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.

Metabolic syndrome, inflammatory and vascular injury markers measured in serum after World Trade Center (WTC) exposures predict abnormal FEV1. We hypothesized that elevated LPA levels predict FEV₁ < LLN. Nested case-control study of WTC-exposed firefighters. Cases had FEV₁ < LLN. Controls derived from the baseline cohort. Demographics, pulmonary function, serum lipids, LPA and ApoA1 were measured. LPA and ApoA1 levels were higher in cases than controls and predictive of case status. LPA increased the odds by 13% while ApoA1 increased the odds by 29% of an FEV₁ < LLN in a multivariable model. Elevated LPA and ApoA1 are predictive of a significantly increased risk of developing an FEV₁ < LLN.

Rationale: Low FEV1 is a biomarker of increased mortality. The association of normal lung function and mortality is not well described. Objectives: To evaluate the FEV1–mortality association among participants with normal lung function. Methods: A total of 10,999 Fire Department of the City of New York (FDNY) responders and 10,901 Third National Health and Nutrition Examination Survey (NHANES III) participants, aged 18–65 years with FEV1 ≥80% predicted, were analyzed, with FEV1 percent predicted calculated using Global Lung Function Initiative Global race-neutral reference equations. Mortality data were obtained from linkages to the National Death Index. Cox proportional hazards models estimated the association between FEV1 and all-cause mortality, controlling for age, sex, race/ethnicity, smoking history, and, for FDNY, work assignment. Cohorts were followed for a maximum of 20.3 years. Measurements and Main Results: We observed 504 deaths (4.6%) of 10,999 for FDNY and 1,237 deaths (9.4% [weighted]) of 10,901 for NHANES III. Relative to FEV1 ≥120% predicted, mortality was significantly higher for FEV1 100–109%, 90–99%, and 80–89% predicted in the FDNY cohort. In the NHANES III cohort, mortality was significantly higher for FEV1 90–99% and 80–89% predicted. Each 10% higher predicted FEV1 was associated with 15% (hazard ratio, 0.85; 95% confidence interval, 0.80–0.91) and 23% (hazard ratio, 0.77; 95% confidence interval, 0.71–0.84) lower mortality for FDNY and NHANES III, respectively. Conclusions: In both cohorts, higher FEV1 is associated with lower mortality, suggesting higher FEV1 is a biomarker of better health. These findings demonstrate that a single cross-sectional measurement of FEV1 is predictive of mortality over two decades, even when FEV1 is in the normal range.

Rationale: The World Trade Center (WTC) collapse generated caustic airborne particulates that caused chronic rhinosinusitis in exposed Fire Department of New York firefighters. Surgery was performed when symptoms remained uncontrolled despite medical management. Objectives: To identify predictors of surgical intervention for chronic rhinosinusitis in firefighters exposed to airborne irritants at the WTC collapse site. Methods: We assessed in 8,227 firefighters with WTC exposure between September 11, 2001 (9/11), and September 25, 2001, including WTC-site arrival time, months of rescue and recovery work, and eosinophil concentration measured between 9/11 and March 10, 2003. We assessed the association of serum cytokines and immunoglobulins with eosinophil concentration and surgery for rhinosinusitis in 112 surgical cases and 376 control subjects with serum available from the first 6 months after exposure to the WTC collapse site. Measurements and Main Results: Between 9/11 and March 10, 2015, the surgery rate was 0.47 cases per 100 person-years. In the first 18 months post-9/11, surgical patients had higher mean blood eosinophil levels than study cohort patients (219 ± 155 vs. 191 ± 134; P < 0.0001). Increased surgery risk was associated with increasing blood eosinophil counts (hazard ratio [HR], 1.12 per 100 cells/μl; 95% confidence interval [CI], 1.07–1.17; P < 0.001); arriving at the WTC site on 9/11 or September 12, 2001 (HR, 1.43; 95% CI, 1.04–1.99; P = 0.03); and working 6 months or longer at the WTC site (HR, 1.48; 95% CI, 1.14–1.93; P < 0.01). Median blood eosinophil levels for surgical patients were above levels for the cohort in all 18-month intervals March 11, 2000, through March 10, 2015, using 51,163 measurements representing 97,733 person-years of observation. Increasing age, increasing IL-17A, and low IgA in serum from 2001 to 2002 predicted blood eosinophil concentration in surgical patients but not in control subjects (R 2 = 0.26, P < 0.0001; vs. R 2 = 0.008, P = 0.56). Conclusions: Increasing blood eosinophil concentration predicts surgical intervention for chronic rhinosinusitis, particularly in those with intense acute and prolonged exposure to airborne irritants. WTC-exposed Fire Department of New York firefighters who underwent irritant-associated sinus surgery are immunologically different from the cohort. Surgical patients have a higher blood eosinophil levels that is associated with mediators of mucosal immunity.

Objective To determine whether lung function trajectories after 9/11/2001 (9/11) differed by sex or race/ethnicity in World Trade Center-exposed Fire Department of the City of New York emergency medical service (EMS) workers. Method Serial cross-sectional study of pulmonary function tests (PFTs) taken between 9/11 and 9/10/2015. We used data from routine PFTs (forced expiratory volume in 1 s (FEV₁) and FEV₁% predicted), conducted at 12–18 month intervals. FEV₁ and FEV₁% predicted were assessed over time, stratified by sex, and race/ethnicity. We also assessed FEV₁ and FEV₁% predicted in current, former and never-smokers. Results Among 1817 EMS workers, 334 (18.4%) were women, 979 (53.9%) self-identified as white and 939 (51.6%) were never-smokers. The median follow-up was 13.1 years (IQR 10.5–13.6), and the median number of PFTs per person was 11 (IQR 7–13). After large declines associated with 9/11, there was no discernible recovery in lung function. In analyses limited to never-smokers, the trajectory of decline in adjusted FEV₁ and FEV₁% predicted was relatively parallel for men and women in the 3 racial/ethnic groups. Similarly, small differences in FEV₁ annual decline between groups were not clinically meaningful. Analyses including ever-smokers were essentially the same. Conclusions 14 years after 9/11, most EMS workers continued to demonstrate a lack of lung function recovery. The trajectories of lung function decline, however, were parallel by sex and by race/ethnicity. These findings support the use of routine, serial measures of lung function over time in first responders and demonstrate no sex or racial sensitivity to exposure-related lung function decline.

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.