Tuberculin skin test – Outdated or still useful for Latent TB infection screening?

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Whilst the tuberculin skin test (TST) (better known as the Mantoux Test to older-generation physicians) is over a century old, it continues to be used in high endemic TB settings as a diagnostic tool for determining latent Mycobacterium tuberculosis (MTB) infection (LTBI) (World Health Organization, 2018). WHO define latent tuberculosis infection as “a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB”. The TST measures delayed type hypersensitivity (DTH) response to intradermal injection of purified protein derivative (PPD), a crude mixture of several mycobacterial antigens which are common to M. tuberculosis, Mycobacterium bovis BCG, and non-tuberculous mycobacteria (NTM). Thus, a positive TST test is of low specificity and cannot differentiate between M. tuberculosis infection, prior BCG vaccination, infection with, or exposure to NTM. It also has a low sensitivity in individuals with immunosuppression such as people living with HIV. Operational limitations of test include requirement for two visits up to 72 h apart, between initial intradermal injection of PPD to reading the skin PPD-DTH response, reader variability, and the need for trained personnel to read the test results.

Interferon-g release assays versus TST While TST encompasses antigens recognized by a vast pool of circulating T lymphocytes, the two interferon-g release assays (IGRAs), the QuantiFERON-TB1 assay (Cellestis Limited, Australia) and T SPOT-TB1 (Oxford Immunotec, UK), focus on interferon-g responses to epitopes from two specific MTB complex associated antigens, namely ESAT-6 and CFP-10. When IGRAs were intro- duced into clinical practice a decade ago, it was anticipated that they would rapidly replace TST which would become redundant. The reasons were that: IGRAs do not cross-react with BCG, they are less likely to cross-react with NTM and they require only one health-care visit during which a blood sample is drawn and results can be available within 24 h. Disadvantages of IGRAs are that they require blood samples and a laboratory to process them, quickly after collection (Wilson et al., 2016). While hundreds of papers have been published on comparing performance of TST and IGRAs much remains unknown about the efficacy of IGRAs relative to TST due methodological limitations, the lack of a compactor gold standard for detecting LTBI and the small sample size and inadequate statistical power (LoBue and Castro, 2012). IGRAs appear to have a higher specificity than TST in persons vaccinated with BCG, although they have similar sensitivity to TST. TST versus IGRAs for predicting the risk of LTBI progressing to active TB disease A large prospective cohort study in the United Kingdom showed that positive IGRAs were significantly better than the TST-10 mm and TST-5 mm strategies in predicting the development of active TB among high-risk individuals from TB-endemic countries. TST-5 mm identified a higher proportion of participants who progressed to active TB (64 [83%] of 77 tested) than all other tests and TST thresholds (
75%) (Abubakar et al., 2018). Several published studies have addressed these issues with different results and conclusions: Pai et al. reported a pooled specificity of 99% among non-BCG vaccinated and 96% among BCG vaccinated low- risk groups (Pai et al., 2008). Vesembecth et al. assessed the diagnostic accuracy (21% of controls showed test results above 0.35 IU/mL) of the latest generation IGRA in low-incidence areas in Germany (Vesen- beckh et al., 2012). In a recent meta-analysis by Sester et al. not restricting studies on specificity to low-risk groups (a situation that is closer to the clinical setting), the specificity of QFT-GIT was only 0.79 (95% CI 0.75–0.82) (Sester et al., 2011). Rangaka et al. systematic review and meta-analysis showed neither TST nor IGRAs have a high accuracy for predicting active TB (Rangaka et al., 2012).