H. Pylori Stool Antigen Test

Evidence Based Pathology

H. pylori stool antigen test Shubnum Chaudhery Medical College of Georgia 12.7.06

Introduction • First described in 1984 • Curvilinear, Gram Negative Rod • Colonizes gastric mucosa only • over 200 genetically diverse strains identified

Introduction • • •

Epidemiology Most prevalent infection world wide Commonly acquired during childhood – 10% by age 10 – 60% by age 60

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Low socioeconomic In U.S., more common in Blacks/Hispanics Transmission Route – Fecal-oral – Oral-oral

Introduction • Spectrum of H. pylori disease – Asymptomatic infection in most (>70%) – Establishes a chronic infectious state – Peptic ulcer disease and chronic gastritis in 15% of infected individuals – Cofactor in development of gastric adenocarcinoma and mucosal associated lymphoid tissue lymphoma (MALT)

• European Helicobacter pylori Study Group (1987) – – – – –

Maastricht-3 2005 Consensus Report promote research in pathogenesis annual meetings task forces clinical trials

• Cochrane Systematic Review

Five initial approaches to management of dyspepsia 1. Empirical acid suppression 2. Noninvasive HP testing 3. HP test & treat 4. Empirical HP eradication 5. Early endoscopy • Patients 55 or younger without alarm features should receive Hp test followed by acid suppression • Hp testing should no longer be performed with serologic testing & instead a Urea Breath Test or stool antigen test should be used • Patients older than 55 with alarm features presenting with new dyspepsia or if upper GI malignancy is of concern then upper endoscopy is indicated (with biopsy) American Gastroenterological Association, 2005

Mayo Clinic definition of Alarm Features in dyspepsia • • • • • • • • • •

Age older than 55 years with new-onset dyspepsia Family history of upper GI cancer Unintended weight loss GI bleeding Progressive dysphagia Odynophagia Unexplained iron deficiency anemia Persistent vomiting Palpable mass or lymphadenopathy Jaundice

American Gastroenterological Association, 2005

Patients < 55 years without alarm features – H. pylori test & treat followed by acid suppression if symptoms remain • C-urea breath test or stool antigen test • PPIs are drug class of choice for acid suppression – Recommendation to test & treat • based on randomized controlled trials • the potential effect of eradication in preventing future gastric cancer – Further investigation is seldom needed – Endoscopy has low probability of demonstrating relevant organic disease in these patients – Compared with alternative, such as screening for colorectal ca, endoscopy does not appear to be a cost –effective use of resources – Endoscopy is recommended • after age 55 years, when upper GI malignancy becomes more common • for younger patients with alarm features presenting with new onset dyspepsia

American Gastroenterological Association, 2005

Benefits of implementing guidelines • Potential benefits – – – –

Fewer upper GI endoscopies performed, particularly in pts 55 or younger Increase in number of noninvasive Hp tests performed Decrease in overall cost of managing dyspepsia Increase in number of patients w/ dyspepsia receiving effective treatment

– Risks of upper endoscopy are very low • • • • •

1 in 330 to 1 in 2700 Most frequent is cardiopulmonary complications (1/690 to 1/2600) Followed by perforation (1/900 to 1/4200) Bleeding (1/3400 to 1/10,000) Deaths are rare (1/3300 to 1/40.000)

American Gastroenterological Association, 2005

Choice of test? • Diagnostic test • Clinical circumstances – pre-test probability of infection – sensitivity and specificity of the test – cost-effectiveness – availability

• Post-eradication assessment – higher sensitivity -to recognize patients still infected

Evaluation of H. pylori infection • Invasive Test – Endoscopy with biopsy • • • •

Histology Culture w/ microbial resistance Rapid Urease test (CLO-test) PCR

• Noninvasive Test – serology (ELISA) – 13C or 14C urea breath test (UBT) – stool antigen test

Usefullness of Noninvasive tests • Research • Pre-endoscopic screening of patients for referral to a GI service for investigation of dyspepsia

• Therapeutic monitoring following eradication therapy to confirm elimination of infection

H. Pylori testing Serology • Serology – IgG, IgA, IgM – Multiple antibodies provide higher sensitivity than any single antibody – only indicates infection, does not confirm if active – Unreliable indicator of H. pylori status in patients who have received treatment – Very Specific (few false-positive results)

