Browsing by Author "Filander, Elizabeth"
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- ItemDetection of tuberculosis recurrence, diagnosis and treatment response by a blood transcriptomic risk signature in HIV-infected persons on antiretroviral therapy(Frontiers Media, 2019) Darboe, Fatoumatta; Mbandi, Stanley Kimbung; Naidoo, Kogieleum; Yende-Zuma, Nonhlanhla; Lewis, Lara; Thompson, Ethan G.; Duffy, Fergal J.; Fishe, Michelle; Filander, Elizabeth; Van Rooyen, Michele; Bilek, Nicole; Mabwe, Simbarashe; McKinnon, Lyle R.; Chegou, Novel; Loxton, Andre; Walzl, Gerhard; Tromp, Gerard; Padayatchi, Nesri; Govender, Dhineshree; Hatherill, Mark; Karim, Salim Abdool; Zak, Daniel E.; Penn-Nicholson, Adam; Scriba, Thomas J.; SATVI Clinical Immunology TeamENGLISH ABSTRACT: HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58–0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94–1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81–0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.
- ItemImmune profiling enables stratification of patients with active tuberculosis disease or mycobacterium tuberculosis infection(Oxford University Press, 2020-10) Duffy, Darragh; Nemes, Elisa; Llibre, Alba; Rouilly, Vincent; Musvosvi, Munyaradzi; Smith, Nikaïa; Filander, Elizabeth; Africa, Hadn; Mabwe, Simbarashe; Jaxa, Lungisa; Charbit, Bruno; Mulenga, Humphrey; Tameris, Michele; Walzl, Gerhard; Malherbe, Stephanus; Thomas, Stephanie; Hatherill, Mark; Bilek, Nicole; Scriba, Thomas J.; Albert, Matthew L.Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection.