TB Infection Diagnosis Recommendations Talk Developed by Lisa Y. Armitige, MD, PhD Medical Consultant, Heartland National TB Center Associate Professor Internal Medicine/Pediatrics/Infectious Disease UT Health Northeast, Tyler, Texas Presented by Linda Dooley, MD TB Physician Austin Public Health September 20, 2017 Screening for Tuberculosis Infection September 20, 2017 Harlingen, TX EXCELLENCE EXPERTISE INNOVATION Linda Dooley, 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
TB Infection Diagnosis Recommendations September 20, 2017 Harlingen,Texas Talk Developed by Lisa Y. Armitige, MD, PhD Medical Consultant, Heartland National TB Center Associate Professor Internal Medicine/Pediatrics/Infectious Disease UT Health Northeast, Tyler, Texas Presented by Linda Dooley, MD TB Physician Austin Public Health Screening for Tuberculosis Along the US/Mexico Border San Antonio, Texas June 10, 2016 EXCELLENCE EXPERTISE INNOVATION TB INFECTION 2
TB EXPOSURE Your patient and someone who has active pulmonary TB have been sharing airspace CHARACTERIZING THE EXPOSURE Frequency and duration of exposure Dilution effect (volume of air) Ventilation Exposure to ultraviolet light AJCCRM. 2005: 170;1169 1227. 3
RISK OF TB TRANSMISSION AJCCRM. 2005: 170;1169 1227. TB INFECTION The TB organism has breached the barriers set up by the immune system and has caused infection Outcome of TB Infection Latent TB Infection (LTBI) (90%) No Active TB Disease Active TB Disease (10%) 50% Primary Progression in first 2 years 50% Reactivation later in life 4
Clinical Presentation of LTBI No symptoms or signs of infection Positive tuberculin skin test or IGRA Chest x ray may be normal, or show granulomata, pleural or parenchymal scarring NOT infectious LTBI ACTIVE TB DISEASE Recent infection HIV infection Chest x ray abnormality Underweight by >10% Intravenous drug use Immunosuppression ATS CDC. Am J Respir Crit Care Med 2000;161:S221 5
LTBI ACTIVE TB DISEASE Immunosuppression HIV Hematologic cancers Medical Co morbidities Medications TNF α inhibitors Prednisone >15 mg, > 4 weeks Chemotherapy Other immunosuppressive drugs (e.g. other biologics, anti rejection medications) 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 6
LATENT TB INFECTION What s really happening? The bacteria that cause disease are dormant (metabolically inactive). For reasons that are not clear, they wake up and start to divide. OR Bacteria are metabolically active and dividing, but the infection is somehow controlled by the immune system. i.e. disease develops when immunity is somehow compromised TB Infection Diagnosis 7
Who Should be Tested for TB Infection? Targeted Testing for TB Infection The simplified version: Persons who are at increased risk for M. tuberculosis infection Persons at increased risk for progression to active disease if infected with M. tuberculosis (even if not at increased exposure risk) And those who tend to be tested in addition: Persons tested for administrative reasons (e.g., mandatory employment testing) Persons with symptoms of active TB disease (fever, night sweats, cough, and weight loss) Who Should be Tested for TB Infection? Targeted Testing for TB Infection Contacts of persons with active TB HIV positive individuals Recent immigrants (<5 yrs) from high prevalence countries Injection Drug Users Residents and Employees of high risk congregate settings: Correctional facilities and Homeless Shelters Hospitals, Clinics, Nursing Homes, Substance Abuse Facilities Newest Category: Patients considering treatment with TNF α Antagonists Children exposed to high risk adults or environments 8
Contacts of Active TB Case Among close contacts to a TB Case: 30% have TB Infection 1 3% have active TB disease Without TB Infection treatment: 10% with TB Infection with 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 TB Infection diagnosis and TB control! MMWR December 16, 2005 / Vol. 54 / No. RR 15 30,000 Reported TB Cases United States, 1982 2014* 25,000 No. of Cases 20,000 15,000 10,000 5,000 0 *Updated as of June 5, 2015. Year 9
20,000 Number of TB Cases in U.S.-born vs. Foreign-born Persons, United States, 1993 2014* 15,000 No. of Cases 10,000 5,000 0 U.S. born Foreign born *Updated as of June 5, 2015. No. of Cases Trends in TB Cases in Foreign born Persons, United States, 1993 2014* Percentage 9000 70% 8000 60% 7000 6000 50% 5000 40% 4000 30% 3000 2000 20% 1000 10% 0 0% Number of Cases Percent of Total Cases *Updated as of June 5, 2015. 10
