Bronchiectasis and chronic airway infection

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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).