Influence of high-dose rifampin on Mycobacterial load and inflammatory mediators in pericardial TB patients

总结/摘要 在结核病（TB）发病率高的国家，TB是心包积液的最常见原因。 心包结核（PCTB）是一种严重的肺外结核，可引起血流动力学不稳定， 需要心包穿刺术的心脏压塞3.尽管抗结核治疗（ATT），并发症 艾滋病仍然很常见，死亡率很高（8 - 34%，在艾滋病毒合并感染者中最严重）。PCTB死亡的原因是 这两种情况都是由于高心包液（PCF）细菌负荷， 心包，并通过免疫反应的失调，试图清除感染。因此存在 一个重要的需要，以改善目前的PCTB治疗方法，无论是在效率的细菌杀死， 以及鉴定可被特异性调节的有害炎症途径。这种合作 因此将确定： 1：高剂量利福平是否增加PCF中的药物暴露，从而导致 mtb负载。假设PCF中的利福平（RIF）暴露量将随着剂量的增加而增加（35 mg/kg， RIF 35）与标准品（RIF 10 mg/kg，RIF 10）相比，细菌减少将与PCF中的RIF暴露相关 和血浆。一项每日35 mg/kg RIF与标准剂量的 其他3种抗结核药物（吡嗪酰胺、乙胺丁醇和异烟肼）与标准治疗相比， 进行。这将评估0和72小时PCF细菌负荷的安全性和主要疗效终点。 次要终点将是临床指标和精确心血管磁共振的复合终点 (CMR)心包炎症、增厚、积液、纤维化或收缩的证据。药代动力学 并测定PCF中抗结核药物的药效学。 图2：心包结核杆菌特异性T细胞与细菌载量和治疗结果之间的关系， PCTB。PCF中存在多种类型的T细胞，但仍不清楚哪些亚群有助于保护 和/或病理学。常规和供体非限制性（例如MAIT细胞，CD1-T细胞）的表型和功能 来自HIV感染和未感染的配对血液和PCF中的Mtb特异性T细胞亚群 将对PCTB患者进行调查。在PCF中，CD4 + T细胞生物标志物（CD153，HLA-DR， CD38，Ki67）与细菌负荷和结果也将进行。 3：Mtb诱导的宿主细胞死亡途径的标志物与PCTB中的细菌负荷之间的关系。 在模型系统中，坏死（细胞溶解）细胞死亡有利于结核分枝杆菌的传播，而凋亡细胞死亡有利于结核分枝杆菌的传播。 与宿主细菌控制有关。目前尚不清楚不同细胞死亡途径的诱导如何与 结核病患者的疾病。因此，PCF中溶细胞巨噬细胞死亡途径的明确标记物（和 血液），并探索它们与临床终点的相关性。

SUMMARY/ABSTRACT In countries with high tuberculosis (TB) incidence, TB is the most common cause of pericardial effusion. Pericardial tuberculosis (PCTB) is a severe form of extrapulmonary TB causing hemodynamic instability and cardiac tamponade requiring pericardiocentesis3. Despite anti-tuberculosis treatment (ATT), complications remain frequent and mortality high (8-34%, worst in HIV co-infected persons). Death in PCTB is contributed to both by a high pericardial fluid (PCF) bacillary load that may arise from inadequate penetration of ATT into pericardium, and by dysregulation of the immune response, which attempts to clear the infection. Thus there is an important need to improve the current PCTB treatment approach both in terms of efficiency of bacterial killing and identification of deleterious inflammatory pathways that could be specifically modulated. This collaboration will therefore determine: 1: Whether high dose rifampin increases drug exposure in PCF and thus results in a greater decline in Mtb load. The hypothesis is that rifampin (RIF) exposure in PCF will increase with a higher dose (35mg/kg, RIF35) versus standard (RIF 10mg/kg, RIF10) and that decline in bacteria will correlate with RIF exposure in PCF and plasma. A randomized controlled clinical trial of 35mg/kg RIF daily in combination with standard doses of the 3 other antitubercular drugs (pyrazinamide, ethambutol and isoniazid), versus standard of care will be conducted. This will assess safety and the primary efficacy endpoint of PCF bacillary burden at 0 and 72 hrs. Secondary endpoints will be a composite of clinical measures and precise cardiovascular magnetic resonance (CMR) evidence of pericardial inflammation, thickening, effusion, fibrosis or constriction. The pharmacokinetics and pharmacodynamics of antitubercular drugs in PCF will also be determined. 2: Relationships between pericardial Mtb-specific T cells with bacterial load and treatment outcome in PCTB. Multiple types of T cells are found in PCF, but it remains unknown which subsets contribute to protection and/or pathology. The phenotype and function of conventional and donor unrestricted (e.g. MAIT cells, CD1- restricted T cells, γδ T cells) Mtb-specific T cell subsets in paired blood and PCF from HIV infected and uninfected persons with PCTB will be investigated. The relationship in PCF of CD4+ T cell biomarkers (CD153, HLA-DR, CD38, Ki67) with bacillary load and outcome will also be undertaken. 3: Relationships between Mtb-induced markers of host cell death pathways and bacterial load in PCTB. In model systems, necrotic (cytolytic) cell death benefits dissemination of Mtb, while apoptotic cell death associates with host bacterial control. It is unknown how the induction of varying cell death pathways relate to disease in TB patients. Therefore well-defined markers of cytolytic macrophage cell death pathways in PCF (and blood) will be determined and their correlation with clinical endpoints explored.