H. Pylori testing UBT • Urea breath test – gold standard for 1o diagnosis and monitoring of eradication-has excellent sensitivity & specificity – expensive instruments – requires trained staff for air sampling – time consuming – requires use of isotopically labeled urea – difficult for children and neurologically handicapped patients

H. Pylori testing HpSA • Stool antigen enzyme immunoassay • Based on detection of H. pylori stool antigen – Polyclonal antigen tests • older - lower sensitivity in comparison to UBT and considerable inter-test variability • antigenic composition could change from batch to batch

– Monoclonal antigen test • EIA based on a mix of monoclonal abs

Stool Antigen Test for the Diagnosis of Helicobacter pylori Infection: a Systematic Review HELICOBACTER Volume 9-Number 4-2004

Review article key points •

Aim was to review systematically the diagnostic accuracy of HP stool antigen test

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Evaluate the stool antigen in untreated pts

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Confirmation of H. pylori eradication 4-8 wks after treatment

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Polyclonal vs monoclonal test for detection of H. pylori antigens in

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H. pylori stool antigen test accuracy in specific conditions – PPI, Children

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Cost effectiveness

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Outcome variables - Sensivity, Specificity, PPV, NPV

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Most of the studies differed on several variables, subanalyses planned to calculate diagnostic accuracy

Accuracy for the diagnosis of infection in untreated patients Overall- 89 studies (10,858 patients) mean weighted- 91%, 90%, 93%, 92% Gold standard of at least 2 diagnostic methods (78 studies, 9306 patients) 91%, 94%, 92%, 87% Vaida et al, 2000- mean weighted sensitivity 94% and specificity 94% •

HpSA test can be definitively considered an accurate noninvasive method for diagnosis of H. pylori infection in untreated patients

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Recently approved by FDA for use in primary diagnosis of H. pylori and in monitoring of posttreatment outcome

Accuracy to confirm eradication 4 or more weeks after completing therapy • Until recently UBT was only available noninvasive test • Serology requires several months for accurate detection of significant fall in antibody titer • Maconi et al, 2002, showed HpSA test accurate in posttreatment setting • 39 studies (3147 patients) – 86%, 92%, 76%, 93%

• Vaira et al, 2000 – sensitivity 92% and specificity 92%

Accuracy to confirm eradication 4 or more weeks after completing therapy “True gold standard” • Most noteworthy variable involving comparison of HpSA tests – Gold standard used- Method or combination of methods used in study – Need “true gold standard” – Most used UBT, like HpSA is indirect test • Measurement of enzymatic activity vs

• Immunlogical identification of bacterial antigens

– May account for differences evaluating accuracy – Review results similarly accurate when a gold standard based on at least 2 methods used • 85%, 91%, 77%, 89%

• Stool antigen test adds another option to be used in posttreatment setting

Accuracy to confirm eradication 4 or more weeks after completing therapy UBT Better? • Bilardi et al, 2002- suggested HpSA was less reliable than UBT – High false positive – indicating lower specificity of stool antigen test – Overall favorable results BUT some studies showed >10% of false positives or false negatives

• Significantly higher specificity of HpSA in untreated patients (90%) than treated (82%) (Trevasani et al, 1999) • Overall percentage of contradictory results between UBT and HpSA of 30% (Masoero et al, 2000) – Positive HpSA associated with a negative UBT

Accuracy to confirm eradication 4 or more weeks after completing therapy Why false positives in HpSA?

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Antigens eliminated in feces for a long period after eradication –

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Gastric mucosal replacement takes less than 1 week

H. pylori can survive in gastric environment – –

Biologically active spiral form Dormant coccoid form- does not produce urease •

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Biopsy based test showed neither

Cross-reaction with other organisms? Long-term retention of H. pylori antigen in colon (appendix, diverticula)

False Negatives?

