Practical Aspects for Using the Interferon Gamma Release Assay (IGRA) Test Live Webinar July 14, 2017 Barbara J Seaworth MD Medical Director, Heartland National TB Center Professor, Internal Medicine and Infectious Disease UT Health Northeast EXCELLENCE EXPERTISE INNOVATION Barbara Seaworth, MD has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1
Practical Aspects for Using the Interferon Gamma Release Assay (IGRA) Test Live Webinar July 14, 2017 Lisa Y Armitige, MD, PhD Medical Consultant, Heartland National TB Center Associate Professor, Medicine, Pediatrics, Adult Infectious Disease UT Health Northeast EXCELLENCE EXPERTISE INNOVATION Lisa Armitige, MD, PhD., has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 2
What We Will Cover? Discuss: ATS/IDSA/CDC 2016 Guideline: Diagnosis of Tuberculosis in Adults and Children Who to test Identifying those at risk of TB exposure Identifying those at risk of progression to TB disease Which test to use 3
Objectives of the Diagnostic Guideline Define high and low risk patient populations based upon the results of epidemiological studies Provide diagnostic recommendations that lead to beneficial treatment and favorable clinical outcomes Describe a classification scheme for tuberculosis that is based on pathogenesis. Latent TB Infection Infected with Mycobacterium tuberculosis but: No Active TB Symptoms Chest X ray may be normal, show granuloma, or scarring Positive TST or IGRA The TB organism is in your body! NOT infectious 90 +% chance of never getting Active TB Disease 4
LATENT TB INFECTION Previously thought the bacteria were in a resting state or dormant but more data now reveals that even though the patient is asymptomatic, the bacteria are in various states of activity a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB WHO 2015 Guidelines on the management of LTBI TB Bacteria are metabolically active and dividing, but infection is controlled by the immune system. Active TB Disease may develop if immunity wanes. The Spectrum of Activity of MTB One Could Think of Popcorn (I do) 5
Active TB Disease Active infectious process involving the lungs ± other organs CXR abnormal in pulmonary TB in most persons Positive TST or IGRA supports the diagnosis in smear/naat negative persons and especially in those with negative cultures. Symptoms (may be absent in those persons found during a CI) Fever Chills Night Sweats Weight Loss Cough Productive Cough Hemoptysis When TB disease involves the lungs, the person is infectious until adequately treated WHO SHOULD WE TEST? The more people tested the better. 6
Diagnosis of TB We do not test everyone! We must identify those at risk first Of being infected Of progressing to active TB disease if infected. Those with both risks at highest priority for screening Those with both risks most likely to benefit from treatment screening changes management! Diagnosis of LTBI Determining Which Persons Should Be Tested Those likely to be infected If infected, likely to progress to TB disease Benefit from treatment 7
Those Likely to Be Infected Groups with Increased Likelihood of Infection Household contact or recent exposure to an active case of TB Mycobacteriology laboratory personnel Immigrants from high burden countries (> 20/100,000) Residents and employees of high risk congregate settings 8
Groups with Increased Risk of Progression to Active TB Disease Immunosuppression HIV Hematologic cancers Medical Co morbidities (renal disease, silicosis, diabetes) Medications TNF α inhibitors Prednisone >15 mg, > 4 weeks Chemotherapy Underweight by > 10% CXR consistent with previous inadequately treated TB 9
Contacts of Active TB Case Among close contacts to a TB Case: ~30% have TB Infection ~1 3% have active TB disease Without TBI treatment: Up to 10% with TB Infection may develop Active TB Approximately 5% of contacts with newly acquired TB Infection progress to TB disease within 2 years The other 5% activate > 2 years after acquisition Examination of contacts is one of the most effective strategies for finding persons with TB and stopping transmission in our community. Percent Risk of Disease by Age Age at Infection Risk of Active TB Birth 1 year* 43% 1 5 years* 24% 6 10 years* 2% 11 15 years* 16% Healthy Adults 5 10% lifetime risk HIV Infected Adults + 30 50% lifetime *Miller, Tuberculosis in Children Little Brown, Boston, 1963 + WHO, 2004 10
No definitive test for LTBI exists Recommendations based on: Likelihood of infection Likelihood of progression Evidence about the accuracy of various tests combined with evidence that treatment of LTBI improves clinical outcomes. 11
ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children Recommend IGRA rather than TST for persons 5 1) likely to be infected with MTB 2) low or intermediate risk of progression to disease 3) decided testing is warranted and 4) have either a history of BCG or are unlikely to return for reading (Strong recommendation, moderate quality evidence) TST acceptable if IGRA not available, too costly, too burdensome. CID 2016 Justification Accuracy studies indicate that IGRAs are more specific and equally or more sensitive than TST in individuals who have received BCG Testing with an IGRA dose not depend on a return visit for a result. 12
ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children Suggest IGRA rather than TST for all other persons 5: 1) likely to be infected with MTB 2) low or intermediate risk of progression to disease 3) decided testing is warranted and (Conditional recommendation, moderate quality evidence) TST acceptable if IGRA not available, too costly, too burdensome. CID 2016 Justification Accuracy of TST and IGRAs appears similar in those without a history of BCG Despite the similar test characteristics, the guideline development committee chose to suggest IGRA over TST in such patients because it was concerned about the reliability of a history of BCG vaccination. Individuals from areas with routine BCG should be treated as though they received BCG 13
ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children Insufficient data to recommend a preference either a TST or IGRA for all other persons 5: 1) likely to be infected with MTB 2) have a high risk of progression to disease 3) decided testing is warranted and CID 2016 ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children Guidelines recommend persons at low risk for MTB infection and disease progression NOT be tested. If testing is performed in those unlikely to be infected despite guidelines to contrary: We suggest performing an IGRA instead of a TST. (conditional recommendation, very low quality evidence) We suggest a 2 nd diagnostic test if initial test positive Confirmatory test may be either IGRA or TST Person considered infected only if both tests positive. (conditional recommendation, very low quality evidence) CID 2016 14
ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children We suggest performing a TST rather than an IGRA in healthy children under 5: 1) for whom it has been decided testing is warranted (conditional recommendation, very low quality evidence) CID 2016 IGRAs and the 2015 AAP RED BOOK Can use IGRAs in immunocompetent children > 4 years of age in all situations when a TST would be used (New in 2017 > 2) Particularly useful/preferred for children who have received a BCG vaccination Neither IGRAs nor the TST are perfect; always need clinical judgment! 15
Evaluate to Exclude Active TB Disease If the TST or IGRA is Positive»OR Child < 5 or immunocompromised person with recent exposure even if TST/IGRA negative History Physical examination Chest X Ray WHO Guidelines on the management of latent tuberculosis infection 2015 start with a symptom screen. Remember: TST or IGRA may be negative in those with active TB! 16
Radiologic Exam CXR must be done before treatment of TB Infection Must be read as normal Or IF abnormal: Not consistent with Active TB Stable abnormality confirmed over a 3 month period 17
CDC Recommendations Repeating an IGRA or performing a TST may be useful when the initial IGRA result is indeterminate, borderline, or invalid, and a reason for testing persists CDC Recommendations A diagnosis of M. tuberculosis infection, and the decisions about medical or public health management should include epidemiological, historical, and other clinical information when using IGRA or TST results Decisions should not be based on IGRA or TST results alone Particularly relevant for managing discordant test results (e.g., TST+/QFT ) 18
TST vs. IGRAs Discordance between the TST and IGRAs has been measured up to 20% in patients known to be infected with Mtb IGRAs shine when used in BCG vaccinated populations (increased specificity) NO study has shown the IGRA to be better in US born (or non BCG vaccinated) individuals. The TST can be used and be trusted in this population No test (TST or IGRA) overrides clinical, epidemiologic or historical data What do the current WHO guidelines say about LTBI testing? *Remember that in the United States, we re still waiting on updated LTBI guidelines from ATS / IDSA / CDC 19
