Faculty Bibliography

Serum IgA ≤70 mg/dL (low IgA) is associated with exacerbations of chronic obstructive pulmonary disease. The association of low IgA with longitudinal lung function is poorly defined. This study included 917 World Trade Center (WTC)-exposed firefighters with longitudinal spirometry measured between September 2001 and September 2018 and IgA measured between October 2001 and March 2002. Low IgA, compared with IgA >70 mg/dL, was associated with lower forced expiratory volume in 1 s (FEV₁) % predicted in the year following 11 September 2001 (94.1% vs 98.6%, p<0.001), increased risk of FEV₁/FVC <0.70 (HR 3.8, 95% CI 1.6 to 8.8) and increased antibiotic treatment (22.5/100 vs 11.6/100 person-years, p=0.002). Following WTC exposure, early IgA ≤70 mg/dL was associated with worse lung function and increased antibiotic treatment.

Importance/UNASSIGNED:Published studies examining the association between World Trade Center (WTC) exposure on and after September 11, 2001, and longer-term cardiovascular disease (CVD) outcomes have reported mixed findings. Objective/UNASSIGNED:To assess whether WTC exposure was associated with elevated CVD risk in Fire Department of the City of New York (FDNY) firefighters. Design, Settings, and Participants/UNASSIGNED:In this cohort study, the association between WTC exposure and the risk of CVD was assessed between September 11, 2001, and December 31, 2017, in FDNY male firefighters. Multivariable Cox regression analyses were used to estimate CVD risk in association with 2 measures of WTC exposure: arrival time to the WTC site and duration of work at the WTC site. Data analyses were conducted from May 1, 2018, to March 8, 2019. Main Outcomes and Measures/UNASSIGNED:The primary CVD outcome included myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death. The secondary outcome (all CVD) included all primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either use of angina medication or cardiac catheterization without intervention; cardiomyopathy; and other CVD (aortic aneurysm, peripheral arterial vascular intervention, and carotid artery surgery). Results/UNASSIGNED:There were 489 primary outcome events among 9796 male firefighters (mean [SD] age on September 11, 2001, was 40.3 [7.4] years and 7210 individuals [73.6%] were never smokers). Age-adjusted incident rates of CVD were higher for firefighters with greater WTC exposure. The multivariable adjusted hazard ratio (HR) for the primary CVD outcome was 1.44 (95% CI, 1.09-1.90) for the earliest arrival group compared with those who arrived later. Similarly, those who worked at the WTC site for 6 or more months vs those who worked less time at the site were more likely to have a CVD event (HR, 1.30; 95% CI, 1.05-1.60). Well-established CVD risk factors, including hypertension (HR, 1.41; 95% CI, 1.10-1.80), hypercholesterolemia (HR, 1.56; 95% CI, 1.28-1.91), diabetes (HR, 1.99; 95% CI, 1.33-2.98), and smoking (current: HR, 2.13; 95% CI, 1.68-2.70; former: HR, 1.55; 95% CI, 1.23-1.95), were significantly associated with CVD in the multivariable models. Analyses with the all-CVD outcome were similar. Conclusions and Relevance/UNASSIGNED:The findings of the study suggest a significant association between greater WTC exposure and long-term CVD risk. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. It may develop in response to an exposure or inflammatory trigger in the background of a genetically primed abnormal immune response. Thus, genetic studies are potentially important to our understanding of the pathogenesis of sarcoidosis. We developed a case-control study which explored the genetic variations between firefighters in the Fire Department of the City of New York (FDNY) with World Trade Center (WTC)-related sarcoidosis and those with WTC exposure, but without sarcoidosis. The loci of fifty-one candidate genes related to granuloma formation, inflammation, immune response, and/or sarcoidosis were sequenced at high density in enhancer/promoter, exonic, and 5' untranslated regions. Seventeen allele variants of human leukocyte antigen (HLA) and non-HLA genes were found to be associated with sarcoidosis, and all were within chromosomes 1 and 6. Our results also suggest an association between extrathoracic involvement and allele variants of HLA and non-HLA genes found not only on chromosomes 1 and 6, but also on chromosomes 16 and 17. We found similarities between genetic variants with WTC-related sarcoidosis and those reported previously in sporadic sarcoidosis cases within the general population. In addition, we identified several allele variants never previously reported in association with sarcoidosis. If confirmed in larger studies with known environmental exposures, these novel findings may provide insight into the gene-environment interactions key to the development of sarcoidosis.

Fire Department of the City of New York (FDNY) firefighters experienced intense dust exposure working at the World Trade Center (WTC) site on and after 11/9/2001 (9/11). We hypothesized that high-intensity WTC exposure caused abnormalities found on chest computed tomography (CT). Between 11/9/2001-10/9/2018, 4277 firefighters underwent a clinically-indicated chest CT. Spirometric measurements and symptoms were recorded during routine medical examinations. High-intensity exposure, defined as initial arrival at the WTC on the morning of 9/11, increased the risk of bronchial wall thickening, emphysema, and air trapping. Early post-9/11 symptoms of wheeze and shortness of breath were associated with bronchial wall thickening, emphysema, and air trapping. The risk of accelerated forced expiratory volume at one second (FEV₁) decline (>64 mL/year decline) increased with bronchial wall thickening and emphysema, but decreased with air trapping. The risk of airflow obstruction also increased with bronchial wall thickening and emphysema but decreased with air trapping. In a previously healthy occupational cohort, high-intensity WTC exposure increased the risk for CT abnormalities. Bronchial wall thickening and emphysema were associated with respiratory symptoms, accelerated FEV₁ decline, and airflow obstruction. Air trapping was associated with respiratory symptoms, although lung function was preserved. Physiologic differences between CT abnormalities suggest that distinct types of airway injury may result from a common exposure.

RATIONALE/BACKGROUND:Obstructive Sleep Apnea (OSA) is associated with recurrent obstruction, sub-epithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. OBJECTIVES/OBJECTIVE:To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. METHODS:Two large cohorts were utilized: 1) a discovery cohort of 472 subjects from the WTCSNORE cohort; and 2) a validation cohort of 93 subjects from the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing); 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3 months samples were obtained in the validation cohort including post-CPAP treatment when indicated. RESULTS:In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of co-occurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea-hypopnea index. Three months of treatment with CPAP did not change the composition of the nasal microbiota. CONCLUSIONS:We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.

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.

OBJECTIVES/OBJECTIVE:Chronic rhinosinusitis (CRS) has high socioeconomic burden but underexplored risk factors. The collapse of the World Trade Center (WTC) towers on 11 September 2001 (9/11) caused dust and smoke exposure, leading to paranasal sinus inflammation and CRS. We aim to determine which job tasks are risk factors for CRS in WTC-exposed Fire Department of the City of New York (FDNY) firefighters and emergency medical services (EMS) workers. METHODS:This cohort study included a 16-year follow-up of 11 926 WTC-exposed FDNY rescue/recovery workers with data on demographics, WTC exposure, job tasks and first post-9/11 complete blood counts. Using multivariable Cox regression, we assessed the associations of WTC exposure, work assignment (firefighter/EMS), digging and rescue tasks at the WTC site and blood eosinophil counts with subsequent CRS, adjusting for potential confounders. RESULTS:The rate of CRS was higher in firefighters than EMS (1.80/100 person-years vs 0.70/100 person-years; p<0.001). The combination of digging and rescue work was a risk factor for CRS (HR 1.54, 95% CI 1.23 to 1.94, p<0.001) independent of work assignment and WTC exposure. CONCLUSIONS:Compared with EMS, firefighters were more likely to engage in a combination of digging and rescue work, which was a risk factor for CRS. Chronic irritant exposures associated with digging and rescue work may account for higher post-9/11 CRS rates among firefighters.

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.