Faculty Bibliography

INTRODUCTION/BACKGROUND:-variation with greater time post-9/11/2001 will be a mortality risk-factor associated with cross sectional BMI and longitudinal weight-variation. METHODS:-variation. RESULTS:-variation (OR = 1.18; 95% CI 1.06, 1.27 and OR = 1.17; 95% CI 1.07, 1.27 respectively). INTERPRETATION/CONCLUSIONS:-variation and weight-variation may reflect concurrent metabolic and pulmonary instability that increase vulnerability to death.

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.

RATIONALE/BACKGROUND:-variation is a risk-factor for death in cystic fibrosis but has not been studied in other cohorts. OBJECTIVE:-variation is a mortality risk-factor in World Trade Center (WTC) exposed FDNY rescue/recovery workers. METHODS:related risk-factors and mortality. Receiver operating characteristic area under the curve (ROC-AUC) assessed predictive model performance. MEASUREMENTS AND MAIN RESULTS/RESULTS:-variation (top-quartile, ≥10.35 ml/year) increased 25% (OR=1.25; 95%CI=1.12-1.40). CONCLUSIONS:-decline. Further investigation in other cohorts is needed to assess the generalizability of this rarely studied mortality risk-factor.

Variations in the airway microbiome are associated with inflammatory responses in the lung and pulmonary disease outcomes. Regional changes in microbiome composition could have spatial effects on the metabolic environment, contributing to differences in the host response. Here, we profiled the respiratory microbiome (metagenome/metatranscriptome) and metabolome of a patient cohort, uncovering topographical differences in microbial function, which were further delineated using isotope probing in mice. In humans, the functional activity of taxa varied across the respiratory tract and correlated with immunomodulatory metabolites such as glutamic acid/glutamate and methionine. Common oral commensals, such as Prevotella, Streptococcus, and Veillonella, were more functionally active in the lower airways. Inoculating mice with these commensals led to regional increases in several metabolites, notably methionine and tyrosine. Isotope labeling validated the contribution of Prevotella melaninogenica in generating specific metabolites. This functional characterization of microbial communities reveals topographical changes in the lung metabolome and potential impacts on host responses.

PURPOSE/OBJECTIVE:World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS:This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS:ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS:The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.