Bronchiectasis and chronic airway infection

支气管扩张和慢性气道感染

• 批准号: 10253887
• 负责人: Kenneth Olivier
• 金额: $ 257.72万
• 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/10253887
• 关键词: 2019-nCoV; AIDS/HIV problem; Acanthamoeba castellanii; Adult; Aerosols; Amoeba genus; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Asians; Attention; Bacteria; Blood specimen; Bronchiectasis; Bronchoalveolar Lavage; COVID-19 pandemic; Cells; Characteristics; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Code; Cohort Studies; Collaborations; Colony-Stimulating Factors; Complex; Cooperative Research and Development Agreement; Coughing; Cystic Fibrosis; Data; Databases; Development; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Dose; Drug resistance; Educational workshop; Electronic Health Record; Enrollment; Epithelial Cells; Europe; Extramural Activities; Fennel - dietary; Frequencies; Genetic; Genetic Diseases; Genetic Risk; Genome; Genomics; Genus Mycobacterium; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Guidelines; Health; Heterogeneity; Hospitalization; Host Defense; IgE; Immunophenotyping; In Vitro; Individual; Infection; Ingestion; Inhalation; Interferons; Interleukin-12; International; Job' s Syndrome; Lung; Lung diseases; Lung infections; Marfan Syndrome; Measurable; Measures; Medicare; Microbe; Microbiology; Mucociliary Clearance; Multi-Drug Resistance; Mutation; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium kansasii; Mycobacterium tuberculosis; Mycobacterium xenopi; Natural History; Nitric Oxide; North America; Nose; Organism; Outcome; Outcome Measure; Pathogenesis; Pathogenicity; Pathway interactions; Patient Isolators; Patients; Persons; Pharmaceutical Preparations; Phase I/II Trial; Phenotype; Placebo Control; Population; Population Study; Population-Based Registry; Pre-Clinical Model; Predisposition; Prevalence; Primary Ciliary Dyskinesias; Production; Protocols documentation; Pseudomonas Infections; Pseudomonas aeruginosa; Quality of life; Rare Diseases; Refractory; Regimen; Registries; Regulatory T-Lymphocyte; Reporting; Research; Research Design; Resistance; Resources; Respiratory System; Role; STAT3 gene; Side; Site; Societies; Source; Sputum; Structure; Techniques; Testing; Time; Transgenic Mice; Treatment Protocols; Tuberculosis; United States National Institutes of Health; Vertebral column; Virulence; Virulence Factors; Virus; Work; Zebrafish; airway epithelium; analog; antibiotic tolerance; antimicrobial peptide; arm; base; biobank; clinical center; clinical effect; clinical encounter; cystic fibrosis patients; cytokine; data registry; early phase clinical trial; experience; health plan; heritable connective tissue disorder; industry partner; inhibitor/antagonist; interest; monocyte; mouse model; mycobacterial; new therapeutic target; non-tuberculosis mycobacteria; novel; novel therapeutics; older women; patient population; population based; portability; primary endpoint; recruit; repository; resistant strain; respiratory; response; risk variant; sildenafil; therapeutic development; transmission process; trend; trial design

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 primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) (Richards CJ, 2019). Population based data from large existing sources such as Medicare and health plan consortia indicate increasing prevalence of NTM pulmonary disease. However, it is not clear from these diagnostic coding based analyses how much increased testing for NTM contributes to disease reporting. To examine testing trends, we recently analyzed microbiologic data from 10.8 million patients in the Cerner HealthFacts Electronic Health Record database, a repository of clinical encounter data at 31 US facilities. From 2009-2015, average annual increases in both mycobacterial testing (3.2%/year; 95% CI 1.9%4.5%) and culture positivity for pathogenic NTM species (4.5%/year; 95% CI 1.2%7.9%) were noted across all facilities. Testing was more common in older individuals and both testing and positivity rates increased at a higher rate among Asians (9.8%/year; 95% CI 6.4%13.4%) and persons with CF (26.6%/year; 95% CI 15.2%39.8%); these groups also had higher rates of positive cultures for NTM (Dean SG, 2020). Pulmonary infection with NTM is thought to likely be acquired from inhalation of environmental aerosols. However, increasing concern for person-person transmission of M. abscessus associated with outbreaks predominantly in CF patients has suggested a possible investigative role for cough aerosol transmission studies similar to those assessing transmissibility in patients with tuberculosis or Pseudomonas infections in CF patients. Expertise in TB aerosol infection assessment techniques within our lab has garnered increased attention due to the current transmission concerns of the COVID-19 pandemic (Dheda K, 2019; Fennelly KP, 2020; Fennelly KP, 2019; Theron G, 2020). Our observational cohort study serves as the backbone for pathogenesis research focused on patients with idiopathic NTM infection occurring predominantly in older women. Familial clustering, shared phenotypic characteristics and associated genetic risk alleles previously reported by our group all suggest a key role for altered