Interferon-Gamma Release Assays: Summary of the evidence ...globaltb.njms.rutgers.edu/downloads/courses/2011... · TB Clinician’s Meeting, Washington, DC November 17, 2011 Karen

Interferon-Gamma Release Assays: Summary of the evidence and practical approaches

TB Clinician’s Meeting, Washington, DC November 17, 2011

Karen R Steingart, MD, MPH [email protected]

Disclosure • I serve as Coordinator of the Evidence Synthesis &

Policy subgroup of Stop TB Partnership’s New Diagnostics Working Group

• I am an Editor with the Cochrane Collaboration’s Infectious Diseases Group

• I have no financial conflict of interest

• Summarize the evidence from systematic reviews on interferon-gamma release assays

• Discuss who should be tested and what test to use for latent TB Infection

• Discuss case examples

“How on earth do you keep up- there’s an IGRA paper published every minute……….?’ PhD student

Session objectives

Presenter

Presentation Notes

How on earth do you keep up- there’s an IGRA paper published every minute……….?’ A PhD student Medline Search Nov 16, 2011 interferon-gamma and M tuberculosis or tuberculosis 3729 papers 328 review articles 27 meta-analyses

Latent TB Infection • Test for TB infection is

positive • CXR is negative • No symptoms or

physical findings suggestive of TB disease

• Respiratory specimens are negative

Pulmonary TB • Test for TB infection

usually positive • CXR may be abnormal • Symptoms may include:

fever, cough, night sweats, weight loss, fatigue, hemoptysis

• Respiratory specimens may be culture or smear positive

LTBI versus Pulmonary TB

Presenter

Presentation Notes

This slide presents our customary way of thinking about TB in a binary model with TB divided into latent infection and active disease In this model, latent TB infection is defined by a positive test for TB infection meaning evidence of immunological sensitization by mycobacterial proteins and the absence of clinical signs and symptoms of active disease. Historically, sensitization has been defined by reactivity in the tuberculin skin test. Recently, more specific tests of sensitization that measure interferon-gamma in response to specific TB antigens have been developed. Both the TST and IGRAs determine that infection has at some point led to an acquired immune response that is detectable following re-challenge with antigen.

Barry et al. Nature Reviews Microbiol 2009

Presenter

Presentation Notes

In this paper, Clifton Barry and colleagues propose a continuous model of TB with a spectrum extending from immunity without T-cell priming to immunity with T-cell priming to subclinical active disease to fulminant active disease. Latent infection and active disease partially overlapping in this continuum. One consequence of this model is that there may be a subpopulation within the group that is currently defined as having latent TB that should be preferentially targeted for preventive therapy rather than the estimated 2 billion people who are immunologically positive.

- “Uncertain what proportion of individuals remain infected

with M. tuberculosis after TST or IGRA conversion”

- “Uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria”

Presenter

Presentation Notes

Similarly, in this consensus statement by the Tuberculosis Network European Trials Group, latency, as assayed by the TST and IGRA, is defined as a state of persistent mycobacteria-specific T-cell responses in the absence of clinical evidence for tuberculosis disease. Some important questions remain: What is the proportion of individuals who truly remain infected with M tb after TST or IGRA conversion? How long do adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria?

QuantiFERON®-TB Gold In-Tube (Cellestis) measures interferon gamma T-SPOT®.TB test (Oxford

Immunotec) measures peripheral blood mononuclear cells that produce interferon gamma

Approved tests for LTBI

• Measures cell-mediated immune response • Uses PPD • Measure reaction at 48-72 hrs • Measure induration, not erythema • Record reaction in millimeters • Positive TST can be read up to 7 days • Negative TST can be read up to 72 hrs

