Faculty Bibliography

BACKGROUND:Previously healthy firefighters with World Trade Center (WTC) dust exposure developed airway disease. Risk factors for irritant-associated asthma/COPD overlap are poorly defined. METHODS:/FVC ratio, and BMI included as covariates. RESULTS:BD-PFT diagnosed asthma/COPD overlap in 99 individuals (4.6%), isolated-asthma in 202 (9.5%), and isolated-COPD in 215 (10.1%). Eosinophil concentration≥300 cells/μl was associated with increased risk of asthma/COPD overlap (HR: 1.85, 95% CI: 1.16-2.95), but not with isolated-asthma or isolated-COPD. Serum IL-4 also predicted asthma/COPD overlap (HR: 1.51 per doubling of cytokine concentration, 95% CI: 1.17-1.95). Greater IL-21 concentration was associated with both isolated-asthma and isolated-COPD (HR: 1.73, 95% CI: 1.27-2.35 and HR: 2.06, 95% CI: 1.31-3.23, respectively). CONCLUSIONS:In WTC-exposed firefighters, elevated blood eosinophils and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific Th-2 biomarkers present years before diagnosis suggest patient-intrinsic predisposition to irritant-associated asthma/COPD overlap.

BACKGROUND:The goals of this study were to assess the impact of work at the World Trade Center (WTC) site in relation to new, post-9/11/2001 (9/11) antibody to hepatitis C Virus (anti-HCV); and, evaluate secular trends in WTC-exposed male Fire Department of New York City (FDNY) Firefighters and Emergency Medical Services (EMS) responders. METHODS:FDNY monitors responder health through physical exams and routine blood work. We used descriptive statistics to compare trans-9/11 and post-9/11 incidence and to assess trends in prevalence from 2000 to 2012. RESULTS:Trans-9/11 incidence of new anti-HCV was 0.42 per 100 persons compared with post-9/11 incidence of 0.34 (P = 0.68). Overall seroprevalence was 1.3%; rates declined from 1.79 per 100 to 0.49 per 100 over time (P < 0.0001). CONCLUSIONS:Work at the WTC was not associated with new infection. Biennial seroprevalence in responders declined over time, supporting the FDNY decision to discontinue routine annual testing in this cohort.

BACKGROUND:In lung cancer, upregulation of the PI3K pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS:Airway brushes were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with non-cancer diagnosis. Additionally, samples from 10 healthy control subjects were included. 16S rRNA gene amplicon sequencing and paired transcriptome sequencing (RNAseq) were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. RESULTS:The composition of the lower airway transcriptome in the cancer patients was significantly different from the controls, which included upregulation of ERK and PI3K signaling pathways. The lower airways of lung cancer patients were enriched for oral taxa (Streptococcus and Veillonella), which was associated with upregulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. CONCLUSIONS:The data presented here shows that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.

RATIONALE: Rescue/recovery work at the World Trade Center (WTC) disaster site caused a proximate decline in lung function in Fire Department of the City of New York (FDNY) firefighters. A subset of this cohort experienced an accelerated rate of lung function decline over 15 years of post-9/11 follow-up. OBJECTIVES: To determine if post-exposure inflammatory cell concentrations are biomarkers for subsequent forced expiratory volume (FEV1) decline and incident airflow limitation. METHODS: Individual rates of FEV1 change were calculated for 9,434 firefighters using 88,709 spirometric measurements taken between 9/11/2001 (9/11) and 9/10/2016. We categorized FEV1 change rates into three trajectories: accelerated FEV1 decline (FEV1 loss >64 ml/year), expected FEV1 decline (FEV1 loss between 0-64 ml/year), and improved FEV1 (positive rate of change >0 ml/year). Occurrence of FEV1/FVC<0.70 after 9/11 defined incident airflow limitation. Regression models assessed associations of post-9/11 blood eosinophil and neutrophil concentrations with subsequent FEV1 decline and airflow limitation, adjusted for age, race, smoking, height, WTC exposure level, weight change and baseline lung function. RESULTS: Accelerated FEV1 decline occurred in 12.7% of participants (1,199/9,434), while post-9/11 FEV1 improvement occurred in 8.3% (780/9,434). Eosinophil and neutrophil concentrations were both associated with accelerated vs. expected FEV1 decline after adjustment for covariates (OR: 1.10 per 100 eosinophils/microl, 95% CI: 1.05-1.15 and OR: 1.10 per 1,000 neutrophils/microl, 95% CI: 1.05-1.15). Multivariable-adjusted linear regression models showed that neutrophil concentration was associated with FEV1 decline rate (1.14 ml/year decline per 1000 neutrophils/microl, 95% CI: 0.69-1.60 ml/year, p<0.001), while eosinophil concentration was associated with FEV1 decline rate in ever-smokers (1.46 ml/year decline per 100 eosinophils/microl, 95% CI: 0.65-2.26 ml/year, p<0.001) but not in never-smokers (p for interaction=0.004). Eosinophil concentration was also associated with incident airflow limitation (adjusted HR: 1.10 per 100 eosinophils/microl, 95% CI: 1.04-1.15). Compared with the expected FEV1 decline group, individuals experiencing accelerated FEV1 decline were more likely to have incident airflow limitation (adjusted OR: 4.12, 95% CI: 3.30-5.14). CONCLUSIONS: Elevated post-9/11 blood inflammatory cell concentrations were risk factors for subsequent accelerated FEV1 decline in WTC-exposed firefighters. Accelerated FEV1 decline was associated with incident airflow limitation, suggesting progressive airway injury in this subgroup.

