Understanding acquisition and evolution of antifungal resistance in chronic respiratory disease

了解慢性呼吸道疾病抗真菌耐药性的获得和演变

• 批准号: MR/T005572/1
• 负责人: Anand Shah
• 金额: $ 26.13万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT005572%2F1
• 关键词: Understanding; acquisition; evolution; antifungal; resistance

Aspergillus fumigatus is a mould that can cause a wide spectrum of clinical syndromes. The effects of A. fumigatus depend largely on the interplay between the pathogen and host immune response ranging from asymptomatic colonisation to life-threatening infection. Invasive aspergillosis (IA), the most severe form of A. fumigatus infection, predominantly affects immunocompromised patients while immune hyperactivity that can lead to allergic bronchopulmonary aspergillosis (ABPA), characterised with progressive airway destruction and mucus impaction. Patients with pre-existing chronic respiratory disease (e.g. bronchiectasis including cystic fibrosis (CF)) are particularly susceptible to infection and allergy to A. fumigatus. In these individuals, A. fumigatus can result in lung cavity formation or infection of pre-existing cavities (mycetoma), ABPA development, or airway limited infection called tracheobronchitis. There is an increasing recognition of the causative and destructive role of A. fumigatus within chronic respiratory disease. Global estimates of chronic pulmonary aspergillosis are ~3 million cases. A high prevalence of Aspergillus-associated disease in non-CF bronchiectasis has recently been shown with ~300,000 bronchiectasis patients estimated in the UK. Aspergillus-associated lung disease (e.g. ABPA, bronchitis, colonisation) has been shown in up to ~20% of individuals with CF and has been shown to be associated with an increased hospitalisation rate. Chronic obstructive pulmonary disease remains a significant risk factor for development of invasive aspergillosis with high mortality.Triazoles are the most widely used antifungal agents in treatment of Aspergillus-related infection and allergy in chronic respiratory disease. Over the last decade, however, there has been increasing reports of A. fumigatus multiple tri-azole resistance (MTR) with subsequent treatment failure and increased mortality. Within individuals with chronic respiratory disease we have shown a prevalence of azole resistant A. fumigatus of ~15%. In the majority of these isolates, an environmentally driven mutation (TR34) is the cause of resistance; however the route of acquisition and evolution of MTR within individuals with chronic respiratory disease is as yet unclear. The rapid emergence and global spread of A. fumigatus MTR isolates, however, has raised the realistic possibility that in the future mould-active azoles may cease to be effective.Early detection of infection and resistance is key to outcome within chronic respiratory disease. Detection of A. fumigatus and MTR, however, is hampered by limitations in current fungal culture diagnostics which have poor sensitivity, and resistance detection, which is time-consuming, labour-intensive and costly. Through this project, we aim to validate a novel rapid assay (TR34-LAMP) to detect A. fumigatus and MTR isolates and advance our understanding of the evolution of MTR in chronic respiratory disease. The TR34-LAMP assay will be used to detect A. fumigatus and MTR directly in sputum from individuals with chronic respiratory disease whilst analysing prevalence of MTR in a large well-characterised cohort of bronchiectasis patients. This assay has the potential through a 'lab-on-a-chip' based format to enable accurate, low-cost, rapid, point-of-care detection of A. fumigatus MTR. To further understand the genomic evolution and acquisition of A. fumigatus MTR in chronic respiratory disease, a prospective whole genome sequencing approach will be used to analyse longitudinal A. fumigatus isolates from individuals with chronic respiratory disease starting antifungal therapy across 2 distinct clinical and geographical sites. Comprehensive environmental and cohort sampling will be performed to analyse acquisition and evolution of A. fumigatus MTR. This information will critically inform future infection control and antimicrobial stewardship strategies across chronic respiratory care.

