BlueCross and BlueShield of Montana Medical Policy/Codes
Tuberculosis Screening Using Diagnostic Blood Assays
Chapter: Medicine: Tests
Current Effective Date: October 25, 2013
Original Effective Date: October 25, 2013
Publish Date: July 25, 2013
Revised Dates: This policy is no longer scheduled for routine literature review and update.
Description

The presence of latent tuberculosis is routinely assessed by a tuberculin skin test (TST), which detects a cell-mediated immune response to the injected tuberculin purified protein derivative (PPD).  Although TST has been in use for over a century, its limitations include poor specificity (i.e., numerous false positive results), the need to examine the site 48-72 hours after injection, and the subjective interpretation of results (i.e., estimation of the diameter of induration).  For example, a negative result may indicate no exposure to the organism, or simply an inability of the lymphocytes to respond.  A positive result may indicate acute current infection, past exposure without infection, or exposure to other mycobacterial antigens, including prior immunization with Bacillus Calmette-Guérin vaccine (BCG).  In addition, the underreporting of positive TSTs by health care workers has been an ongoing concern that has led to an educational campaign, the National Tuberculosis Training Initiative, sponsored by the Centers for Disease Control and Prevention and other national medical and nursing organizations.

One of the tests investigated is an in vitro assay as an alternative to TST.  The assay, originally investigated in cattle, is based on the incubation of whole blood with antigens specific for TB and the subsequent immunoassay of gamma interferon released from reactive T cells, if present. The production of gamma interferon represents activation of the cell-mediated immune system, similar in concept to the immunologic basis of the tuberculin skin test.  However, the in vitro blood test avoids the problem of requiring a second office visit to interpret the tuberculin skin test, and the well-known variability in the subjective assessment of intradermal skin reaction. Another feature of the in vitro assay is its ability to distinguish between reactivity from Mycobacterium tuberculosis (M. tuberculosis) reactivity related to mycobacteria other than tuberculosis (MOTT). MOTT is a significant cause of false positive TST results.

The QuantiFERON-TB® assay (CSL Biosciences, Australia) for detection of gamma interferon production is a blood test that has been used in humans in Australia.  In November 2001, this test received approval from the U.S. Food and Drug Administration (FDA) in the United States for the following indication:

"The QuantiFERON-TB® test is intended as an aid in the detection of latent Mycobacterium tuberculosis infection."

In December of 2004, QuantiFERON-TB® GOLD received FDA approval for the detection of latent TB.  This test differs from the first generation test in that instead of using PPD as the stimulus for interferon production, two antigens, ESAT-6 and CFP-10, are used.  These antigens are present in mycobacterium tuberculosis, but are not present in those exposed to BCG or non-tuberculous mycobacteria.

In May of 2005, QuantiFERON-TB® Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), received final approval from the U.S. Food and Drug Administration as an aid for diagnosing Mycobacterium tuberculosis infection.  This test detects the release of interferon-gamma (IFN-g) in fresh heparinized whole blood from sensitized persons when it is incubated with mixtures of synthetic peptides representing two proteins present in M. tuberculosis: early secretory antigenic target-6 (ESAR-6) and culture filtrate protein-10 (CFP-10).  These antigens impart greater specificity than is possible with tests using purified protein derivative as the tuberculosis (TB) antigen.  

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there is any exclusion or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Medically Necessary

Blue Cross and Blue Shield of Montana (BCBSMT) may consider diagnostic blood assays for tuberculosis (TB) medically necessary in patients considered at high risk for latent tuberculosis infection and who have frequent false-negative and false-positive tuberculin skin testing (TST).  Such patients include, but are not limited to, HIV-infected patients and intravenous drug abusers.