TST – Key Points

Presenter

Presentation Notes

These key points about the TST are probably familiar to you, but just to review…. The reaction to the TST should be read 48 to 72 hours after the injection by a trained health care worker. The skin test is read by palpating the site of injection to find an area of induration The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis). Erythema (redness) should not be measured. Indurations should be recorded in millimeters, even those classified as negative. If no induration is found, "0 mm" should be recorded. The TST has a few downsides�Requires return visit May result in ‘overtreatment’ due to BCG effect Results depend upon observer and technique The TST may boost subsequent TST reactions Clin Infect Dis. 2005 Jan 15;40(2):246-50. Comparing interferon- gamma release assay with tuberculin skin test readings at 48-72 hours and 144-168 hours with use of 2 commercial reagents.�Tat D, Polenakovik H, Herchline T.�BACKGROUND: Despite widespread use, the tuberculin skin test (TST) has many limitations, including a requirement for a second visit between 48 and 72 hours. The goal of this study was to determine the reliability of a TST reading between 144 and 168 hours. METHODS: Tuberculin antigen was applied into both forearms (Aplisol in one arm and Tubersol in the other, from single lots of each product) by the Mantoux method. Blood samples were obtained for interferon- gamma release assay. Subjects were seen at 48-72 hours for the initial (day 2) TST reading and returned at 144-168 hours for a second (day 7) reading. RESULTS: A total of 116 subjects at increased risk for tuberculosis were studied; 25 (22%) had positive results at day 2 with Tubersol and 27 (23%) had positive results at day 2 with Aplisol. Overall agreement between Tubersol and Aplisol at day 2 was 93% (kappa = 0.80) and at day 7 was 94% (kappa = 0.76). Overall agreement between day 2 and day 7 was 89% for Tubersol and 86% for Aplisol. Discordant results between day 2 and day 7 occurred mostly in persons with a history of bacille Calmette-Guerin vaccination. CONCLUSIONS: Subjects who fail to present at 48-72 hours for TST reading may still have a reliable TST reading at up to 168 hours. Aplisol and Tubersol reagents produce comparable results when compared with the interferon- gamma release assay.

ELISA QuantiFERON®-TB Gold In Tube

IFN-γ Nil

Negative control

IFN-γ PHA

Positive control

16-24 hour incubation

ESAT-6

CFP-10

TB 7.7 IFN-γ

Presenter

Presentation Notes

The QFT test is based on measurement of a cell-mediated immune response. The T cells of TB-infected individuals respond to stimulation with peptides simulating those expressed by TB bacteria by secreting interferon-gamma. QFT accurately measures the interferon-gamma response by ELISA. QFT uses ESAT-6 ( early secreted antigenic target-6); CFP 10 (Culture filtrate protein) and TB 7.7 as antigens. These proteins are absent from all BCG strains and from most nontuberculosis mycobacteria with the exception of M. kansasii, M. szulgai and M. marinum. This slide shows the 2 stages of the QuantiFERON®-TB Gold IT test. In stage 1, whole blood is collected into 3 tubes, (include TB Antigen tube, a Nil Control tube, and a Positive (Mitogen) Control tube; the Positive tube is a control for correct blood handling and incubation and an individual’s ability to respond in the test). The tubes should be incubated at 37°C as soon as possible, and within 16 hours of collection. In stage 2, the tubes are centrifuged, the plasma is removed and the amount of IFN-γ (IU/mL) measured by ELISA.

Measurement of IFN-γ secreted by antigen specific T cells

T-SPOT.TB ®

ESAT-6

ELISPOT

PHA

Positive control

Nil

Negative control

CFP-10 CFP-10

ESAT-6

Overnight incubation

Presenter

Presentation Notes

Slide 10: This slide demonstrates how the T-SPOT.TB assay is performed using peripheral blood mononuclear cells. IFN-γ is detected using an enzyme-linked immunospot (Elispot) method. TSPOT uses ESAT-6 and CFP-10 as antigens. Each spot represents the footprint of an individual interferon-gamma secreting T cell, and counting the number of spots provides a measurement of the abundance of M. tuberculosis sensitive T cells. Peripheral blood mononuclear cells (PBMCs) are separated from a whole blood sample and washed to remove any interfering substances. A defined number of PBMCs are then added to four wells for each sample. Figure 20. A Nil Control to identify non-specific cell activation TB-specific antigens, Panel A (ESAT-6) ESAT-6, early secreted antigenic target-6; TB-specific antigens, Panel B (CFP10) A Positive Control containing phytohaemagglutinin as a test for PBMC functionality. During an overnight incubation the PBMCs interact with the ESAT-6 and CFP10 antigens so that any T cells that are sensitized to TB antigens will secrete interferon gamma. This interferon gamma is captured by antibodies on the base of the well. This interferon gamma is visualized using a conjugated secondary antibody / substrate complex Nil = spots in media The test result is ‘Positive’ if (Panel A minus Nil Control) and / or (Panel B minus Nil Control) 6 spots. The test result is ‘Negative’ if both (Panel A minus Nil Control) and (Panel B minus Nil Control) 5 spots. This includes values less than zero.