Who Should be Tested for TB Infection? Targeted Testing for TB Infection Contacts of persons with active TB HIV positive individuals Recent immigrants (<5 yrs) from high prevalence countries Injection Drug Users Residents and Employees of high risk congregate settings: Correctional facilities and Homeless Shelters Hospitals, Clinics, Nursing Homes, Substance Abuse Facilities Newest Category: Patients considering treatment with TNF α Antagonists Children exposed to high risk adults or environments Percent of Foreign born with TB by Time of Residence in U.S. Prior to Diagnosis, 2014 100% 80% 60% 40% 20% 0% Mexico Philippines Vietnam All Other Foreignborn Unknown* <1 year 1 4 years 5 years *Foreign born TB patients for whom information on length of residence in the U.S. prior to diagnosis is unknown or missing. 11
Tests for Diagnosis of TB Infection TB Infection Diagnostics TB Skin Test (TST) Interferon Gamma Release Assays (IGRA) 12
TB Skin Test (TST) Uses Purified Protein Derivative (PPD) PPD is given via intradermal injection Read induration, not erythema, at 48 72 hrs 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 BCG vaccination 13
Reading the TB Skin Test Measure induration, not erythema!!! 14
Induration of 5mm Considered a Positive TST HIV positive persons Recent contacts of TB cases Fibrotic Changes on CXR c/w prior TB Patients with organ transplants or other immunosuppression Prednisone therapy 15 mg/day > 1 month CDC. June 2000 Induration of 10mm Considered a Positive TST Recent arrivals (<5 yrs?) high prevalence countries IVDU Residents/employees high risk congregate facilities (health care, prisons, shelters, etc.) TB lab personnel Children < 4 years old or exposed to adults at risk Persons with high risk medical conditions CDC. June 2000 15
Induration of 10mm Considered a Positive TST Persons with high risk medical conditions Silicosis Diabetes Chronic renal failure Hematologic disorders/leukemia/lymphoma Cancers, particularly head/neck and lung Low body weight less than 10% below ideal body weight Gastrectomy Jejunal bypass CDC. June 2000 Induration of 15mm Considered a Positive TST Persons with no risk factors (Why was a TST placed?) CDC. June 2000 16
Interferon Gamma Release Assays (IGRAs) TST vs In vitro Assays Andersen et al. Lancet 2000;356:1099 17
Antigens Specific to M. tuberculosis Cole et al, Nature 1998 Ganguly et al, Tuberculosis (2008):88, 510-517 Genetic Region of Difference 1 (RD 1) Not found in BCG or most NTM NTM exceptions: M. kansasii, M. szulgai, M. marinum Codes for 9 proteins Two proteins were found to produce strong immunologic responses in persons infected with M. tuberculosis 10 kda culture filtrate protein (CFP 10) 6 kda early secreted target antigen (ESAT 6) 18
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 (actually simulated using overlapping peptides) Antigens for Gamma Release Assays www.cellestis.com 19
FDA Approved IGRAs 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 20
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 What Result is Considered Positive? Depends on the test Based on calculation of IFN response to TB antigens relative to IFN response to nil Unlike TST, not risk stratified (i.e., there are not multiple cutoffs for different risk groups) Still somewhat complicated Software performs calculations 21
Nil (IU/mL) Interpretation Criteria for the QFT GIT Test TB Antigen minus Nil (IU/mL) QFT-GIT (IU/mL) Mitogen Interpretation 8.0 0.35 or < 25% of Nil value Negative 5.0 M. tuberculosis infection unlikely 8.0 0.35 and 25% of Nil value Positive ANY M. tuberculosis infection likely 8.0 ANY Indeterminate ANY Indeterminate 8.0 0.35 and or < 25% of Nil value Indeterminate < 5.0 Indeterminate QuantiFERON TB Gold Mori et al 2004 Am J Respir Crit Care Med,170: 59 64 22
Interpretation Criteria for the T Spot.TB Result Nil* TB Response# # Mitogen++ Interpretation+ Positive 10 spots 8 spots Any M.tuberculosis infection likely Borderline 10 spots 5, 6, or 7 spots Any Uncertain likelihood of M. tuberculosis infection Negative 10spots 4 spots M Tb infection unlikely Indeterminate > 10 10 Any < 5 spots Any < 20 spots Uncertain likelihood of M. tuberculosis infection T Spot.TB 23
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 Borderline (T Spot only) Falls within borderline zone close to negative/positive cut point CDC Guidelines 24
Recommendations 25
