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

项目摘要/摘要 艾滋病毒感染者（PWH）由于慢性肺部疾病而具有很高的呼吸道症状负担，其中 最好研究通过肺功能测试（PFT）上的肺量测定阻塞诊断的COPD。最 然而，PFT的常见发现是一氧化碳弥散量（DLco）异常， 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中比在一般人群中更常见，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具有增加的呼吸道症状 与威尔斯亲王医院及普通家庭医生比较。Iso↓DLco还与一组独特的血浆相关， 与其他PFT表型（如肺功能障碍）相比，炎症/免疫生物标志物提示 iso↓DLco PFT和生物标志物模式具有独特的临床相关性。病理生理学基础 这一发现尚不清楚，但可能与早期结构性肺病（肺气肿或间质性肺）有关 疾病）或肺动脉高压。或者，iso↓DLco可能是慢性炎症的后遗症， 长期HIV感染和可能与其他病毒如巨细胞病毒（CMV）合并感染， 影响艾滋病毒的持久性和免疫激活。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。研究将嵌套在I AM中 OLD-DA是一个在美国旧金山弗朗西斯科和乌干达坎帕拉建立的PWH纵向队列， 利用现有的研究基础设施。在旧金山弗朗西斯科，我们将使用先进的胸部成像分析， CT以了解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， 间质性肺病、肺动脉高压和空气潴留;根据我们的初步研究，我们预计， 大约一半的PWH伴iso↓DLco，成像分析无法确定PFT结果的原因。在目标3中， 我们将检测iso↓DLco、CMV和远端肺血管重塑（“血管重塑”）之间的相关性， 修剪“）使用定量CT方法，工作假设CMV介导的血管修剪是 与iso↓DLco相关。在乌干达的坎帕拉，我们将研究人口统计学和临床上不同的队列， PWH和HIV阴性对照，以确定iso↓DLco及其相关呼吸道症状的患病率 负担（目标2）。总而言之，本研究的结果将有助于更深入地了解这种PFT 表型，并确定CMV是否是iso↓DLco的可改变的风险因素和治疗干预的靶点。 该项目的完成还将为培训Katerina Byanova博士提供一个平台， 护理研究员在加州旧金山弗朗西斯科，在进行高质量，以病人为导向的临床 research.这笔赠款将为Byanova博士提供必要的支持，以获得知识和技能， 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。 .

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. .