In the absence of a gold standard, a hierarchy of evidence for tests of LTBI

WHO Expert Group on IGRAs

Presenter

Presentation Notes

One of the challenges in evaluating IGRAs is the lack of a reference standard for LTBI Concordance of tests Sensitivity and specificity in active TB Correlation with exposure gradients Compare rates of disease in untreated cohorts Compare benefit of preventive tx in Test+ and Test- individuals In this hierarchy, concordance with TST is the weakest and efficacy of preventive treatment is the strongest level of evidence

Efficacy of preventive therapy based on IGRA test results

?? No data

Treatment of latent tuberculosis infection in HIV infected persons

• 12 trials (8,578 randomized participants) • Intervention: preventive therapy (any anti-TB drug) • Comparison: placebo • Outcome : active tuberculosis - Overall RR 0.68, 95% CI 0.54 to 0.85 - TST pos RR 0.38, 95% CI 0.25 to 0.57 - TST neg RR 0.89, 95% CI 0.64 to 1.24 Protection against TB In HIV (+) who are TST (+)

Akolo C. Cochrane Database Syst Rev 2010

Presenter

Presentation Notes

For TST, on the other hand, there is evidence of benefit in test positive individuals. Here is one recent example The authors of this systematic review included RCTs in which people living with HIV were randomly allocated to TB preventive therapy or placebo, or to alternative TB preventive therapy regimens. Participants could be TST positive or negative, but without active tuberculosis. 12 trials were included with a total of 8578 randomized participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54 to 0.85). This benefit was more pronounced in individuals who were TST positive (RR 0.38, 95% CI 0.25 to 0.57) than in those who were TST negative (RR 0.89, 95% CI 0.64 to 1.24).

• Several large scale studies now completed • Predictive ability of IGRA is better than TST, but not

significantly better • Neither TST nor IGRAs accurately predict who should

be treated for LTBI • . The decision to choose one test (IGRA or TST)

over the another should be based on specificity, logistics, cost, and patient preference

Figure. Unadjusted incidence rate ratios (IRR) for positive versus negative test result, by test type. Rangaka et al The Lancet Infect Dis 2011

IGRA: IRR 2.11 (1.29, 3.46) TST : IRR 1.60 (0.94, 2.72)

IGRA vs TST, which has greater predictive value for active tuberculosis? 15 studies (26,680 participants)

Presenter

Presentation Notes

In this systematic review, Lele Rangaka and colleagues aimed to assess whether IGRAs can predict the development of active TB in individuals without active disease at baseline and to determine whether IGRA predictive ability is higher than that of TST. 15 studies (26,680 participants) were included ; 9 from low/middle-income countries. Median study period of 4 years Compared with test-negative results, IGRA-positive and TST-positive results were similar with respect to the risk of developing active TB: pooled IRR in the five studies that used both IGRA and TST was 2.11 (95% CI 1.29, 3.46) for IGRA versus 1.60 (95% CI 0.94, 2.72) for TST (at the 10 mm cutoff). The authors concluded the strength of the association between IGRA-positive results and development of active TB in the studies was modest, with relative risks of about 2 to 3. Hence, the most important finding in this review is that none of the commercially available tests for LTBI have high predictive value. The decision to choose one test (IGRA or TST) over another should be based on specificity, logistics, cost, and patient preference.

