Download IFN-* Release Assays in the Diagnosis of Latent Tuberculosis

Concise Clinical Review
IFN-γ Release Assays in the Diagnosis of Latent Tuberculosis
Infection among Immunocompromised Adults
Gil Redelman-Sidi and Kent A. Sepkowitz
Am J Respir Crit Care Med 2013;188:422-431.
호흡기 내과 / R4 이민혜
Introduction
• Tuberculosis(TB)
~10%: active TB
3~4%
Active TB within the
1st year
Initial
infection
Lifetime risk of
progressing to active TB
5%
Latent tuberculosis
infection(LTBI)
~90%: LTBI
Introduction
•
Tuberculin skin test (TST): several limitations
– False positive
• Prior bacillus Calmette-Guérin(BCG) vaccination
• Exposure to other nontuberculous mycobacteria(NTM)
• Variability in results due to the operator bias that is inherent to the test
– False negative
•
•
•
•
•
Anergy
Recent live virus vaccination (measles, mumps, polio)
Recent or overwhelming active TB infection
Improper administration of TST
Repeatedly tested by TST: booster phenomenon
– Sensitivity↑: detection of prior false negative
– Specificity↓: false positive(prior BCG vaccination, exposure to NTM)
Introduction
•
Immunocompromised persons with LTBI
– ↑Risk of progression to active TB
– Treatment of LTBI: ↓risk of progression
– Already receiving complicated medical regimensempiric treatment for LTBI
impractical
– TST: ↑false negative
– Alternative methods for diagnosing LTBI
IFN-γ Release Assays
•
IFN- γ release assays (IGRAs)
– In vitro blood tests
– Cell-mediated immune response that measure T-cell release of IFN- γ after
stimulation by antigens unique to Mycobacterium tuberculosis
•
Two IGRAs
– T-SPOT.TB assay (Oxford Immunotec, Abingdon, UK)
– QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie,
Australia)
•
Immunocompetent persons: both assays, equal sensitivity to the TST, with
improved specificity
IFN-γ Release Assays
•
QFT-GIT
– 3rd-generation enzyme-linked immunosorbent assay
– Measures the amount of IFN-γ released in response to in vitro stimulation of
whole blood with peptides from three TB-specific antigens (ESAT-6, CFP-10,
and TB7.7)
– International units (IU) per milliliter
•
T-SPOT.TB
– Enzyme-linked immunospot (ELISPOT) assay
– Count the number of IFN-γ–producing cells (spot-forming cells) in response
to stimulation with the TB-specific antigens ESAT-6 and CFP-10
– Performed on separated and counted peripheral blood mononuclear cells
IFN-γ Release Assays
•
Both T-SPOT.TB and QFT-GIT: negative and positive controls
– Negative control: measures response in the absence of antigen
– Positive control: measures response in the presence of a known mitogen
– Indeterminate
• (1) the negative control tests positive regardless of the response to TB-specific
antigens
• (2) the positive control tests negative, as does the response to TB-specific antigens
• The response to TB-specific antigens cannot be interpreted in the presence of an
indeterminate result
– Borderline: T-SPOT.TB
• Uncertainty for results near the defined cut point, and to increase the certainty that
a conversion from a negative to a positive result truly represents newly acquired
infection
Centers for Disease Control and Prevention
IFN-γ Release Assays
Centers for Disease Control and Prevention
IFN-γ Release Assays
•
Aadvantages of IGRAs
– Results are numerical less subject to reader bias
– No need for a follow-up visit for reading of results
– Not affected by BCG vaccination status
•
Disadvantages of IGRAs
– Costs
• More expensive reagents
• Need for laboratory
• Blood-drawing equipment and expertise
– Clinical experience is relatively short
• Prognostic value with respect to the subsequent development of active TB is not as
well defined as for TST
Use of IGRAs to Diagnose LTBI in Immunocompromised Patients
Use of IGRAs to Diagnose LTBI in Immunocompromised Patients
•
LTBI in immunocompromised patients
– High risk for TB reactivation
– Impaired immunity low sensitivity of TST more difficult to diagnose
•
IGRAs have been studied in various populations of immunocompromised
patients in the hope that they would perform more reliably than TST
Use of IGRAs to Diagnose LTBI in Immunocompromised Patients
HIV-infected Patients
•
HIV-infected patients with LTBI: annual risk of TB reactivation as high as
10%
•
The risk of reactivation decreases in patients treated with antiretrovirals, but
it is still twice that of the general population
•
HIV-infected patients
– CD4+ lymphocyte count<100–200 cells/mm3: frequently anergic to skin testing
– TST: unreliable method
– Both QFT-GIT and T-SPOT.TB: alternative methods to diagnose LTBI
HIV-infected Patients
•
•
•
•
Birth or long-term residence in a TB-endemic country
Contact with a patient with active TB
Lifestyle-related risk factors (homelessness, incarceration, injection drug use, or work in health care)
Chest X-ray findings suggestive of past TB or a history of prior active TB
HIV-infected Patients
• QFT-GIT: increase in indeterminate results(1.5~16%)
–
–
–
–
Lower CD4 + lymphocyte counts
Injection drug use
Elevated viral load
Clinical history of prior manifestations of acquired immunodeficiency syndrome (AIDS)
Patients with Immune-mediated Inflammatory Diseases and Candidates
for Treatment with Tumor Necrosis Factor-α Inhibitors
•
Patients receiving tumor necrosis factor(TNF)-α inhibitors, which are used in
an increasing number of IMIDs
– Particularly high risk of TB reactivation