host susceptibility in the pathogenesis of these infections. Genetic defects in the IL-12/IFN- axis are associated with disseminated NTM infections. To assess the immunophenotype of patients with pulmonary infections, we measured the stimulatory Th1, Th2, Th17 and Treg cytokine and colony-stimulating factor responses in cells from idiopathic NTM patients in comparison to healthy donors and pulmonary NTM disease patients with CF or PCD. The IL-12/IFN- axis function was normal in patients with idiopathic PNTM disease. However, idiopathic PNTM patients had reduced Th17 response and higher mycobacteria-induced monocyte GM-CSF expression (Wu UI, 2019). Previous pathogenesis work by our group demonstrated altered respiratory ciliary function in patients with idiopathic NTM infection and we previously demonstrated the ability to restore ciliary beat frequency to normal in vitro by applying nitric oxide (NO) analogues or the PDE5 inhibitor sildenafil to ex vivo primary epithelial cells from pulmonary NTM patients. In a proof of concept Phase I/II trial, pulmonary NTM patients received sildenafil for 30 days with escalation from 20 to 40 mg three times per day. A dose response to sildenafil was seen with increased ciliary beat frequency following a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil which was not seen with 20 mg dosing. There were no changes in sputum production, nasal NO production, or quality of life measures (Fowler C, 2020). Further studies to assess the long term clinical effect of sildenafil on NTM infection susceptibility may be warranted. Treatment of pulmonary NTM relies on complex, prolonged, poorly tolerated antibiotic regimens which are not as effective as similar regimens for tuberculosis. International guidelines for the diagnosis and management of NTM were recently revised by a four society (ATS, IDSA, ERS and ESCMID) collaboration on both sides of the Atlantic. This PICO question based revision focuses on pulmonary disease in adults (without CF or HIV/AIDS) and four of the species more commonly associated with disease in North America and Europe: M. avium complex, M. kansasii, M. xenopi and M. abscessus (Daley CL, 2020). Better treatments are desperately needed. The FDA convened a workshop in April 2019 to discuss clinical trial design challenges and considerations related to treatment of NTM pulmonary disease including topics such as clinical trial endpoints, duration, and populations. The workshop emphasized that trial designs for new therapeutics should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary endpoints, and placebo control arms was highlighted during the workshop (Flume PA, 2020). In 2008 our lab along with extramural academic partners developed a US Bronchiectasis Research Registry with a current enrollment of over 3000 patients to serve in part as a resource for treatment assessment and recruitment into clinical trials. Continued analysis of Registry data focused on the association between airway clearance techniques (ACTs) use and clinical outcomes in patients with bronchiectasis and a productive cough. The ACTs were used more often if patients experienced a prior exacerbation, hospitalization for pulmonary illness, or had P. aeruginosa. The odds of development of a bronchiectasis exacerbation were higher in patients who use ACTs continuously suggesting more frequent use in an ill bronchiectasis population (Basavaraj A, 2020). Our wet lab focusses on assessment of NTM virulence and development of novel therapeutic strategies. The lab takes advantage of a rich biorepository of serial NTM isolates obtained from patients in our clinical cohort study. Many of these isolates have sequenced genomes and well characterized in vitro growth and resistance phenotypes. Preclinical models used in the lab range from amoeba to zebrafish to a transgenic mouse model with altered airway clearance. Recent work focused on assessment of antimicrobial peptides (APs) against multi-drug resistant (MDR) strains of M. abscessus. Synthetic short cationic APs have shown good activity against various bacteria including M. tuberculosis. We assessed the activity APs against a battery of reference and clinical M. abscessus strains including a MDR outbreak strain and observed minimal inhibitory concentrations of 1.6 to >50 g/mL. Further work with the most active AP demonstrated protection of Acanthamoeba castellanii from killing by ingested M. abscessus. Antimicrobial peptides offer an attractive potential option for treatment of drug resistant M. abscessus (da Silva JL, 2020). Under a Cooperative Research and Development Agreement with an industry partner, our lab investigated the antibacterial activity of high-dose nitric oxide against pulmonary M. abscessus disease. In the compassionate-use treatment, a CF patient with treatment refractory pulmonary M. abscessus was treated via a novel, portable generator with two courses of adjunctive intermittent NO ranging from 160 p.p.m. for 21 days to 240 p.p.m for 8 days. In vitro susceptibility tests utilizing a novel NO exposure chamber performed against this patients isolate and comparison clinical isolates demonstrated heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains (Access Microbiology 2020).

