Prospective Longitudinal Assessment of Culture-Independent Molecular Airway Markers of Nontuberculous Mycobacteria

非结核分枝杆菌培养独立分子气道标志物的前瞻性纵向评估

• 批准号: 10063561
• 负责人: Jane HIll
• 金额: $ 41万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-23 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063561
• 关键词: Adult; Advanced Development; Airway Disease; Algorithms; Ancillary Study; Antibiotic Resistance; Bacteria; Base Sequence; Biological Assay; Childhood; Clinical; Clinical Research; Clinical Trials Design; Cross-Sectional Studies; Cystic Fibrosis; Data; Data Analyses; Decontamination; Detection; Diagnosis; Disease; Early Diagnosis; Evaluation; Foundations; Functional disorder; Future; Genes; Goals; Gold; Growth; Individual; Indolent; Infection; Lung diseases; Metabolic; Molecular; Monitor; Mycobacterium Infections; National Heart, Lung, and Blood Institute; Obstructive Lung Diseases; Pathogenesis; Patient Care; Patients; Pattern; Periodicity; Physicians; Population; Populations at Risk; Procedures; Protocols documentation; Research; Risk; Sampling; Signal Transduction; Sputum; Standardization; Surveys; Testing; Time; base; clinical predictors; clinically significant; co-infection; cystic fibrosis airway; cystic fibrosis patients; disability; longitudinal analysis; molecular marker; non-tuberculosis mycobacteria; pathogen; patient population; patient screening; programs; prospective; resistance mutation; respiratory; response; treatment duration; treatment response

A preponderance of evidence has identified nontuberculous mycobacteria (NTM) as important pathogens in cystic fibrosis (CF) and other obstructive lung diseases. Currently, airway cultures are the “gold standard” by which all diagnosis and treatment decisions are based. The lack of sensitive and specific markers of NTM in the airway impedes patient care and clinical trial design. Culture-independent markers of NTM infection have the potential to overcome many of the limitations of standard NTM cultures, especially the very slow growth (up to 8 weeks), inability to quantitate bacterial burden, and low sensitivity due to required decontamination procedures. Preliminary data from analysis of volatile metabolites and multiplex gene sequencing performed simultaneously on the same sputum samples have demonstrated rapid, quantifiable detection of the presence of NTM that exceeds the sensitivity of standard cultures. In 2018, the CF Foundation-sponsored PREDICT (PRospective Evaluation of NTM Disease In CysTic Fibrosis, NCT02073409) and PATIENCE (Prospective Algorithm for Treatment of NTM in Cystic Fibrosis, NCT02419989) trials will be expanded to 10 CF Programs nationwide to standardize the diagnosis and test a protocol-based approach to treatment of NTM pulmonary disease. These trials represent an ideal platform to advance development of molecular markers of NTM disease status. In response to PAR-18-643 NHLBI Clinical Ancillary Studies, this proposal will test the Central Hypothesis: Culture-independent marker sets have advantages over sputum cultures for detecting presence of bacteria, predicting clinical significance and assessing treatment response of NTM in the CF airway. As a time-sensitive ancillary study to the PREDICT and PATIENCE trials, Aim 1 will test the utility of sputum volatile metabolites as culture-independent markers of airway NTM. Aim 2 will test the utility of sputum multiplex gene sequencing as molecular markers of airway NTM, and Aim 3 will test the combination of volatile metabolites and multiplex gene sequencing data combined with standard culture results to identify subjects more likely to develop NTM disease and/or respond to treatment. If successful, the cross-sectional and longitudinal analyses of samples from pediatric and adult patients with well-defined NTM infection status will reveal the strengths and weakness of each assay alone and combined, in comparison to standard culture for the detection and identification of NTM in the presence of bacterial co- infection. These markers can be applied to periodic screening of patient populations at risk for NTM to facilitate early detection. In addition, these assays have the potential to differentiate between indolent infection and NTM disease, as well as longitudinal monitoring of response to treatment and determination if eradication of the pathogen has been achieved or a subclinical threshold has been reached, which could signal end of treatment. The long-term goal is to deliver validated markers of NTM airway disease to the CF patient population, with applicability to all patient populations with respiratory conditions at risk for NTM disease.

大量证据表明，非结核分枝杆菌（NTM）是一种重要的致病菌