Faculty Bibliography

RATIONALE/BACKGROUND:The discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps still remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. OBJECTIVES/OBJECTIVE:Evaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. METHODS:16S rRNA gene sequencing, cell counts, and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. MEASUREMENTS AND MAIN RESULTS/RESULTS:Lower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella and Streptococcus). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa were associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, γδT cells, PD-1+ T lymphocytes as well as higher NET levels. CONCLUSIONS:Our analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

INTRODUCTION: Bronchiectasis is a common chronic pulmonary condition characterized by inflammation and recurrent infections. There is evidence that gastroesophageal reflux disease (GERD) is associated with bronchiectasis and can increase the severity of pulmonary disease. Data regarding esophageal function in this population is sparse. We aimed to assess whether patients with bronchiectasis have an increased prevalence of esophageal motility disturbances and GERD.
METHOD(S): We conducted a single-center matched cohort study of all adult patients with confirmed bronchiectasis who underwent esophageal high-resolution manometry (HRM) between 11/ 2014-3/2018. All cases were randomly matched with a control by age (65 years) and sex. Chicago Classification 3.0 was used to characterize HRM findings. Combined multichannel intraluminal impedance-pH (pH-MII) was utilized to assess reflux burden. Statistical relationships between proportions were evaluated by Chi-square or Fisher's exact test and continuous variables were compared using t-test or rank sum test.
RESULT(S): 63 bronchiectasis patients underwent HRM, of which 54 underwent pH-MII. Of the controls, 63 underwent HRM, of which 39 underwent pH-MII. Baseline characteristics between cases and controls were similar. Mean age of bronchiectasis patients was 65 (SD 12.73), mean body mass index was 25.51 (SD 8.50), 70% were female, and 48% had a smoking history (Table). HRM did not demonstrate any significant differences between cases and controls. pH-MII trended towards a greater reflux burden among controls. However, nearly half of cases had conclusive evidence of pathologic reflux by esophageal acid exposure on pH-MII. On endoscopy, no significant differences were noted.
CONCLUSION(S): Esophageal motility and acid exposure did not significantly differ among patients with bronchiectasis and controls, which may indicate that esophageal physiology in bronchiectasis is not unique. Nevertheless, more than half of the bronchiectasis group had evidence of abnormal esophageal motility and almost half of patients had conclusive evidence of pathologic reflux. Small differences are likely due to the high prevalence of GERD and associated motility disorders in the control group. Larger studies are warranted to further characterize esophageal physiology in these patients and the potential impact on pulmonary pathology. (Table Presented)

Introduction: Non-tuberculous mycobacteria (NTM) is an intracellular microorganism that causes cavitary disease and nodular bronchiectatic disease of the lung. Patients with NTM appear to have impaired swallow function as represented by impaired airway protection and pharyngeal bolus clearance. It is unknown whether impaired swallowing contributes to the pathophysiology of NTM. Our aim is to determine swallow physiology in patients with bronchiectasis and NTM compared with a control group.
Method(s): Video fluoroscopy (VF) was prospectively collected from 195 patients: 132 patients with NTM (90 females; ages 30-90) and 63 agematched and sex-matched controlswith noNTM(39 females; ages 27-92). Two boluses of 3, 5, 10ml thin liquid, two 5ml puree Varibar, and cracker were analyzed per subject (N = 1755 swallows). Outcome measures included ordinal ratings of residue in the valleculae and pyriform sinuses.
Result(s): Inter-and intra-rater reliability of the ordinal ratings were assessed using one-way mixed intraclass correlation coefficients (ICC) (ICC(2,1)) on 20% of the data with good results (intra-rater: ICC = 0.92, 95% range CI 0.70-0.97 and inter-rater: ICC = 0.92, 95% range CI 0.81-0.97). The ratings of residue in the valleculae were significantly higher (worse) in the NTM group compared to the control group for one of the 3mL bolus (p = 0.008), for both 5 mL boluses (p = 0.009 and p = 0.004), both 10mL boluses (p = 0.0005 and p = 0.0006), puree (p = 0.006), cracker (p = 0.005). The ratings of residue in the pyriform sinuses were also significantly higher in the NTM group for 3 mL boluses (p = 0.0002 and p = 0.01), both 5 mL boluses (p = 0.0003 and p = 0.002), both 10mL boluses (p = 0.001 and p = 0.001), both puree trials (p<0.0001 and p<0.0001).
Conclusion(s): Future work is needed to elucidate responsiveness to swallowing treatment for patients with NTM