• Several large scale studies now completed • Predictive ability of IGRA is better than TST, but not

significantly better • Neither TST nor IGRAs accurately predict who should

be treated for LTBI • . The decision to choose one test (IGRA or TST)

over the another should be based on specificity, logistics, cost, and patient preference

Sensitivity Quantiferon-Gold, adults, all settings

16 studies pooled sensitivity = 78%

Pai M et al Annals Intern Med 2008

Sensitivity TSPOT.TB, adults, all settings



Sensitivity TST, adults, all settings



Presenter

Presentation Notes

For studies assessing sensitivity, the study sample had to comprise participants with microbiologically confirmed active tuberculosis, but not include only immunocompromised participants.

Interferon-Gamma Release Assays for Active Pulmonary TB Diagnosis in Adults in Low- and Middle-Income Countries: Systematic Review and Meta- Analysis, Metcalfe J et al, J of Infection, 2011

.

.

QFT-GITAabye 2009Chegou 2009Chen (a) 2009Dheda (d) 2009Katiyar 2008Pai 2007Raby 2008Tahereh 2010Tsiouris 2006Subtotal (I-squared = 59.8%, p = 0.011)

TSPOTDheda (c) 2009Ozekinci (a) 2007Shao-ping 2009Soysal (a) 2008Subtotal (I-squared = 27.5%, p = 0.247)

authoryear

TanzaniaSouth AfricaChinaSouth AfricaIndiaIndiaZambiaIranSouth Africa

South AfricaTurkeyChinaTurkey

country

81 (71, 88)96 (78, 100)85 (71, 94)73 (45, 92)95 (87, 99)74 (60, 84)84 (68, 94)77 (59, 90)77 (46, 95)84 (78, 91)

93 (68, 100)93 (76, 99)91 (71, 99)81 (72, 88)88 (81, 95)

Sensitivity (95% CI)

15.1512.8112.025.2617.8311.8011.099.025.02100.00

15.4726.1318.9539.45100.00

Weight%

81 (71, 88)96 (78, 100)85 (71, 94)73 (45, 92)95 (87, 99)74 (60, 84)84 (68, 94)77 (59, 90)77 (46, 95)84 (78, 91)

93 (68, 100)93 (76, 99)91 (71, 99)81 (72, 88)88 (81, 95)


15.1512.8112.025.2617.8311.8011.099.025.02100.00

15.4726.1318.9539.45100.00

Weight%

0 20 40 60 80 100

.

.

QFT-GITAabye (h) 2009Kabeer 2009Leidl (b) 2009Markova (b) 2009Raby (h) 2008Tsiouris (h) 2006Veldsman 2009Subtotal (I-squared = 76.2%, p = 0.000)

TSPOTCattamanchi 2010Jiang 2009Leidl (a) 2009Markova (a) 2009Oni 2010Subtotal (I-squared = 71.8%, p = 0.007)

authoryear

TanzaniaIndiaUgandaBulgariaZambiaSouth AfricaSouth Africa

UgandaChinaUgandaBulgariaSouth Africa

country

65 (52, 76)66 (50, 80)74 (49, 91)92 (64, 100)63 (49, 75)65 (44, 83)30 (15, 49)65 (52, 77)

54 (45, 64)66 (47, 81)89 (67, 99)62 (32, 86)68 (57, 78)68 (56, 80)


16.2715.0512.3013.5915.8313.0713.89100.00

25.2318.5819.7311.8824.58100.00

Weight%

65 (52, 76)66 (50, 80)74 (49, 91)92 (64, 100)63 (49, 75)65 (44, 83)30 (15, 49)65 (52, 77)

54 (45, 64)66 (47, 81)89 (67, 99)62 (32, 86)68 (57, 78)68 (56, 80)


16.2715.0512.3013.5915.8313.0713.89100.00

25.2318.5819.7311.8824.58100.00

Weight%

0 20 40 60 80 100

HIV infected Pooled sensitivity

QFT-GIT 65%, TSPOT 68%

HIV uninfected Pooled sensitivity

QFT-GIT 84%, TSPOT 88%

Presenter

Presentation Notes

27 studies (10 TSPOT; 17 QFT-GIT) 590 HIV-uninfected, 844 HIV-infected individuals Countries: Bulgaria, China, India, Iran, Turkey, S Africa, Uganda, Zambia Reference standard was culture

Specificity of QFT-Gold and QFT-GIT and effect of BCG vaccination

BCG-nonvaccinated Pooled specificity 99%

BCG-vaccinated Pooled specificity 96%


Presenter

Presentation Notes

What about the effect of BCG on IGRAs? Pooled T-Spot specificity was 88% (CDC)

BCG-nonvaccinated Pooled specificity 97%

BCG-vaccinated Pooled specificity 59%

Specificity of the TST and effect of BCG vaccination


Presenter

Presentation Notes

What about the effect of BCG on the TST?

