Bronchiectasis and chronic airway infection

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

The development or progression of chronic airway disease associated with nontuberculous mycobacteria (NTM) is seen in association with known genetic diseases such as cystic fibrosis (CF) or primary ciliary dyskinesia and with underlying structural lung diseases such as COPD and bronchiectasis. The pathogenesis of chronic NTM lung infection in many cases is likely a combination of genetic risk and environmental factors. Ongoing collaborative work on environmental risks has focused on high risk geographic areas such as the Hawaiian islands which also have a diverse ethnic population with varying risks (Blakney. Emerg Infect Dis, 2022). The high prevalence of NTM in CF Centers has led to work on development of a tool for combining mycobacterial genomic comparison of patient isolates with environmental source investigations within CF Centers to distinguish NTM transmission from nosocomial and home environmental acquisition (Gross. PLoS, 2021; Olivier 2022). Environmental and host factors related to person-to-person spread of other infections such as tuberculosis and COVID-19 have also been a focus of lab members with recent work drawing similarity between these two infections (Dheda. Lancet Respir Med, 2022; Fennelly. Am J Respir Crit Care Med, 2021). The ongoing bronchiectasis and NTM natural history study has continued to focus on patients with more advanced stages of disease and infection which has allowed work on both therapeutic development and assessment of factors leading to disease progression. Recent retrospective analysis of our cohort identified quantifiable disease measures such as the distance achieved on a standardized 6 minute walk test and progression of symptoms on a standardized patient reported outcome measure which predict short term mortality in patients with bronchiectasis and a predominance of chronic NTM infections (Blakney. BMC Infect Dis, 2022). Historically, treatment options for patients with chronic NTM lung infections have been limited with poor efficacy and tolerability and requiring treatment course of many months to years. Fortunately, following FDA approval of the first drug targeting pulmonary NTM infections in 2018, there has been a steady increase in interest among academia, biotech and biopharma in redirecting and developing drugs with target NTM disease. This has led to increased attention from FDA on providing guidance for clinical trial design and outcome measures for drugs entering this field. A recent collaborative workshop between investigators, industry and FDA led to the first ever drug development guideline for pulmonary M. avium complex disease (Flume. Chest 2021). Multi-society and multi-national guidelines have also been published to guide the treatment of both common causes of NTM lung disease and more recently, less common causes of NTM lung disease (Lange. Lancet Infect Dis, 2022). Lab efforts have continued to focus on preclinical model development for assessment of NTM virulence factors and identification of therapeutic targets as well as assessment of safety and efficacy of promising compounds which might be candidates for further therapeutic development. We have found that myosteatosis, i.e., intramuscular fat in chest wall muscles, is a predictor of mortality and poor outcomes in our cohort. We are now engaging in studies of myokines and adipokines that may be associated with myosteatosis. The use of highly effective CFTR modulator therapy has resulted in quite remarkable improvements in many aspects of CF disease status. Recent interested has looked at the role these drugs may have in reducing the significance of chronic infections such as Pseudomonas and NTM. Data from the US CF Foundation Patient Registry was used to examine the effect of CFTR modulators on the risk of positive NTM sputum cultures and showed a notable reduction in incidence among those on monotherapy and combination CFTR modulator therapy (Ricotta. ERJ Open Res, 2022). There remain delays in disease recognition and diagnosis, questions related to modifiable risk factors, and work to be done to improve therapeutic options for bronchiectasis and chronic airway infections like NTM. New diagnostics we are developing include the collection of microbial aerosols using the PExA instrument and face-mask sampling. This may be especially helpful for patients who cannot produce sputum specimens. However, the increased attention to addressing these issues is resulting in a brighter outlook for those affected by these conditions.