Rationale

The published medical literature regarding the QuantiFERON® TB test consists of several articles comparing the sensitivity and specificity of the gamma interferon blood test with the TST in various populations of patients.  Streeton and colleagues compared the results of a tuberculin skin test and a gamma interferon blood test in 952 Australian volunteers, including both a group of military recruits and those attending a specialist respiratory medicine practice.   The purpose of the study was to determine appropriate cut-off levels for interpreting the results of the gamma interferon TB blood test such that the blood test would be equivalent to the TST.  Using the designated cut-off point, the specificity of the gamma interferon blood tests was 98% (407/417 individuals with no known exposure to tuberculosis were negative) and sensitivity was 90% (163/182 untreated patients with positive TST results were positive).  The gamma interferon blood test was also positive in 43% (55/128) of those with known exposure to TB but TST negative.  These results suggest that the blood test may be more sensitive than the TST, but the investigators did not pursue microbiological or histopathologic confirmation of these results.

Converse and colleagues compared the results of the gamma interferon blood test with the TST in a high-risk population of 67 patients, consisting of HIV seropositive and HIV seronegative intravenous drug users.  The participants in the study were categorized into six groups according to their HIV status, TST status, and presence of anergy (immune unresponsiveness).  The results of the gamma interferon test were then compared with the results of the TST for each group.  The gamma interferon blood test agreed 89%-100% of the time with a positive TST in both HIV positive and negative subjects, but the blood test was positive 52% of the time among those with a negative TST or with anergy.  Similar to the Streeton study above, these results suggest the gamma interferon blood test may be more sensitive than the TST, although further investigation is needed to assess the clinical significance of discordant results.

The available data suggest that the gamma interferon blood test can be calibrated to produce results comparable to the TST.  Whether or not the blood test will be more sensitive than the skin test requires further research.   Aside from the diagnostic performance, an advantage of the blood test is that only one office visit is required, unlike the skin test in which a repeat office visit to assess results of the skin test may be required.   While a repeat office visit may not be considered necessary in screening reliable, low-risk patients, a second office visit is considered more important in high-risk patients, i.e., in HIV-positive patients or intravenous drug users.   In some studies, the call back rates of these patients have been below 50%.  The objective interpretation of the blood test, compared to the subjective interpretation of skin test, is also perceived as a potential advantage.

Further data are available from the FDA Summary of Safety and Effectiveness, representing the data presented to the FDA as part of the FDA-approval process.  The clinical data included 1,042 individuals undergoing screening for latent M. tuberculosis infection.  Patients underwent both a TST and a QuantiFERON TB® test.  The results of this trial have also been published in the peer-reviewed literature. 

Agreement of the QuantiFERON TB® with the TST was 84.8%.  Within this group agreement was 88.1% for subjects with no history of BCG vaccination and 70% for those who had. Reactivity to mycobacteria other than MOTT can also cause false positive TST reactions.  Of the 80 individuals with TST positive discordant results, 13 were classified as QuantiFERON TB® negative due to reactivity to MOTT.  The authors concluded that QuantiFERON TB® was equivalent to TST in its ability to detect latent M. tuberculosis infection.  As noted in the discussion section, a patient only needs to be seen once for the QuantiFERON TB® test, whereas for TST the patient needs to self-evaluate or return for evaluation at 48 to 72 hours later to have their adverse reaction measured.  In some situations, as many as 65% of individuals fail to return to have their TST read.  As noted in the FDA summary of safety and effectiveness, "Whatever the merits of accuracy of the TST itself, the failure to obtain a result for the test, in such a large proportion of individuals, has considerable public health implications.  A test for latent TB infection, which has equivalent performance to the TST and does not require subject to return to have the test read, has obvious public health benefits and can only lead to more truly infected individuals being treated than is currently the case."