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中，例如慢性阻塞性肺病 (COPD) 或与原发性纤毛运动障碍 (PCD) 或囊性纤维化 (CF) 相关的支气管扩张 (Richards CJ, 2019)。 来自医疗保险和健康计划联盟等大型现有来源的基于人口的数据表明，NTM 肺部疾病的患病率不断增加。 然而，从这些基于诊断编码的分析中尚不清楚增加 NTM 检测对疾病报告有多大贡献。为了研究检测趋势，我们最近分析了 Cerner HealthFacts 电子健康记录数据库中 1080 万患者的微生物数据，该数据库是美国 31 家机构的临床数据存储库。从 2009 年至 2015 年，所有设施的分枝杆菌检测（3.2%/年；95% CI 1.9%4.5%）和致病性 NTM 菌种培养阳性率（4.5%/年；95% CI 1.2%7.9%）平均每年都有所增加。检测在老年人中更为常见，亚洲人（9.8%/年；95% CI 6.4%13.4%）和 CF 患者（26.6%/年；95% CI 15.2%39.8%）的检测率和阳性率均以更高的速度增加；这些群体的 NTM 培养阳性率也较高（Dean SG，2020）。 NTM 肺部感染被认为可能是通过吸入环境气溶胶而获得的。 然而，人们越来越关注与主要在 CF 患者中爆发相关的脓肿分枝杆菌人际传播，这表明咳嗽气溶胶传播研究可能具有类似于评估结核病患者或 CF 患者中假单胞菌感染的传播性的研究作用。 由于当前 COVID-19 大流行的传播问题，我们实验室的结核气溶胶感染评估技术专业知识受到越来越多的关注（Dheda K，2019；Fennelly KP，2020；Fennelly KP，2019；Theron G，2020）。 我们的观察性队列研究是针对主要发生在老年女性的特发性 NTM 感染患者的发病机制研究的支柱。 我们小组之前报道的家族聚集、共同的表型特征和相关的遗传风险等位基因都表明宿主易感性改变在这些感染的发病机制中发挥着关键作用。 IL-12/IFN-轴的遗传缺陷与播散性 NTM 感染有关。为了评估肺部感染患者的免疫表型，我们测量了特发性 NTM 患者细胞中的刺激性 Th1、Th2、Th17 和 Treg 细胞因子和集落刺激因子反应，并与健康供体和患有 CF 或 PCD 的肺部 NTM 疾病患者进行比较。特发性 PNTM 疾病患者的 IL-12/IFN-轴功能正常。然而，特发性 PNTM 患者的 Th17 反应降低，分枝杆菌诱导的单核细胞 GM-CSF 表达较高（Wu UI，2019）。 我们小组之前的发病机制研究表明，特发性 NTM 感染患者的呼吸纤毛功能发生了改变，并且我们之前证明了通过对来自肺 NTM 患者的离体原代上皮细胞应用一氧化氮 (NO) 类似物或 PDE5 抑制剂西地那非，能够在体外将纤毛搏动频率恢复到正常。 在 I/II 期概念验证试验中，肺部 NTM 患者接受西地那非治疗 30 天，剂量从 20 毫克逐渐增加到 40 毫克，每天 3 次。 单次服用 40 mg 西地那非和延长服用 40 mg 西地那非后，观察到西地那非的剂量反应，纤毛搏动频率增加，而 20 mg 西地那非的剂量反应则没有出现这种情况。