1.
Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB.
Leong, S, Zhao, Y, Ribeiro-Rodrigues, R, Jones-López, EC, Acuña-Villaorduña, C, Rodrigues, PM, Palaci, M, Alland, D, Dietze, R, Ellner, JJ, et al
Tuberculosis (Edinburgh, Scotland). 2020;:101898
Abstract
The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy.
2.
The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals.
Kassa, D, de Jager, W, Gebremichael, G, Alemayehu, Y, Ran, L, Fransen, J, Wolday, D, Messele, T, Tegbaru, B, Ottenhoff, TH, et al
Tuberculosis (Edinburgh, Scotland). 2016;:131-40
Abstract
Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART.
3.
Use of Xpert for the diagnosis of pulmonary tuberculosis in severely malnourished hospitalized Malawian children.
LaCourse, SM, Chester, FM, Preidis, G, McCrary, LM, Arscott-Mills, T, Maliwichi, M, James, G, McCollum, ED, Hosseinipour, MC
The Pediatric infectious disease journal. 2014;(11):1200-2
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Abstract
BACKGROUND Pulmonary tuberculosis contributes to increased morbidity and mortality in severely malnourished children in endemic settings. Despite high clinical suspicion, few tuberculosis prevalence estimates exist in malnourished African children. Diagnostics such as Xpert MTB/RIF may help to determine pulmonary tuberculosis prevalence, however its performance in severely malnourished children is largely unknown. METHODS We conducted a prospective observational study evaluating Xpert compared to smear microscopy and liquid culture on induced sputums among severely malnourished children (aged 6 to 60 months) at Kamuzu Central Hospital in Lilongwe, Malawi. From February 1 to May 30, 2012, children who met World Health Organization 2006 guidelines for severe acute malnutrition were evaluated using clinical symptoms, tuberculin skin tests, chest radiographs, and induced sputums. National Institute of Health (NIH) consensus case definitions were used to estimate tuberculosis prevalence. RESULTS Three hundred severely malnourished children (median age 18.5 months, IQR 12.1-25.6) had one induced sputum performed; 295 (98.3%) received two. Fifty-two (17.6%) were HIV-infected. Over 25% had tuberculosis exposure with 48/297 (16.2%) reporting contact and 40/287 (13.9%) with positive TST. Two (0.7%) patients had confirmed tuberculosis by Xpert and culture, but only one had positive smear microscopy. Twenty (6.7%) patients fulfilled probable and 97 (66%) met possible tuberculosis NIH case definitions. Overall mortality was 9.7%. CONCLUSIONS Microbiologic confirmation likely underestimates the prevalence of pulmonary tuberculosis in severely malnourished children. In our study, Xpert on induced sputums did not increase case finding. Future studies are needed using Xpert among targeted groups of severely malnourished children and on non-sputum specimens.