International HIV-associated Opportunistic Pneumonias (IHOP) Study

描述(由申请人提供)： 从历史上看，肺孢子虫肺炎(PCP)和其他机会性肺炎一直是人类免疫缺陷病毒(HIV)感染者发病和死亡的主要原因。这项研究的长期目标是创建一个反映非洲(乌干达)、欧洲(英国)和北美(美国)艾滋病毒/艾滋病流行的国际、多中心、纵向队列，以研究卡介苗肺炎和机会性肺炎。我们提出了一项前瞻性的纵向队列研究，每年将招募600-750名因肺炎入院的艾滋病毒感染患者，他们分别住在穆拉戈医院(乌干达坎帕拉)、伦敦大学学院医院(英国伦敦)和旧金山综合医院(美国旧金山)。将在患者住院期间和出院后每6个月对患者进行跟踪，以确定PCP和艾滋病毒相关机会性肺炎的频率和死亡率。我们还将收集血清、口咽冲洗、镜下漱口水、痰和支气管镜标本，以解决假说驱动的研究问题。我们提出了以下目标：目标1：在国际、多中心、纵向队列中确定HIV相关机会性肺炎的发生率和死亡率，并检验PCP与死亡率增加相关的假设。目的：评价PCP和TB分子诊断工具的敏感性和特异性，并验证60s口咽冲洗(OPW)结合聚合酶链式反应(PCR)是诊断PCP和TB的敏感试验的假设。目的：验证肺孢子虫二氢翼酸合成酶(DHPS)基因突变与死亡率增加相关的假说，并探讨其可能的机制。目的：确定各部位受试者识别的肺孢子虫MSG-C主要变异株的特征，检测全身(血清)和局部(BAL)抗体反应，并验证针对该变异株的抗体水平与PCP状态相关的假设。未来，我们计划将科学重点扩大到包括其他肺炎，如结核病和细菌性肺炎，这些都不在这项提案的范围内， 与公共卫生的相关性：肺孢子虫肺炎(PCP)是人类免疫缺陷病毒(HIV)感染者和其他免疫受损人员患病和死亡的重要原因。这项研究将检查诊断PCP的新方法，并将确定肺孢子虫是否对用于治疗PCP的药物产生抗药性。开发快速、非侵入性的方法来诊断PCP将是一个重大的进步，而鉴于目前可用的治疗PCP的药物有限，显示耐药性将产生严重影响。

DESCRIPTION (provided by applicant): Historically, Pneumocystis pneumonia (PCP) and other opportunistic pneumonias have been major causes of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. The long-term objective of this study is to create an international, multi-center, longitudinal cohort that reflects the HIV/AIDS epidemic in Africa (Uganda), Europe (United Kingdom), and North America (United States) to study PCP and opportunistic pneumonias. We propose a prospective, longitudinal cohort study that will enroll and follow 600-750 HIV-infected patients per year who are admitted with pneumonia to Mulago Hospital (Kampala, Uganda); University College London Hospitals (London, UK); and San Francisco General Hospital (San Francisco, CA, US). Patients will be followed throughout their hospitalization and every 6 months after hospital discharge to determine the frequency and mortality of PCP and HIV-associated opportunistic pneumonias. We will also collect serum, oropharyngeal wash, Scope mouthwash, sputum, and bronchoscopy specimens to address hypothesis-driven research questions. We propose the following aims: Aim 1: To determine the frequency and mortality of HIV-associated opportunistic pneumonias in an international, multi-center, longitudinal cohort and to test the hypothesis that PCP is associated with increased mortality. Aim 2: To estimate the sensitivity and specificity of molecular tools for PCP and tuberculosis (TB) diagnosis and to test the hypotheses that 60-second oropharyngeal washing (OPW, gargle) specimens combined with polymerase chain reaction (PCR) assays are sensitive tests to diagnose PCP and TB. Aim 3: To test the hypothesis that Pneumocystis dihydropteroate synthase (DHPS) gene mutations are associated with an increased mortality and to explore potential mechanisms. Aim 4: To characterize the predominant Pneumocystis Msg-C variant recognized by subjects at each site, to examine systemic (serum) and local (BAL) antibody responses, and to test the hypothesis that the level of antibodies to the predominant variant is correlated with PCP status. In the future, we plan to expand the scientific focus to include other pneumonias, such as TB and bacterial pneumonia that are beyond the scope of this proposal, Relevance to public health: Pneumocystis pneumonia (PCP) is a significant cause of illness and death among human immunodeficiency virus (HIV)-infected and other immunocompromised persons. This study will examine newer methods to diagnose PCP and will determine whether Pneumocystis is becoming resistant to medications that are used to treat PCP. The development of rapid, non-invasive methods to diagnose PCP would be a significant advance, while the demonstration of drug resistance would have serious implications, given the limited PCP treatment medications currently available.