Learning Objectives. Speaker Disclosures. Use of QuantiFERON TB Gold In Tube for TB Surveillance 5/3/2013

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1 Use of QuantiFERON TB Gold In Tube for TB Surveillance May 8, 2013 Landa A. PoianiDarocki RN, MSN, APN BC, COHN S, FAAOHN L. PoianiDarocki, Meridian Health Learning Objectives Describe Interferon Gamma Release Assays (IGRAs) and how they work in TB surveillance Discuss the benefits of using IGRAs over TST Discuss transitioning a Health Care Organization from TB surveillance with TST to QFT L. PoianiDarocki, Meridian Health Speaker Disclosures Employed by Meridian Health as a Sr. Manager of Occupational Health where we use QFT TB Gold for our TB surveillance program QIAGEN will be covering my travel expenses and offering an honorarium No conflicts of interest L. PoianiDarocki, Meridian Health

2 Tuberculosis in USA Million People with LTBI (4% of population) ,951 new cases of TB reported 6.1% decrease from th consecutive yr of declining rate 44.2% of counties did NOT report a new case during % of active cases = result of reactivation of LTB MMWR March 22, 2013 Vol 62 No.11 L. PoianiDarocki, Meridian Health Definitions Sensitivity True Positive The probability that the test indicates a person has the disease when in fact that person does have the disease Specificity True Negative The probability that the test indicates a person does not have the disease when that person is disease free L. PoianiDarocki, Meridian Health Predictive Value Higher prevalence of disease higher the predictive value of the test! Positive Predictive Value (PPV) High PPV= strong chance that a person with a positive test has TB Negative Predictive Value (NPV) High NPV = strong chance that a person with a negative test does not have TB QFT 100% NPV Sources: Diel, R. et al. (2011) Am J Respir Crit Care Med 183(1):88 95 L. PoianiDarocki, Meridian Health

3 Use of IGRAs testing for TB Surveillance IGRAs 1 st new tools in past 130 yrs introduced to screen for LTBI More accurate and logistically efficient IGRA is preferred over TST for BCG vaccinated populations CDC supports the use of IGRAs in all situations where TSTs can be used Sources: CDC MMWR 2010 L. PoianiDarocki, Meridian Health IGRAs preferred for the BCG vaccinated and those unlikely to return for their TST reading L. PoianiDarocki, Meridian Health Interferon Gamma Release Assays: Principle Individuals exposed to diseases (i.e. M. tuberculosis) have specific T cell lymphocytes in their blood that maintain a memory for specific antigens. Sources: L. PoianiDarocki, Meridian Health

4 Interferon Gamma Release Assays: Principle Exposing blood collected from an infected individual to specific disease antigens results in the rapid release of the cytokine interferon gamma Sources: L. PoianiDarocki, Meridian Health Interferon Gamma Release assays and how they work in TB surveillance IGRA evaluates an individual s immune response to prior TB exposure. They detect the immune response of T cells found in peripheral blood that have been sensitized to M. tuberculosis antigens. Can aid in diagnosing both latent TB infection (LTBI) and tuberculosis disease. They do NOT differentiate LTBI from TB disease. L. PoianiDarocki, Meridian Health Interferon gamma release assays (IGRAs) Two IGRAs approved by the U.S. Food and Drug Administration (FDA) are commercially available in the U.S.: 1. QuantiFERON TB Gold In Tube (QFT ) 3 Generations since T SPOT.TB L. PoianiDarocki, Meridian Health

5 T SPOT FDA approved 2008 BCG (foreign born) & immunocompromised Sensitivity & Specificity exceeded 95% in clinical trials* 1 Visit, 1 tube** Interferon gamma is captured and presented as individual spots from T cells sensitized to TB infection *These values do not incorporate the FDA approved borderline zone **Recommended to send two tubes if suspected or known immunocompromised due to likelihood of invalid results Sources: L. PoianiDarocki, Meridian Health Interpretation of Results: Spots are visually counted Invalid >10 spots in the Nil. OR <20 spots in the Mitogen (and not Positive or Equivocal) Positive > 8 spots Negative < 4 spots Borderline 5, 6, or 7 spots Retest borderline & invalid results T Spot NOTE: the European PI and many studies use a 6 spot cut off; this WILL affect the results L. PoianiDarocki, Meridian Health QuantiFERON Technology The stimulation of effector T cells in whole blood with a specific antigen(s) or mitogen, and the subsequent simple quantification of the resulting interferon gamma, is the basis of the QuantiFERON technology. The skin test (TST) uses a nonspecific purified protein derivative (PPD) QFT uses highly specific TB antigens Sources: QFT Brochure L. PoianiDarocki, Meridian Health