痰液产生、鼻腔 NO 产生或生活质量指标没有变化（Fowler C，2020）。 可能需要进一步研究来评估西地那非对 NTM 感染易感性的长期临床效果。 肺部 NTM 的治疗依赖于复杂、长期、耐受性差的抗生素治疗方案，这些治疗方案不如结核病的类似治疗方案有效。大西洋两岸的四个学会（ATS、IDSA、ERS 和 ESCMID）合作最近修订了 NTM 诊断和管理的国际指南。 这一基于 PICO 问题的修订版重点关注成人肺部疾病（无 CF 或 HIV/AIDS）以及北美和欧洲更常见的与疾病相关的四种物种：鸟分枝杆菌、堪萨斯分枝杆菌、爪蟾分枝杆菌和脓肿分枝杆菌（Daley CL，2020）。迫切需要更好的治疗方法。 FDA 于 2019 年 4 月召开了一次研讨会，讨论与 NTM 肺病治疗相关的临床试验设计挑战和注意事项，包括临床试验终点、持续时间和人群等主题。研讨会强调，新疗法的试验设计应结合微生物学和临床结果测量，并选择能够对这些结果测量进行可测量改变的适当研究候选者。研讨会期间强调了对较短研究设计、早期主要终点和安慰剂对照组的需求（Flume PA，2020）。 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登记处，目前登记了 3000 多名患者，部分作为治疗评估和临床试验招募的资源。对注册数据的持续分析侧重于气道清除技术（ACT）的使用与支气管扩张和咳痰患者的临床结果之间的关联。如果患者先前经历过病情加重、因肺部疾病住院或患有铜绿假单胞菌，则更频繁地使用 ACT。持续使用 ACT 的患者出现支气管扩张恶化的几率较高，这表明支气管扩张患病人群应更频繁地使用 (Basavaraj A, 2020)。 我们的湿实验室专注于 NTM 毒力评估和新型治疗策略的开发。该实验室利用了从我们的临床队列研究中的患者身上获得的丰富的系列 NTM 分离物生物储存库。 其中许多分离株已进行基因组测序，并对其体外生长和抗性表型进行了充分表征。实验室使用的临床前模型包括阿米巴原虫、斑马鱼以及气道清除能力改变的转基因小鼠模型。 最近的工作重点是评估针对脓肿分枝杆菌多重耐药（MDR）菌株的抗菌肽（AP）。合成的短阳离子 AP 对包括结核分枝杆菌在内的多种细菌表现出良好的活性。我们针对一系列参考和临床脓肿分枝杆菌菌株（包括 MDR 爆发菌株）评估了 AP 的活性，并观察到最低抑制浓度为 1.6 至 >50 g/mL。 对最活跃的 AP 的进一步研究表明，卡氏棘阿米巴能防止被摄入的脓肿分枝杆菌杀死。抗菌肽为治疗耐药脓肿分枝杆菌提供了一种有吸引力的潜在选择（da Silva JL，2020）。 根据与行业合作伙伴的合作研究和开发协议，我们的实验室研究了高剂量一氧化氮对肺脓肿分枝杆菌疾病的抗菌活性。 在同情使用治疗中，一名患有难治性肺脓肿的 CF 患者接受了新型便携式发生器的治疗，该发生器具有两个疗程的辅助间歇性 NO，范围从 160 p.p.m. 到 160 p.p.m.持续 21 天至下午 240 点，持续 8 天。利用新型 NO 暴露室对该患者分离株进行体外药敏试验，并比较临床分离株，证明脓肿分枝杆菌对 NO 的敏感性存在异质性，并表明可能需要更长的治疗方案才能减少或根除更具耐药性的肺部菌株 (Access Microbiology 2020)。