Phenotype, Progression and Immune Correlates of Post-Tuberculosis Lung Disease

项目摘要 肺结核(PTB)与肺损伤有关，尽管治疗成功，但肺损伤仍可持续。肺 经治疗的肺结核后遗症日益被认为是慢性阻塞性肺疾病的独立危险因素 肺部疾病(COPD)和过度发病率和死亡率的一个重要因素。我们之前的工作 测量一组患有肺结核的年轻且主要从不吸烟的成年人的肺功能，这些患者成功地 完成结核病治疗后，14%的人患有COPD，另外10%的人有气流阻塞，对 接受支气管扩张剂治疗的患者中，有近50%的患者有限制性的肺活量测定模式。这些数据表明， 肺结核后慢性肺部疾病(CLD)的主要表型可能与吸烟相关的不同 慢性阻塞性肺疾病（慢阻肺）。PTB后CLD可能有不同的自然病史、预后和治疗策略，到目前为止， 还没有被调查。我们先前的工作还发现，PTB后CLD与PTB持续时间有关 在开始结核病治疗之前的疾病，以及在晚期结核病治疗期间高水平的缓慢分解的促纤维化细胞因子。 综上所述，这些数据表明，绝大多数与肺结核相关的急性肺损伤可能发生在 在开始结核病治疗之前和之后不久，关键免疫标记物的升高或持续水平可能是 通过它们对肺组织重塑的影响而有害。然而，很少有研究具有前瞻性。 与肺结核患者长期功能结局相关的特征性免疫标记物。这是一个重要的 阻止识别靶向宿主定向的潜在可修改免疫途径的知识鸿沟 治疗方法，以及使用这些治疗方法进行干预的最佳时机，以预防PTB后的CLD。致信地址 这些知识差距，我们将在报告中嵌套一项前瞻性队列研究-印度结核病研究 联合会将1)描述肺结核后CLD的早期自然病程，并为长期的 受影响病例的监测和支气管扩张剂治疗，2)功能和形态特征 连续肺功能检测和多层螺旋CT对肺结核后慢性阻塞性肺疾病表型的研究 确定在治疗早期、晚期和治疗后与PTB后CLD相关的免疫指标。穿过 此次K99/R00大奖，古普特博士将通过获得 指导1)临床相关肺功能和影像的识别、测量和解释 CLD研究的结果；2)慢性肺损伤的潜在可修改免疫标记物，用于未来的治疗 试验；3)肺功能、影像和免疫学综合分析的先进统计方法 数据。这一K99/R00奖项将帮助古普特博士发展成为一名独立的调查员，进行有影响力的 在全球传染病和慢性肺部疾病的交叉点进行临床研究，同时也在建设网站 容量和生成新数据以支持旨在识别诊断的后续R01应用， 治疗后肺结核患者慢性肺病的预后和治疗策略。

PROJECT ABSTRACT Pulmonary tuberculosis (PTB) is associated with lung injury which can persist despite successful therapy. Lung sequelae of treated PTB are increasingly recognized as an independent risk factor for chronic obstructive pulmonary disease (COPD) and, an important contributor of excess morbidity and mortality. Our prior work measuring lung function in a cohort of young and predominantly never-smoking adults with PTB who successfully completed TB therapy found 14% had COPD, an additional 10% had airflow obstruction which responded to bronchodilator therapy, and nearly 50% had a restrictive spirometry pattern. These data suggest that the predominant phenotype of post-PTB chronic lung disease (CLD) may differ from that seen in smoking-associated COPD. Post-PTB CLD may have distinct natural history, prognosis and therapeutic strategies which, till date, have not been investigated. Our prior work also found that post-PTB CLD was associated with the duration of illness prior to initiating TB therapy and high levels of slow-to-resolve pro-fibrotic cytokines during late TB therapy. Together, these data suggest that the vast majority of acute lung injury associated with PTB likely occurs prior to and shortly after initiating TB therapy, and that elevated or persistent levels of key immune markers may be detrimental through their impact on lung tissue remodeling. However, few studies have prospectively characterized immune markers associated with long-term functional outcomes in PTB. This is an important knowledge gap preventing the identification of potentially modifiable immune pathways for targeted host-directed therapies, and the optimal timing of intervention with these therapies, to prevent post-PTB CLD. To address these knowledge gaps, we will nest a prospective cohort study within the RePORT-India TB Research Consortium to 1) characterize the early natural history of post-PTB CLD and provide rationale for long-term monitoring and bronchodilator therapy in affected cases, 2) characterize the functional and morphological phenotype of post-PTB CLD by serial pulmonary function testing and multi-detector computed tomography, 3) identify immune profiles measured during early, late and post-therapy associated with post-PTB CLD. Through this K99/R00 award, Dr. Gupte will complement his prior training in infectious disease epidemiology by obtaining mentorship in the identification, measurement and interpretation of 1) clinically relevant lung function and imaging outcomes for CLD research; 2) potentially modifiable immune markers of chronic lung injury for future therapeutic trials; and 3) advanced statistical methods for the integrated analysis of lung function, imaging and immunological data. This K99/R00 award will help Dr. Gupte develop into an independent investigator conducting impactful clinical research at the intersection of infectious and chronic lung diseases globally, while also building site capacity and generating novel data to support subsequent R01 applications aimed at identifying diagnostic, prognostic and therapeutic strategies for CLD in treated PTB.