6 QuantiFERON TB Gold In Tube FDA approved May 2005 Test unaffected by BCG Sensitivity 89% & Specificity >99% Blood collection, tube handling technique, incubation 3 tubes GRP: GREY cap: Nil or negative control tube RED cap: TB Antigen tube with 3 TB specific antigens dried onto inner wall. PURPLE cap: Mitogen or positive control tube with phytohemagglutinin (PHA) dried onto inner wall Results in 24 hrs Negative < 0.35 Positive > 0.35 (Reversion/Wobblers <1.1) Indeterminate (High Nil, Low Mitogen); can be valuable info! Sources: QFT Package Insert L. PoianiDarocki, Meridian Health Tuberculin Skin Test and it s Limitations Antiquated: Skin test developed in 1890 s, no updates Placement and reading needs minimum 2 visits Loss in time of both clinic employees and patient Poor Compliance Measured in millimeters with a ruler Results are subjective and dependent on the individual reading 17 Tuberculin Skin Test and it s Limitations Non tuberculous mycobacterium (NTM) are responsible for the majority of 5 14 mm TST reactions among US born HCWs* Inaccurate w/bcg vaccinated population Lacking controls; Sensitivity 70% Specificity 35% Antiquated False Negatives/Positives Sources: von Reyn CF, 2001;5: ; Diel R. et.al L. PoianiDarocki, Meridian Health

7 Recent Study on IGRAs in HCWs Title: Delineating a Retesting Zone Using Receiver Operating Characteristic Analysis on Serial QuantiFERON Tuberculosis Test Results in US Healthcare Workers Objective: To find a statistically significant separation point for the QuantiFERON Gold In Tube (QFT) interferon gamma release assay that could define an optimal retesting zone for use in serially tested lowrisk populations who have test reversions from initially positive to subsequently negative results. L. PoianiDarocki, Meridian Health Recent Study on IGRAs in HCWs Done where population included HCWs who were screened for LTB using QFT assay between at three ctrs: University of Illinois Chicago, Cleveland Clinic & Dept of Veterans Affairs, Palo Alto CA. All reported an average positive test rate of 8 10% using QFT assay. All HCWs with at least 1+ results were selected from group for further study L. PoianiDarocki, Meridian Health Study Conclusion Reversion likelihood increases as the TBag nil approaches the manufacturer s cut point of 0.35IU/mL. Range IU/ml = 75% reversion Range IU/mL = 80% reversion Separation point applied based on clinical situation Ex: 5, 10, 15MM TST cut off points L. PoianiDarocki, Meridian Health

8 Study Conclusion The most statistically significant separation point between those who test repeatedly positive and those who revert is 1.11 IU/ML. For healthy persons who have a low risk for both infection & progression, discounting an isolated positive result as a false positive is reasonable. CDC.. Retest low risk individuals with initial QFT results < 1.11IU/Ml. L. PoianiDarocki, Meridian Health Take away: Protocols need to be followed to get accurate results Trust Negative result (<0.35) Clinical judgment continues to be the most important factor in determining a treatment protocol for HCWs with Positive QFT results. All TB Ag nil values that remain > 1.1 for two tests should be considered infected & recommend be treated for LTBI Low positive Retest before treating <1.11 If no risk for TB & result < 1.1 repeat in 1 yr If known exposure consider tx L. PoianiDarocki, Meridian Health SWITCH Study Screening healthcare Workers with IGRA vs TST: impact on Costs and adherence to testing IGRA T Spot vs TST Fact or Fiction: TST is inexpensive L. PoianiDarocki, Meridian Health

9 SWITCH Study TST average cost > $73.20/person New Hire cost $81.38 Annual cost $54.09, non compliant cost rose to $88.15 IGRA cost < $54.83/person, with greater completion rates HCW past identified as TST+ = QFT L. PoianiDarocki, Meridian Health Our Transition 2009 Organizational decision to consider use of IGRAs for Tb Surveillance NJDHSS approval: based on 2005 CDC guidelines Commit to one test method taking advantage of IGRA technology T Spot vs QFT meetings w/both vendors Supported by IC Committee Director of Microbiology Lab Strategic Goal: In house testing w/qft Sept/Oct 2010; delayed due to lab renovations, staffing, licensing inspections L. PoianiDarocki, Meridian Health Implementation of QFT: 6/2010 Participants: OH leadership, Microbiology director, ID physician chair, IC nurses Salient points of discussion included: Clinically efficacious test recommended by infectious disease. Should be done for both new hires and annual screening purposes, even if history of past TST + (establish baseline for all!) If QFT +, CXR required & referral to the appropriate County TB Clinic. Those who have tested positive w/ QFT will not get repeat testing as following serial QFT levels is not currently recommended. L. PoianiDarocki, Meridian Health

