Inflammation and Fibrosis in Pulmonary TB: the INFIN-TB Study

肺结核中的炎症和纤维化：INFIN-TB 研究

• 批准号: 10661832
• 负责人: Sara Auld
• 金额: $ 112.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661832
• 关键词: Address; Adult; Automobile Driving; Basement membrane; Binding; Biological; Biological Markers; Cause of Death; Cessation of life; Chronic; Chronic lung disease; Cicatrix; Collagen; Communicable Diseases; Complication; Coughing; Data; Dedications; Deposition; Disease; Dyspnea; Enrollment; Enzymes; Epithelium; Exhalation; Extracellular Matrix; Fibrosis; Functional disorder; Future; Gene Expression; Goals; HIV; HIV Infections; HIV/TB; Heterogeneity; High Resolution Computed Tomography; Human; Immune response; Impairment; Incidence; Inflammation; Intervention; Knowledge; Left; Leukocyte Elastase; Longitudinal Studies; Lung; Lung diseases; Lung immune response; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mediator; Modification; Mycobacterium tuberculosis; Nature; Neutrophil Collagenase; Newly Diagnosed; Outcome; Pathogenesis; Pathway interactions; Patient Care; Patients; Persons; Pharmaceutical Preparations; Physical condensation; Populations at Risk; Positron-Emission Tomography; Predisposition; Prospective cohort; Pulmonary Tuberculosis; Pulmonary function tests; Quality-Adjusted Life Years; Research Design; Respiratory Signs and Symptoms; Risk; Risk Factors; Role; Sampling; Severities; Site; South African; Sputum; Survivors; Syndrome; Testing; Therapeutic; Therapeutic Studies; Thoracic Radiography; Time; Transforming Growth Factor beta; Transforming Growth Factors; Tuberculosis; Tuberculosis diagnosis; X-Ray Computed Tomography; acute infection; advanced disease; cell type; clinically significant; co-infection; healing; high risk; immune activation; immunopathology; improved; lung injury; mortality; neutrophil; novel; novel marker; pathogen; prevent; pulmonary function; repaired; response; restoration; secondary analysis; therapy design; translational study; treatment strategy; tuberculosis treatment; years of life lost

Tuberculosis (TB) is a leading global killer among infectious diseases and the leading cause of death among people with HIV. Among the estimated 9 million TB survivors each year, up to half are left with impaired lung function and chronic respiratory symptoms. More than four times as many quality-adjusted life years (QALYs) are lost to post-TB lung disease (PTLD) as are lost to TB mortality. Although there has been growing recognition of PTLD in recent years, there are no known interventions to prevent or treat this devastating outcome. This knowledge gap is due in large part to a fundamental lack of data on mechanisms driving PTLD. Lung damage from TB is often viewed as an inevitable consequence in those who present “too late;” however, recent studies by our group and others suggest an alternative paradigm where much of PTLD can be prevented by giving host-directed therapies during TB treatment. Defining the biological pathways that drive PTLD and the populations at risk will provide a rare opportunity to address one of the most common global causes of chronic lung disease in people with and without HIV. In the Inflammation and Fibrosis in Pulmonary TB (INFIN-TB) study, we will test the hypothesis that pulmonary neutrophilic inflammation (Aim 1) and profibrotic activity (Aim 2) occurring early during TB treatment increase the risk of PTLD. We will enroll a prospective cohort of 250 people, 125 with HIV and 125 without HIV, with newly diagnosed, drug-susceptible pulmonary TB and will follow them for 12 months, from the time of TB diagnosis and treatment initiation until 6 months after completion of TB treatment. To ascertain relevant pathophysiology from the site of disease, we will collect airway samples at multiple time points in addition to comprehensive measurements of lung function and high-resolution CT scans. For Aim 1, we will determine the association between sputum levels of matrix metalloproteinase (MMP)-8, a matrix-degrading enzyme released by neutrophils, and the risk of PTLD, as measured by formal lung function testing. For Aim 2, we will determine the association between sputum levels of transforming growth factor (TGF)-β, a master regulator of fibrosis, and PTLD. Secondary analyses will determine whether HIV modifies the relationship between neutrophilic or profibrotic activity and PTLD, and will include additional biomarkers of neutrophil and profibrotic activity in both sputum and exhaled breath condensate, in addition to direct assessment of collagen deposition in the lungs using a novel collagen-binding PET probe. By focusing on the complementary pathways of neutrophil-mediated lung damage and profibrotic repair and remodeling, and then connecting activity in those biological pathways to clinically significant impairments in lung function among TB survivors, this study will be the most comprehensive study of PTLD to date. The knowledge gained from this study will directly inform future mechanistic and therapeutic studies with the goal of reducing rates and severity of PTLD and improving long-term outcomes for millions of TB survivors each year.

结核病（TB）是传染病中的主要全球杀手，也是人类死亡的主要原因。 艾滋病毒感染者。在每年估计的900万结核病幸存者中，多达一半的人肺部受损 功能和慢性呼吸道症状。质量调整生命年（Qs）的四倍多 与结核病死亡率一样，结核病后肺病（PTLD）也会导致死亡。尽管人们越来越认识到 近年来，PTLD的发病率不断上升，但目前还没有已知的干预措施来预防或治疗这种毁灭性的后果。这 知识差距在很大程度上是由于从根本上缺乏关于PTLD驱动机制的数据。 肺结核造成的肺损伤通常被认为是那些“太迟”出现的人不可避免的后果;然而， 我们小组和其他人最近的研究提出了另一种模式，即PTLD的大部分可以预防 通过在结核病治疗期间给予宿主导向疗法。定义驱动PTLD的生物学途径， 风险人群将提供一个难得的机会，以解决全球最常见的慢性病原因之一， 感染和未感染艾滋病毒的人的肺部疾病。 在肺结核的炎症和纤维化（INFIN-TB）研究中，我们将检验肺结核 TB治疗早期发生的嗜酸性炎症（Aim 1）和促纤维化活性（Aim 2）增加 PTLD的风险。我们将招募一个250人的前瞻性队列，其中125人感染艾滋病毒，125人未感染艾滋病毒， 诊断为药物敏感性肺结核，并将从结核病诊断开始随访12个月 并且治疗开始直到TB治疗完成后6个月。确定相关病理生理学 从发病部位，我们将在多个时间点收集气道样本， 肺功能测量和高分辨率CT扫描。对于目标1，我们将确定关联 痰液中基质金属蛋白酶（MMP）-8水平之间存在显著性差异，MMP-8是一种基质降解酶， 中性粒细胞和PTLD的风险，如通过正式的肺功能测试测量的。对于目标2，我们将确定 痰液中转化生长因子（TGF）-β（纤维化的主要调节因子）水平与 PTLD。二次分析将确定HIV是否改变了嗜酸性粒细胞和嗜酸性粒细胞之间的关系， 促纤维化活性和PTLD，并将包括中性粒细胞和促纤维化活性的额外生物标志物， 除了直接评估肺中的胶原蛋白沉积外， 使用一种新的胶原蛋白结合PET探针。通过聚焦于嗜中性粒细胞介导的 肺损伤和促纤维化修复和重塑，然后将这些生物途径中的活性连接到 肺结核幸存者肺功能的临床显著损害，这项研究将是最全面的 PTLD研究至今。从这项研究中获得的知识将直接为未来的机械和 旨在降低PTLD的发生率和严重程度并改善长期结局的治疗研究 每年有数百万结核病幸存者。