24 studies with 240,243 subjects

BCG given in infancy: false-positive TST results due to BCG occurred in only 6% of vaccinated subjects

BCG given after infancy: false-positive TST results due to BCG occurred in 40% of vaccinated subjects

How BCG affects TST results

Presenter

Presentation Notes

TST specificity is reduced by BCG vaccination and the aim of this study was to estimate the absolute effect. METHODS: For each TST size category, the difference between vaccinated and non-vaccinated was assumed to represent the percentage with false-positive (FP) TST due to BCG (the FPTSTBCG). For each study, the number BCG-vaccinated was multiplied times this percentage to estimate the total number of individuals with FP-TSTBCG in that TST size range. These values from all studies were combined in a weighted average FP-TSTBCG for each TST size category.

Online Atlas: www.bcgatlas.org

www.bcgatlas.org

India, BCG given at birth has limited effect on TST

Japan, BCG given after birth has major effect on TST

• 18-month-old adopted male arrived in San Francisco from China

• No known TB exposure • TST= 15 mm, QFT-GIT indeterminate • Chest radiograph PA and lateral normal • Parents are wary of medications and have read on

the internet about isoniazid and liver toxicity

• What else would you like to know? • Could TST be a false positive result? • How would you manage this child?

Case 1

Presenter

Presentation Notes

In china, BCG vaccination is given at birth.

Interferon-gamma release assays and childhood tuberculosis: Systematic review and meta-analysis, Mandalakas et al, Int J

Tuberc Lung Dis 2011

High income: sensitivity 81% Low/middle: sensitivity 78%

High income: sensitivity 86% Low/middle: sensitivity 84%

Presenter

Presentation Notes

32 studies involving 4122 children were included in the analyses. The average age of the children was 8 years; BCG vaccination ranged from 8% to 100%. The review found no difference in performance between TST and IGRAs for the diagnosis of active TB and LTBI in children

Mandalakas • Pooled specificities were similar among the 3 tests

(~90%) • Decreased sensitivity of TST, QFT-Gold/QFT-GIT and

T-SPOT.TB when

• average age was < 5 years, • all children were HIV-infected • > 50% were BCG-vaccinated

Presenter

Presentation Notes

Spec: TST85, QFT 91, TSPOT 94

American Academy of Pediatrics Red Book 2009

“IGRAs cannot be recommended routinely for use in children younger than 5 years of age or for immunocompromised children of any age because of a lack of published data about their utility with these groups”

http://www.cps.ca/english/statements/id/tuberculosis.htm

Summing up: IGRAs versus TST sensitivity

• QFT = TST (~80%) in immunocompetent • TSPOT (~90%) > TST or QFT • Lower in HIV infection • Lower in high-incidence countries • Similar sensitivity for detection of LTBI in children

• TST specificity is high in BCG non-vaccinated, but low and variable in BCG vaccinated

• IGRAs have high specificity (>95%) in low-incidence settings – IGRA > TST – IGRAs are not affected by BCG vaccination – IGRAs may be helpful in settings that give BCG after

infancy or give multiple vaccinations

Summing up: IGRAs versus TST specificity

• 35-year-old Bosnian female arrived in the US 2 yrs ago • Diabetes mellitus treated with oral medication • Received BCG vaccine as child, does not recall when • TST = 12 mm • No signs or symptoms of TB, CXR normal • No known contact with a TB patient • Bosnia TB incidence = 51 per 100,000 per year • Could TST be a false positive result? • What are this patient’s risk factors for TB? • How would you manage this patient?