For which people? In high and upper middle income countries with estimated TB incidence less than 100/100,000 Systematic test & treat of LBTI should be performed in Systematic test & treat of LTBI should be considered in Systematic testing for LTBI is not recommended in People living with HIV adult & child contacts of pulmonary TB cases patients on TNF treatment patients on dialysis patients with silicosis patients preparing for organ transplantation Prisoners health workers immigrants from high TB burden countries homeless persons people who use drugs People with diabetes people with harmful alcohol use tobacco smokers underweight people For resource limited countries and other middle income countries that do not belong to the previous category Systematic test & treat of LBTI should be performed in People living with HIV Children below 5 years of age who are household or close contacts of people with TB for whom active TB has been ruled out 20
Getting Started I need to pick a test. TB Skin Test (TST) Pros: Inexpensive Simple to perform (if you know what you are doing.) Cons: Must return in 48 72 hrs Interpretation is somewhat subjective False Negatives: Elderly Immunosuppressed False Positives: Low risk populations Non tuberculous Mycobacteria 21
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Reading the TB Skin Test Measure induration, not erythema!!! Antigens for Newer Generation IGRAs Negative control or nil (e.g., saline, heparin) Positive control or mitogen: non specific immune response stimulator (e.g., phytohemagglutinin) M. tuberculosis specific antigens Unlike PPD used in TST, do not cross react with BCG or NTM (some exceptions) ESAT 6, CFP 10, TB 7.7 23
Antigens for Gamma Release Assays www.cellestis.com FDA Approved IGRAs Quantiferon Gold In Tube (QFT GIT) T spot.tb (T spot) 24
How are the two tests different? QuantiFERON TB Gold In Tube (QFT GIT) Stage 1: Whole Blood Culture in special blood collection tubes Mtb* Nil PHA Collect 1mL of blood in 3 tubes Incubate at 37ºC for 16 24 hours Centrifuge 5 minutes to separate plasma above gel Stage 2: Measure [IFN ] & Interpret Mtb COLOR Nil PHA TMB Collect 50 µl of plasma for ELISA Measure [ IFN ] in Sandwich ELISA Software calculates results and prints report *Mtb = ESAT 6 + CFP 10 + TB 7.7 25
T Spot.TB (T Spot) Collect blood in CPT tube Recover, wash, & count PBMCs Aliquot 250,000 PBMCs to 4 wells with anti IFN Add saline, PHA, ESAT 6 or CFP 10 & incubate Wash away cells Develop & count spots where cells produced IFN IFN Antibody Sensitized T cell IFN Captured Detection Antibody Chromogen Spot Saline ESAT 6 CFP 10 PHA Which is the better test? For use in testing, the QFT GIT and T spot can be considered equivalent. The goal is to get an answer! 26
Indeterminate and Borderline Results Indeterminate Negative control result is too high High background production of IFN Positive control result is too low Immunocompromised patients may not respond to mitogen Something went wrong with the performing of the test Borderline (T Spot only) Falls within borderline zone close to negative/positive cut point Potential sources of variability and their impact on results in IGRAs Banaei, Gaur, Pai. J. Clin. Microbiol. April 2016 54 (4): 845 850 27
CDC Recommendations Repeating an IGRA or performing a TST may be useful when the initial IGRA result is indeterminate, borderline, or invalid, and a reason for testing persists Associated cost of a repeat test, time delay scheduling the patient to return, diagnostic delays while repeating the test Recommendations and Reports June 25, 2010 / Vol. 59 / No. RR 5 More important questions Who are you testing? What does your lab say? Where are you testing/how often do you test? 28
Who are you testing? BCG vaccinated populations Those unlikely to return for a reading Children 3 tubes of blood from little people that don t like needles Persons living with HIV/persons with low WBCs (such as with chemotherapy) May not have that many cells to start with, concentrating them may help What does your lab say? Where will the tubes go once the blood is drawn? How can we make our clinic hours and lab hours work together? Is my lab giving me what I need or do I need to consider other options? 29
Where are you testing and how often? Hospitals and low volume clinics may have more issues with QFT Get to know your rep and have them come out for training if need be What about boosting? IGRAs can be boosted by performing a TST then following with an IGRA What this means is not entirely clear You can t boost something that s not there! 30
Remember A decision to test is a decision to treat think! No definitive test for LTBI exists No test (TST or IGRA) overrides clinical, epidemiologic or historical data Questions? Barbara.Seaworth@dshs.texas.gov Lisa.Armitige@dshs.texas.gov 1 800 TEX LUNG 31