Interstitial Lung Disease and Progressive Pulmonary Fibrosis: a World Trade Center Cohort 20-Year Longitudinal Study.

PURPOSE: 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.

Normal Lung Function and Mortality in World Trade Center Responders and National Health and Nutrition Examination Survey III Participants.

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.

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

Association of Lung Function Decline with All-Cause and Cancer-Cause Mortality after World Trade Center Dust Exposure.

Rationale: In numerous cohorts, lung function decline is associated with all-cause and cardiovascular-cause mortality, but the association between the decrease in forced expiratory volume in 1 second (FEV1) and cancer-cause mortality, particularly after occupational/environmental exposure(s), is unclear. Exposure to dust/smoke from the World Trade Center (WTC) disaster caused inflammation and lung injury in Fire Department of the City of New York rescue/recovery workers. In addition, prior research found that >10% of the cohort experienced greater than twice the age-related decrease in FEV1 (⩾64 ml/yr). Objectives: To evaluate the association of longitudinal lung function with all-cause and cancer-cause mortality after exposure to the WTC disaster. Methods: We conducted a prospective cohort study using longitudinal prebronchodilator FEV1 data for 12,264 WTC-exposed firefighters and emergency medical service providers. All-cause and cancer-cause mortality were ascertained using National Death Index data from September 12, 2001, through December 31, 2021. Joint longitudinal survival models evaluated the association of baseline FEV1 and change in FEV1 from baseline with all-cause and cancer-cause mortality adjusted for age, race/ethnicity, height, smoking, work assignment (firefighters vs. emergency medical service providers), and WTC exposure. Results: By December 31, 2021, 607 of the 12,264 individuals in the cohort (4.9%) had died (crude rate = 259.5 per 100,000 person-years), and 190 of 12,264 (1.5%) had died from cancer (crude rate = 81.2 per 100,000 person-years). Baseline FEV1 was ⩾80% predicted in 10,970 of the 12,264 (89.4%); final FEV1 was ⩾80% in 9,996 (81.5%). Lower FEV1 at baseline was associated with greater risk for all-cause mortality (hazard ratio [HR] per liter = 2.32; 95% confidence interval [95% CI] = 1.98-2.72) and cancer-cause mortality (HR per liter = 1.99; 95% CI = 1.49-2.66). Longitudinally, each 100-ml/yr decrease in FEV1 was associated with an 11% increase in all-cause mortality (HR = 1.11; 95% CI = 1.06-1.15) and a 7% increase in cancer-cause mortality (HR = 1.07; 95% CI = 1.00-1.15). Compared with FEV1 decrease <64 ml/yr, those with FEV1 decrease ⩾64 ml/yr had higher all-cause (HR = 2.91; 95% CI = 2.37-3.56) and cancer-cause mortality (HR = 2.68; 95% CI = 1.90-3.79). Conclusions: Baseline FEV1 and longitudinal FEV1 decrease are associated with increased risk of all-cause and cancer-cause mortality in a previously healthy occupational cohort, the majority of whom had normal lung function, after intense exposure to dust/smoke. Further investigation is needed to define pathways by which lung function impacts mortality after an irritant exposure.

Relationship between low serum immunoglobulin E levels and malignancies in 9/11 World Trade Center responders.

