Choices for Testing Latent TB

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.  

CNS Tuberculosis

Motivation: As one of my attendings put it after morning rounds filled with arcane diagnoses, "By the time you end up at MGH, you the definition of atypical."  One of the atypical diagnoses we often consider is central nervous system tuberculosis - entering into the differential for both persistent meningitis and brain masses.  Every time you mention CNS TB, some smirk while others edge towards a face mask.  I am torn between the two largely because I do not know what the typical presentation is or even how to diagnose it prior to a culture that takes weeks to mature.  So, how do you diagnose CNS TB?

As way of background, central nervous system tuberculosis is thought to occur from hematogenous spread of TB from a primary pulmonary focus.  There is TB deposition and formation of subpial and subependymal foci - called Rich foci.  If these foci rupture, TB meningitis results.  Otherwise, growth of these foci results in tuberculomas.

Paper: Systematic review of diagnoses of CNS TB by British Infectious Society. "British Infectious Society guidelines for the diagnosis and treatement of tuberculosis of the central nervous system in adults and children" Journal of Infection (2009); 59: 167-187.

Methods: Systematic clinical evidence review of papers published in Medline and Pubmed between 1966 and 2008 dealing with CNS TB.  The working group consisted of an interdisciplinary group of specialists.

Results:
Basic Clinical and Laboratory Features of CNS TB:
TB Meningitis: The top three clinical features were fever (60-95%), headache (50-80%), and anorexia/weight loss (60-80%).  Top three clinical signs were neck stiffness (40-80%), focal cranial nerve palsy (30-50%), and coma (30-60%).  On CSF examination, majority have clear appearance (80-90%) with 50% having opening pressure > 25 cm H2O.  CSF glucose:blood glucose ratio was < 0.5 in 95% of patients with TB meningitis.  The leucocyte count varies between 5-1000 cells with variable neutrophilic and lymphocytic predominance.  Protein was also variable ranging from 45 to 300 mg/dL.
CNS Tuberculoma: Few large case series but most common presenting feature is seizure with complaints of headache, fever, and weight loss.  CSF pleocytosis of 10-100 cells is present in only 50%.

Microbiology:
TB Meningitis: Sensitivity of AFB smear up to 80% provided that multiple large volume (>6 mL) taps are submitted for analysis.  Culture media usually takes > 2 weeks to be positive and not helpful with decision making.
Tuberculoma: CSF AFB smear usually not positive and require stereotactic biopsy, which is diagnostic in about 94% of patients.

Nucleic Acid Amplification:
TB Meningitis: Currently available nuceic acid amplification tests about 56% sensitive (95% CI 46-66%) and 98% specific (95% CI 97-99%).  After start of anti-TB treatment, PCR test may retain sensitivity even when AFB smear turns negative.  PCR methods of CSF have not been well studies with tuberculomas.

PPD: Rates of positive PPD with CNS TB vary widely with reported ranges around 10-50%.
CSF adenosine deaminase activity: Unclear sensitivity (estimated around 57%) with CNS TB but lack of specificity with false positives from lymphoma, malaria, crytococcoal meningitis, and other etiologies.

Interferon-gamma release assay: Estimated sensitivity of about 50% since CSF lymphocytes may die more rapidly than peripheral lymphocytes.

Discussion: Analysis of the literature supports why TB occupies such a murky place in the differential for brain masses or meningitis.  There are no very sensitive ways to prove TB meningitis.  In some sense, the history of subacute onset of symptoms with a suggestive CSF profile is the best clue for TB meningitis.  The rest of diagnostic tests are not sensitive enough to rule out TB meningitis over clinical suspicion alone.  One point that I was especially surprised to learn is that although TB is acquired via pulmonary source and spread hematogenously, the PPD is positive in only 50%.  Other assays like CSF adenosine deaminase or even interferon-gamma release assay are relatively insensitive.  So, one has to be careful to over-rule clinical suspicion!