Utility of PPD or IGRA to answer the age old question of "TB or not TB

Transcription

1 Utility of PPD or IGRA to answer the age old question of "TB or not TB Thomas S. Alexander, Ph.D., D(ABMLI) Immunologist Summa Health

2 Yes, The reservation is in the name of Dr. Alexander. May I ask, is that an actual medical degree, or merely a Ph.D.? Adapted from The New Yorker, 1987

3 Acknowledgements and Disclosure I thank Qiagen for providing some of the slides and references I thank Dr. Anthony Catanzaro for helpful discussions in preparing the talk No conflicts to disclose

4 Talk Outline Quick TB review TB Skin Test (TST) Problems with the TST Difficulties in developing in vitro TB assays Development of IGRAs Quantiferon iterations Performance of Quantiferon Plus T-Spot Assay Performance of T-Spot Some recent literature Use of IGRAs prior to starting anti TNF agents Current Recommendations

5 What Is Tuberculosis? Tuberculosis (TB) overview Infectious communicable disease Caused by Mycobacterium tuberculosis complex organisms M. tuberculosis M. bovis M. africanum M. canetti M. microti Affects different parts of the body: Lungs - Pulmonary TB (> 70% of all TB cases) Other organs - Extra-pulmonary TB Infection may be: Active (with symptoms, highly contagious) Latent (asymptomatic, not contagious) Photo courtesy of WHO Stop TB initiative. Website: FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 5

6 What Is Tuberculosis? Outcomes of transmission of TB infection No infection Majority of these people eradicate the infection and never develop active disease Some of these people become ill from TB within weeks to months and develop Active TB Individual with infectious tuberculosis TB Infection Some of these people remain asymptomatically infected for years with Latent TB infection Outcome depends partially on the person s immune status FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 6

7 What Is Tuberculosis? From latent to active TB People with LTBI have a lifetime risk of developing TB of 10% 1 The greatest risk occurs within the first 2 years after infection Some groups of people are at even higher risk of TB: Risk group TB risk, times HIV/AIDS TNF-α therapy Diabetes Healthcare workers Corticosteroid therapy > 5 4 LTBI treatment can prevent later development of TB 1 World Health Organization 2 Winthrop KL et al. Arthritis Rheum 2005, Gardam MA et al. Lancet infect Dis Baussano I et al. Emerg Infect Dis Cisneros JR at al. Ann Pharmacother 1996 FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 7

8 No. of Cases Cases per 100,000 Population Reported Tuberculosis (TB) Cases and Rates United States, ,000 25,000 20,000 15,000 10,000 5, Year No. of Cases Incidence Rate

9 TB Case Rates,* United States, 2017 NY C DC *Cases per 100,000 DC, District of Columbia; NYC, New York City (excluded from New York state) 2.8 (2017 national average) >2.8

10 Cases per 100,000 Population TB Cases and Rates Among U.S.-Born versus Non-U.S. Born Persons, United States, No. of cases 30,000 25,000 20,000 15,000 U.S.-born Cases Non-U.S. born Cases U.S.-born Rate Non-U.S. born Rate ,000 5, Year

11 Coinfection (%) Estimated HIV Coinfection Among Persons Reported with TB, United States, * All ages Ages yrs Year * Minimum estimates are based on reported HIV-positive status among all TB patients in the age group.

12 Diagnosis And Treatment: LTBI Current practices There is no gold standard to determine if a person has LTBI Currently there are two classes of diagnostic test for LTBI: Interferon-gamma release assays (IGRAs) Tuberculin skin test No test can discriminate between old and new infection LTBI testing is usually only performed on those: At increased risk of being infected: - Healthcare workers, contacts of active TB cases, etc. At risk of developing active TB: Immunosuppressed Enrolled in schools FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 12

