Bronchiectasis and chronic airway infection

支气管扩张和慢性气道感染

• 批准号: 10008823
• 负责人: Kenneth Olivier
• 金额: $ 259.14万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008823
• 关键词: Agar; Amikacin; Amoeba genus; Antimicrobial susceptibility; Arrhythmia; Asthma; Blood specimen; Bronchiectasis; Bronchoalveolar Lavage; Caring; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Common Variable Immunodeficiency; Comorbidity; Complex; Control Groups; Coronary Arteriosclerosis; Cystic Fibrosis; Databases; Detection; Development; Disease; Effectiveness; Enrollment; Epidemiology; Epithelial Cells; Extramural Activities; Foundations; Genetic; Genetic Diseases; Genetic Markers; Genetic Risk; Genomics; Goals; Guidelines; Health; Heart failure; Hospitals; Host Defense; IgE; Infection; Inhalation; Intervention Trial; Job' s Syndrome; Laboratories; Liposomes; Lung; Lung diseases; Lung infections; Macrolide-resistance; Malignant Neoplasms; Managed Care; Marfan Syndrome; Modeling; Mucociliary Clearance; Mutation; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium tuberculosis; Natural History; Nose; Organism; Participant; Pathogenesis; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Phenotype; Population; Population Study; Population-Based Registry; Positioning Attribute; Predisposition; Prevalence; Primary Ciliary Dyskinesias; Protocols documentation; RNA, Ribosomal, 16S; Rare Diseases; Recovery; Regimen; Registries; Research; Resistance; Resources; Respiratory System; Risk; STAT3 gene; Site; Source; Specimen; Structure; Suspensions; System; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Treatment Protocols; United States National Institutes of Health; Vertebral column; Virulence; Virulence Factors; Work; Zebrafish; alpha 1-Antitrypsin Deficiency; antimicrobial peptide; base; cohort; data registry; disease heterogeneity; drug efficacy; epidemiology study; hazard; heritable connective tissue disorder; improved; interest; microbial; mortality; mouse model; mycobacterial; new therapeutic target; non-tuberculosis mycobacteria; novel; older women; patient population; respiratory; risk variant; success; therapeutic development; therapy development; transmission process

1) Host Pathogenesis. Chronic lung infections associated with nontuberculous mycobacteria (NTM) often occur in the setting of known structural lung disease such as COPD or bronchiectasis associated with cystic fibrosis or primary ciliary dyskinesia. Our observational cohort study serves as the backbone for pathogenesis research focused on patients with idiopathic nodular bronchiectasis associated with NTM infection occurring predominantly in older women. We recently described the importance of careful phenotyping, endotyping and assessment of associated genetic risk alleles in characterizing bronchiectasis and associated infections such as NTM (Lancet 2018). The success of therapeutic interventional trials, such as those leading to FDA approval of amikacin liposome inhalation suspension as the first approved drug for management of pulmonary NTM disease, is dependent on careful selection of target populations and reduction of underlying disease heterogeneity to accurately detect drug efficacy (Am J Respir Crit Care Med 2018). With success of these trials, interest is building in better characterizing pulmonary nontuberculous mycobacterial infections and we participated in defining a roadmap for advancing translational science in this field (Am J Respir Crit Care Med 2019). (2) Epidemiology. In 2008 our lab along with extramural academic partners developed a US Bronchiectasis Research Registry that has been administered by the COPD Foundation. This Registry has enrolled over 3000 patients in the US and is being used as a source of participants in clinical trials and for epidemiologic research. Continued analysis of Registry data focused on describing differences in patients with bronchiectasis associated with alpha-1 antitrypsin deficiency, common variable immunodeficiency and primary ciliary dyskinesia (Chronic Obstr Pulm Dis 2019). To assess the burden of NTM pulmonary disease, we examined claims from a large US managed care database to determine all-cause mortality in patients with NTM lung disease. Patients with NTM lung disease had substantially higher co-morbidities of asthma (23.3% versus 3.5%), bronchiectasis (36.5% versus 0.1%), COPD (52.0% versus 5.9%), arrhythmia (22.6% versus 6.5%), coronary artery disease (18.5% versus 6.6%), heart failure (11.9% versus 4.1%), and cancer (18.5% versus 5.0%) and a doubling risk of all-cause mortality (adjusted hazard ratio HR=2.06; CI: 1.52-2.79; P<0.001) compared to a control group (Respir Med 2018). Considerable variability of treatment for pulmonary NTM has been previously noted. We examined treatment of pulmonary M. avium complex (MAC) utilizing a national hospital database and noted of 1326 MAC patients, 645 (49%) received treatment. Only 10% received guidelines-based treatment and 18% received treatment that has been associated with development of macrolide resistance. (3) Microbial pathogenesis and therapeutics assessment. Work over the past year has focused on utilizing a laboratory zebrafish infection model to assess relative virulence of serial clinical isolates of M. abscessus obtained from patients over the course of their disease. An amoeba model was used to assess the effectiveness of synthetic antimicrobial peptides against clinical strains of M. abscessus. In collaboration with the NIH Clinical Center Mycobacteriology Lab we assessed the performance of a new selective media to improve detection of NTM in respiratory specimens from our patients. Recovery of NTM was significantly higher with the RGM30 media than that of either the MGIT system (76.7% versus 59.4%; P=0.01) or Middlebrook 7H11 agar (76.7% versus 47.4%; P=0.0001) alone (J Clin Microbiol 2019). Amikacin is a highly effective drug against many species of NTM but it has a limited therapeutic window and mutations associated with constitutive resistance have been described in association with reduced clinical benefit. We assessed the potential for amikacin resistance in a selected cohort of patients with prolonged exposure (median 2.3, range 0.6-8.6 years) to amikacin treatment. Only 1 of 16 patients with antimicrobial susceptibility testing by broth microdilution and genetic markers of resistance of 1st and last isolates was noted to have a resistant final isolate (MIC >64gmL-1), accompanied by an AG mutation at position 1408 of the 16S ribosomal RNA (ERJ Open Research 2019). Work has begun on development of an altered airway clearance mouse model of chronic M. abscessus infection to further aid with virulence and therapeutic intervention development studies.

