Evidence Based Pathology H. pylori stool antigen test

1
Evidence Based PathologyH. pylori stool antigen
test

• Shubnum Chaudhery
• Medical College of Georgia
• 12.7.06

2
Introduction

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

3
Introduction

• Epidemiology
• Most prevalent infection world wide
• Commonly acquired during childhood
• 10 by age 10
• 60 by age 60
• Low socioeconomic
• In U.S., more common in Blacks/Hispanics
• Transmission Route
• Fecal-oral
• Oral-oral

4
Introduction

• Spectrum of H. pylori disease
• Asymptomatic infection in most (gt70)
• 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)

5

• European Helicobacter pylori Study Group (1987)
• Maastricht-3 2005 Consensus Report
• promote research in pathogenesis
• annual meetings
• task forces
• clinical trials
• Cochrane Systematic Review

6
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
7
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
8
Patients lt 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
9
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
10
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

11
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

12
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

13
H. Pylori testingSerology

• 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)

14
H. Pylori testingUBT

• 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

15
H. Pylori testingHpSA

• 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

16
Stool Antigen Test for the Diagnosis of
Helicobacter pylori Infection a Systematic Review

• HELICOBACTER
• Volume 9-Number 4-2004

17
Review article key points

• Aim was to review systematically the diagnostic
  accuracy of HP stool antigen test
• Evaluate the stool antigen in untreated pts
• Confirmation of H. pylori eradication 4-8 wks
  after treatment
• Polyclonal vs monoclonal test for detection of H.
  pylori antigens in
• H. pylori stool antigen test accuracy in specific
  conditions
• PPI, Children
• Cost effectiveness
• Outcome variables - Sensivity, Specificity, PPV,
  NPV
• Most of the studies differed on several
  variables, subanalyses planned to calculate
  diagnostic accuracy

18
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
• Recently approved by FDA for use in primary
  diagnosis of H. pylori and in monitoring of
  posttreatment outcome

19
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

20
Accuracy to confirm eradication 4 or more weeks
after completing therapyTrue 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

21
Accuracy to confirm eradication 4 or more weeks
after completing therapyUBT 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
  gt10 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

22
Accuracy to confirm eradication 4 or more weeks
after completing therapy

• Why false positives in HpSA?
• Antigens eliminated in feces for a long period
  after eradication
• 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
• Biopsy based test showed neither
• Cross-reaction with other organisms?
• Long-term retention of H. pylori antigen in colon
  (appendix, diverticula)

• False Negatives?
• Decreased bacterial density low stool antigen
  optical densities
• High genetic variability of bacterium leading to
  high variability of antigenic epitopes

23
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

24
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

25
Test accuracy in childhood

• Seems to perform well in children, independent of
  age
• Lower sensitivity reported in children lt 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

26
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

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

27
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)

28
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
  OMorain, Colm. Guidelines for the Management of
  Helicobacter pylori Infection, Summary of the
  Maastricht-3 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.

29
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.

30
(No Transcript)