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Decreased bacterial density = low stool antigen optical densities

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High genetic variability of bacterium leading to high variability of antigenic epitopes

Polyclonal vs. Monoclonal HpSA test • Pretreatment – 8 studies (1399 patients) – – – –

Sensitivity: 90% vs. 96% Specificity: 94% vs. 97% PPV: 91% vs. 96% NPV: 85% vs. 97%

• Posttreatment of Polyclonal– 33 studies (2729 patients) vs. monoclonal- 6 studies (418 patents) – – – –

Sensitivity: 84% vs. 95% Specificity: 91% vs. 97% PPV: 74% vs. 91% NPV: 92% vs. 98%

Effect of antisecretory drugs on accuracy • Assessed the effect of previous therapy with proton pump inhibitors on performance of HpSA test. • PPI cause false negative results in HpSA & UBT • Dose related 7 day 14 day 2 wks post discontinuation – 20mg omeprazole 20% 24% all positive – 40mg omeprazole 28% 36% all positive – No statistically significant difference b/w HpSA & UBT (Manes et al, 1999)

• Effect of PPI nullified 2 weeks after removal of medication

Test accuracy in childhood • Seems to perform well in children, independent of age • Lower sensitivity reported in children < 5 y/o • Pretreatment setting- 20 studies (16,149 patients) – 90%, 96%, 93%, 93%

• Posttreatment – 8 studies (307 patients) – 97%, 97%, 88%, 99%

• Advantages – UBT may be difficult to perform in children

Advantages and Disadvantages Advantages • • • • • • •

Easy & simple to perform Rapid (approximately 90 minutes) Requires only 1 stool specimen (UBT needs 2 breath samples) Does not require technician or nurse Can be collected in privacy of home Stored at 2-8o C up to 3 days, indefinitely at -20o C Unfrozen should be sent within 1 day to lab; risk decreased sensitivity

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Disadvantages Disagreeable task / compliance 60% pts prefer UBT vs. 5% for stool, 35% no preference

Cost Effectiveness • Before treatment – Serology had lowest cost per correct diagnosis, but low diagnostic accuracy – At low (30%) & intermediate (60%) prevalence, HpSA test more accurate (93%), average cost $126 per correct diagnosis (Vakil et al, 2000)

• Cost of HpSA test in state of flux • Confirmation of eradication (cost per correct diagnosis) – UBT - $136 – Rapid urease test- $1105 – HpSA – $82 (Vakil et al, 2000)

References Bilardi C, Biaginni R, Dulbecco P, et al. Stool antigen assay (HpSA) is less reliable than urea breath test for post-treatment diagnosis in Helicobacter pylori infection. Aliment Pharmacology Therapy 2002; 16: 1733-8. Gatta, Luigi et al. Effect of Proton Pump Inhibitors and antacid Therapy on 13C Urea Breath Tests and Stool Test for Helicobacter Pylori infection. American Journal of Gastroenterology 2004; 10: 823-829. Gisbert, Javier P., Pajares, Jose Maria. Stool Antigen Test for the Diagnosis of Helicobacter pylori Infection: a Systematic Review. Helicobacter 2004; 9: 347-368. Kindermann, Angelika et al. Influence of Age on C-Urea Breath Test Results in Children. Journal of Pediatric Gastroenterology 2000; 30: 85091. Malfertheiner, Peter, Megraud, Francis and O’Morain, Colm. Guidelines for the Management of Helicobacter pylori Infection, Summary of the Maastricht3 2005 Consensus Report. European Gastroenterology Review 2005. Makristathis, a. Non-invasive Helicobacter pylori diagnosis: Stool of breath tests? Digestive and Liver Disease 2005; 37: 732-734. Masoero G, Lombardo L, Della Monica P, et al. Discrepancy between Helicobacter pylori stool antigen assay and urea breath test in the detection of Helicobacter pylori infection. Dig Liver Disease 2000; 32: 285-290.

References Treviasani L, Sartori S, Galvani F, et al. Evaluation of a new enzyme immunoassay for detecting Helicobacter pylori in feces: a prospective pilot study. Am J Gastroenterolgy 1999; 94: 1830-3. Vakil NB, Ofman J, Vaira D. Cost-effectivenss of tests for the detection of failed eradication after treatment of H. pylori infection. Gastroenterolgy 2000: 118: A508. Vakil N, Rhew D, Soll A, Ofman JJ. The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori. Am J Gastroenterology. 20000: 95: 1691-8. Varia D, Holton J, Menegatti M, et al. Invasive and non-invasive tests for Helicobacter pylori infection. Alimentary Pharmacology Therapy 2000: 14: 13-22. Varia, D., Gatta, L., Ricci, C. Stool Test for Helciobacter pylori. Digestive and Liver Disease 2004; 36: 446-447.