1)宿主发病机制。与非结核分枝杆菌（NTM）相关的慢性肺部感染通常发生在已知的结构性肺部疾病（如COPD或与囊性纤维化或原发性纤毛运动障碍相关的支气管扩张）的背景下。 我们的观察性队列研究作为发病机制研究的骨干，重点关注与NTM感染相关的特发性结节性支气管扩张患者，主要发生在老年女性中。我们最近描述了在表征支气管扩张和相关感染（如NTM）时仔细进行表型分型、内定型和相关遗传风险等位基因评估的重要性（Lancet 2018）。治疗性干预试验的成功，例如FDA批准阿米卡星脂质体吸入混悬液作为首个获批用于治疗肺部NTM疾病的药物，取决于仔细选择目标人群和降低基础疾病异质性，以准确检测药物疗效（Am J Respir Crit Care Med 2018）。 随着这些试验的成功，人们对更好地表征肺部非结核分枝杆菌感染的兴趣越来越浓厚，我们参与了制定推进该领域转化科学的路线图（Am J Respir Crit Care Med 2019）。(2)流行病学。2008年，我们的实验室沿着与校外学术合作伙伴一起开发了一个美国支气管扩张症研究登记处，该登记处由COPD基金会管理。 该登记研究已在美国招募了3000多名患者，并被用作临床试验和流行病学研究的参与者来源。登记研究数据的持续分析重点描述了与α-1抗胰蛋白酶缺乏症、常见变异性免疫缺陷和原发性纤毛运动障碍相关的支气管扩张患者的差异（Chronic Obstr Pulm Dis 2019）。为了评估NTM肺病的负担，我们检查了来自美国大型管理式医疗数据库的索赔，以确定NTM肺病患者的全因死亡率。NTM肺病患者的哮喘合并症显著较高（23.3% vs 3.5%），支气管扩张（36.5% vs 0.1%），COPD（52.0% vs 5.9%），心律失常（22.6% vs 6.5%），冠状动脉疾病（18.5% vs 6.6%），心力衰竭（11.9%对4.1%），以及癌症（18.5% vs 5.0%）和全因死亡风险加倍（校正风险比HR=2.06; CI：1.52-2.79; P<0.001）（Respir Med 2018）。先前已经注意到肺NTM治疗的相当大的变化。 我们检查了肺M的治疗。利用国家医院数据库，对1326例MAC患者进行了研究，其中645例（49%）接受了治疗。 只有10%的患者接受了基于指南的治疗，18%的患者接受了与大环内酯类药物耐药相关的治疗。(3)微生物发病机制和治疗评估。过去一年的工作集中在利用实验室斑马鱼感染模型来评估M.从患者在其疾病过程中获得的样本。变形虫模型用于评估合成的抗微生物肽对临床M.你好我们与NIH临床中心分枝杆菌学实验室合作，评估了一种新的选择性培养基的性能，以提高对患者呼吸道标本中NTM的检测。RGM 30培养基的NTM回收率显著高于MGIT系统（76.7% vs 59.4%; P=0.01）或Middlebrook 7 H11琼脂（76.7% vs 47.4%; P=0.0001）（J Clin Microbiol 2019）。阿米卡星是一种针对许多种NTM的高效药物，但其治疗窗有限，并且已描述了与组成型耐药相关的突变与临床获益降低相关。 我们评估了一组长期暴露于阿米卡星治疗（中位数2.3，范围0.6-8.6年）的患者中阿米卡星耐药的可能性。通过肉汤微量稀释法进行抗菌药物敏感性试验的16例患者中，仅1例患者的第1株和最后1株分离株的耐药遗传标记物具有耐药最终分离株（MIC > 64 gmL-1），并伴有16 S核糖体RNA第1408位的AG突变（ERJ Open Research 2019）。已经开始了开发改变气道清除率的慢性M.进一步协助毒力和治疗干预开发研究。