Motivation: You suspect latent TB in a high-risk patient. Which test do you order: an expensive blood test or a cheaper skin test that needs to be read after two days? Ever since the interferon-gamma release assay for latent TB testing has been available, I have noticed that we often use the blood test rather than PPD to screen for TB. Is there a rational basis for this? Are we driven by convenience or by sound science?
As way of background, there are two commercial interferon-gamma release assays (QuantiFERON and T-SPOT) available. The assay depends on in-vitro production of interferon-gamma by patient's immune cells in response to M. tuberculosis specific antigens. In contrast to the PPD testing which also cross-reacts with bacille Calmette-Guerin (BCG) vaccine and many nontuberculous mycobacteria (NTM), the interferon release assay is more specific for tuberculosis though M. marinum and M. kansasei also cross-react in the interferon release assay.
Paper: Menzies, D., Pai, M., and Comstock, G. "Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research" Ann Intern Med. (2007); 146: 340-354.
Methods: Meta-analysis of studies measuring sensitivity and specificity of interferon-gamma release assays and tuberculin skin testing. For sensitivity, the study sample was counted positive if the person had active TB (therefore should also test positive for latent infection) or exposure to person with active TB. For specificity, healthy life-long residents of low-incidence populations without high-risk exposure were counted as negative for TB.
Results:
Tuberculin Skin Test: There were fourteen studies assessing sensitivity and eight studies measuring specificity. For the skin test, the sensitivity depends on diameter of induration set as the threshold for positive testing.
Sensitivity:
- 5 mm cutoff, sensitivity of 74% (95% CI of 0.66-0.82)
- 10 mm cutoff, sensitivity of 72% (CI: 0.50-0.95)
- 15 mm cutoff, sensitivity of 40% (CI: 0.25-0.56)
- Pooled pediatric data, sensitivity of 55% (0.43-0.67)
Specificity:
- All studies: 66% (CI: 0.46-0.86)
- Non-BCG vaccinated: 98% (0.96-1.0)
- BCG vaccinated: 0.56 (0.34-0.78)
- 10 mm cutoff: 58% (0.37-0.79)
- 15 mm cutoff: 87% (0.7-1.0)
QuantiFERON: Thirteen studies assessed sensitivity and nine studies measured specificity
Sensitivity:
- All studies: 76% (CI: 0.7-0.83)
- Pediatric: 66% (CI: 0.5-0.83)
Specificity:
- All studies: 97% (CI: 0.95-0.99)
- BCG vaccinated: 96% (CI: 0.93-0.99)
- Non-vaccinated: 100% (CI: 0.94-1.0)
T-SPOT: Twelve studies assessed sensitivity and four studies measured specificity.
Sensitivity:
- All studies: 88% (CI: 0.81-0.95)
- Pediatric: 62% (CI: 0.43-0.81)
Specificity:
- All studies: 92% (CI: 0.88-0.95)
No data available for assessing specificity based on BCG status.
Discussion: For patients at risk of latent tuberculosis, screening by tuberculin skin test or interferon release assay is acceptable. Although the confidence intervals overlap, there is a trend for higher sensitivity for the T-spot assay compared to the tuberculin skin testing and QantiFERON assay. This will need to be verified further in future studies. The specificity of the tubeculin skin testing is affected primarily by BCG status. For patients without BCG vaccine, specificity is quite high for skin testing as well. Skin testing is additionally affected by multiple non-tuberculous mycobacteria (NTM) strains. There was no data presented on results of interferon-release assay or skin testing on patients with confirmed NTM infections. Another point of caution in the results is that testing data in adults do not necessarily translate to pediatrics, where the sensitivity of the assays could be lower.
One of the major problems with this field at large is that there is no gold standard for latent tuberculosis. By definition, latent TB does not cause symptoms and is held in check. So far, the only way to verify prior exposure is when patients develop active TB or have high exposure to active TB infection. Of the estimated 2 billion people with TB, only a minority will ever develop active TB. It is quite unclear what the sensitivity of these assays are in patients with well-controlled TB for years.
As way of background, there are two commercial interferon-gamma release assays (QuantiFERON and T-SPOT) available. The assay depends on in-vitro production of interferon-gamma by patient's immune cells in response to M. tuberculosis specific antigens. In contrast to the PPD testing which also cross-reacts with bacille Calmette-Guerin (BCG) vaccine and many nontuberculous mycobacteria (NTM), the interferon release assay is more specific for tuberculosis though M. marinum and M. kansasei also cross-react in the interferon release assay.
Paper: Menzies, D., Pai, M., and Comstock, G. "Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research" Ann Intern Med. (2007); 146: 340-354.
Methods: Meta-analysis of studies measuring sensitivity and specificity of interferon-gamma release assays and tuberculin skin testing. For sensitivity, the study sample was counted positive if the person had active TB (therefore should also test positive for latent infection) or exposure to person with active TB. For specificity, healthy life-long residents of low-incidence populations without high-risk exposure were counted as negative for TB.
Results:
Tuberculin Skin Test: There were fourteen studies assessing sensitivity and eight studies measuring specificity. For the skin test, the sensitivity depends on diameter of induration set as the threshold for positive testing.
Sensitivity:
- 5 mm cutoff, sensitivity of 74% (95% CI of 0.66-0.82)
- 10 mm cutoff, sensitivity of 72% (CI: 0.50-0.95)
- 15 mm cutoff, sensitivity of 40% (CI: 0.25-0.56)
- Pooled pediatric data, sensitivity of 55% (0.43-0.67)
Specificity:
- All studies: 66% (CI: 0.46-0.86)
- Non-BCG vaccinated: 98% (0.96-1.0)
- BCG vaccinated: 0.56 (0.34-0.78)
- 10 mm cutoff: 58% (0.37-0.79)
- 15 mm cutoff: 87% (0.7-1.0)
QuantiFERON: Thirteen studies assessed sensitivity and nine studies measured specificity
Sensitivity:
- All studies: 76% (CI: 0.7-0.83)
- Pediatric: 66% (CI: 0.5-0.83)
Specificity:
- All studies: 97% (CI: 0.95-0.99)
- BCG vaccinated: 96% (CI: 0.93-0.99)
- Non-vaccinated: 100% (CI: 0.94-1.0)
T-SPOT: Twelve studies assessed sensitivity and four studies measured specificity.
Sensitivity:
- All studies: 88% (CI: 0.81-0.95)
- Pediatric: 62% (CI: 0.43-0.81)
Specificity:
- All studies: 92% (CI: 0.88-0.95)
No data available for assessing specificity based on BCG status.
Discussion: For patients at risk of latent tuberculosis, screening by tuberculin skin test or interferon release assay is acceptable. Although the confidence intervals overlap, there is a trend for higher sensitivity for the T-spot assay compared to the tuberculin skin testing and QantiFERON assay. This will need to be verified further in future studies. The specificity of the tubeculin skin testing is affected primarily by BCG status. For patients without BCG vaccine, specificity is quite high for skin testing as well. Skin testing is additionally affected by multiple non-tuberculous mycobacteria (NTM) strains. There was no data presented on results of interferon-release assay or skin testing on patients with confirmed NTM infections. Another point of caution in the results is that testing data in adults do not necessarily translate to pediatrics, where the sensitivity of the assays could be lower.
One of the major problems with this field at large is that there is no gold standard for latent tuberculosis. By definition, latent TB does not cause symptoms and is held in check. So far, the only way to verify prior exposure is when patients develop active TB or have high exposure to active TB infection. Of the estimated 2 billion people with TB, only a minority will ever develop active TB. It is quite unclear what the sensitivity of these assays are in patients with well-controlled TB for years.
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