10 Implementation of QFT: 6/2010 Those who test + will be followed annually with the clinical questionnaire. The cost to the lab will be approximately $25/test. In order to determine the final cost the lab will need to know what volume of tests will be expected. The blood draw requires three tubes, 1ml each, which must be agitated after being drawn. There would be no restrictions regarding what day of the week the test is done. There will obviously be an increase in number of phlebotomies performed. L. PoianiDarocki, Meridian Health Implementation of QFT: 6/2010 Discussed practical questions: Will there be resistance from team members to have blood drawn? Will an educational campaign be helpful? What if the phlebotomy is not successful do we then revert to PPD? Will phlebotomy require a more private setting than we use for planting a PPD? Should we offer this test to our external clients who require PPD testing? If there are additional costs how will they be financed? Target date of 1/1/11: Lead time will allow us to work out the process, costs, logistical and practical aspects of this transition. L. PoianiDarocki, Meridian Health Anticipated 1/1/11 kick off! 8/2010 Creating a budget for 2011 switch from TST to QFT Consider who s paying for kits: OH vs Lab OH Projected volume: screenings for incumbents 1200 for new hires test code to revise current lab slip Ordering info for kits/tubes lab cost based on the projected volume. Schedule for the annual 2011 surveillance screenings At this time we are sending out QFT to ARUP. Bringing in house will ONLY require 0.5 FTE in lab. L. PoianiDarocki, Meridian Health

11 Vendor Inservice 9/2010 QFT & blood collection/tube handling inservice on by Vendor for OH staff & lab personnel Microbiology director anticipates bringing in house QuantiFERON before the end of the year. L. PoianiDarocki, Meridian Health Policy & Procedure Development Occupational health: Staff competency assessments Phlebotomy Training check list Proficiency Test Data entry Pre emp Surveillance Annual Surveillance Post Exposure L. PoianiDarocki, Meridian Health Formulating Plan Continues 12/2010 Screening of inpatient & outpatient population Nursing Education Involvement inservice Attending provider notification HCW option of drawing their own blood to improve compliance OH lab slip on intranet for QFT only Access to kits Approval from HR L. PoianiDarocki, Meridian Health

12 Go LIVE 6/6/11 New Hires only Provider ownership Result process flow & interpretation Specimen pick up temperature sensitive Boosting effects If TST within past 90 days L. PoianiDarocki, Meridian Health L. PoianiDarocki, Meridian Health TST impact on IGRAs Doing TST & drawing IGRA same day is not a problem TST induced boosting of IGRA responses was demonstrated in several studies More pronounced in IGRA+ individuals Smaller but NOT insignificant in IGRA TST affected IGRA after 3 days for several months (6 months between)* Sources: R. Van Ayl-Smit PLoS One. Dec 2009 Vol 4 Issue 12 L. PoianiDarocki, Meridian Health

13 QFT & TB Surveillance Communication Policy revisions Regarding drawing of specimens Grey Nil negcontrol (problem with test) Red Tb antigen Purple Mitogen tube (problem with w/donor or w/technique) Revised Flow Chart Monthly updates presented to IC Huddles announcing surveillance program changes 1/1/12. HR s to Leadership L. PoianiDarocki, Meridian Health L. PoianiDarocki, Meridian Health Communication Let them know it s coming Education Education Education Lab processing days to avoid draws Friday after 9pm Monday morning Anticipate the impact on OH nurse & time management L. PoianiDarocki, Meridian Health

14 March 2012 Reformat of Lab Result Report Interpretation now part of report Added mitogen result needed for interpretations especially indeterminates. Indeterminate result Immunosuppressed (a low response to mitogen) Errors in performance of test Improper transport, handling, storage of blood specimen (over/under fill tubes GRP, vigorous shaking dislodging gel causes false +) L. PoianiDarocki, Meridian Health L. PoianiDarocki, Meridian Health L. PoianiDarocki, Meridian Health

15 L. PoianiDarocki, Meridian Health Reversions vs Wobblers! March 2012 Non negative range increased to 1 HCW low risk, low prevalence, serially tested need to be viewed differently (Thanassi, MD) Inherent and expected variability in serial testing with IGRAs in a low risk, low incidence population T cell responses can vary In the same person From person to person % will revert to Negative 1.1 = statistically significant trigger for recommending treatment for LTBI of HCWs* *Thanassi MD, Hospital Employee Health, Oct L. PoianiDarocki, Meridian Health L. PoianiDarocki, Meridian Health