13 Diagnosis And Treatment: LTBI Tuberculin Skin Test (TST) The TST (also known as the Mantoux or a PPD test ) was originally developed as a diagnostic test for active TB Many people without active TB were positive to the test and significant proportion of these later developed active TB Led to the term latent TB infection (LTBI) to describe people who presumably were infected, but had no symptoms LTBI was (crudely) defined on the basis of a positive TST However, the TST employs tuberculin PPD, a poorly defined, complex mixture of antigens which is non-specific for TB since many of its proteins are found in different mycobacterial species This is just one of the many limitations of the TST FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 13

14 Diagnosis And Treatment: LTBI Tuberculin Skin Test (TST) First used in 1906 as a diagnostic for TB Measures a person s cell mediated immune (CMI) response to M. tuberculosis Tuberculin Purified Protein Derivative (PPD) is injected intra-dermally into the forearm and hours later the size of the resultant reaction is measured: Induration (firm area) Erythema (redness) Requires two visits: to have the test administered and read FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 14

15 The TST detects a delayed type hypersensitivity reaction T cells, antigen presenting cells and cytokines are involved Reaction is localized at the site of antigen presence Redness (erythema) due to inflammation and induration (swelling) due to cellular influx will occur With respect to the TST, only induration is measured Inexperienced or poorly trained readers may measure erythema leading to false positive results

16 PPD Skin test

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18 TST erythema and induration

19 Measure Induration Only

20 Interpretation of PPD High-risk patients (>5X5 mm= positive). Patients infected with HIV Those who have had close recent contact with a person who has active TB Those who have symptoms or a chest X-ray that shows TB. Patients taking immunosuppressive medications Moderate-risk patients. (>10 X 10 mm= positive) TB; People who have recently moved from or traveled in a country with a high rate of IV Drug users Nursing home residents and staff Hospital workers Those in schools, and prisons Children younger than 4 years old; Children (ages 4 to 18) who are exposed to high-risk adults Homeless people. Those who are 10% or more below their ideal body weight People with renal failure, diabetes, leukemia, cancer, or hose who have had part of their stomach removed (gastrectomy). Low-risk group >15 X 15 mm = positive) groups. people who do not have any likely exposure to TB or are listed in the other risk

21 1950s TB Testing in School One of my earliest memories!

22 Two Step PPD Algorithm

23 Diagnosis And Treatment: LTBI People without TB may be falsely positive due to many reasons, including: BCG vaccination MAC Exposure Immune reactivity to non-tuberculous mycobacteria (NTM) - In US-born individuals, up to 50% of TST responses can be due to NTM infections (1) People with TB may be falsely negative Difficulty in proper intradermal injection of PPD The need read the test 2-3 days after PPD injection People may not return for reading Subjective: Two different readers, two answers Different cut-offs for different situations ( 5mm, 10mm, 15mm) Boosting: as PPD antigen is injected into the person, this can lead to the boosting of a subsequent test and a false-positive result, especially in those BCG vaccinated. Limitations of the TST 1. von Reyn CF, Horsburgh CR, Olivier KN, et al. Skin test reactions to Mycobacterium tuberculosis purified protein derivative and Mycobacterium avium sensitin among health care workers and medical students in the United States. Int J Tuberc Lung Dis 2001; 5 (12): FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 23

24 SUMMARIZING THE PROBLEM TB is a highly contagious disease, with great morbidity and mortality and is difficult to eliminate from an infected individual. Identifying and treating individuals with current or latent TB infections is important from a public health standpoint. Toward this end, TB testing has long been required by schools and health care related work environments. TB testing has classically been performed by the tuberculin skin test (TST), an intradermal injection of protein (PPD), inducing a cell mediated immune (CMI) response in those previously or currently infected, or exposed to M. tuberculosis. The patient must return to have the test evaluated. Results are determined subjectively and reader inexperience may lead to errors in interpretation. PPD cross reacts with non TB mycobacteria. False positive and false negative results do occur.

