Browsing by Author "Duffy, Fergal J."

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    Detection 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 Team
    ENGLISH 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.
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    A serum circulating miRNA signature for short-term risk of progression to active tuberculosis among household contacts
    (Frontiers Media, 2018) Duffy, Fergal J.; Thompson, Ethan; Downing, Katrina; Suliman, Sara; Mayanja-Kizza, Harriet; Boom, W. Henry; Thiel, Bonnie; Weiner III, January; Kaufmann, Stefan H. E.; Dover, Drew; Tabb, David L.; Dockrell, Hazel M.; Ottenhoff, Tom H. M.; Tromp, Gerard; Scriba, Thomas J.; Zak, Daniel E.; Walzl, Gerhard; GC6-74 Consortium
    ENGLISH ABSTRACT: Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk.