Faculty Bibliography

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/UNASSIGNED:Biomarkers of metabolic syndrome expressed soon after World Trade Center (WTC) exposure predict development of WTC Lung Injury (WTC-LI). The metabolome remains an untapped resource with potential to comprehensively characterise many aspects of WTC-LI. This case-control study identified a clinically relevant, robust subset of metabolic contributors of WTC-LI through comprehensive high-dimensional metabolic profiling and integration of machine learning techniques. Methods/UNASSIGNED:Never-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated by post-9/11 lung function. Cases of WTC-LI (forced expiratory volume in 1s <lower limit of normal, n=15) and controls (n=15) were identified from previous cohorts. The metabolome of serum drawn within 6 months of 9/11 was quantified. Machine learning was used for dimension reduction to identify metabolites associated with WTC-LI. Results/UNASSIGNED:580 metabolites qualified for random forests (RF) analysis to identify a refined metabolite profile that yielded maximal class separation. RF of the refined profile correctly classified subjects with a 93.3% estimated success rate. 5 clusters of metabolites emerged within the refined profile. Prominent subpathways include known mediators of lung disease such as sphingolipids (elevated in cases of WTC-LI), and branched-chain amino acids (reduced in cases of WTC-LI). Principal component analysis of the refined profile explained 68.3% of variance in five components, demonstrating class separation. Conclusion/UNASSIGNED:Analysis of the metabolome of WTC-exposed 9/11 rescue workers has identified biologically plausible pathways associated with loss of lung function. Since metabolites are proximal markers of disease processes, metabolites could capture the complexity of past exposures and better inform treatment. These pathways warrant further mechanistic research.