Screening tests for tuberculosis before starting biological therapy

Dear Editor,

We read with interest the article by Hewitt et al., ‘Screening tests for tuberculosis before starting biological therapy’.[1] We agree with the authors’ conclusion that a combination of an interferon-gamma release assay (IGRA) [either QuantiFERON-TB Gold in-Tube (QFT-IT) or TSPOT.TB assay] and a tuberculin skin test (TST) is the most sensitive approach to screening for latent tuberculosis infection (LTBI) in patients with a rheumatological disease prior to starting biological therapies.

Hewitt et al. highlight the fact that patients receiving corticosteroids can have false-negative TST results. However, it is important to emphasise that IGRAs, which are designed primarily to achieve high specificity (rather than high sensitivity), are also prone to false-negative results in this setting.

Although a recent meta-analysis found no statistically significant reduction in positive IGRA results in patients on corticosteroids, this does not constitute evidence for ‘no effect’.[2] Importantly, only nine studies were included in this particular subgroup analysis, and there was significant heterogeneity between those studies.

QFT-IT assays rely on the detection of interferon-gamma responses induced by stimulation of blood with TB-specific antigens and can produce either ‘determinate’ (ie positive or negative) or ‘indeterminate’ results.[3] The latter occur when the IFN-gamma concentration in the nil (negative) control sample exceeds a pre-defined threshold, or the IFN-gammaγ response in the mitogen (positive) control sample is insufficient. In our recently published ex vivo study, we found that therapeutic levels of dexamethasone significantly reduce TB antigen-induced IFN-gammaγresponses in the QFT-IT assay, without causing a significant reduction in positive control responses (ie without resulting in ‘indeterminate’ assay results).[4]. Our results show that patients on corticosteroids are at increased risk of false-negative QFT-IT results. Moreover, they highlight that a ‘determinate’ result (due to a sufficient positive control response) in this situation does not provide reassurance that a low or absent IFN-γ response to TB antigens represents absence of LTBI. These data are consistent with Belard et al.’s finding that prednisolone significantly reduces QFT-IT performance in patients screened for LTBI prior to biological therapy.[5]

Interestingly, we found that a different cytokine, IFN-gamma inducible protein 10 (IP-10), was a more sensitive marker of LTBI in TB antigen-stimulated assays in the presence of dexamethasone.[4] This is consistent with a recent study in patients with rheumatoid arthritis receiving corticosteroids and/or biological therapies, which also found that TB antigen-induced IP-10 responses have greater sensitivity than IFN-gamma responses in this setting.[6]

Until more robust and more accurate immune-based tests for TB become available, we strongly endorse Hewitt et al.’s recommendation that a combination of both TST and IGRA should be used to determine the TB infection status of immunosuppressed patients, whilst remaining vigilant to the fact that even this cautious approach cannot definitively exclude the presence of LTBI in this group of patients.

References

1. Hewitt RJ, Francis M, Singanayagam A, et al. Screening tests for tuberculosis before starting biological therapy. BMJ (Clinical Research Ed.) 2015;350:h1060.
2. Ruan Q, Zhang S, Ai J, et al. Screening of latent tuberculosis infection by interferon-gamma release assays in rheumatic patients: a systemic review and meta-analysis. Clin Rheumatol 2014. doi: 10.1007/s10067-014-2817-6.
3. Tebruegge M, de Graaf H, Sukhtankar P, et al. Extremes of age are associated with indeterminate QuantiFERON-TB gold assay results. J Clin Microbiol 2014;52(7):2694-7.
4. Clifford V, Zufferey C, Germano S, et al. The impact of anti-tuberculous antibiotics and corticosteroids on cytokine production in QuantiFERON-TB Gold In Tube assays. Tuberculosis (Edinb) 2015. doi: 10.1016/j.tube.2015.02.039.
5. 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(11):2340-9.
6. Chen DY, Shen GH, Chen YM, et al. Interferon-inducible protein-10 as a marker to detect latent and active tuberculosis in rheumatoid arthritis. Int J Tuberc Lung Dis 2011;15(2):192-200.