BACKGROUND: Individuals with very low immunoglobulin E (IgE) levels have a high risk of developing malignancy. Previous studies have revealed that World Trade Center (WTC) responders exposed to carcinogens have an elevated risk of some cancers. OBJECTIVE: To evaluate the association between low-serum IgE levels and cancer development in WTC-exposed responders. METHODS: IgE levels were measured in 1851 WTC responders after September 11, 2001. This is the first pilot study in humans comparing the odds of developing cancer in this high-risk population, between the "low-IgE" (IgE in the lowest third percentile) vs "non-low-IgE" participants. RESULTS: A significantly higher proportion of hematologic malignancies was found in low-IgE (4/55, 7.3%) compared with non-low-IgE (26/1796, 1.5%, P < .01) responders. The proportion of solid tumors were similar in both groups (5.5% vs 11.4%, P > .05). After adjustment for relevant confounders (race, sex, age at blood draw, WTC arrival time, smoking status), the low-IgE participants had 7.81 times greater odds (95% confidence interval, 1.77-29.35) of developing hematologic cancer when compared with non-low-IgE participants. The hematologic cancers found in this cohort were leukemia (n = 1), multiple myeloma (n = 1), and lymphoma (n = 2). No statistical significance was found when estimating the odds ratio for solid tumors in relation to IgE levels. CONCLUSION: WTC responders with low serum IgE levels had the highest odds of developing hematologic malignancies. This hypothesis-generating study suggests that low serum IgE levels might be associated with the development of specific malignancies in at-risk individuals exposed to carcinogens. Larger, multicenter studies with adequate follow-up of individuals with different IgE levels are needed to better evaluate this relationship.

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.

Twenty-Year Reflection on the Impact of World Trade Center Exposure on Pulmonary Outcomes in Fire Department of the City of New York (FDNY) Rescue and Recovery Workers.

After the terrorist attacks on September 11, 2001 (9/11), many rescue/recovery workers developed respiratory symptoms and pulmonary diseases due to their extensive World Trade Center (WTC) dust cloud exposure. Nearly all Fire Department of the City of New York (FDNY) workers were present within 48 h of 9/11 and for the next several months. Since the FDNY had a well-established occupational health service for its firefighters and Emergency Medical Services workers prior to 9/11, the FDNY was able to immediately start a rigorous monitoring and treatment program for its WTC-exposed workers. As a result, respiratory symptoms and diseases were identified soon after 9/11. This focused review summarizes the WTC-related respiratory diseases that developed in the FDNY cohort after 9/11, including WTC cough syndrome, obstructive airways disease, accelerated lung function decline, airway hyperreactivity, sarcoidosis, and obstructive sleep apnea. Additionally, an extensive array of biomarkers has been identified as associated with WTC-related respiratory disease. Future research efforts will not only focus on further phenotyping/treating WTC-related respiratory disease but also on additional diseases associated with WTC exposure, especially those that take decades to develop, such as cardiovascular disease, cancer, and interstitial lung disease.

Lung function decline before and after treatment of World Trade Center associated obstructive airways disease with inhaled corticosteroids and long-acting beta agonists.

BACKGROUND: Greater than average loss of one-second forced expiratory volume (FEV1 ) is a risk factor for asthma, chronic obstructive pulmonary disease (COPD), and asthma/COPD overlap syndrome in World Trade Center (WTC)-exposed firefighters. Inhaled corticosteroids and long-acting beta agonists (ICS/LABA) are used to treat obstructive airways disease but their impact on FEV1 -trajectory in this population is unknown. METHODS: The study population included WTC-exposed male firefighters who were treated with ICS/LABA for 2 years or longer (with initiation before 2015), had at least two FEV1 measurements before ICS/LABA initiation and two FEV1 measurements posttreatment between September 11, 2001 and September 10, 2019. Linear mixed-effects models were used to estimate FEV1 -slope pre- and post-treatment. RESULTS: During follow-up, 1023 WTC-exposed firefighters were treated with ICS/LABA for 2 years or longer. When comparing intervals 6 years before and 6 years after treatment, participants had an 18.7 ml/year (95% confidence interval [CI]: 11.3-26.1) improvement in FEV1 -slope after adjustment for baseline FEV1 , race, height, WTC exposure, weight change, blood eosinophil concentration, and smoking status. After stratification by median date of ICS/LABA initiation (January 14, 2010), earlier ICS/LABA-initiators had a 32.5 ml/year (95% CI: 19.5-45.5) improvement in slope but later ICS/LABA-initiators had a nonsignificant FEV1 -slope improvement (7.9 ml/year, 95% CI: -0.5 to 17.2). CONCLUSIONS: WTC-exposed firefighters treated with ICS/LABA had improved FEV1 slope after initiation, particularly among those who started earlier. Treatment was, however, not associated with FEV1 -slope improvement if started after the median initiation date (1/14/2010), likely because onset of disease began before treatment initiation. Research on alternative treatments is needed for patients with greater than average FEV1 -decline who have not responded to ICS/LABA.