25 Why Was There Not a Laboratory Test for TB for Many Years? Many in vitro clinical assay techniques exist for detecting organism specific antibody Anti M. tuberculosis antibody is not useful for diagnosis An in vitro assay measuring cell mediated immunity to M. tb would be useful In vitro CMI assays are difficult to develop due to MHC Restriction

26 MHC Restriction? What the &%^^ is that? Antibodies react directly with their antigenic targets T cells recognize antigen only when a portion of the antigen is bound to a major histocompatability complex molecule (MHC or, in the human, HLA) T cells only recognize antigen bound to self MHC molecules on antigen presenting cells Thus, it is difficult to develop a single system to measure CMI in all patients.

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28 Interferon Gamma Release

29 Diagnosis And Treatment: LTBI Interferon-gamma release assays (IGRAs) In response to the limitations of the TST, IGRAs have been developed and have become available over the last decade More specific and sensitive than TST for diagnosis of LTBI Two IGRAs commercially available: QuantiFERON -TB Gold (QFT ) in tube Plus and T-Spot.TB (Elispot-based IGRA) Both IGRAs measure the secretion of the cytokine interferon-gamma (IFN-γ) by lymphocytes stimulated in vitro with TB-specific antigens FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 29

30 Immunological Basis for IGRAs In normal circumstances, there is little Interferon Gamma (IFN- ) within the blood. T-cells activate and secrete IFN-γ. In the presence of the TB specific antigens, T cells of infected persons are stimulated to produce IFN- In the QFT and T-spot tests whole blood is exposed to TB specific antigens T cells of infected persons are activated and secrete IFN- Measurement of IFN- using an ELISA assay is the basis for the QFT test Measurement of IFN-gamma using an ELISPOT assay is the basis for the T-spot test FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 30v

31 IGRAs are not affected by BCG vaccination (1) Tuberculosis Complex QFT TB-Specific Antigens ESAT -6 TST Antigens CFP-10 TB 7.7 PPD Environmental strains QFT TB-Specific Antigens TST Antigens ESAT-6 CFP-10 TB 7.7 PPD M. tuberculosis M. africanum M. bovis BCG Sub- Substrain QFT TB-Specific Antigens ESAT -6 TST Antigens CFP-10 TB 7.7 PPD Gothenberg Moreau Tice Tokyo Danish Glaxo Montréal Pasteur M. abcessus M. avium M. branderi M. celatum M. chelonae M. fortuitum M. gordonii M. intracellulare M. kansasii M. malmoense M. marinum M. oenavense M. scrofulaceum M. smegmatis M. szulgai M. terra M. vaccae M. xenopi QuantiFERON-TB Gold Package Insert, July 2011 /2. Matulis G et al Ann Rhuem Dis 2008; 67(1): FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 31

32 QuantiFERON-TB Gold Plus Blood Collection Tubes Nil (grey cap) Negative control Adjusts for background noise or non-specific IFN- in blood samples TB1 Antigen (green cap) Contains TB antigens that primarily stimulate CD4 T cells TB2 Antigen (yellow cap) Contains TB antigens optimized to stimulate both CD4 and CD8 T cells Mitogen (purple cap) Positive control May indicate: Decreased patient immune status Incorrect blood handling & incubation Nil TB 1 TB 2 Mitogen 32

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34 Data Sheet

35 Result Interpretation

36 Data Interpretation Guide Although TB-Nil values >0.35 are positive, values <1.0 may repeat negative Interpret all, but primarily low, values within clinical context Results are reported as positive, negative or Indeterminate Positive values are reported with the TB-Nil value Indeterminate values indicate low mitogen response and do not mean the patient has a borderline TB result Immune suppression Collection or processing error

37 Indeterminate

38 Are Shaking, Blood Volume and Incubation Times Limiting Factors? (Gaur, et al., JCM, 2013) Vigorous shaking increased nil and TB IFN levels in 33 uninfected individuals compared to gentle shaking TB values went from 0.12 (gentle) to 0.24 (vigorous), p= Nil values went from , p<0.001 Blood Volume did not show differences in uninfected controls but a lower blood volume (0.8 ml) had a lower number of false negative results compared to 1.0 (p=0.2) and 1.2 ml (p=0.05) draws Incubation times of 16, 20 and 24 hours did not affect results.