– As high as 12 times that of the normal population
•
Adalimumab(Humira®)and infliximab(Remicade®): greatest risk
•
LTBI treatment with isoniazid before beginning TNF-α inhibitor therapy:
74% reduction in the risk of TB activation
Patients with Immune-mediated Inflammatory Diseases and
Candidates for Treatment with Tumor Necrosis Factor-a Inhibitors
• In patients with IMID, use of immunosuppressive medications, particularly corticosteroids: negative
and indeterminate QFT-GIT results/not with a negative or indeterminate T-SPOT.TB
Patients Receiving Dialysis for End-Stage Renal Disease
•
Uremia is associated with impaired immunity
•
Chronic renal failure, whether or not they are receiving dialysis: increased
risk for reactivation of latent TB, estimated to be 2.4-fold higher than the
risk of a healthy person
•
Patients receiving dialysis frequently exhibit anergy to skin testing
Patients Receiving Dialysis for End-Stage Renal Disease
• In patients receiving dialysis for ESRD, QFT-GIT may be more sensitive for diagnosing LTBI than TST
and perhaps T-SPOT.TB
• A systematic review evaluated 30 studies comparing the IGRAs with TST in patients with ESRD
– QuantiFERON assays were more strongly associated with clinical risk factors for TB than TST
– T-SPOT.TB did not significantly differ from TST regarding association with clinical risk factors
Other Immunocompromised Populations, Including Cancer and Transplant
•
Hematologic malignancies or head and neck cancers: increased risk of
developing active TB compared with the general population
•
Solid organ transplant recipients: risk of developing active TB may be 20- to
74-fold higher than in the general population
Other Immunocompromised Populations, Including Cancer and Transplant
•
One of the studies: T-SPOT.TB may be more sensitive than TST in the presence of leukopenia,
and that it may correlate better than TST with clinical risk factors for LTBI
Other Immunocompromised Populations, Including Cancer and Transplant
•
In a one study, all solid organ transplant candidates were tested by QuantiFERON Gold or QFT-GIT
–
–
IGRA positivity correlated with the presence of clinical risk factors for LTBI
Interestingly, more than 40% of liver transplant candidates had an indeterminate result, compared with only
10% of kidney transplant candidates
Other Immunocompromised Populations, Including Cancer and Transplant
•
•
Given the paucity of data, it is difficult to make any definite recommendations regarding the use of
IGRAs to diagnose LTBI in these populations
As TST remains the best studied test in these populations, we would suggest that it be the test of
choice pending further data
Available Guidelines
•
The CDC(US)
– Use of IGRAs in place of (but not in addition to) TST in any situation in which
TST is recommended
– High-risk population, if initial testing by TST or IGRA is negative
performance of both tests should be considered positive result on either
sufficient to diagnose LTBI
•
The ECDC(Europe)
– Immunocompromised patientsTST+IGRAs
•
The CDC and the ECDC both guidelines
– Repeating testing in the case of an indeterminate result (in either T-SPOT.TB
or QFT-GIT) or a borderline result (in T-SPOT.TB) in all patients
Available Guidelines
•
The U.K. guidelines
– HIV and CD4+ cell counts<200 cells/mm3: TST+IGRAconsider LTBI treatment if
either test is positive
– HIV and CD4+ cell counts of 200–500 cells/mm3: TST+IGRA or IGRA alone
– HIV-infected persons with higher CD4+ cell counts: treated as immunocompetent
individuals
– For other immunocompromised persons: IGRA alone or TST+IGRA consider LTBI
treatment if either test is positive
•
The Canadian guidelines
– Immunocompromised patients: initially by TST
– If TST is negative and the clinician is still concerned about the possibility of LTBI
IGRA can be performed: positive result considered diagnostic for LTBI
– T-SPOT.TB: preferable to QFT-GIT retain sensitivity in immunocompromised
patients
Available Guidelines
•
The WHO guideline: discourage the use of IGRAs among HIV-infected
patients in resource limited settings
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Neither IGRA is consistently more sensitive than the TST
More data are available supporting the predictive value of TST
Cost of IGRAs
Need for well-equipped laboratories with trained personnel
May not be readily available in resource-limited settings
Available Guidelines
•
The Korean guidelines (2011)
Use of IGRAs to Diagnose Active TB
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Two meta-analyses: IGRAs were neither sensitive nor specific in diagnosing
active TB among HIV-infected patients
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Discourage use of IGRAs as stand alone tests to diagnose active TB
Conclusions
•
Current data do not suggest that IGRAs have a clear across-the-board
advantage over TST in immunocompromised patients, and they are unlikely
to entirely replace TST in this role
•
However, data do suggest that IGRAs have specific advantages in certain
patient populations and in particular situations
– T-SPOT.TB: less affected by low CD4+ cell count in HIV-infected persons, and by
corticosteroid use in patients with IMID
– QFT-GIT: retain sensitivity in patients with dialysis compared with TST and, perhaps,
T-SPOT.TB
•
Better studies are needed to more accurately define the usefulness of IGRAs
in immunocompromised patients