Faculty Bibliography

BACKGROUND: This study utilizes a four-level pyramid framework to understand the relationship between symptom reports and/or abnormal pulmonary function and diagnoses of airway diseases (AD), including asthma, recurrent bronchitis and COPD/emphysema in WTC-exposed firefighters. We compare the distribution of pyramid levels at two time-points: by 9/11/2005 and by 9/11/2010. METHODS: We studied 6,931 WTC-exposed FDNY firefighters who completed a monitoring exam during the early period and at least two additional follow-up exams 9/11/2005-9/11/2010. RESULTS: By 9/11/2005 the pyramid structure was as follows: 4,039 (58.3%) in Level 1, no respiratory evaluation or treatment; 1,608 (23.2%) in Level 2, evaluation or treatment without AD diagnosis; 1,005 (14.5%) in Level 3, a single AD diagnosis (asthma, emphysema/COPD, or recurrent bronchitis); 279 (4.0%) in Level 4, asthma and another AD. By 9/11/2010, the pyramid distribution changed considerably, with Level 1 decreasing to 2,612 (37.7% of the cohort), and Levels 3 (N = 1,530) and 4 (N = 796) increasing to 22.1% and 11.5% of the cohort, respectively. Symptoms, spirometry measurements and healthcare utilization were associated with higher pyramid levels. CONCLUSIONS: Respiratory diagnoses, even four years after a major inhalation event, are not the only drivers of future healthcare utilization. Symptoms and abnormal FEV-1 values must also be considered if clinicians and healthcare administrators are to accurately anticipate future treatment needs, years after initial exposure. Am. J. Ind. Med. (c) 2013 Wiley Periodicals, Inc.

BACKGROUND: Active TB disease can destroy lung parenchyma leading to cavities. Immune responses that predispose or protect individuals from lung damage during TB are poorly defined. OBJECTIVE: To sample lung immune cells and assay bronchoalveolar lavage (BAL) cell cytokine production. DESIGN: Enrolled subjects (n = 73) had bilateral infiltrates and underwent BAL. RESULTS: All had sputum culture demonstrating Mycobacterium tuberculosis and 22/73 (30%) had cavities on their chest radiograph. Those with cavities at presentation had a higher percentage of polymorphonuclear neutrophils (PMN) in BAL as well as lower inducible protein (IP) 10 (P < 0.01) and interleukin (IL) 6 (P = 0.013) in BAL cell supernatants compared to those without cavities. There was no correlation between cavities and other BAL or serum cytokines. IP-10 was negatively associated with BAL PMN. IP-10 and IL-6 expression above median reduces the odds of cavities by 79% and 78% in logistic regression models. IP-10 and IL-6 clustered with interferon-gamma and tumour necrosis factor-alpha in a principal component analysis, while IL-4 clustered with PMN. CONCLUSION: Increasing IP-10 and IL-6 production by BAL cells is associated with non-cavitary TB in patients who present with radiographically advanced TB. IP-10 and IL-6 may reflect an effective T-helper 1 immune control pathway for TB, attenuating tuberculous lung destruction.

PURPOSE: World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction. METHODS: With a nested case-control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after 1 second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N = 125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N = 126). In a secondary analysis, resistant cases (N = 66) had FEV1 (>/=107 %) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function. RESULTS: Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1 >/= 107 %. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort. CONCLUSIONS: Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline.

Mycobacterium tuberculosis infection alters macrophage gene expression and macrophage response to IFN-gamma, a critical host defense cytokine. However, regulation of these changes is poorly understood. We report discordance of changes in nascent transcript and total nuclear RNA abundance for the transcription factors STAT1 and IRF1, together with lack of effect on their RNA half-lives, in human THP-1 cells infected with M. tuberculosis and stimulated with IFN-gamma. The results indicate that negative postinitiation regulation of mRNA biogenesis limits the expression of these factors, which mediate host defense against M. tuberculosis through the cellular response to IFN-gamma. Consistent with the results for STAT1 and IRF1, transcriptome analysis reveals downregulation of postinitiation mRNA biogenesis processes and pathways by infection, with and without IFN-gamma stimulation. Clinical relevance for regulation of postinitiation mRNA biogenesis is demonstrated by studies of donor samples showing that postinitiation mRNA biogenesis pathways are repressed in latent tuberculosis infection compared with cured disease and in active tuberculosis compared with ongoing treatment or with latent tuberculosis. For active disease and latent infection donors from two populations (London, U.K., and The Gambia), each analyzed using a different platform, pathway-related gene expression differences were highly correlated, demonstrating substantial specificity in the effect. Collectively, the molecular and bioinformatic analyses point toward downregulation of postinitiation mRNA biogenesis pathways as a means by which M. tuberculosis infection limits expression of immunologically essential transcription factors. Thus, negative regulation of postinitiation mRNA biogenesis can constrain the macrophage response to infection and overall host defense against tuberculosis.

