Quantitative lung T cell responses aid the rapid diagnosis of pulmonary tuberculosis

Abstract

Background: The diagnosis of smear-negative pulmonary tuberculosis (TB) is problematic. There are limited data on the profile of alveolar TB antigen-specific T cells, and their utility for the rapid immunodiagnosis of pulmonary TB is unclear. Methods: Antigen-specific interferon c (IFNc) responses to the RD-1 antigens ESAT-6 and CFP-10 (T-SPOT.TB and QuantiFERON-TB-Gold-In-Tube), heparin-binding haemagglutinin and purified protein derivative were evaluated, using alveolar lavage cells, in 91 consecutively recruited South African patients suspected of having TB. Results: Of 85 evaluable patients (29% HIV+), 24, 11, 48 and 2 had definite TB, probable TB, non-TB and an uncertain diagnosis, respectively. Between 34% (T-SPOT.TB) and 41% (QuantiFERON-TB-Gold-In-Tube) of all test results were inconclusive. Failure of the positive control was significantly higher with the QuantiFERON-TBGold-In-Tube than with T-SPOT.TB (85% vs 46% of inconclusive results; p = 0.001). Using staphylococcal enterotoxin B, compared with phytohaemagglutinin, substantially reduced failure of the positive control (25% to 3%; p = 0.02). In evaluable samples, when the definite and non-TB groups were used for outcome analysis, the percentage sensitivity, specificity, positive predictive value and negative predictive value for T-SPOT.TB (>20 spots/million alveolar mononuclear cells) and QuantiFERON-TB-Gold-In-Tube (0.35 IU/ml) were 89, 94, 89 and 94% (n = 55) and 55, 86, 77 and 69% (n = 46), respectively. Rapid diagnosis of TB was achieved more frequently with T-SPOT.TB than with smear microscopy (14/24 (58%) vs. 7/24 (29%) of definite TB cases; p = 0.02). Heparin-binding haemagluttinin and purified protein derivative alveolar lymphocyte IFNc responses had poor performance outcomes. Conclusion: Provided evaluable results are obtained, the RD-1, but not the heparin-binding haemagglutinin or purified protein derivative, alveolar lymphocyte IFNc ELISPOT response is a useful rapid immunodiagnostic test for TB. However, test utility in high-burden settings may be limited by the high proportion of inconclusive results.

Interferon- release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis

“…Among the studies in which the NPV was evaluated in patients with confirmed tuberculosis (387 tuberculosis cases with a valid T-SPOT1.TB result and 304 with valid QFT-G-IT result), the NPV varied greatly, irrespective of the IGRA used. Among the 13 articles, the NPV ranged between 74.4% [36] and 100% [22,34], with a pooled value of 94% (95% CI 92.1-95.6%) for the T-SPOT1.TB and 88% (95% CI 84.6-91.5%) for the QFT-G-IT (figs 2 and 3).…”

“…In nine of these, TST positivity was significantly associated with BCG vaccination as an independent predictor in multivariate analysis [47,50,55,62,67,71,72,74,77] with odd ratios ranging between 3.8 (95% CI 1.0-13.9) [50] [35] GOLETTI [36] JAFARI [37] JAFARI [38] KAMPMANN [39] KANG [40] LEE [41] MARKOVA [42] WANG [43] DETJEN [26] DHEDA [34] GOLETTI [36] KAMPMANN [39] KANG [40] MARKOVA [42] odds for test positivity with M. tuberculosis exposure gradients, or using chest radiography lesions as a surrogate of prior exposure, the IGRAs associated better with exposure than the TST, irrespective of the setting's disease burden. Furthermore, there was generally a poor agreement between IGRAs and TST results (for k statistics, see table 3).…”

“…NPV in patients with active tuberculosis 18 articles satisfied our inclusion criteria for evaluating the NPV; 13 assessed the NPV among confirmed tuberculosis cases [22,26,[34][35][36][37][38][39][40][41][42][43][44] and six assessed the prospective outcome in IGRA-negative individuals after an average of 2 yrs [19-22, 45, 46]. Among the studies in which the NPV was evaluated in patients with confirmed tuberculosis (387 tuberculosis cases with a valid T-SPOT1.TB result and 304 with valid QFT-G-IT result), the NPV varied greatly, irrespective of the IGRA used.…”

Cerebrospinal T-Cell Responses Aid in the Diagnosis of Tuberculous Meningitis in a Human Immunodeficiency Virus– and Tuberculosis-Endemic Population

“…An alternative approach is to quantify the frequency of antigen-specific effector cells at the site of disease rather than in whole blood. This approach has recently been shown to be highly accurate when using bronchial alveolar lavage lymphocytes to diagnose pulmonary TB (22)(23)(24) but not when using site-specific lymphocytes to diagnose pleural TB (25). Case reports and small series suggest that this approach may also be useful for the diagnosis of TBM (26)(27)(28)(29).…”

“…A count of 20 or higher SFCs per million cells in the ESAT-6 or CFP-10 wells was deemed a positive result (see online supplement for further details). Given the use of different cut points in specific body compartments (22,25) when compared with peripheral blood and that none has been defined for CSF, which has unique physiologic and anatomic characteristics, we derived new cut-offs using receiver operating characteristic (ROC) curves analysis. The manufacturer's cut-off and cut-offs generated from the study were used for reporting results.…”