It should be noted that for many patients undergoing routine screening for TB, such as the routine screening of schoolchildren with no other known risk factors, self assessment of the skin reaction by parents or care givers is considered adequate.  In contrast, patients at high risk for latent TB infection, such as patients with HIV infection or intravenous drug use, are typically called back to have formal interpretation of the skin reaction.  This population of patients would probably derive the most benefit from an in vitro assay.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

V01.1, V71.2, V74.1

Procedural Codes: 86480
References
  1. Chaisson, R.E., Keruly, J.C., et al.  Effects of an incentive and education program on return rates for PPD test reading in patients with HIV infection.  Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology (1996)11(5):455-9.
  2. Converse, P.J., Jones, S.L., et al.  Comparison of a tuberculin interferon-gamma assay with the tuberculin skin test in high-risk adults: effect of human immunodeficiency virus infection. Journal of Infectious Disease (1997)176(1):144-50.
  3. Streeton, J.A., Desem, N., et al.  Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection.  International Journal of Tuberculosis and Lung Disease (1998) 2(6): 443-50.
  4. Caciedes, L., Lee, T.S., et al.  Rapid efficient detection and drug susceptibility testing of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.  Journal of Clinical Microbiology (2000) 38: 1203-1208.
  5. Mazurek, G.H., LoBue, P.A., et al.  Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection.  Journal of the American Medical Association (2001) 286(14):1740-7.
  6. Gamma Interferon Blood Test for Diagnosis of Latent Tuberculosis.  Chicago, Illinois:  Blue Cross Blue Shield Association Medical Policy Reference Manual (2002 May 15).  Medicine 2.04.28.
  7. Moore, D.A., Mendoza, D., et al.  Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor settings.  Journal of Clinical Microbiology (2004 October) 42(10): 4432-7.
  8. Mori, T., Sakatani, M., et al.  Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens.  American Journal of Respiratory Critical Care Medicine (2004 July 1) 170(1): 59-64.
  9. Meier, T., Eulenbruch, H.P., et al.  Sensitivity of a new commercial enzyme-linked immunospot assay (T SPOT-TB™) for diagnosis of tuberculosis in clinical practice.  European Journal of Clinical Microbiology and Infectious Diseases (2005 August) 24(8): 529-36.
  10. Taggart, E.W., Hill, H.R., et al.  Evaluation of an in vitro assay for interferon gamma production in response to the Mycobacterium tuberculosis-synthesized peptide antigens ESAT-6 and CFP-10 and the PPD skin test.  American Journal of Clinical Pathology (2006 March) 125(3): 467-73.
  11. Moore, D.A, Caviedes, L., et al.  Infrequent MODS TB culture cross-contamination in a high-burden resource-poor setting. Diagnostic Microbiology and Infectious Disease (2006) 56: 35-43.
  12. Wagstaff, A.J., and J.P. Zellweger.  T-SPOT. TB: an in vitrodiagnostic assay measuring T-cell reaction to Mycobacterium tuberculosis-specific antigens.  Molecular Diagnosis and Therapy (2006) 10(1): 57-63.
  13. Ota, M.O., Goetghebuer, T., et al.  Dissociation between tuberculin skin test and in vitro IFN-gamma responses following neonatal BCG vaccination.  Journal of Tropical Pediatrics (2006 April) 52(2): 136-40.
  14. QuantiFERON TB® GOLD – An innovation in tuberculosis screening.  AAOHN (Journal of the American Association of Occupational Health Nurses) (2006 June) 54(6): 245-7.
  15. Connell, T.G., Rangaka, M.X., et al.  QuantiFERON-TB® GOLD:  state of the art for the diagnosis of tuberculosis infection.  Expert Reviews in Molecular Diagnostics (2006 September) 6(5): 663-77.
  16. Moore, D.A.J., Carlton, A.W., et al.  Microscopic-observation drug-susceptibility Assay for the Diagnosis of TB.  The New England Journal of Medicine (2006 October 12) 355(15): 1539-1550.
  17. Iseman, M.D., and L.B. Heifets.  Rapid detection of tuberculosis and drug-resistant tuberculosis. The New England Journal of Medicine (2006 October 12) 355(15): 1606-1608.
History
July 2013  New 2013 BCBSMT medical policy.  Diagnostic blood assays for tuberculosis (TB) may be considered medically necessary in patients considered at high risk for latent tuberculosis infection and who have frequent false-negative and false-positive tuberculin skin testing (TST).  Such patients include, but are not limited to, HIV-infected patients and intravenous drug abusers.
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Tuberculosis Screening Using Diagnostic Blood Assays