Conventional wisdom has been that in active tuberculosis (TB) patients harbor large numbers of replicating Mycobacterium tuberculosis (Mtb), requiring multiple antibiotics to prevent the emergence of resistant mutants. In contrast, Mtb under latent or “inactive” conditions is presumed to have little capacity for mutation due to reduced bacterial replication, thus generally requiring only one antibiotic for preventive therapy.1
However, the assumption that Mtb has a low capacity for mutation in latent TB due to slow bacterial replication has been challenged in recent years. An experimental study in macaque monkeys with latent Mtb infection using whole genome sequencing demonstrated that despite reduced replication, Mtb acquires a similar number of chromosomal mutations during latency as it does during active infection.1
This finding supports the more current and evolving concept of latent TB which assumes diverse mycobacterial growth states, ranging from complete absence of organisms to actively replicating bacterial populations.2 It also explains why, although effective, isoniazid monotherapy may be a risk factor for the emergence of INH resistance in latent TB. 1,3
Bonus Pearl: Did you know that INH treatment of latent TB in adults is 60-80% protective when given for 6 months, and 90% protective when given for 9 months? 4
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- Ford CB, Lin PL, Chase M, et al . Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43:482-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101871/
- Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res 2011;50:202-12. https://www.ncbi.nlm.nih.gov/pubmed/21717066
- Balcells ME, Thomas SL, Faussett PG, et al. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51. https://www.ncbi.nlm.nih.gov/pubmed/16704830
- Piccini P, Chiappini E, Tortoli E, et al. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014; 14 (Suppl 1):S4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015485/
The weight of the evidence to date suggests that immunosuppressive therapy, including corticosteroids, other oral immunosuppressants and anti-tumor-necrosing factor (TNF) drugs, may negatively impact IGRA results.1-5
Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 2-4 In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone.4
A meta-analysis of the performance of IGRAs (including T-SPOT.TB) in patients with inflammatory bowel disease concluded that these assays were negatively affected by immunosuppressive therapy.5
So, be cautious in interpreting a negative or indeterminate results of IGRAs in patients on corticosteroid therapy or other immunosuppressants.
See also a related P4P post: https://pearls4peers.com/2020/01/20/my-patient-with-rheumatoid-arthritis-might-have-been-exposed-to-tuberculosis-does-immunosuppressive-therapy-affect-the-results-of-interferon-gamma-release-assay-igra-testing-for-latent-tuberculosis/
Bonus Pearl: Did you know that IGRA is not affected by prior Bacillus Calmette-Guerin (BCG) vaccination, a significant advantage over PPD skin tests?
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- Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
- Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
- Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
- Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349. https://academic.oup.com/ibdjournal/article/17/11/2340/4631016
- Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042. https://www.researchgate.net/publication/265093409_Performance_of_Interferon-gamma_Release_Assay_for_Tuberculosis_Screening_in_Inflammatory_Bowel_Disease_Patients