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Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk.

ABSTRACT: In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the "0" time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α-dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.

SUBMITTER: Devalraju KP

PROVIDER: S-EPMC8410087 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk.

Devalraju Kamakshi Prudhula KP Tripathi Deepak D Neela Venkata Sanjeev Kumar VSK Paidipally Padmaja P Radhakrishnan Rajesh Kumar RK Singh Karan P KP Ansari Mohammad Soheb MS Jaeger Martin M Netea-Maier Romana T RT Netea Mihai G MG Park Sunmi S Cheng Sheue-Yann SY Valluri Vijaya Lakshmi VL Vankayalapati Ramakrishna R

JCI insight 20210708 13

In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the "0" time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progre ...[more]

PMID: 34236051

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Project description:BackgroundThe progression from Mycobacterium tuberculosis infection to active tuberculosis disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index patients with pulmonary tuberculosis, who either progressed to tuberculosis or remained as nonprogressors.MethodsA cohort of household contacts of adults with pulmonary tuberculosis was enrolled, consisting of 15 contacts who progressed to tuberculosis disease and 15 nonprogressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive tuberculosis progression markers.ResultsOur findings revealed that individuals in the progressor group exhibited significantly decreased levels of interferon (IFN) γ, tumor necrosis factor α, interleukin 2, IL-1α, IL-1β, and 17A, and interleukin 1 receptor antagonist (IL-1Ra) at baseline, month 4, and month 12. In contrast, the progressor group displayed significantly elevated levels of IFN-α, IFN-β, interleukin 6 and 12, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10) and 33 (IL-33), CCL2, CCL11, CXCL8, CXCL10, CX3CL1, vascular endothelial growth factor, granzyme B, and programmed death ligand -1 compared to the nonprogressor group at baseline, months 4 and 12. Receiver operating characteristic analysis (ROC) identified IFN-γ, GM-CSF, IL-1Ra, CCL2, and CXCL10 as the most promising predictive markers, with an area under the receiver operating characteristic curve of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10, and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active tuberculosis disease.ConclusionsOur study suggests that a specific set of plasma biomarkers, GM-CSF, CXCL10, and IL-1Ra, can effectively identify household contacts at significant risk of developing tuberculosis disease. These findings have important implications for early intervention and preventive strategies in tuberculosis-endemic regions.

Project description:BackgroundDespite free TB services available in public health facilities, TB patients often face severe financial burden due to TB. WHO set a new global target that no TB-affected families experience catastrophic costs due to TB. To monitor the progress and strategize the optimal approach to achieve the target, there is a great need to assess baseline cost data, explore potential proxy indicators for catastrophic costs, and understand what intervention mitigates financial burden. In Cambodia, nationwide active case finding (ACF) targeting household and neighbourhood contacts was implemented alongside routine passive case finding (PCF). We analyzed household cost data from ACF and PCF to determine the financial benefit of ACF, update the baseline cost data, and explore whether any dissaving patterns can be a proxy for catastrophic costs in Cambodia.MethodsIn this cross-sectional comparative study, structured interviews were carried out with 108 ACF patients and 100 PCF patients. Direct and indirect costs, costs before and during treatment, costs as percentage of annual household income and dissaving patterns were compared between the two groups.ResultsThe median total costs were lower by 17% in ACF than in PCF ($240.7 [IQR 65.5-594.6] vs $290.5 [IQR 113.6-813.4], p = 0.104). The median costs before treatment were significantly lower in ACF than in PCF ($5.1 [IQR 1.5-25.8] vs $22.4 [IQR 4.4-70.8], p<0.001). Indirect costs constituted the largest portion of total costs (72.3% in ACF and 61.5% in PCF). Total costs were equivalent to 11.3% and 18.6% of annual household income in ACF and PCF, respectively. ACF patients were less likely to dissave to afford TB-related expenses. Costs as percentage of annual household income were significantly associated with an occurrence of selling property (p = 0.02 for ACF, p = 0.005 for PCF).ConclusionsTB-affected households face severe financial hardship in Cambodia. ACF has the great potential to mitigate the costs incurred particularly before treatment. Social protection schemes that can replace lost income are critically needed to compensate for the most devastating costs in TB. An occurrence of selling household property can be a useful proxy for catastrophic cost in Cambodia.

Project description:BackgroundGlobally, there has been growing evidence that suggests the effectiveness of active case finding (ACF) for tuberculosis (TB) in high-risk populations. However, the evidence is still insufficient as to whether ACF increases case notification beyond what is reported in the routine passive case finding (PCF). In Cambodia, National TB Control Programme has conducted nationwide ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts alongside routine PCF. This study aims to investigate the impact of ACF on case notifications during and after the intervention period.MethodsUsing a quasi-experimental cluster randomized design with intervention and control arms, we compared TB case notification during the one-year intervention period with historical baseline cases and trend-adjusted expected cases, and estimated additional cases notified during the intervention period (separately for Year 1 and Year 2 implementation). The proportion of change in case notification was compared between intervention and control districts for Year 1. The quarterly case notification data from all intervention districts were consolidated, aligning different implementation quarters, and separately analysed to explore the additionality. The effect of the intervention on the subsequent case notification during the post-intervention period was also assessed.ResultsIn Year 1, as compared to expected cases, 1467 cases of all forms (18.5%) and 330 bacteriologically-confirmed cases (9.6%) were additionally notified in intervention districts, whereas case notification in control districts decreased by 2.4% and 2.3%, respectively. In Year 2, 2737 cases of all forms (44.3%) and 793 bacteriologically-confirmed cases (38%) were additionally notified as compared to expected cases. The proportions of increase in case notifications from baseline cases and expected cases to intervention period cases were consistently higher in intervention group than in control group. The consolidated quarterly data showed sharp rises in all forms and bacteriologically-confirmed cases notified during the intervention quarter, with 64.6% and 68.4% increases (compared to baseline cases), and 46% and 52.9% increases (compared to expected cases), respectively. A cumulative reduction of case notification for five quarters after ACF reached more than -200% of additional cases.ConclusionsThe Cambodia's ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts resulted in the substantial increase in case notification during the intervention period and reduced subsequent case notification during the post-intervention period. The applicability of retrospective contact investigation in other high-burden settings should be explored.

Dataset Information

Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk.

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Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk.

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