CDC Recommendations TST or IGRAs should be used as aids in diagnosing infection with M. tuberculosis Both the standard qualitative test interpretation and the quantitative assay measurements should be reported As with the TST, IGRAs generally should not be used for testing persons who have a low risk of infection and a low risk of disease due to M. tuberculosis CDC Recommendations Populations/situations in which IGRAs are preferred testing persons from groups that historically have poor rates of return for TST reading testing persons who have received BCG (as a vaccine or for cancer therapy) 26
CDC Recommendations Populations/situations in which TST is preferred testing children younger than 5 years old 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 Preferred test for children 5 years and older who have received a BCG vaccination Data shows IGRAs perform consistent well in children 5 years and older, some experts use down to 3 y/o Neither IGRAs nor the TST are perfect; always need clinical judgment! 27
AAP RedBook 2015 CDC Recommendations Populations/situations in which there is no preference between IGRAs and TST testing recent contacts of persons with infectious tuberculosis periodic screening that addresses occupational exposure to TB (e.g., surveillance programs for healthcare workers) 28
CDC Recommendations Routine testing with both TST and an IGRA is not recommended Results from both tests may be useful when the initial test is negative if increased sensitivity is desired (considered infected if either test is positive) risk of infection, the risk of progression, and the risk of a poor outcome are increased clinical suspicion of active tuberculosis and confirmation of M. tuberculosis infection is desired Results from both tests may be useful when the initial test is positive if increased specificity is desired (considered infected only if both tests are positive) additional evidence of infection is required to encourage compliance (such as in foreignborn healthcare workers who believe their positive TST is due to BCG) in healthy persons who have a low risk of both infection and progression 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 29
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 ) Sources of variability for QFT GIT Clin. Microbiol. Rev. 2014, 27(1):3 20 30
Pearls for TST vs. IGRAs Discordance between the TST and IGRAs has been measured up to 20% in patients known to be infected with Mtb. Don t order both tests, pick the right test to start with! Who are you testing? IGRAs shine when used in BCG vaccinated populations (increased specificity) NO study has shown the IGRA to be better in US born (or non BCGvaccinated) individuals. The TST can be used AND trusted in this population No test (TST or IGRA) overrides clinical, epidemiologic or historical data Testing is good and necessary! But is it funded..? 31
USPSTF recommendations for LTBI Examples of USPSTF A and B ratings Topic Grade Release Date Bacteriuria screening: pregnant women A July 2008 Blood pressure screening in adults A October 2015 Cervical cancer screening A March 2012 Cholesterol abnormalities screening: men 35 and older A June 2008 Cholesterol abnormalities screening: women younger than 45 A June 2008 Abdominal aortic aneurysm screening: men B June 2014 Alcohol misuse: screening and counseling B May 2013 Aspirin preventive medication: Adults aged 50 to 59 years with a 10% 10 year cardiovascular risk B April 2016 BRCA risk assessment and genetic counseling/testing B December 2013 http://www.uspreventiveservicestaskforce.org/page/name/uspstf a and b recommendations/ 32
USPSTF and the Affordable Care Act (Coverage of Preventive Services) Public Health Service (PHS) Act section 2713 and the interim final regulations relating to coverage of preventive services require non grandfathered group health plans and health insurance coverage offered in the individual or group market to provide benefits for, and prohibit the imposition of cost sharing requirements with respect to, the following: Evidenced based items or services that have in effect a rating of "A" or "B" in the current recommendations of the United States Preventive Services Task Force (USPSTF) with respect to the individual involved, except for the recommendations of the USPSTF regarding breast cancer screening, mammography, and prevention issued on or around November 2009, which are not considered current CMS.gov: https://www.cms.gov/cciio/resources/fact Sheets and FAQs/aca_implementation_faqs18.html Questions? Easy Questions: Linda.Dooley@austintexas.gov All Other Questions: Lisa.Armitige@dshs.state.tx.us Or Heartland Consultants 1 800 TEX LUNG 33