What defines latent infection with Mycobacterium tuberculosis in patients with autoimmune diseases?

Screening for latent infection with Mycobacterium tuberculosis (LTBI) and treatment of test-positives is the cornerstone in the prevention of TB and should be performed preferably among individuals with risk for progression. Progression from LTBI to active TB is highest in recent contacts of patients with active TB. Moreover, it is considered particularly high in latently infected patients if they are also immunodeficient. Therefore, screening for evidence of LTBI is recommended for HIV-infected individuals, patients with chronic renal failure, individuals receiving immunosuppressive drug therapy following solid organ or stem cell transplantation, and patients with autoimmune diseases. 2 Since by definition LTBI lacks the gold standard of bacteriological confirmation, the condition is diagnosed indirectly by detection of an immune response towards mycobacterial antigens with either the tuberculin skin test (TST) or interferon-γ release assays (IGRA) performed from whole blood. IGRA may have test-intrinsic and operational advantages over the TST: due to the use of M. tuberculosis-specific antigens, IGRA have been shown to be more specific than the TSTand allow distinction of infections with M. tuberculosis from immunity towards bacille Calmette– Guérin (BCG) or most non-tuberculous mycobacteria. Moreover, unlike the TST, which has been shown to be of low sensitivity in immunocompromised patients, IGRA seem to be less affected by immunodeficiency, as frequently reflected by a higher percentage of positive test results in IGRA compared with TST in head-to-head comparative analyses. Finally, as IGRA are performed along with negative and positive controls, indeterminate results due to failure of responses in the positive control (phytohaemagglutinin) may increase with increasing immunodeficiency and potentially allow to discriminate true negative from falsely negative test results. Our knowledge about the effect of immunosuppressive drugs on TST and IGRA results remains somewhat limited as the individual studies published to date suffer from sample sizes, frequently too small to show significant effects. In this issue of the journal, Wong et al report their results of a systematic review and meta-analysis on the effect of immunosuppressive drug treatment on LTBI testing in patients with autoimmune diseases. Studies were included where the two commercially available IGRA tests, the QuantiFERON-TB gold in tube assay (QFT) or the T-SPOT.TB assay, had been performed with or without the TST. Subgroup analyses were performed to address whether IGRA were affected by the underlying disease types or individual drugs. A total of 17 studies with 3197 patients were included in the analyses of which three-quarters received immunosuppressive single or combination drug therapy. Importantly, most studies (14/17) originated from low TB prevalence countries in Western Europe. Of note, the percentage of positive test results was highest in the two studies from Turkey and one study from Hong Kong, where the prevalence of TB is higher than in other parts of Western Europe. Overall, the percentage of positive tests was adversely affected by immunosuppressive drugs in all studies. Interestingly, the OR was similar for the TST and the QFT (OR 0.51 and 0.65, respectively), indicating that the drugs affected both tests to a similar extent. In contrast, this finding was not significant for the T-SPOT.TB assay (OR 0.81), but this assay was used less frequently in the summarised studies. In general, the percentage of indeterminate result was rather low (1.1–17.6%) and did not differ in patients with and without immunosuppressive therapy. Subgroup analyses of patients with rheumatoid arthritis and inflammatory bowel disease, the two main groups of patients with the largest samples sizes, revealed that the adverse effect of immunosuppressive drug therapy on IGRA positivity was significant in both groups and, therefore, independent of the underlying disease. Likewise, all three main drug types, namely steroids, oral immunosuppressive drugs and tumour necrosis factor antagonists, were associated with a significant decrease in the percentage of positive IGRA tests. This result was obtained by pooling large data sets in the meta-analysis as none of the individual studies had shown statistical significance. Taken together, these data suggest that the immunosuppressive drugs used in autoimmune diseases affect both IGRA and the TST to a similar extent. It deserves further study, whether the less pronounced effect of immunosuppressive drugs on T-SPOT.TB results may be due to differences in the assay principle and/or the lower number of studies where this test was performed. Looking closer at the data presented in the article, a surprising finding worth emphasising is the consistently higher percentage of positive test results in the TST compared with the IGRA. In pooled analysis, 26.6% of patients were positive in the TST, whereas only 13.6% and 16.8% had positive test results in the QFT or T-SPOT.TB assay, respectively. Although 57.6% of patients were BCG-vaccinated, vaccination did not seem to account for this fact as there was no relationship between TST positivity and prior BCG rates in the individual studies in the systematic review. Of note, TST positivity predominated also when stratifying patients with and without immunosuppression, indicating that the high percentage of positive TST results appears to be a particular finding in patients with autoimmune diseases. This has recently also been shown in a large multicentre study from the Tuberculosis network European trials group (TBnet). In this study, test performance of TST and IGRA was compared among five different groups of immunocompromised individuals, namely HIV-infected individuals, patients with chronic renal failure, solid organ and stem cell transplant recipients and patients with rheumatoid arthritis. The data showed that the percentage of positive test results was remarkably different from one patient group to the other. Interestingly, as in the present meta-analysis, patients with rheumatoid arthritis had far higher percentages of positive TSTs compared with the IGRA, which applied to both patients receiving higher and lower levels of immunosuppressive drugs. This predominance of TST positivity contrasted with Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany; Department of Paediatrics, Imperial College, London, UK; Vaccines & Immunity Theme MRC Unit, The Gambia Correspondence to Professor Beate Kampmann, Imperial College London, Academic Department of Paediatrics, 2nd Floor Wright-Fleming Building, St. Marys Campus, London W2 1PG, UK; [email protected]