Isolated Abnormality in the Diffusion Capacity for Carbon Monoxide in People Living with HIV – Epidemiology, Etiology and Pathogenesis

HIV 感染者一氧化碳扩散能力的孤立性异常 — 流行病学、病因学和发病机制

• 批准号: 10548647
• 负责人: Katerina L. Byanova
• 金额: $ 8.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548647
• 关键词: Acute; Affect; Africa South of the Sahara; Air; Biological Markers; Blood Vessels; Bronchodilator Agents; California; Carbon Monoxide; Chest; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Clinical Investigator; Clinical Research; Cohort Studies; Critical Care; Cytomegalovirus; Cytomegalovirus Infections; DNA; Data; Diagnosis; Diffuse; Diffusion; Disease; Distal; Endothelium; Epidemiology; Etiology; Foundations; Functional disorder; General Population; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; Image; Immunoglobulin G; Immunoglobulin M; Immunologic Markers; Individual; Infection; Inflammation; Inflammatory; Interstitial Lung Diseases; Intervention; K-Series Research Career Programs; Knowledge; Link; Literature; Longitudinal cohort; Lung; Lung diseases; Measurement; Measures; Mediating; Methods; Obstruction; Participant; Pathogenesis; Pattern; Persons; Phenotype; Pilot Projects; Plasma; Population; Prevalence; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Hypertension; Pulmonary function tests; Pulmonary vessels; Quality of life; Questionnaires; Research; Research Infrastructure; Respiratory Signs and Symptoms; Risk Factors; San Francisco; Serum; Spirometry; Symptoms; Techniques; Testing; Therapeutic Intervention; Thrombosis; Training; Uganda; Universities; Vascular Diseases; Virus; Work; base; carotid intima-media thickness; clinically relevant; co-infection; cohort; comorbidity; design; immune activation; immunosuppressed; improved; interstitial; modifiable risk; novel strategies; patient oriented; prevent; pulmonary function; pulmonary vascular remodeling; respiratory morbidity; skills; targeted treatment

Project Abstract/Summary People with HIV (PWH) have a high burden of respiratory symptoms due to chronic lung disease, of which COPD, diagnosed by spirometric obstruction on pulmonary function testing (PFT), is best studied. The most common finding on PFTs, however, is an abnormal diffusing capacity for carbon monoxide (DLco) with normal spirometry, or iso↓DLco. The clinical relevance of the iso↓DLco PFT phenotype is not known. Iso↓DLco is more common in PWH than in the general population, and HIV is an independent risk factor for reduced DLco. Preliminary work from our lab has shown that PWH with iso↓DLco have an increased respiratory symptom burden compared to PWH with normal PFTs. Iso↓DLco is also associated with a unique set of plasma inflammatory/immune biomarkers compared to other PFT phenotypes like spirometric obstruction, suggesting that the iso↓DLco PFT and biomarker pattern has a unique clinical correlate. The pathophysiology underlying this finding is not known but may be related to early structural lung disease (emphysema or interstitial lung disease) or pulmonary hypertension. Alternatively, iso↓DLco may be a sequela of chronic inflammation in the setting of long-standing HIV infection and possibly co-infection with other viruses like cytomegalovirus (CMV), which affect HIV persistence and immune activation. The central hypothesis for this study is that iso↓DLco is a unique HIV phenotype, possibly mediated by CMV-induced vasculopathy. The study will be nested within I AM OLD-DA, an established longitudinal cohort of PWH in San Francisco, USA and Kampala, Uganda, and will leverage the existing research infrastructure. In San Francisco we will use advanced imaging analyses of chest CTs to understand the etiology and potential causes of iso↓DLco. In Aim 1, we will evaluate CTs for emphysema, interstitial lung disease, pulmonary hypertension and air trapping; based on our pilot study, we expect that in about half of the PWH with iso↓DLco, imaging analysis will not identify a reason for the PFT finding. In Aim 3, we will test for association between iso↓DLco, CMV and distal pulmonary vascular remodeling (‘vascular pruning’) using quantitative CT methods with a working hypothesis that CMV-mediated vascular pruning is associated with iso↓DLco. In Kampala, Uganda, we will study a demographically and clinically distinct cohort or PWH and HIV-negative controls to determine the prevalence of iso↓DLco and its associated respiratory symptom burden (Aim 2). Altogether, the results from this study will help generate a deeper understanding of this PFT phenotype and determine if CMV is a modifiable risk factor for iso↓DLco and a target for therapeutic intervention. Completion of this project will also provide a platform for training Dr. Katerina Byanova, a pulmonary and critical care fellow at the University of California San Francisco, in the conduct of high-quality, patient-oriented clinical research. This grant will provide Dr. Byanova with the support necessary to acquire the knowledge and skills to become an independent clinical investigator and a leader in HIV-related lung disease. .

项目摘要/总结 HIV 感染者 (PWH) 由于慢性肺部疾病而承受着沉重的呼吸道症状负担，其中 慢性阻塞性肺病 (COPD) 通过肺功能测试 (PFT) 中的肺量计阻塞来诊断，研究最多。 然而，PFT 的常见发现是一氧化碳 (DLco) 扩散能力异常，而正常情况下 肺活量测定法，或 iso↓DLco iso↓DLco PFT 表型的临床相关性尚不清楚。 在 PWH 中比在一般人群中更常见，HIV 是 DLco 减少的独立危险因素。 我们实验室的初步工作表明，使用 iso↓DLco 的 PWH 呼吸道症状增加 与具有正常 PFT 的 PWH 相比，负担也与一组独特的血浆有关。 与肺活量阻塞等其他 PFT 表型相比，炎症/免疫生物标志物 iso↓DLco PFT 和生物标志物模式具有独特的临床相关性。 这一发现尚不清楚，但可能与早期结构性肺疾病（肺气肿或间质性肺疾病）有关 或者，iso↓DLco 可能是慢性炎症的后遗症。 长期感染 HIV 并可能与巨细胞病毒 (CMV) 等其他病毒合并感染， 影响 HIV 持久性和免疫激活的因素 本研究的中心假设是 iso↓DLco 是一种 独特的 HIV 表型，可能由 CMV 诱导的血管病变介导 该研究将嵌套在 I AM 中。 OLD-DA，是在美国旧金山和乌干达坎帕拉建立的 PWH 纵向队列，并将 利用旧金山现有的研究基础设施，我们将使用先进的胸部成像分析。 通过 CT 了解 iso↓DLco 的病因和潜在原因 在目标 1 中，我们将评估肺气肿的 CT， 根据我们的初步研究，我们预计间质性肺疾病、肺动脉高压和空气滞留； 大约一半的 PWH 患有 iso↓DLco，影像分析无法确定 PFT 发现的原因。 我们将测试 iso↓DLco、CMV 与远端肺血管重塑（“血管 修剪’）使用定量 CT 方法，并假设 CMV 介导的血管修剪是 在乌干达坎帕拉，我们将研究人口统计学和临床​​上不同的队列或 PWH 和 HIV 阴性对照以确定 iso↓DLco 的患病率及其相关呼吸道症状 总而言之，本研究的结果将有助于加深对 PFT 的理解。 表型并确定 CMV 是否是 iso↓DLco 的可改变危险因素以及治疗干预的目标。 该项目的完成还将为培训肺部和重症患者 Katerina Byanova 博士提供一个平台。 加州大学旧金山分校的护理研究员，从事高质量、以患者为导向的临床研究 这笔赠款将为 Byanova 博士提供获取知识和技能所需的支持。 成为一名独立的临床研究者和艾滋病毒相关肺部疾病的领导者。 。