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

项目摘要/摘要 艾滋病毒携带者(PWH)因慢性肺部疾病而出现呼吸道症状的负担很高，其中 通过肺功能测试(PFT)的肺活量阻塞诊断的COPD是最好的研究对象。最多的 然而，PFTs的共同发现是一氧化碳(DLCO)弥散能力异常，而正常 肺活量测定，或iso↓dlco。Iso↓DLCO PFT表型的临床相关性尚不清楚。ISO↓DLCO更多 与普通人群相比，HIV在PWH中更常见，并且HIV是DLCO减少的独立危险因素。 我们实验室的初步工作表明，带有iso↓dlco的pwh患者的呼吸道症状增加。 与具有正常PFT的PWH相比，负担更大。Iso↓dlco还与一组独特的血浆有关 炎症/免疫生物标志物与其他PFT表型的比较，如肺活量测定梗阻，提示 Iso、↓、DLCO、PFT和生物标记物模式具有独特的临床相关性。其背后的病理生理学 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)有关 疾病)或肺动脉高压。另外，iso↓dlco可能是慢性炎症的后遗症。 长期感染艾滋病毒并可能与巨细胞病毒(CMV)等其他病毒混合感染的背景， 这会影响艾滋病毒的持久性和免疫激活。这项研究的中心假设是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，在美国旧金山和乌干达坎帕拉建立的PWH纵向队列，将 利用现有的研究基础设施。在旧金山，我们将使用先进的胸部成像分析 目的：了解iso↓DLCO的病因和潜在病因。在目标1中，我们将评估CT对肺气肿的诊断， 间质性肺疾病、肺动脉高压和空气滞留；基于我们的初步研究，我们预计在 大约一半的pwh与iso↓dlco，成像分析将找不到pft发现的原因。在《目标3》中， 我们将测试iso↓dlco、cmv和远端肺血管重构(血管)之间的关系。 修剪‘)使用定量CT方法，其工作假设是CMV介导的血管修剪 与ISO↓dlco相关联。在乌干达的坎帕拉，我们将研究人口统计学和临床上截然不同的队列或 确定iso↓dlco的患病率及其相关呼吸道症状的pwh和hiv阴性对照 负担(目标2)。总之，这项研究的结果将有助于加深对PFT的理解 并确定巨细胞病毒是否是iso↓DLCO的可改变的危险因素和治疗干预的靶点。 该项目的完成还将为培训Katerina Byanova医生提供一个平台，Katerina Byanova医生是一名肺部和危重患者 加州大学旧金山分校的护理研究员，在进行高质量、以患者为导向的临床 研究。这笔赠款将为Byanova博士提供必要的支持，以获得 成为一名独立的临床调查员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. .