39 Bad Lot of Tubes Slater, JCM, 2012 (Stanford) Sudden Increase in Positivity from 10-31% Compared different lot numbers and found different rates Confirmed at ARUP (Couterier, et al., JCM, 2013) Summa Health Issues We had the bad lots and found increased positive and indeterminate rates Indeterminate rate is now a QA monitor (<6%)

40 T-Spot IGRA Assay 1-2 Heparin Tubes required Simpler collection protocol than Quantiferon Separate mononuclear cells prior to incubating with TB antigens Allows standardization of antigen:cell concentration Postulated to increase sensitivity in immunosuppressed individuals Overnight incubation in plates followed by ELISA type stain for cells producing gamma interferon Cell colonies producing interferon are enumerated

41 T-Spot

42 T-Spot Result Interpretation Mitogen-Nil >8 spots- Valid Assay Mitogen-Nil <8 spots- Indeterminate Panel A and/or Panel B-Nil Spots <5- Negative 5-7- Borderline >8- Positive

43 Our T-Spot Experience Two small evaluations No difference between T-spot and Quantiferon in HIV positive patients More up front processing time, not conducive to automation or handling large volumes of specimens Subjective interpretation, although magnifier provided by the company was helpful

44 Current T-Spot Availability Few clinical laboratories perform the test due to upfront processing time Oxford, the manufacturer, has set up their own laboratory to receive and process specimens collected at clinics, hospitals or physician offices Specimens must be received in the testing facility within 32 hours of collection

45 Characteristic Tuberculin skin test (TST) IGRA Single patient visit NO YES Use of positive and negative controls NO YES Objective results NO YES Unaffected by BCG vaccination NO YES Unaffected by most environmental nontuberculosis mycobacteria Set interpretation criteria NO NO YES YES Cost Low High

46 T Spot vs Quantiferon In Tube From Oxford BioTech Standard blood collection tubes are used Blood collection tube is filled using standard phlebotomy practices Phlebotomist gently inverts blood tube after drawing specimen, consistent with standard phlebotomoy practices Butterfly needles may be used without the need for a purge tube A borderline zone is used, consistent with the recommendations of the 2010 CDC Guidelines Specimens can be maintained at room temperature for up to 32 hours T-SPOT.TB Test Yes Yes Yes Yes Yes Yes In-Tube No; requires three specialized tubes drawn in specific order. No; specialized tubes must be filled between 0.8mL and 1.2mL or within the black mark on the side of the tube label.³ Over or underfilling of the tubes outside the range may lead to erroneous results. 4 No; once filled, each tube must be mixed by shaking 10 times.³ Over-energetic shaking should be avoided to minimize erroneous results due to gel dislodgement.³ No; when a butterfly needle is used, a purge tube should be used to fill the tubing with blood prior to filling the Nil tube.³ No; Although not included in FDA-approved interpretation criteria for QFT-GIT an appropriate borderline category for QFT-GIT might increase its accuracy 5 No; tubes must be transferred to an incubator as soon as possible but within 16 hours.³

47 Quantiferon Goes After T-Spot s Single tube Collection From Qiagen, except for last sentence Experience the benefits of QFT-Plus single tube blood collection Geographic expansion Inventory control Centralized tube handling Up to 53 hours from sample collection at the draw site to sample incubation at your testing laboratory No need to supply specialized blood collection tubes to draw site blood is drawn to a single lithiumheparin tube Increase efficiency and consistency with centralized sample processing Additional Laboratory Staff may be required

48 T spot vs Quantiferon QTF is more sensitive to collection technique QTF must be processed within 16 hours for four tube collection; 53 hours for single tube collection; T spot within 32 hours. T spot is more labor intensive and less amenable to automation Some data suggest T-spot is more sensitive in immune suppressed individuals. Quantiferon is read objectively; T spot is read subjectively with an optical aid CDC study showed conversions from negative to positive in 2767 health care workers were 6.1% for Quantiferon and 8.3% for T spot (Catanzaro and Daley, 2013) High number (unspecified) of conversions reverted to and remained negative upon retesting