Case 2

Presenter

Presentation Notes

Bosnia gives BCG vaccine at birth and oes not give multiple vaccinations

Presenter

Presentation Notes

Christie Jeon and Megan Murray 13 observational studies (1,786,212 participants) with 17,698 TB cases. DM was associated with an increased risk of TB (relative risk = 3.11, 95% CI 2.27–4.26) The 3-fold increased risk of tuberculosis associated with diabetes that the meta-analysis reveals suggests that diabetes may already be responsible for more than 10% of tuberculosis cases in countries such as India and China, a figure that will likely increase as diabetes becomes more common.

After a short stay in the US, Michelangelo’s David returns to Italy.

Diabetes and LTBI

Case 3

• Patient is referred for possible LTBI • 55-year-old female emigrated from El Salvador to

Texas in 1985 • Employed at a poultry processing plant for 15 years • Diagnosed with rheumatoid arthritis • Prescribed prednisone 20 mg twice daily,

methotrexate and Humira [adalimumab-a tumor necrosis factor alpha antagonist]

• How would you evaluate this patient? Case courtesy of Heartland National TB Center

• Individuals with immune-mediated inflammatory disorders (IMIDs) are at increased risk of developing active TB

• Current evidence does not suggest that IGRAs >TST in identifying patients with IMID who could benefit from LTBI treatment

• Tendency for guidelines to prefer IGRA over TST in IMIDs or to recommend both tests

• If high index of suspicion for LTBI, perform both tests

Current Opinion in Rheumatology 2011

Two strategies to detect LTBI in patients with immune-mediated inflammatory disease, Smith, Current Opinion Rheumatol 2011

Strategy 1: either test positive to maximize sensitivity; best used in areas that have not used BCG vaccine. Benefit: fewer false negatives. Drawback: in areas that do use BCG vaccine, some patients with discordant TST+/IGRA- will be incorrectly classified as LTBI Strategy 2: maximize specificity; best used in areas that have used BCG vaccine. Benefit: fewer false positives. Drawback: false negative IGRA results are possible and more likely in IMID patients

Presenter

Presentation Notes

Strategy 1: some patients with IMID could have positive results to either IGRA or TST Strategy 2: maximize specificity, with fewer false + results

Case 4

• 40-year-old male living with HIV • CD4 count of 337 cells/mm3 • On antiretroviral therapy with undetectable HIV RNA

level • Presents for routine follow-up, asymptomatic • States that his partner was recently diagnosed with

active pulmonary TB and is currently receiving TB treatment

• How would you evaluate this patient? Would you do anything different if CD4 count were 100 cells/mm3?

Case courtesy of Ingrid A. Binswanger, MD, MPH

• All persons should be tested for LTBI at time of HIV diagnosis

• Persons with negative tests for LTBI and CD4+ count <200 cells/µL should be re-tested once they start ART and attain CD4+ count >200 cells/µL

• Annual testing for LTBI is recommended for HIV-infected persons at high risk (jail, congregate settings, IDU, etc)

• All HIV-infected persons with a positive test for LTBI should receive CXR and clinical evaluation to rule out active TB

“Although desirable, a substantially improved test to better define individuals at risk of future tuberculosis does not seem imminent. It is thus all the more important that only individuals are tested who are at a high risk of tuberculosis in the future and who are fully appraised of the treatment consequences.”

Lange C and Rieder H, AJRCCM 2011

Presenter

Presentation Notes

Clinical risk stratification is crucial and more emphasis needs to be put on compliance and completion of preventive therapy

Pai & Menzies. UpToDate 2009

Who should be tested?

Presenter

Presentation Notes

Clinical risk stratification is crucial and more emphasis needs to be put on compliance and completion of chemoprophylaxis

CDC Updated Guidelines for Using IGRAs – Key Points

• TST, QFT-GIT, TSPOT measure different aspects of the immune response

- use different antigens - use different interpretation criteria • Different tests can yield different results • IGRA may be used in place of (not in addition to) TST

in all situations in which CDC recommends TST as an aid in diagnosing M. tuberculosis infection

MMWR. June 25, 2010 / Vol. 59 / No. RR-5

IGRA Preferred but TST Acceptable for:

• Persons from groups that historically have low rates of returning to have TSTs read (homeless persons)