Serum Th-2 cytokines and FEV1 decline in WTC-exposed firefighters: A 19-year longitudinal study.

BACKGROUND: Accelerated-FEV1 -decline, defined as rate of decline in FEV1 > 64 ml/year, is a risk factor for asthma and chronic obstructive pulmonary disease in World Trade Center (WTC)-exposed firefighters. Accelerated-FEV1 -decline in this cohort is associated with elevated blood eosinophil concentrations, a mediator of Th-2 response. We hypothesized that an association exists between Th-2 biomarkers and FEV1 decline rate in those with accelerated-FEV1 -decline. METHODS: Serum was drawn from Fire Department of the City of New York (FDNY) firefighters 1-6 months (early) (N = 816) and 12-13 years (late) (N = 983) after 9/11/2001. Th-2 biomarkers IL-4, IL-13, and IL-5 were assayed by multiplex Luminex. Individual FEV1 decline rates were calculated using spirometric measurements taken: (1) between 9/11/2001 and 9/10/2020 for the early biomarker group and (2) between late measurement date and 9/10/2020 for the late biomarker group. Associations of early and late Th-2 biomarkers with subsequent FEV1 decline rates were analyzed using multivariable linear regression controlling for demographics, smoking status, and other potential confounders. RESULTS: In WTC-exposed firefighters with accelerated-FEV1 -decline, IL-4, IL-13, and IL-5 measured 1-6 months post-9/11/2001 were associated with greater FEV1 decline ml/year between 9/11/2001 and 9/10/2020 (-2.9 ± 1.4 ml/year per IL-4 doubling; -8.4 ± 1.2 ml/year per IL-13 doubling; -7.9 ± 1.3 ml/year per IL-5 doubling). Among late measured Th-2 biomarkers, only IL-4 was associated with subsequent FEV1 decline rate (-4.0 ± 1.6 ml/year per IL-4 doubling). CONCLUSIONS: In WTC-exposed firefighters with accelerated-FEV1 -decline, elevated serum IL-4 measured both 1-6 months and 12-13 years after 9/11 is associated with greater FEV1 decline/year. Drugs targeting the IL-4 pathway may improve lung function in this high-risk subgroup.

Performance of Risk Factor-Based Guidelines and Model-Based Chest CT Lung Cancer Screening in World Trade Center-Exposed Fire Department Rescue/Recovery Workers.

BACKGROUND: Lung cancer is a leading cause of cancer incidence and death in the United States. Risk factor-based guidelines and risk model-based strategies are used to identify patients who could benefit from low-dose chest CT (LDCT) screening. Few studies compare guidelines or models within the same cohort. We evaluate lung cancer screening performance of two risk factor-based guidelines (US Preventive Services Task Force 2014 recommendations [USPSTF-2014] and National Comprehensive Cancer Network Group 2 [NCCN-2]) and two risk model-based strategies, Prostate Lung Colorectal and Ovarian Cancer Screening (PLCOm2012) and the Bach model) in the same occupational cohort. RESEARCH QUESTION: Which risk factor-based guideline or model-based strategy is most accurate in detecting lung cancers in a highly exposed occupational cohort? STUDY DESIGN AND METHODS: Fire Department of City of New York (FDNY) rescue/recovery workers exposed to the September 11, 2001 attacks underwent LDCT lung cancer screening based on smoking history and age. The USPSTF-2014, NCCN-2, PLCOm2012 model, and Bach model were retrospectively applied to determine how many lung cancers were diagnosed using each approach. RESULTS: Among the study population (N = 3,953), 930 underwent a baseline scan that met at least one risk factor or model-based LDCT screening strategy; 73% received annual follow-up scans. Among the 3,953, 63 lung cancers were diagnosed, of which 50 were detected by at least one LDCT screening strategy. The NCCN-2 guideline was the most sensitive (79.4%; 50/63). When compared with NCCN-2, stricter age and smoking criteria reduced sensitivity of the other guidelines/models (USPSTF-2014 [44%], PLCOm2012 [51%], and Bach[46%]). The 13 missed lung cancers were mainly attributable to smoking less and quitting longer than guideline/model eligibility criteria. False-positive rates were similar across all four guidelines/models. INTERPRETATION: In this cohort, our findings support expanding eligibility for LDCT lung cancer screening by lowering smoking history from ≥30 to ≥20 pack-years and age from 55 years to 50 years old. Additional studies are needed to determine its generalizability to other occupational/environmental exposed cohorts.