16 Decision Making for Non Negative Results No diagnostic test can replace clinical judgment!! L. PoianiDarocki, Meridian Health TB Risk Assessment Tool TB Risk Assessment Team Member: Date: QFT Date drawn: Numerical Result: Historv of TB Skin Test/QFT and Treatment: Prior Mantoux Tuberculin Skin Test (TST): _No _Yes Date: _/_/_lnduration: mm Prior QFT lab test: No Yes Date: Numerical result: ; Positive or Negative Ever been diagnosed with Active or Latent Tuberculosis? No Yes; If yes provide details: Prior TB treatment N0 Yes Location of treatment: Year of treatment; Duration of Treatment: TB Medication(s) taken: Date of Last Chest X Ray: Result: L. PoianiDarocki, Meridian Health TB Risk Assessment Tool Screen for TB Symptoms (Check all that apply): cough for > 3 weeks Productive Yes No; Hemoptysis? Yes No Fever, unexplained Unexplained weight loss poor appetite Night sweats Fatigue Screen for TB Infection Risk (Check all that apply): Assess Risk for Acquiring LTBI: Foreign born Name of country of birth ; Year of US arrival: has lived in a country for > 3 months where TB is common, and has been in US for < 5 years is a close contact of a person know or suspected to have active TB disease. is a volunteer, resident or an employee of a HIGH TB risk congregate setting (homeless shelter, prison, LTC, hospital) Traveled out of US to high prevalence area since last negative TST/QFT screening Had any visitors from outside the US stay in your home L. PoianiDarocki, Meridian Health

17 TB Risk Assessment Tool Medical Conditions known to increase risk of TB disease (Check all that apply): Chest X ray with fibrotic changes suggestive of inactive or past TB Immunosuppressive condition or therapy > 3 weeks (steroids or chemotherapy). HIV infection Organ transplant recipient Injection drug user Diabetic Silicosis Autoimmune disease Cancer end stage kidney disease intestinal bypass or gastrectomy Current Medications: Finding(s) (Check all that apply): No identifiable Risk Factors for TB Previous treatment for LTBI and/or TB disease Previous positive TST/QFT, no prior treatment QFT Result Intrepretaion: QFT Negative QFT Positive Action(s) (Check all that apply): Repeat Screening CxR PA & Lat Referred to TB clinic/pmd Annual Surveillance Screener s signature and title: Provider s signature: Provider Name: L. PoianiDarocki, Meridian Health Results Compliance QFT increased compliance Results Positivity 70% reduction!! L. PoianiDarocki, Meridian Health

18 2012 Overall Results Big picture and perspective on converters L. PoianiDarocki, Meridian Health References Centers for Disease Control and Prevention. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection United States, MMWR 2010; 59 (RR 5):1 25 Centers for Disease Control and Prevention. Guidelines for Preventing the Transmission of Myco bactedrium tuberculosis in Health Care settings, MMWR 2005; 54 (No.RR 17): CDC 2010 Guidelines David C. Marder, MD, MPH,, Virginia A. Evans MD, FACEP, Paul Terpeluk, DO, Wendy Thanassi, MA, MD. Developing a Database Driven Algorithm for the Clinical Management of HCWs With Fluctuations in Serial QuantiFERON (IGRA) Tests A Multi Center Study. L. PoianiDarocki, Meridian Health References Edward Bernacki, MD. Screening healthcare Workers with Interferon y Release Assay Versus Tuberculin Skin Test: impact on Costs and Adherence to Testing (the SWITCH study). Journal of Occupational and Environmental Medicine. 54(7): , July 2012 Diel R. et al. Evidence Based Comparison of Commercial Interferon Release Assays for Detecting Active TB Metaanalysis Chest 2012; Apr: 137(4) R. Loddenkemper, R. Diel, and A. Nienhaus, To repeat or not to repeatthat is the question!; serial testing of health care wokrers for TB infection, vol. 142, no. 1, pp.10 11, 2012 von Reyn CF, Horsburgh CR, Olivier KN. International Journal of Tuberculosis & Lung Disease. 2001;5: L. PoianiDarocki, Meridian Health

19 References W. Thanassi, A. Noda, B. Hernandez< J. Newell, P. Terpeluk, D. Marder et al. Delineating a Retesting Zone Using Receiver Operating Characteristic Analysis on Serial QuantiFERON Tuberculosis Test results in US Healthcare Workers. Pulmonary Medicine Vol 2012, Article ID , 7 pages Hospital Employee Health October 2012, pg PloA ONE. December 2009 Vol4 Issue 12 A. Zwerling, E. van den Hof, J. Scholten et al., Interferon y release assays for tuberculosis screening of healthcare workers: a systemacit review, Thorax, vol 67, no. 1, pp.62 70, 2012 MMWR March 22, 2013 Trends in Tuberculosis United States Vol 62. No. 11 L. PoianiDarocki, Meridian Health Questions? L. PoianiDarocki, Meridian Health