Faculty Bibliography

BACKGROUND:Individuals with very low immunoglobulin E-(IgE)-levels have a high risk of developing malignancy. Previous studies have shown 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 1,851 WTC-responders after 9/11/2001. 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 3 rd percentile) versus "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 (26/1,796, 1.5%, p<0.01) responders. The proportion of solid tumors were similar in both groups (5.5% vs 11.4%, p>0.05). 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% CI=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/CONCLUSIONS: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.

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.

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.

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.

BACKGROUND:-decline. METHODS:decline rates were analyzed using multivariable linear regression controlling for demographics, smoking status, and other potential confounders. RESULTS:decline rate (-4.0 ± 1.6 ml/year per IL-4 doubling). CONCLUSIONS:decline/year. Drugs targeting the IL-4 pathway may improve lung function in this high-risk subgroup.

BACKGROUND:-trajectory in this population is unknown. METHODS:-slope pre- and post-treatment. RESULTS:-slope improvement (7.9 ml/year, 95% CI: -0.5 to 17.2). CONCLUSIONS:-decline who have not responded to ICS/LABA.

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.

Objective/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

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.