Blood transcriptional signatures of asymptomatic FDG-PET/CT-defined Subclinical TB lesions and their prediction of future TB progression

Diagnostic tests for tuberculosis (TB) infection poorly predict future incident disease risk. We investigated a cohort of asymptomatic HIV-uninfected household contacts of TB in South Africa in which baseline lung lesions indicative of Subclinical TB identified by [18F]-fluoro-2-deoxy-D-glucose (FDG)-positron emission/computed tomography (PET/CT) had high predictive value for future TB over 5 years. RNA-sequencing analysis of whole blood samples at baseline PET/CT, 5-15m PET/CT2, and the TB diagnosis of incident TB revealed persistent enrichment of neutrophil and monocyte transcriptional modules in those with Subclinical TB and worsening and discrete lung abnormalities, while expression of a core set of type I IFN genes related to FDG-avid lymph nodes. Leveraging multiple machine learning algorithms, we derived gene signatures of various PET/CT lesion Subclinical phenotypesTB, future lesion worsening and TB diagnosis. prevalent and incident TB. Validating signatures in two independent cohorts against TB progression within 6,12,18 and fup to 24-29-months, confirmed gave AUC of 0.75-0.95 and 0.77-0.87 with performance above optimal sensitivity and wminimum specificity for the WHO target product profile for TB progression. Overall design: Asymptomatic, HIV uninfected, adult, household contacts of drug-resistant (at least Rifampin resistant) TB were recruited. Their sputa (induced/spontaneous) underwent Xpert MTB/RIF and culture and blood was drawn for QuantiFERON in-tube-Gold (QFT-Gold), QFT-Plus, and Tempus tubes for RNA. A baseline PET/CT was performed in 250 individuals who were Xpert negative at baseline, and a second PET/CT was performed in 112 participants after 5 to 15 months and XX participants had a third PET/CT at endpoint TB diagnosis. Participants were followed for up to five years, with repeat symptom and induced sputum screening between years 2-3 at any time when they presented to the clinical with TB signs or symptoms and at completion of follow-up via interrogation of their health service encounters via the Western Province Provincial Health Data Centre and clinic medical records. PET/CT features at baseline consistent with TB were assessed by readers blinded to clinical details and classified by prespecified radiographic and microbiologic criteria. This repository consists of the first 131 RNA-seq samples (87 visit 1, 37 visit 2, 5 TB endpoint, 3 visit post TB treatment (Tx)), categorized primarily by PET/CT features identified at the visit, changes between visit 1 and visit 2 or visit 2and visit 3, and TB diagnosis at baseline (prevalent TB) or during folllow-up (incident TB).