Bronchiectasis and chronic airway infection

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的背景下，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。我们的观察性队列研究为特发性结节性支气管扩张与NTM感染相关的发病机制研究提供了基础，NTM感染主要发生在老年女性中。我们最近描述了仔细的表型分型、内分型和评估相关遗传风险等位基因在表征支气管扩张和相关感染（如NTM）中的重要性（Lancet 2018）。治疗性介入性试验的成功，例如导致FDA批准阿米卡星脂质体吸入混悬液作为首个被批准用于治疗肺部NTM疾病的药物，取决于仔细选择目标人群和减少潜在疾病异质性，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正在增强，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，我们的实验室与校外学术合作伙伴一起开发了美国支气管扩张研究注册表，该注册表由COPD基金会管理。该登记处已在美国登记了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。继续分析Registry数据，重点描述与α -1抗胰蛋白酶缺乏症、常见变异性免疫缺陷症和原发性纤毛运动障碍相关的支气管扩张患者的差异（Chronic obstpulm 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医疗数据库的索赔，以确定NTM肺病患者的全因死亡率。与对照组相比，NTM肺病患者的哮喘（23.3%对3.5%）、支气管扩张（36.5%对0.1%）、COPD（52.0%对5.9%）、心律失常（22.6%对6.5%）、冠状动脉疾病（18.5%对6.6%）、心力衰竭（11.9%对4.1%）和癌症（18.5%对5.0%）的合并症明显更高，全因死亡风险增加一倍（校正风险比HR=2.06; CI: 1.52-2.79； P<0.001） （Respir Med 2018）。以前已经注意到肺NTM的治疗有相当大的可变性。我们利用国家医院数据库检查了肺部鸟分枝杆菌复合体（MAC）的治疗，并注意到1326例MAC患者中，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性相关的治疗。(3)微生物发病机制及治疗评价。过去一年的工作重点是利用实验室斑马鱼感染模型来评估从患者疾病过程中获得的一系列脓肿分枝杆菌临床分离株的相对毒力。采用变形虫模型评价合成抗菌肽对脓肿支原体临床菌株的抑制作用。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，以提高患者呼吸道标本中NTM的检测。RGM30培养基的NTM回收率显著高于单独使用MGIT系统（76.7%对59.4%，P=0.01）或Middlebrook 7H11琼脂（76.7%对47.4%，P=0.0001） （J clinin Microbiol 2019）。阿米卡星是一种对许多NTM物种非常有效的药物，但它的治疗窗口有限，并且与本构性耐药相关的突变已被描述为与临床获益降低有关。我们对长期接受阿米卡星治疗的患者（中位2.3年，范围0.6-8.6年）进行了阿米卡星耐药的可能性评估。通过肉汤微量稀释和第一株和最后一株耐药遗传标记进行抗菌药敏试验的16例患者中，只有1例发现最终分离物（MIC >64gmL-1）具有耐药性，并伴有16S核糖体RNA 1408位点的AG突变（ERJ Open Research 2019）。慢性脓分枝杆菌感染的气道清除改变小鼠模型的开发工作已经开始，以进一步帮助毒性和治疗干预开发研究。

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.