Am J Gastroenterol 2002;97(7):1668-73.

Koletzko S, Jones NL, Goodman KJ, Gold B, Rowland M, Cadranel S, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2011;53(2):230-43.

Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 2006;19(3):449-90.

Lee HS, Gwee KA, Teng LY, Kang JY, Yeoh KG, Wee A, Chua BC. Validation of [13C]urea breath test for Helicobacter pylori using a simple gas chromatograph-mass selective detector. Eur J Gastroenterol Hepatol 1998;10(7):569-72.

Logan RPH, Dill S, Bauer FE, Walker MM, Hirschl AM, Gummet P. The European 13C-urea breath test for the detection of Helicobacter pylori. Eur J Gastroen Hepat 1991;3:915-21.

Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut 2012;61(5):646-64.

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Mion F. Digestive functional investigation: Interest of 13CO2 breath tests. Acta Endoscopica 2000;30 (3):237-42.

Mion F, Ecochard R, Guitton J, Ponchon T. 13CO2 breath tests: comparison of isotope ratio mass spectrometry and non-dispersive infrared spectrometry results. Gastroenterol Clin Biol 2001;25(4):375-9.

Muccio Z and Jackson GP. Isotope Ratio Mass Spectrometry. Analyst 2009;134(2):213-22.

Naja F, Kreiger N, Sullivan T. Helicobacter pylori infection in Ontario: prevalence and risk factors. Can J Gastroenterol 2007;21(8):501-6.

Neale KR and Logan RP. The epidemiology and transmission of Helicobacter pylori infection in children. Aliment Pharmacol Ther 1995;9(Suppl 2):77-84.

Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 1991;325(16):1132-6.

Ogata SK, Kawakami E, Patricio FR, Pedroso MZ, Santos AM. Evaluation of invasive and non-invasive methods for the diagnosis of Helicobacter pylori infection in symptomatic children and adolescents. Sao Paulo Med J 2001;119(2):67-71

Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325(16):1127-31.

Parsonnet J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, Jellum E, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 1994;330(18):1267-71.

Peng NJ, Lo CC, Lai KH, Liu RS, Lee SC, Tsay DG, et al. Comparison of infrared spectrometer and mass spectrometry for 13C-urea breath test in the diagnosis of Helicobacter pylori infection. Ann Nucl Med Sci 2004;17(2):69-75.

Savarino V, Landi F, Dulbecco P, Ricci C, Tessieri L, Biagini R, et al. Isotope ratio mass spectrometry (IRMS) versus laser-assisted ratio analyzer (LARA): A comparative study using two doses of [13C]urea and two test meals for pre- and posttreatment diagnosis of Helicobacter pylori infection. Digestive Diseases and Sciences 2000;45 (11):2168-74.

Sheu BS, Lee SC, Yang HB, Wu HW, Wu CS, Lin XZ, Wu JJ. Lower-dose 13C-urea breath test to detect Helicobacter pylori infection-comparison between infrared spectrometer and mass spectrometry analysis. Aliment Pharmacol Ther 2000;14(10):1359-63.

Talley NJ and Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100(10):2324-37.

Vandenplas 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(4):608-11.

Veldhuyzen van Zanten SJ, Pollak PT, Best LM, Bezanson GS, Marrie T. Increasing prevalence of Helicobacter pylori infection with age: continuous risk of infection in adults rather than cohort effect. J Infect Dis 1994;169(2):434-7.

Verkouteren RM, Klouda G, Currie L. Reference and intercomparison materials for stable isotopes of light elements. In: International Atomic Energy Agency. Vienne, Autriche 1995 ׃.

Wang S, Zhang WM, Reineks E. Chapitre 2. Breath tests for detection of Helicobacter pylori and Aspergillus fumigatus. In: Tang YM and Stratton CW, ed. Advanced techniques in diagnostic microbiology. New York, NY ׃ Springer Science; 2013.

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Table 1: Clinical Validity

Abbreviations: CI = confidence interval; N = number of patients in the study; NS = not specified in the study; PPV = positive predictive value; NPV = negative predictive value.

* Any combination of 3 or more positive results among the following 5 diagnostic methods: quick urease test, histological examination, bacterial culture, serology test and 13C-UBT. † Any combination of 2 or more positive results among the 3 diagnostic methods requiring a biopsy (quick urease test, histological examination, bacterial culture).

STUDY NUMBER AND AGE OF PATIENTS

COMPARATOR PARAMETER

SENSITIVITY %

(95% CI)

SPECIFICITY %

(95% CI)

PPV %

NPV %

ACCURACY %

Bilal et al., 2007 n = 90 17-70 years

Histological examination

95.0 96.0 98.0 95.6

Quick urease test 100 82.0 90.0 93.3

Bacterial culture 100 55.0 63.0 74.4

Ogata et al., 2001 n = 47 4-19 years

* 93.1 (82.2% to 97.5%)

78.9 (65.3% to 88.1%)

87.8 88.2 87.5

Savarino et al., 2000 n = 354 Mean: 51 years

Quick urease test and histological examination

98.0 97.0 98.0 97.0 98.0

Sheu et al., 2000 n = 177 NS

Bacterial culture or histological examination

96.4 98.9 98.7 96.8

Vandenplas et al., 1992 n = 95 2-15 years

Bacterial culture 96.0 93.0 83.0 99.0 83.0

Logan et al., 1991 n = 195 14-82 years

† 99.0 98.0

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Table 2: Analytical Validity

STUDY NUMBER AND AGE OF PATIENTS

COMPARATOR PARAMETER

REPEATABILITY CV%

REPRODUCIBILITY CV%

CONCORDANCE %

Ogata et al., 2001 n = 47 4-19 years

Histological examination

83.3

Quick urease test 81.2

Serology test 79.1

Braden et al., 1994 n = 63 18-62 years

n.a. 0.30 - 2.89

Logan et al., 1991 n = 195 14-82 years

* 21.6†

Abbreviations: CV = coefficient of variation; n = number of patients in the study; n.a. = not applicable.

* Any combination of 2 or more positive results among the 3 diagnostic methods requiring a biopsy (quick urease test, histological examination, bacterial culture).

† n = 11.