Bacterial Infection in COPD

描述(由申请人提供)： 慢性阻塞性肺疾病(COPD)的发病率、死亡率、健康状况影响和护理费用的一个重要因素是间歇性加重，目前COPD的最佳治疗仅防止40%的恶化，多达25%的恶化患者在1个月内表现出不完全缓解或复发。大多数病情恶化是由细菌和病毒呼吸道感染引起的。因此，为了改善我们对COPD恶化的管理，很重要的一点是准确地阐明COPD中细菌和病毒感染的程度及其与呼吸道炎症的关系，正如本研究应用所建议的那样。该提案的核心是继续对50名COPD患者进行纵向前瞻性队列研究，这项研究自1994年以来一直得到这项功绩回顾的支持。参与者每4周在研究诊所和病情恶化时接受一次治疗。在每次就诊时，都要对患者进行临床评估，并采集痰和血清样本。具体目标和计划实验如下。分子技术将用于确定COPD患者细菌感染的特征，并将结果与培养结果进行比较。将从COPD研究诊所每月获取的痰样本中提取DNA，并作为实时荧光聚合酶链式反应(RT-PCR)的模板，以定量检测四种主要病原体的存在，即流感嗜血杆菌、肺炎链球菌、卡他支原体和铜绿假单胞菌。为了确定病原体检测的意义，将对呼吸道炎症进行量化，并检查病情恶化后对细菌病原体的免疫反应。新的观察将包括COPD的分子诊断技术与培养的比较，以及对仅通过分子技术检测病原体的含义的理解。病情恶化的症状缓解将通过有效的患者报告结果指标Exact-PRO进行客观评估。是否通过根除致病病原体(细菌或病毒)，以及通过呼吸道和全身炎症的消退来确定这一临床解决方案，将进行评估。当在临床就诊中被诊断为病情恶化时，将在28天内总共获得5份痰样本和3份血清样本，以及每日电子记录的Exact-PRO。痰标本将接受细菌和病毒检测。还将对痰中的呼吸道炎症进行全面评估。血清C反应蛋白和纤维蛋白原将被用来衡量全身炎症。恶化的确切解决是否与微生物根除和炎症解决有关，将进行分析。对感染、炎症和临床症状的仔细研究将提供有关这些因素在病情恶化中如何联系的新信息。它还将告知是否需要更好的抗菌或抗炎疗法来改善结果。新的肠杆菌科菌株和金黄色葡萄球菌的获得与病情恶化的关系将被系统地研究。对分离菌株的系统免疫反应和获得菌株后的呼吸道炎症将进行系统评估。肠杆菌科菌株将通过rep-PCR进行分型。金黄色葡萄球菌菌株的特征将是spa分型。在新的或先前存在的毒株特征之后，将确定新的毒株获得和恶化之间的关系。将研究与这些病原体的新菌株相关的恶化中的炎症和免疫反应。这将提供对肠杆菌科革兰氏阴性杆菌和金黄色葡萄球菌在急性加重中的作用的严格评估，并告知我们在急性加重中治疗这些病原体的必要性。 公共卫生相关性： 慢性阻塞性肺疾病(COPD)患者经常经历称为恶化的急性发作。COPD是退伍军人中的常见问题，COPD加重是退伍军人住院的主要原因。病情恶化通常由呼吸道感染、细菌和/或病毒引起。在这项研究中，将基于DNA的新技术与培养法进行比较，将提供更好的COPD细菌感染情况，并帮助我们解释这些新的测试。确定恶化症状与呼吸道感染和炎症的关系将有助于深入了解为什么多达25%的恶化在一个月内复发。我们还将确定某些耐药细菌物种是否会导致病情恶化。更好地了解慢性阻塞性肺疾病的恶化将使我们预防和治疗它们的努力更加有效，这无疑将使大量患有这种疾病的退伍军人受益。

DESCRIPTION (provided by applicant): A significant contributor to the morbidity, mortality, health status impact and cost of care of chronic obstructive pulmonary disease (COPD) are intermittent exacerbations, Current optimal treatment of COPD prevents only 40% of exacerbations and as many as 25% of patients with an exacerbation either display incomplete resolution or relapse within 1 month. Most exacerbations are caused by bacterial and viral airway infection. Therefore, to improve our management of COPD exacerbations, it is important to elucidate precisely the extent of bacterial and viral infection in COPD and its relation to airway inflammation, as proposed in this research application. Central to the proposal is continuation of a longitudinal prospective cohort study in 50 patients with COPD that has been supported by this Merit Review since 1994. Participants are seen every 4 weeks in the Study Clinic and at exacerbation. At each visit the patient is evaluated clinically and sputum and serum sample are obtained. Specific Aims and planned experiments are as follows. Molecular techniques will be used to characterize bacterial infection in COPD and results will be compared with culture. DNA will be extracted from sputum samples obtained on a monthly basis in the COPD study clinic and used as template in real time PCR (RT-PCR) to make a quantitative determination of the presence of the 4 major pathogens, H. influenzae, S. pneumoniae, M. catarrhalis and P. aeruginosa. In order to determine the significance of pathogen detection, airway inflammation will be quantified and immune response to bacterial pathogens following exacerbations will be examined. Novel observations will include a comparison of molecular