BACKGROUND: Sarcoidosis is thought to represent a genetically-primed, abnormal immune response to an antigen exposure or inflammatory trigger, with both genetic and environmental factors playing a role in disease onset and phenotypic expression. In a population of firefighters with post-WTC-9/11/2001 (9/11) sarcoidosis, we have a unique opportunity to describe the clinical course of incident sarcoidosis during the 15-years post-exposure and, on average, 8-years after diagnosis. METHODS: Among the WTC-exposed cohort, 74 firefighters with post-9/11 sarcoidosis were identified through medical records review. 59 were enrolled in follow-up studies. For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases organ assessment tool was used to categorize sarcoidosis involvement of each organ system at time of diagnosis and at follow-up. RESULTS: The incidence of sarcoidosis post-9/11 was 25/100,000. Radiographic resolution of intrathoracic involvement occurred in 24 (45%). Lung function for nearly all was within normal limits. Extrathoracic involvement increased, most prominently joints (15%) and cardiac (16%). There was no evidence for calcium dysmetabolism. Few had ocular (5%) or skin (2%) involvement. None had beryllium sensitization. Most (76%) did not receive any treatment. CONCLUSIONS: Extrathoracic disease was more prevalent in WTC-related sarcoidosis than reported for sarcoidosis patients without WTC-exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Cardiac involvement would have been missed if evaluation stopped after electrocardiogram, 48-hour recordings and echocardiogram. Our results also support the need for advanced cardiac screening in asymptomatic patients with strenuous, stressful, public safety occupations, given the potential fatality of a missed diagnosis.

INTRODUCTION: The World Trade Center (WTC) disaster released a huge quantity and variety of toxicants into the environment. To-date, studies from each of the three major cohorts of WTC-exposed workers have suggested "greater than expected" numbers of post-9/11 cases in some workers. We undertook this study to estimate the incidence of post-9/11 sarcoidosis in approximately 13,000 male firefighters and EMS workers enrolled in The Fire Department of the City of New York (FDNY) WTC Health Program; to compare FDNY incidence to rates from unexposed, demographically similar men in the Rochester Epidemiology Project (REP); and, to examine rates by level of WTC exposure. METHODS: We calculated incidence of sarcoidosis diagnosed from 9/12/2001 to 9/11/2015, and generated expected sex- and age-specific rates based on REP rates. Standardized incidence ratios (SIR) based on REP rates, and 95% confidence intervals (95% CI) were estimated. Two sensitivity analyses limited cases to those with intra-thoracic symptoms or biopsy confirmation. RESULTS: We identified 68 post-9/11 cases in the FDNY cohort. Overall, FDNY rates were significantly higher than expected rates (SIR = 2.8; 95% CI = 2.2, 3.6). Including only symptomatic cases, the SIR decreased (SIR = 2.2; 95% CI = 1.5, 3.0), but remained significantly elevated. SIRs ranged from 2.7 (95% CI = 2.0, 3.5) in the lower WTC exposure group to 4.2 (95% CI = 1.9, 8.0) in the most highly exposed. CONCLUSIONS: We found excess incident post-9/11 sarcoidosis in WTC-exposed workers. Continued surveillance, particularly of those most highly exposed, is necessary to identify those with sarcoidosis and to follow them for possible adverse effects including functional impairments and organ damage.

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-gamma and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-gamma and IL-17A production during the cellular immune response to M. tuberculosis.