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.

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.

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.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Prehospital hypoxemia, measured by pulse oximetry, predicts hospital outcomes during the New York City COVID-19 pandemic.

OBJECTIVE: To determine if oxygen saturation (out-of-hospital SpO2), measured by New York City (NYC) 9-1-1 Emergency Medical Services (EMS), was an independent predictor of coronavirus disease 2019 (COVID-19) in-hospital mortality and length of stay, after controlling for the competing risk of death. If so, out-of-hospital SpO2 could be useful for initial triage. METHODS: A population-based longitudinal study of adult patients transported by EMS to emergency departments (ED) between March 5 and April 30, 2020 (the NYC COVID-19 peak period). Inclusion required EMS prehospital SpO2 measurement while breathing room air, transport to emergency department, and a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction test. Multivariable logistic regression modeled mortality as a function of prehospital SpO2, controlling for covariates (age, sex, race/ethnicity, and comorbidities). A competing risk model also was performed to estimate the absolute risks of out-of-hospital SpO2 on the cumulative incidence of being discharged from the hospital alive. RESULTS: In 1673 patients, out-of-hospital SpO2 and age were independent predictors of in-hospital mortality and length of stay, after controlling for the competing risk of death. Among patients ≥66 years old, the probability of death was 26% with an out-of-hospital SpO2 >90% versus 54% with an out-of-hospital SpO2 ≤90%. Among patients <66 years old, the probability of death was 11.5% with an out-of-hospital SpO2 >90% versus 31% with an out-of-hospital SpO2 ≤ 90%. An out-of-hospital SpO2 level ≤90% was associated with over 50% decreased likelihood of being discharged alive, regardless of age. CONCLUSIONS: Out-of-hospital SpO2 and age predicted in-hospital mortality and length of stay: An out-of-hospital SpO2 ≤90% strongly supports a triage decision for immediate hospital admission. For out-of-hospital SpO2 >90%, the decision to admit depends on multiple factors, including age, resource availability (outpatient vs inpatient), and the potential impact of new treatments.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Pre-COVID-19 lung function and other risk factors for severe COVID-19 in first responders.

Risk factors for #COVID19 infection and severe disease (hospitalisation or death) in NYC first responders: greater pre-pandemic rate of FEV1 decline is associated with severe COVID-19, as is emergency medical service work versus firefighting https://bit.ly/3nZPuZY.

Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism.

BACKGROUND: Microbiome studies of the lower airways based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short-chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary. METHODS: Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model. We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole-genome shotgun (WGS) and RNA metatranscriptome sequencing. SCFAs were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed. RESULTS: Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome data were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFA levels were compared with WGS and metatranscriptome data. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing. CONCLUSIONS: Functional characterisation of the lower airway microbiota through metatranscriptome data identifies metabolically active organisms capable of producing metabolites with immunomodulatory capacity, such as SCFAs.

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.

Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to Streptococcus pneumoniae.

Rationale: Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype.Objectives: In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model.Methods: Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of killing. The genetic backgrounds of mice included wild-type, MyD88-knockout, and STAT3C backgrounds.Measurements and Main Results: 16S-rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host-transcriptome sequencing was used to characterize the host immune phenotype. Although MOC aspiration correlated with lower-airway dysbiosis that resolved within 5 days, it induced an extended inflammatory response associated with IL-17-producing T cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-γ expression. MOC aspiration before a respiratory challenge with S. pneumoniae led to a decrease in hosts' susceptibility to this pathogen.Conclusions: Thus, in otherwise healthy mice, a single aspiration event with oral commensals is rapidly cleared from the lower airways but induces a prolonged Th17 response that secondarily decreases susceptibility to S. pneumoniae. Translationally, these data implicate an immunoprotective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower-airway pathogens.

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.

Characteristics Associated With Out-of-Hospital Cardiac Arrests and Resuscitations During the Novel Coronavirus Disease 2019 Pandemic in New York City.

Importance: Risk factors for out-of-hospital death due to novel coronavirus disease 2019 (COVID-19) are poorly defined. From March 1 to April 25, 2020, New York City, New York (NYC), reported 17 118 COVID-19-related deaths. On April 6, 2020, out-of-hospital cardiac arrests peaked at 305 cases, nearly a 10-fold increase from the prior year. Objective: To describe the characteristics (race/ethnicity, comorbidities, and emergency medical services [EMS] response) associated with outpatient cardiac arrests and death during the COVID-19 pandemic in NYC. Design, Setting, and Participants: This population-based, cross-sectional study compared patients with out-of-hospital cardiac arrest receiving resuscitation by the NYC 911 EMS system from March 1 to April 25, 2020, compared with March 1 to April 25, 2019. The NYC 911 EMS system serves more than 8.4 million people. Exposures: The COVID-19 pandemic. Main Outcomes and Measures: Characteristics associated with out-of-hospital arrests and the outcomes of out-of-hospital cardiac arrests. Results: A total of 5325 patients were included in the main analysis (2935 men [56.2%]; mean [SD] age, 71 [18] years), 3989 in the COVID-19 period and 1336 in the comparison period. The incidence of nontraumatic out-of-hospital cardiac arrests in those who underwent EMS resuscitation in 2020 was 3 times the incidence in 2019 (47.5/100 000 vs 15.9/100 000). Patients with out-of-hospital cardiac arrest during 2020 were older (mean [SD] age, 72 [18] vs 68 [19] years), less likely to be white (611 of 2992 [20.4%] vs 382 of 1161 [32.9%]), and more likely to have hypertension (2134 of 3989 [53.5%] vs 611 of 1336 [45.7%]), diabetes (1424 of 3989 [35.7%] vs 348 of 1336 [26.0%]), and physical limitations (2259 of 3989 [56.6%] vs 634 of 1336 [47.5%]). Compared with 2019, the odds of asystole increased in the COVID-19 period (odds ratio [OR], 3.50; 95% CI, 2.53-4.84; P < .001), as did the odds of pulseless electrical activity (OR, 1.99; 95% CI, 1.31-3.02; P = .001). Compared with 2019, the COVID-19 period had substantial reductions in return of spontaneous circulation (ROSC) (727 of 3989 patients [18.2%] vs 463 of 1336 patients [34.7%], P < .001) and sustained ROSC (423 of 3989 patients [10.6%] vs 337 of 1336 patients [25.2%], P < .001), with fatality rates exceeding 90%. These associations remained statistically significant after adjustment for potential confounders (OR for ROSC, 0.59 [95% CI, 0.50-0.70; P < .001]; OR for sustained ROSC, 0.53 [95% CI, 0.43-0.64; P < .001]). Conclusions and Relevance: In this population-based, cross-sectional study, out-of-hospital cardiac arrests and deaths during the COVID-19 pandemic significantly increased compared with the same period the previous year and were associated with older age, nonwhite race/ethnicity, hypertension, diabetes, physical limitations, and nonshockable presenting rhythms. Identifying patients with the greatest risk for out-of-hospital cardiac arrest and death during the COVID-19 pandemic should allow for early, targeted interventions in the outpatient setting that could lead to reductions in out-of-hospital deaths.