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

结核病后肺病的表型、进展和免疫相关性

基本信息

批准号：
10733811
负责人：
Akshay Nitin Gupte
金额：
$ 24.9万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733811
关键词：
Acute Lung Injury Address Adult Affect Award Bronchodilator Agents Cessation of life Chronic Chronic Lung Injury Chronic Obstructive Pulmonary Disease Chronic lung disease Clinical Research Complement Complex Cross-Sectional Studies Data Data Reporting Diagnostic Disease Disease Progression Evaluation Forced expiratory volume function Future High Prevalence Image Immune Immune Targeting Immunologic Markers Immunologics Impairment India Infectious Disease Epidemiology Infectious Diseases Research Inflammation Inflammatory Intervention Knowledge Link Lung Lung diseases Measurement Measures Mentorship Monitor Morbidity - disease rate Morphology Natural History Outcome Oxidative Stress Participant Pathway interactions Patients Pattern Phase Phenotype Plasma Preventive Process Prognosis Prospective, cohort study Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Pulmonary Tuberculosis Pulmonary function tests Relapse Reporting Research Research Personnel Risk Factors Role Secondary to Severities Site Smoking Smoking Status Spirometry Sputum Statistical Methods Structure of parenchyma of lung Testing Therapeutic Therapeutic Trials Tissues Training Tuberculosis Vital capacity Work X-Ray Computed Tomography airway obstruction clinically relevant cohort detector follow-up functional outcomes imaging study immune activation immunoregulation inflammatory marker lung imaging lung injury mortality never smoking novel prevent profibrotic cytokine prognostic prospective pulmonary function pulmonary function decline recruit smoking exposure targeted treatment tuberculosis treatment young adult

项目摘要

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.

项目摘要肺结核 (PTB) 与肺损伤有关，尽管治疗成功，肺损伤仍可能持续存在。肺治疗后的 PTB 后遗症越来越被认为是慢性阻塞性肺疾病的独立危险因素肺部疾病（COPD）是导致发病率和死亡率过高的重要因素。我们之前的工作对一群患有 PTB 的年轻人和主要从不吸烟的成年人进行肺功能测量，他们成功地完成的结核病治疗发现 14% 患有慢性阻塞性肺病，另外 10% 患有气流阻塞，这对治疗有反应支气管扩张剂治疗，近 50% 的人有限制性肺量测定模式。这些数据表明 PTB 后慢性肺病 (CLD) 的主要表型可能与吸烟相关的表型不同慢性阻塞性肺病。 PTB 后 CLD 可能具有独特的自然史、预后和治疗策略，迄今为止，尚未被调查。我们之前的研究还发现，PTB 后 CLD 与治疗持续时间有关。开始结核病治疗之前患有疾病，并且在结核病治疗后期出现高水平的缓慢消退的促纤维化细胞因子。总之，这些数据表明绝大多数与 PTB 相关的急性肺损伤可能发生在开始结核病治疗后不久，关键免疫标志物水平升高或持续存在可能是它们对肺组织重塑的影响是有害的。然而，很少有研究前瞻性地与 PTB 长期功能结果相关的免疫标志物特征。这是一个重要的知识差距阻碍了识别针对目标宿主的潜在可修改免疫途径疗法，以及这些疗法干预的最佳时机，以预防 PTB 后 CLD。致地址针对这些知识差距，我们将在印度结核病研究报告中进行一项前瞻性队列研究联盟旨在 1) 描述 PTB 后 CLD 的早期自然史，并为长期研究提供依据对受影响病例进行监测和支气管扩张剂治疗，2) 描述功能和形态学特征通过连续肺功能测试和多探测器计算机断层扫描确定 PTB 后 CLD 的表型，3) 识别与 PTB 后 CLD 相关的早期、晚期和治疗后测量的免疫特征。通过获得 K99/R00 奖项后，Gupte 博士将通过获得指导识别、测量和解释 1) 临床相关肺功能和影像学 CLD 研究成果； 2）慢性肺损伤的潜在可改变的免疫标志物，用于未来的治疗试验； 3）先进的肺功能、影像学和免疫学综合分析统计方法数据。该 K99/R00 奖项将帮助 Gupte 博士发展成为一名独立调查员，开展有影响力的研究全球传染病和慢性肺部疾病交叉点的临床研究，同时还建立基地容量并生成新数据以支持后续 R01 应用，旨在识别诊断、已治疗 PTB 中 CLD 的预后和治疗策略。