Factors Predicting Treatment of World Trade Center-Related Lung Injury: A Longitudinal Cohort Study.

The factors that predict treatment of lung injury in occupational cohorts are poorly defined. We aimed to identify patient characteristics associated with initiation of treatment with inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) >2 years among World Trade Center (WTC)-exposed firefighters. The study population included 8530 WTC-exposed firefighters. Multivariable logistic regression assessed the association of patient characteristics with ICS/LABA treatment for >2 years over two-year intervals from 11 September 2001-10 September 2017. Cox proportional hazards models measured the association of high probability of ICS/LABA initiation with actual ICS/LABA initiation in subsequent intervals. Between 11 September 2001-1 July 2018, 1629/8530 (19.1%) firefighters initiated ICS/LABA treatment for >2 years. Forced Expiratory Volume in 1 s (FEV1), wheeze, and dyspnea were consistently and independently associated with ICS/LABA treatment. High-intensity WTC exposure was associated with ICS/LABA between 11 September 2001-10 September 2003. The 10th percentile of risk for ICS/LABA between 11 September 2005-10 Septmeber 2007 was associated with a 3.32-fold increased hazard of actual ICS/LABA initiation in the subsequent 4 years. In firefighters with WTC exposure, FEV1, wheeze, and dyspnea were independently associated with prolonged ICS/LABA treatment. A high risk for treatment was identifiable from routine monitoring exam results years before treatment initiation.

Low serum IgA and airway injury in World Trade Center-exposed firefighters: a 17-year longitudinal study.

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.

Long-term Cardiovascular Disease Risk Among Firefighters After the World Trade Center Disaster.

Importance: 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: 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: 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: 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: 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: 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.

Genetic Variants Associated with FDNY WTC-Related Sarcoidosis.

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.

Severe Obstructive Sleep Apnea Is Associated with Alterations in the Nasal Microbiome and an Increase in Inflammation.

RATIONALE: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. OBJECTIVES: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. METHODS: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post-Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom 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), and 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3-month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated. MEASUREMENTS AND MAIN 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; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring 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 continuous positive airway pressure 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.

Predictors of Asthma/COPD Overlap in FDNY Firefighters With World Trade Center Dust Exposure: A Longitudinal Study.

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: This study included 2,137 WTC-exposed firefighters who underwent a clinically indicated bronchodilator pulmonary function test (BD-PFT) between 9/11/2001 and 9/10/2017. A post-BD FEV1 increase of > 12% and 200 mL from baseline defined asthma, and a post-BD FEV1/FVC ratio < 0.7 identified COPD cases. Participants who met both criteria had asthma/COPD overlap. Eosinophil levels were measured on screening blood tests performed shortly after 9/11/2001 and prior to BD-PFT; a subgroup of participants also had serum IgE and 21 cytokines measured (n = 215). Marginal Cox regression models for multiple events assessed the associations of eosinophil levels or serum biomarkers with subsequent diagnosis, with age, race, smoking, WTC exposure, first post-9/11 FEV1/FVC ratio, and BMI included as covariates. RESULTS: BD-PFT diagnosed asthma/COPD overlap in 99 subjects (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 (hazard ratio [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 (HRs of 1.73 [95% CI, 1.27-2.35] and 2.06 [95% CI, 1.31-3.23], respectively). CONCLUSIONS: In WTC-exposed firefighters, elevated blood eosinophil and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific T-helper cell type 2 biomarkers present years before diagnosis suggest patient-intrinsic predisposition to irritant-associated asthma/COPD overlap.

Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung Cancer.

RATIONALE: In lung cancer, upregulation of the PI3K (phosphoinositide 3-kinase) 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. OBJECTIVES: We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS: Airway brushings 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 noncancer diagnoses. In addition, samples from 10 healthy control subjects were included. 16S ribosomal RNA gene amplicon sequencing and paired transcriptome sequencing were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. MEASUREMENTS AND MAIN RESULTS: The composition of the lower airway transcriptome in the patients with cancer was significantly different from the control subjects, which included up-regulation of ERK (extracellular signal-regulated kinase) and PI3K signaling pathways. The lower airways of patients with lung cancer were enriched for oral taxa (Streptococcus and Veillonella), which was associated with up-regulation 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 show that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.

Blood Leukocyte Concentrations, FEV1 Decline, and Airflow Limitation. A 15-Year Longitudinal Study of World Trade Center-exposed Firefighters.

RATIONALE: Rescue/recovery work at the World Trade Center disaster site (WTC) caused a proximate decline in lung function in Fire Department of the City of New York firefighters. A subset of this cohort experienced an accelerated rate of lung function decline over 15 years of post-September 11, 2001 (9/11) follow-up. OBJECTIVES: To determine if early postexposure blood leukocyte concentrations are biomarkers for subsequent FEV1 decline and incident airflow limitation. METHODS: Individual rates of forced expiratory volume in 1 second (FEV1) change were calculated for 9,434 firefighters using 88,709 spirometric measurements taken between September 11, 2001, and September 10, 2016. We categorized FEV1 change rates into three trajectories: accelerated FEV1 decline (FEV1 loss >64 ml/yr), expected FEV1 decline (FEV1 loss between 0 and 64 ml/yr), and improved FEV1 (positive rate of change >0 ml/yr). Occurrence of FEV1/FVC less than 0.70 after 9/11 defined incident airflow limitation. Using regression models, we 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 of 9,434), whereas post-9/11 FEV1 improvement occurred in 8.3% (780 of 9,434). Higher blood eosinophil and neutrophil concentrations were each associated with accelerated FEV1 decline after adjustment for covariates (odds ratio [OR], 1.10 per 100 eosinophils/µl; 95% confidence interval [CI], 1.05-1.15; and OR, 1.10 per 1,000 neutrophils/µl; 95% CI, 1.05-1.15, respectively). Multivariable-adjusted linear regression models showed that a higher blood neutrophil concentration was associated with a faster rate of FEV1 decline (1.14 ml/yr decline per 1,000 neutrophils/µl; 95% CI, 0.69-1.60 ml/yr; P < 0.001). Higher blood eosinophil concentrations were associated with a faster rate of FEV1 decline in ever-smokers (1.46 ml/yr decline per 100 eosinophils/µl; 95% CI, 0.65-2.26 ml/yr; P < 0.001) but not in never-smokers (P for interaction = 0.004). Higher eosinophil concentrations were also associated with incident airflow limitation (adjusted hazard ratio, 1.10 per 100 eosinophils/µl; 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: Higher post-9/11 blood neutrophil and eosinophil concentrations were associated with subsequent accelerated FEV1 decline in WTC-exposed firefighters. Both higher blood eosinophil concentrations and accelerated FEV1 decline were associated with incident airflow limitation in WTC-exposed firefighters.

Post-9/11 sarcoidosis in WTC-exposed firefighters and emergency medical service workers.

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 ∼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.

Post-9/11/2001 lung function trajectories by sex and race in World Trade Center-exposed New York City emergency medical service workers.

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.