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: 10728875
• 负责人: Katerina L. Byanova
• 金额: $ 8.53万
• 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/10728875
• 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; 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 acquisition; Link; Literature; Longitudinal cohort; Lung; Lung diseases; Measurement; Measures; Mediating; Methods; Obstruction; Participant; Pathogenesis; Pattern; Persons; Phenotype; Pilot Projects; Plasma; Population; Prevalence; Proliferating; 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; 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/摘要 艾滋病毒（PWH）患者由于慢性肺部疾病而产生的呼吸道症状高度燃烧，其中 通过肺功能测试（PFT）诊断的COPD是最好的研究。最多 但是，在PFT上的共同发现是正常的碳一氧化碳（DLCO）的异常扩散能力 肺活量测定法或ISO↓DLCO。 ISO↓DLCO PFT表型的临床相关性尚不清楚。 ISO↓DLCO更多 在PWH中，与普通人群相比，HIV是DLCO降低的独立危险因素。 我们实验室的初步工作表明，具有ISO↓DLCO的PWH具有增加的呼吸症状 与正常的PFT相比，伯宁与PWH相比。 ISO↓DLCO也与一组唯一的等离子体相关联 与其他PFT表型（如肺活量测定障碍）相比，炎症/免疫生物标志物相比 ISO↓DLCO PFT和生物标志物模式具有独特的临床相关性。基础的病理生理学 该发现尚不清楚，但可能与早期结构肺部疾病有关（肺气肿或间质性肺 疾病）或肺动脉高压。或者，ISO↓DLCO可能是慢性感染的续集 长期存在HIV感染并可能与其他病毒（例如巨细胞病毒（CMV））共同感染 影响HIV持久性和免疫激活。这项研究的中心假设是ISO↓DLCO是一个 独特的HIV表型，可能由CMV诱导的血管病介导。该研究将嵌套在我的内 Old-da，美国旧金山和乌干达坎帕拉的PWH纵向队列 利用现有的研究基础设施。在旧金山，我们将使用胸部的高级成像分析 CTS了解ISO↓DLCO的病因和潜在原因。在AIM 1中，我们将评估CTS的肺气肿， 间质性肺部疾病，肺动脉高压和空气捕获；根据我们的试点研究，我们希望 使用ISO↓DLCO的PWH大约一半，成像分析将无法确定PFT查找的原因。在AIM 3中， 我们将测试ISO↓DLCO，CMV和圆盘肺血管重塑之间的关联（'血管 修剪’）使用定量的CT方法，有一个可行的假设，即CMV介导的血管修剪为 与ISO↓DLCO相关。在乌干达的坎帕拉，我们将研究一个人口统计学和临床​​上不同的队列或 PWH和HIV阴性控制，以确定ISO↓DLCO的患病率及其相关呼吸道症状 伯恩（AIM 2）。总之，这项研究的结果将有助于更深入地了解此PFT 表型并确定CMV是否是ISO↓DLCO的可修改风险因素，也是治疗干预的目标。 该项目的完成还将为培训Katerina Byanova博士提供平台，这是一种肺而关键的 加利福尼亚大学旧金山大学的护理研究员，以高质量的，以患者为导向的临床 研究。该赠款将为Byanova博士提供获得知识和技能所需的支持 成为独立的临床研究者和与HIV相关肺部疾病的领导者。 。