49 Is the IGRA cutoff Point Appropriate? Fong, et al., (CCF), Chest, 2012 Do not treat positive Quantiferon results <1.0 Daley, et al., Inf. Ctl.Hosp. Epid., 2013 Meeting report concerning variable results around the cutoff point of IGRAs Recommends caution in interpreting low positive values but does not recommend changing the cutoff point Raising the cutoff point reduces sensitivity Individuals with values <1 should have retesting considered Esmail, BMC Infect. Dis /22 HIV patients seroconverted on QTF in tube They had higher baseline TB-nil values than non converters Suggest lowering QTF cutoff in this population 49

50 Are IGRAs Bad Assays? Gamsky, et al., Ann Am thoracic Soc., 2016 Retrospective evaluation of results from serial screening of a cohort from /557 TST negative individuals were positive on the IGRA in that timeframe. 10 individuals remained positive when the test was repeated the following year 9/10 were IGRA negative within 3 years Authors recommend against using the Quantiferon Assay as a screening test in low risk populations.

51 Recently Published Data Ruhwald, et al., Lancet Resp. Med., 2017 C-Tb skin test Uses CFP-6 and ESAT 10 Same antigens as the IGRAs Compared C-Tb, TST and IGRA (n=979) C-Tb skin test had induration the same as TST C-Tb had same specificity as IGRA Study funded and reported by company that makes C-Tb Knierer, J. Occup Med Toxicol, 2017 QFT-Plus; new generation QFT Uses separate CD4 and CD8 Tb analysis tubes 95.1% agreement with QFT in tube Conversion and reversion rates slightly higher in Plus

52 Recently Published Data, 2 Abubaker, et al., Lancet Infection, Oct 2018 UK study comparing TST, T-Spot and QFT in tube N= 9610 ; 4861 contacts 4749 migrants 97 developed active TB NPV was % for all tests PPV 3.3% for QFT 4.2% for T-spot 2.2% for TST-5 2.7% for TST % for tst-15 Overall conclusion- no real difference among tests

53 Abubakar, et al., lancet infection, Oct, 2018

54 Australian National Tuberculosis Advisory Committee Position Statement Bastian, et al., nsf/content/cdi Reviewed three meta alalyses IGRAs and TST have similar (but poor) ability to identify patients with LTBI at risk of developing active disease The Committee recommends either test for LTBI The Committee recommends neither test for active TB investigation

55 And there s more.. Nemes, et al., Clin Infect Dis Jan 21. doi: /cid/ciz034. [Epub ahead of print] South African Study ESAT-6 TB vaccines are being developed ESAT-6 is in the Quantiferon and t-spot tests Developed ESAT-6 free IGRA and tested it vs Quantiferon 91% concordance between the assays Positivity rates were 43% for ESAT-6 free and 45% for QFT Recommended the ESAT-6 free test for vaccine effectiveness studies T-spot panel B does not have ESAT-6

56 IGRA TESTING PRIOR TO STARTING ANTI TUMOR NECROSIS FACTOR ALPHA THERAPY

57 Increased risk of active TB Tuberculosis (TB) exists as active disease or latent infection TNF-a inhibitor therapies can increase the risk of LTBI progressing to active TB (1,2) Compared to the general population, patients on TNF- inhibitor therapy are at 4- to 8-fold increased relative risk of developing active TB (1,2) Knowing the LTBI risk before tumor necrosis factor alpha (TNF- ) inhibitor therapy is vital References: 1. Winthrop KL et al. Arthritis Rheum 2005; 52: Gardam MA et al. Lancet Infect Dis 2003; 3: FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 57

58 TB Refresher reactivation of latent TB Treatment of RA with TNF- inhibitors may predispose to significant increase in TB risk TNF- plays a central part in the host response against tuberculosis including granuloma formation and containment of disease. with TNF- inhibitors Granuloma formation and maintenance No granuloma no containment Reference: Keane et al NEJM 2001 FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background

