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。本研究的长期目标是建立一个国际、多中心、纵向队列，反映非洲（乌干达）、欧洲（英国）和北美（美国）的艾滋病毒/艾滋病流行情况，以研究PCP和机会性肺炎。我们提出了一项前瞻性、纵向队列研究，每年将招募并随访600-750例因肺炎入住Mulago医院（坎帕拉，乌干达）、大学学院伦敦医院（伦敦，英国）和旧金山弗朗西斯科综合医院（旧金山弗朗西斯科，加利福尼亚州，美国）的HIV感染患者。患者将在住院期间和出院后每6个月接受一次随访，以确定PCP和HIV相关机会性肺炎的频率和死亡率。我们还将收集血清、口咽洗液、内镜漱口水、痰液和支气管镜检查标本，以解决假设驱动的研究问题。我们提出以下目标：目标1：确定国际多中心纵向队列中HIV相关机会性肺炎的频率和死亡率，并检验PCP与死亡率增加相关的假设。目标二：评估分子工具用于PCP和结核病（TB）诊断的敏感性和特异性，并检验60秒口咽冲洗（OPW，漱口液）标本结合聚合酶链反应（PCR）检测是诊断PCP和TB的敏感试验的假设。目标3：探讨肺孢子虫二氢蝶酸合成酶（DHPS）基因突变与死亡率增加相关的可能机制。目标4：描述每个研究中心受试者识别的主要肺孢子虫Msg-C变体，检查全身（血清）和局部（BAL）抗体应答，并检验主要变体抗体水平与PCP状态相关的假设。在未来，我们计划扩大科学重点，包括其他肺炎，如结核病和细菌性肺炎，这是超出了本提案的范围， 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）感染者和其他免疫功能低下者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的药物产生耐药性。开发快速、非侵入性的方法来诊断五氯苯酚将是一个重大进步，而鉴于目前可获得的五氯苯酚治疗药物有限，证明抗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.