• Persons who have received BCG as a vaccine or for cancer therapy

TST Preferred but IGRA Acceptable for:

• Children younger than 5 years

Note: Some experts recommend both IGRA and TST to increase sensitivity in this age group

Presenter

Presentation Notes

The higher rate of active tuberculosis and severe forms of the disease in infants and children aged <5 years compared with older children suggests that the immune response to M. tuberculosis infection differs in these groups. Age-related immunologic differences might explain reported variations in IGRA test performance, including poorer test sensitivity, and lower production of IFN-γ in response to mycobacterial antigens and mitogen (used as a positive control) among children aged <4 years compared with children aged 4–15 years (81), an increase in response to mitogen with increasing age (82), and a higher proportion of indeterminate QFT-GIT results among children aged <5 years (43). In contrast, one large study in a tuberculosis-endemic setting found that infants and young children had robust IFN-γ responses to M. tuberculosis antigens, and that their responses were comparable to responses in adults and older children (83). Older children (i.e., those aged ≥5 years) are less likely than children aged <5 years to develop active tuberculosis or to have severe forms of the disease; in this way, older children resemble adults. In addition, for older children, IGRA testing might be logistically easier (e.g., in the ability to draw sufficient quantities of blood). Therefore, less caution might be required when implementing IGRA testing in children aged ≥5 years than in children aged <5 years…. In general, sensitivity of IGRAs in children is expected to be comparable to TST MMWR

Either TST or IGRA Used for:

• Recent contacts of persons known/suspected with active TB – Confirm negative results obtained before 8 weeks

after end of exposure by repeat testing 8-10 weeks after end of exposure

• Surveillance programs for health-care workers - IGRAs do not boost subsequent test results

Both IGRA and TST Used for

• Persons with increased risk for infection, progression, and poor outcome (HIV infected, children <5)

• Suspected active TB (symptoms, signs, and/or radiographic evidence)

• Remember: Even multiple negative results from any combination of these tests CANNOT exclude TB

Discordant Results What do they mean? What should one do?

• Discordant results = IGRA+/TST- or IGRA-/TST+ • Consider positive result of either IGRA or TST as

evidence of TB infection when - Clinically suspect active TB - Risks for infection, progression, and poor

outcome are increased (HIV infection, children <5 yrs)

• In BCG-vaccinated persons (not at risk for poor outcome), can discount TST result <15 mm when IGRA is negative

• High week-to-week variability

TSPOT-TB

Presenter

Presentation Notes

What amount of variation is expected when IGRAs are repeated? In IGRA-negative subjects, if TST is administered more than 3 days prior to an IGRA, the TST may boost the IGRA result and confound the interpretation of results When using a two-step screening strategy it appears safe to perform IGRA within 3 days of performing the TST.

Presenter

Presentation Notes

What do guidelines say?

TST and IGRAs are similar in some ways • Do not distinguish latent infection from active disease • Do not provide any direct evidence of the presence of

viable bacilli • Determine that infection has at some point led to an

acquired immune response that is detectable following re-challenge with antigen

• Are both affected by HIV infection

TST and IGRAs are dissimilar in some ways

• IGRAs are specific in all settings • TST is specific in BCG unvaccinated or those who get

BCG in infancy • IGRAs have operational characteristics that are more

advantageous • IGRAs require more resources

References

• Systematic reviews on IGRAs and other TB diagnostics are available at Evidence-based tuberculosis diagnosis, www.tbevidence.org

• Barry C et al. Nature Reviews Microbiology | AoP, published online 26 October 2009; doi:10.1038/nrmicro2236

• American Academy of Pediatrics. Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009

• ATS/CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000 ;49(RR-6)

• Mazurek GH et al.. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. Jun 25;59(RR-5)

• Mack U et al. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J. 2009 May;33(5):956-73.

• Lange C and Rieder H. Am J Resp and Crit Care Med 2011

Thank you!

Documents

Interferon-Gamma Release Assays: Summary of the evidence ...globaltb.njms.rutgers.edu/downloads/courses/2011... · TB Clinician’s Meeting, Washington, DC November 17, 2011 Karen