Bronchiectasis and chronic airway infection

National Heart, Lung, And Blood Institute

Investigators

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Abstract

Chronic lung infections with environmental organisms such as Pseudomonas are commonly associated with bronchiectasis in patients who do not have cystic fibrosis (CF) and are felt to contribute to disease severity. Utilizing data from the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (USBRR), which includes patients from our natural history cohort, association was assessed between the presence of Pseudomonas and lung disease severity measured with the modified Bronchiectasis Severity Index (m-BSI) and modified FACED bronchiectasis severity instruments. Pseudomonas was identified in 25.4% of patients and was associated with significantly lower mean FEV1% relative to patients without Pseudomonas (62.8% ve 73.7%, p <0.0001). Patients with Pseudomonas had greater odds of high (ORadj 6.15, CI95% 3.98-9.50) and intermediate (ORadj 2.06, CI95% 1.37-3.09) severity relative to low severity on the m-BSI (Choate R, 2020). Similarly, the USBRR was utilized to assess the relationship between nutrition and health outcomes in non-CF bronchiectasis. Patients were stratified into categories using body mass index (BMI) and assessed for association with markers of disease severity. The retrospective study included 496 patients (mean age 64.6+/-13 years; 83.3% female) categorized as underweight (BMI<18.5kg/m2, 12.3%), normal weight (BMI>=18.5 and <25, 17.3%, 63.9%), overweight (BMI>=25 and < 30, 17.3%) and obese (BMI>=30, 6.5%). Underweight patients had lower lung function than other weight groups (FEV1%, 64.5 22, versus 73.5 21, 68.5 20, and 76.5 21 in normal, overweight, and obese groups respectively, p = 0.02). No significant differences were noted between BMI groups for other disease severity markers at baseline (Despotes KA, 2020). Genetic variation in both the host, conferring increased susceptibility and the infecting organisms, affecting transmissibility or virulence, are felt to contribute to disease pathogenesis in patients with bronchiectasis associated with NTM. A genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary infections with M. avium complex (MAC) and healthy controls with subsequent genotyping of single-nucleotide polymorphisms in a 2nd Japanese cohort, a Korean cohort and a cohort from our natural history study comprised of predominantly European ancestry. The GWAS and replication analyses of 591 pulmonary MAC cases and 718 controls revealed an association with rs109592 on chromosome 16p21 (OR 0.54, p=1.64 x10-13). This is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression and CHP2 was expressed in lung tissue from pulmonary MAC disease patients. This SNP was similarly associated with disease in patients of Korean (OR 0.54, p=2.181012) and European (OR 0.63, p=5.121003,) ancestry suggesting a possible common host susceptibility marker for pulmonary MAC disease (Namkoong H, 2021). There have been reports of pulmonary disease outbreaks associated a dominant clone (Clone 1) of Mycobacterium abscessus subspecies massiliense (M. massiliense) in the US and UK. To determine the prevalence of Clone 1 in the US and the relationship of sporadic US isolates to outbreak clones, a reference US mycobacteria laboratory (which included nonCF patient isolates from our cohort) and a US biorepository of CF-associated isolates for Clone 1 and compared genomic variation and antimicrobial resistance mutations between sporadic non-CF, CF and outbreak Clone 1 isolates. Pulmonary and extrapulmonary infections with M. massiliense Clone 1 were noted in 57/147 (39%) of non-CF patients compared with 11/64 (17%) of patients in the CF biorepository. Outbreak and sporadic isolates had similar numbers of SNPs and accessory genes; however, outbreak isolates were more likely to have antimicrobial resistance mutations. Additional studies are needed to better understand routes of transmission and spread (Davidson RM, 2021). Diagnosis and follow-up of bronchiectasis has traditionally relied on CT imaging which can be associated with increased risks of radiation exposure especially in children. A novel low field, respiratory triggered T2-weighted turbo spin-echo 0.55-T MRI system for imaging lung disease was compared with clinical CT images in 24 participants with common lung abnormalities including bronchiectasis. High quality structural pulmonary MR images were attained with an acquisition time of 11+/-3 minutes. The MRI images were of sufficient quality to detect bronchiectasis (k=0.61), consolidation (k=1.00), cavities (k=1.0), mucus plugging (k=0.68) and solide scattered nodules (k=0.82).Tree-in-bud nodules, commonly seen with NTM disease were more difficult to discern with MRI (k=0.48). This initial study shows potential use MRI for evaluation of bronchiectasis (Campbell-Washburn, 2021). 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).