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）宿主发病机理。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疾病（例如COPD或与囊性纤维化或原发性睫状运动障碍相关的支气管扩张）的情况下发生。 我们的观察队列研究是发病机理研究的主链，重点是特发性结节性支气管扩张患者，与NTM感染相关，主要是在老年女性中发生。我们最近描述了对相关遗传风险等位基因的仔细表型，内型和评估在表征支气管扩张和相关感染（例如NTM）中的重要性（Lancet 2018）。治疗性介入试验的成功，例如导致FDA批准amikacin脂质体悬浮悬浮液作为首次批准的肺NTM疾病治疗药物，取决于仔细选择目标人群和减少潜在的疾病异质性异质性异质性，以准确检测药物疗效（AM J Expir Crit Med 2018）。 随着这些试验的成功，兴趣是在更好地描述肺化不结婚的分枝杆菌感染的过程中，我们参与了为该领域推进转化科学的路线图（Am J Respir Crit Care Med 2019）。 （2）流行病学。 2008年，我们的实验室与校外学术伙伴一起开发了由COPD基金会管理的美国支气管扩张研究注册表。 该注册表已招募了3000多名美国患者，并被用作临床试验和流行病学研究的参与者的来源。持续分析注册表数据的重点是描述与α-1抗胰蛋白酶缺乏，常见可变免疫缺陷和原发性睫状运动障碍相关的支气管扩张患者的差异（慢性OBSTR PULM DIS 2019）。为了评估NTM肺部疾病的负担，我们检查了来自美国大型托管护理数据库的主张，以确定NTM肺部疾病患者的全因死亡率。 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％对5.0％）和全因死亡率的两倍风险（调整后的危险比HR = 2.06; CI：1.52-2.79; P <0.001）与对照组相比（Respir Med 2018）。先前已经注意到了肺NTM治疗的显着差异。 我们检查了利用国家医院数据库的肺M. avium综合体（MAC）的治疗，并记录了1326名MAC患者，645例（49％）接受了治疗。 只有10％的人接受了基于准则的治疗，而有18％的治疗方法与大花环耐药性的发展有关。 （3）微生物发病机理和治疗学评估。过去一年中的工作集中在利用实验室斑马鱼感染模型来评估从患者疾病过程中从患者获得的脓肿的连续临床分离株的相对毒力。使用变形虫模型来评估合成抗微生物肽对脓肿的临床菌株的有效性。与NIH临床中心分枝杆菌实验室合作，我们评估了一种新的选择性培养基的性能，以改善患者呼吸标本中NTM的检测。 RGM30培养基的恢复显着高于MGIT系统（76.7％对59.4％; P = 0.01）或Middlebrook 7H11琼脂（仅76.7％v = 0.0001; P = 0.0001）（J Clin Microbiol 2019）。 amikacin是针对许多NTM的一种高效的药物，但与临床益处降低相关，它的治疗窗口有限，与本构耐药相关的突变已被描述。 我们评估了延长暴露（中值2.3，范围为0.6 - 8.6岁）的选定患者中氨基甲酸抗性抗性的潜力。在16例通过肉汤微稀释和抗菌敏感性测试的患者中，只有1例在1st和最后一个分离株的耐药性标记中具有耐药性最终分离株（MIC> 64GML-1），并伴随着16S核糖体RNA的1408位的Ag突变（ERJ Open Research 2019）。研究已经开始开发改变慢性腹肌感染的气道清除小鼠模型，以进一步帮助毒力和治疗干预开发研究。