烟曲霉是一种霉菌，可引起广泛的临床综合征。烟曲霉的影响很大程度上取决于病原体和宿主免疫反应之间的相互作用，从无症状定植到危及生命的感染。侵袭性曲霉病（IA）是烟曲霉感染的最严重形式，主要影响免疫功能受损的患者，而免疫过度活跃可导致过敏性支气管肺曲霉病（ABPA），其特征是进行性气道破坏和粘液淤塞。既往患有慢性呼吸道疾病（如支气管扩张包括囊性纤维化）的患者特别容易感染和对烟曲霉过敏。在这些个体中，烟曲霉可导致肺部空洞形成或先前存在的空洞感染（足菌肿），ABPA发展或气道有限感染（气管支气管炎）。人们越来越认识到烟曲霉在慢性呼吸道疾病中的致病和破坏作用。全球估计慢性肺曲霉病约有300万例。在非cf支气管扩张中，曲霉菌相关疾病的高流行率最近显示在英国估计约有30万名支气管扩张患者。曲霉相关的肺部疾病（如ABPA、支气管炎、菌落）已在多达20%的CF患者中显示，并已显示与住院率增加有关。慢性阻塞性肺疾病仍然是侵袭性曲霉病发展的重要危险因素，死亡率高。三唑类药物是目前应用最广泛的抗真菌药物，用于治疗慢性呼吸道疾病中曲霉相关感染和过敏。然而，在过去十年中，烟曲霉多重三唑耐药（MTR）的报道越来越多，随后的治疗失败和死亡率增加。在患有慢性呼吸道疾病的个体中，我们发现抗唑烟曲霉的患病率约为15%。在大多数分离株中，环境驱动突变（TR34）是耐药性的原因；然而，慢性呼吸道疾病患者体内MTR的获得和进化途径尚不清楚。然而，烟曲霉MTR分离物的迅速出现和全球传播，提出了在未来霉菌活性唑可能不再有效的现实可能性。早期发现感染和耐药性对慢性呼吸道疾病的预后至关重要。然而，烟曲霉和MTR的检测受到当前真菌培养诊断的限制，这些诊断灵敏度较差，而且耐药性检测耗时、费力且昂贵。通过本项目，我们旨在验证一种新的快速检测烟曲霉和MTR分离物的方法（TR34-LAMP），并进一步了解MTR在慢性呼吸道疾病中的演变。TR34-LAMP检测将用于慢性呼吸道疾病患者的痰中直接检测烟曲霉和MTR，同时分析MTR在一大群特征明确的支气管扩张患者中的流行情况。这种基于“芯片实验室”的检测方法有潜力实现烟曲霉MTR的准确、低成本、快速、即时检测。为了进一步了解烟曲霉MTR在慢性呼吸道疾病中的基因组进化和获取，研究人员将采用前瞻性全基因组测序方法分析2个不同临床和地理地点开始抗真菌治疗的慢性呼吸道疾病个体的烟曲霉纵向分离株。将进行全面的环境和群体抽样，分析烟曲霉MTR的获取和进化。这一信息将为未来的感染控制和抗微生物药物管理策略提供重要信息，并贯穿慢性呼吸道护理。

项目成果

Healthcare Utilization and Impact of Antifungal Stewardships Within Respiratory Care Settings: A Systematic Literature Review.

• DOI: 10.1007/s11046-021-00547-z
• 发表时间: 2021-10
• 期刊: Mycopathologia
• 影响因子: 5.5
• 作者: Aldossary S;Shah A
• 通讯作者: Shah A

Using Artificial Intelligence in Fungal Lung Disease: CPA CT Imaging as an Example.

• DOI: 10.1007/s11046-021-00546-0
• 发表时间: 2021-10
• 期刊: Mycopathologia
• 影响因子: 5.5
• 作者: Angelini E;Shah A
• 通讯作者: Shah A

Review of current and future therapeutics in ABPA.

回顾ABPA的当前和未来治疗剂。

• DOI: 10.1177/20406223211047003
• 发表时间: 2021
• 期刊: Therapeutic advances in chronic disease
• 影响因子: 3.5
• 作者: Lewington-Gower E;Chan L;Shah A
• 通讯作者: Shah A

A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

• DOI: 10.1093/jacamr/dlab026
• 发表时间: 2021-03
• 期刊: JAC-antimicrobial resistance
• 影响因子: 3.4
• 作者: Di Paolo M;Hewitt L;Nwanko E;Ni M;Vidal-Diaz A;Fisher MC;Armstrong-James D;Shah A
• 通讯作者: Shah A

CF Fungal Disease in the Age of CFTR Modulators.

• DOI: 10.1007/s11046-021-00541-5
• 发表时间: 2021-10
• 期刊: Mycopathologia
• 影响因子: 5.5
• 作者: Bercusson A;Jarvis G;Shah A
• 通讯作者: Shah A