diagnostic techniques to COPD with cultures, and an understanding of the implication of detecting a pathogen only by molecular techniques. Symptomatic resolution of exacerbations will be assessed objectively with a validated patient reported outcome measure, the EXACT-PRO. Whether this clinical resolution is determined by eradication of the offending pathogen (bacteria or virus) and by resolution of airway and systemic inflammation will be assessed. When an exacerbation is diagnosed in a clinic visit, a total of 5 sputum samples and 3 serum samples will be obtained within 28 days, as well as daily electronic recording of the EXACT-PRO. Sputum specimens will be subjected to bacterial and viral detection. A comprehensive assessment of airway inflammation in sputum will also be made. Serum c-reactive protein and fibrinogen will be used to measure systemic inflammation. Whether EXACT-PRO resolution of exacerbation is related to microbial eradication and inflammatory resolution will be analyzed. A careful study of infection, inflammation and clinical symptoms will provide new information as to how these are linked in exacerbations. It would also inform whether better antimicrobial or anti-inflammatory therapies are needed to improve outcomes. The relationship of acquisition of new strains of Enterobacteriaceae and Staphylococcus aureus with exacerbations will be systematically examined. Systemic immune response to the isolated strains and airway inflammation with strain acquisition will be systematically assessed. The Enterobacteriaceae strains will be typed by REP-PCR. The S. aureus strains will be characterized by spa typing. Following strain characterization as new or pre-existing, the relationship between new strain acquisition and exacerbation will be determined. Inflammatory and immune response in exacerbations associated with new strains of these pathogens will be studied. This will provide a rigorous evaluation of the role of Enterobacteriaceae gram negative bacilli and S. aureus in exacerbations and inform us of the need for treatment of these pathogens in exacerbations. PUBLIC HEALTH RELEVANCE: Patients with chronic obstructive pulmonary disease (COPD) experience frequent acute episodes of worsening known as exacerbations. COPD is a common problem in the VA population and COPD exacerbations are a major cause of hospitalization among veterans. Exacerbations are usually caused by airway infection, with a bacteria and/or a virus. In this study, comparison of new DNA based techniques with cultures will provide a better picture of bacterial infection in COPD and also help us interpret these new tests. Determination of the relation of symptoms of exacerbation with airway infection and inflammation will provide insight in to why as many as 25% of exacerbations relapse within a month. We will also determine if certain antibiotic resistant bacterial species cause exacerbations. A better understanding of COPD exacerbations will make our efforts to prevent and treat them more effective, which will undoubtedly benefit the large number of veterans afflicted with this disease.