Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting?

Abstract

Although interferon-γ release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®.TB) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68-83%) and 42% (36-49%) for QFT-GIT and 84% (77-90%) and 47% (40-53%) for T-SPOT®.TB, respectively. Although interferon-γ responses were significantly higher in the TB versus non-TB groups (p<0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®.TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.

FIGURE 1

Receiver operating characteristic (ROC) analysis for valid a) QuantiFERON_®-TB Gold In-tube (Cellestis, Carnegie, VIC, Australia) (area under ROC curve (AUC) 0.6569; n=346) and b) T-SPOT_®.TB (Oxford Immunotec, Abingdon, UK) (AUC 0.7075; n=371) results.

FIGURE 2

Dot plots of interferon (IFN)-γ response for valid a) QuantiFERON_®-TB Gold In-tube (QFT-GIT; Cellestis, Carnegie, VIC, Australia) and b) T-SPOT_®.TB (Oxford Immunotec, Abingdon, UK) results among tuberculosis (TB) and non-TB patients. Horizontal bars indicate the medians (0.59 versus 2.14 IU·mL⁻¹, p<0.001 for QFT-GIT and 8 versus 28 spot-forming units (SFU), p<0.001 for T-SPOT_®.TB).

FIGURE 3

Dot plots of interferon (IFN)-γ response for valid a, b) QuantiFERON_®-TB Gold In-tube (Cellestis, Carnegie, VIC, Australia) and c, d) T-SPOT_®.TB (Oxford Immunotec, Abingdon, UK). results, stratified by HIV status. The non-tuberculosis group included all culture-negative patients (those empirically treated for tuberculosis (TB) but without culture evidence and culture-negative patients with alternative diagnoses and not treated for TB).