59 LTBI testing in patients receiving TNF- inhibitors Limitations of the TST Most patients awaiting TNF- inhibitor therapy are already treated with immunosuppressive DMARD therapy which impacts on the reliability of the TST (1) Limitations of the TST in inflammatory rheumatic patients: Lack of positive and negative controls: It is impossible to decide whether a negative TST result is a true or false negative. Negative TST results are clearly more common in inflammatory rheumatic patients compared to healthy people, suggesting a high rate of false negative TST results in patients. Negative TST results may give false security and expose patients to a higher risk of developing active TB upon initiation of TNF- inhibitor therapy (2) Reduced sensitivity in patients with immune-mediated diseases with or without immunosuppression (3-7) Insufficient antigen specificity for TB-causing pathogens BCG vaccination or previous infection with non-tuberculosis mycobacteria can cause false positive TST results (8-13) 1. Ledingham j. et al, Rhuematol 20005; 44(10): Gomez-Reino J.J. et al, Arthritis Rheum 2003; 48(8): Inanc, N et al, J Rhuematol 2009; 36(12): ) 4. Belard E et al Inflam Bowel Dies 2011; 17(11): Ponce de Leon D et al J Rhuematol 2008; 35(5): Mow, WS et al Gastroenterol Hepatol 2004; 2(4): Ponce de Leon D et al, Ann Rheum Dis 2005; 64(9): Chiu H-Y et al BR J Dermatol 2011; 164(3); Kwakernak AJ et al Clin Rheumatol 2011; 30(4): Diel R et al Chest 2010; 137(4): Matulis G et al Ann Rhuem Dis 2008; 67(1): Chang B et al Clin Rheumatol Mazurek GH et al JAMA 2001; 286(14): FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 59

60 IGRAs in the Guidelines International and US guidelines and recommendations indicate IGRAs for screening patients on TNF-a inhibitors for LTBI 2010 CDC guidelines* provide recommendations for test selection in the diagnosis of M. tuberculosis infection IGRA may be substituted for TST in all situations as an aid in the diagnosis of M. tuberculosis infection IGRA is preferred over TST in patients who have received BCG as a vaccine or for cancer therapy Both an IGRA and TST may be considered if either initial test is negative and risk for infection, risk for progression and risk for a poor outcome are increased ** Updated 2012 ACR guidelines recommend TB screening in all rheumatoid arthritis (RA) patients being considered for therapy with biological agents regardless of presence of risk factors for TB infection *Guidance for immune-suppressed patients; no specific guidance for TNF- inhibitor therapy ** Situation 1 page 11 TST or IGRA can be performed as an initial test in all such RA patients and annual testing is recommended in patients who live, travel, or work in situations where TB exposure is likely IGRA is preferred over TST in patients who previously received BCG vaccination due to high-false positive rates associated with TST In immunosuppressed RA patients with high risk of TB exposure, a repeat test can be considered 1-3 weeks after initial negative result IGRAs are an aid to the diagnosis of mycobacterium tuberculosis infection and should be used in conjunction with detailed medical history and chest x-ray Skin test reagents currently have limited availability FOR INTERNAL USE ONLY QuantiFERON-TB Gold Product Training Tuberculosis background QM A 60

61 From: Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children Clin Infect Dis. 2016;64(2):e1-e33. doi: /cid/ciw694 Date of download: 2/6/2017 The Author Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions,

62 From: Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children Clin Infect Dis. 2016;64(2):e1-e33. doi: /cid/ciw694 Date of download: 2/6/2017 The Author Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions,

63 Take Home Points Most, but not all, studies suggest that IGRAs are more specific with equal or better sensitivity when compared to the TST IGRAs are more convenient for patients Low level positive IGRA results must be interpreted in light of the patient s clinical history and presentation Indeterminate IGRA results suggest a collection/processing error or poor immune capabilities. Conversion to positive and reversion to negative IGRA results will occur and may be related to the patient s immune capabilities or exposure status. IGRAs provide more accurate TB and immune status information than TSTs for patients about to receive TNF alpha inhibitor therapy

64 Professor, May I please be excused? My brain is full! Adapted from The Far Side, Gary Larson, 1985