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疾病（例如COPD或支气管扩张）的情况下，与原发性纤毛发育不良（PCD）或囊性纤维化相关（CF）（CF）（Richards CJ，2019年）。 来自医疗保险和健康计划联盟等大量现有资源的基于人群的数据表明，NTM肺部疾病的患病率增加。 但是，从这些基于诊断的基于诊断的分析中尚不清楚NTM的测试增加了多少有助于疾病报告。为了检查测试趋势，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，这是31 US设施的临床遭遇数据存储库。从2009 - 2015年开始，分枝杆菌测试的平均年增长率（3.2％/年； 95％CI 1.9％4.5％）和致病性NTM物种的培养阳性（4.5％/年； 95％CI 1.2％1.2％7.9％）在所有设施中都均已发现。测试在老年人中更为普遍，测试和阳性率在亚洲人中以较高的速度（9.8％/年； 95％CI 6.4％13.4％）和CF（26.6％/年； 95％CI 15.2％39.8％）；这些群体的NTM阳性培养率也更高（Dean SG，2020年）。 据认为，肺动物感染可能是从吸入环境气溶胶中获得的。 然而，人们对CF患者主要对与暴发相关的人为人物的传播越来越关注，这表明与评估CF患者的结核病或假单胞菌感染患者的咳嗽气溶胶传播研究可能具有调查作用。 由于目前的Covid-19大流行对TB气溶胶感染评估技术的专业知识，我们实验室中的专业知识吸引了人们的关注越来越高（Dheda K，2019; Fennelly KP，2020; Fennelly KP，2020; Fennelly KP，2019; Theron G，2020年）。 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NTM感染患者，主要发生在老年女性中。 家族聚类，共享的表型特征和相关的遗传风险等位基因先前报道的所有人都表明，在这些感染的发病机理中改变了宿主易感性的关键作用。 IL-12/IFN轴中的遗传缺陷与传播的NTM感染有关。为了评估肺部感染患者的免疫表型，我们测量了刺激性TH1，TH2，TH17和TREG细胞因子，以及与健康的供体和CF或PCD的肺NTM疾病患者相比，特发性NTM患者的细胞中细胞中刺激性刺激因子的反应。特发性PNTM疾病患者的IL-12/IFN轴功能正常。但是，特发性PNTM患者降低了Th17的反应，而分枝杆菌诱导的单核细胞GM-CSF表达（Wu UI，2019）。 我们组的先前发病机理的工作表明，特发性NTM感染患者的呼吸睫状功能改变了，我们先前证明了通过将纤毛频率恢复到正常体外的能力，通过将一氧化氮（NO）类似物或PDE5抑制剂sildenafil应用于骨膜上皮细胞中的PDE55抑制剂Sildenafil，来自肺炎肺部ntm polmonary NTM。 在I/II阶段试验证明中，肺NTM患者接受西地那非30天，每天20毫克升级至40 mg。 单剂量为40 mg西地那非，在纤毛搏动频率上增加了对西地那非的剂量反应，在延长了40毫克西地那非的剂量后，没有看到20毫克的给药。痰于生产，鼻腔无生产或生活质量措施没有变化（Fowler C，2020）。 可能有必要评估西地那非对NTM感染易感性的长期临床影响的进一步研究。 肺NTM的治疗取决于复杂，延长，耐受性较差的抗生素方案，抗生素方案不如结核病那样有效。最近，大西洋两岸的四个社会（ATS，IDSA，ERS和ESCMID）合作对NTM诊断和管理的国际指南进行了修订。 基于PICO问题的修订侧重于成年人（没有CF或HIV/AIDS）的肺部疾病，其中四种与北美和欧洲更常见的物种有关：M。Avium Complex，M。Kansasii，M。Xenopi和M. abscessus（Daley CL，2020年）。迫切需要更好的治疗方法。 FDA于2019年4月召集了一个研讨会，讨论了与NTM肺部疾病治疗有关的临床试验设计挑战和考虑因素，包括临床试验终点，持续时间和人群等主题。研讨会强调，新治疗剂的试验设计应纳入微生物和临床结果指标，并选择具有可测量变化此类结果指标的适当研究候选者。在研讨会期间，突出了对较短的研究设计，早期主要终点和安慰剂控制臂的需求（Flume PA，2020）。 2008年，我们的实验室与校外学术伙伴一起开发了一项美国支气管扩张研究登记册，目前有3000多名患者入学，部分是用于治疗评估和招募临床试验的资源。继续分析注册表数据，重点是气道通关技术（ACT）使用与支气管扩张患者的临床结局与生产性咳嗽之间的关联。如果患者事先经历了病毒，肺部疾病的住院治疗或患有铜绿假单胞菌，则该行为的使用频率更高。在使用行为不断提示在疾病的支气管巴斯班种群中使用更频繁使用的患者，支气管扩张加剧的发展几率较高（Basavaraj a，2020年）。 我们的湿实验室的重点是评估NTM毒力和新型治疗策略的发展。在我们的临床队列研究中，该实验室利用了从患者获得的综合NTM分离株的丰富生物孔。 这些分离株中的许多具有测序的基因组，并且在体外生长和耐药表型中表征良好。实验室中使用的临床前模型范围从变形虫到斑马鱼再到具有改变气道间隙的转基因小鼠模型。 最近的工作着重于评估抗菌肽（AP）针对腹部支原体的多药耐药性（MDR）菌株的评估。合成短阳离子AP对包括结核分枝杆菌的各种细菌表现出良好的活性。我们根据包括MDR爆发菌株（MDR爆发菌株）的一系列参考和临床分枝杆菌菌株评估了活性AP，并观察到最小的抑制浓度为1.6至> 50 g/ml。 与最活跃的AP的进一步合作表明，对Acanthamoeba Castellanii的保护免受摄入的M. Abscessus的杀戮。抗菌肽为治疗耐药性腹部的抗药性选择提供了吸引人的潜在选择（Da Silva JL，2020年）。 根据与行业合作伙伴的合作研究与发展协议，我们的实验室调查了高剂量一氧化氮对肺部腹肌疾病的抗菌活性。 在富有同情心的治疗中，通过一种新型的便携式发电机进行了治疗难治性肺部的CF患者，具有两个辅助性间歇性无范围从160 p.p.p.在21天到240 p.p.m，持续8天。利用新型的NO暴露室对该患者分离型，比较临床分离株表现出在脱绝对的NO敏感性中的异质性，并建议需要更长的治疗方案来查看更长的治疗方案，以查看更耐抗性的肺部菌株（访问微生物学2020），因此对临床分离株进行了异质性（2020年）。