BACKGROUND: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. METHODS: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.5(0) C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. CONCLUSION: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness.

Pulmonary vascular loss is an early feature of chronic obstructive pulmonary disease. Biomarkers of inflammation and of metabolic syndrome, predicts loss of lung function in World Trade Center Lung Injury(WTC-LI). We investigated if other cardiovascular disease (CVD) biomarkers also predicted WTC-LI.This nested case-cohort study used 801 never smoker, WTC exposed firefighters with normal pre-9/11 lung function presenting for subspecialty pulmonary evaluation (SPE) before March, 2008. A representative sub-cohort of 124/801 with serum drawn within six months of 9/11 defined CVD biomarker distribution. Post-9/11/01 FEV1 at subspecialty exam defined cases: susceptible WTC-LI cases with FEV1/=107% (68/801). All models were adjusted for WTC exposure intensity, BMI at SPE, age at 9/11, and pre-9/11 FEV1.Susceptible WTC-LI cases had higher levels of Apo-AII, CRP, and MIP-4 with significant RRs of 3.85, 3.93, and 0.26 respectively with an area under the curve (AUC) of 0.858. Resistant WTC-LI cases had significantly higher sVCAM and lower MPO with RRs of 2.24, and 2.89 respectively; AUC 0.830.Biomarkers of CVD in serum six-month post-9/11 predicted either susceptibility or resistance to WTC-LI. These biomarkers may define pathways producing or protecting subjects from pulmonary vascular disease and associated loss of lung function after an irritant exposure.

BACKGROUND: Few longitudinal studies characterize firefighters' pulmonary function. We sought to determine whether firefighters have excessive FEV1 decline rates compared with controls. METHODS: We examined serial FEV1s from approximately 6 months pre-hire to approximately 5 years post-hire in newly-hired male, never-smoking, non-Hispanic Black and White firefighters, hired between 2003-2006, without prior respiratory disease or World Trade Center exposure. Similarly-defined Emergency Medical Service (EMS) workers served as controls. RESULTS: Through 6/30/2011, 940 (82%) firefighters and 97 (72%) EMS workers who met study criteria had >/=4 acceptable post-hire spirometries. Pre-hire FEV1% averaged higher for firefighters than EMS: 99% vs. 95%, reflecting more stringent job entry criteria. FEV1 (adjusted for baseline age & height) declined by an average of 45ml/yr both for firefighters and EMS, with Fire-EMS decline rate differences averaging 0.2 ml/yr (CI -9.2,9.6). 4% of each group had FEV1<lower limit of normal before hire, increasing to 7% for firefighters and 17.5% for EMS, but similar percentages of both groups had adjusted FEV1 decline rates >10%. Mixed effects modeling showed significant influence of weight gain but not baseline weight: FEV1 declined by approximately 8 ml per kg gained for both groups. Adjusting for weight change, FEV1 decline averaged 38 ml/yr for firefighters, 34 ml/yr for EMS. CONCLUSION: During the first 5 years of duty, firefighters do not show greater longitudinal FEV1 decline than EMS controls, and fewer of them develop abnormal lung function. Weight gain is associated with a small loss of lung function, of questionable clinical relevance in this fit and active population.1Pulmonary Medicine Division, Dept of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY. taldrich@montefiore.org; mdinkels@montefiore.org2Bureau of Health Services and Office of Medical Affairs, New York City Fire Dept, Brooklyn, NY. Yef@fdny.nyc.gov; webberm@fdny.nyc.gov; cosenzka@fdny.nyc.gov; christv@fdny.nyc.gov; kellykj@fdny.nyc.gov; Prezand@fdny.nyc.gov3Biostatistics Division, Dept of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. charles.hall@einstein.yu.edu; hillel.cohen@einstein.yu.edu4Epidemiology Division, Dept of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. webberm@fdny.nyc.gov; hillel.cohen@einstein.yu.edu5Pulmonary Medicine Division, Dept of Medicine, NYU School of Medicine, NY, NY. michael.weiden@nyumc.org; anna.nolan@med.nyu.eduAddress reprint requests to: Thomas Aldrich, MD, Pulmonary Medicine Division, Montefiore Medical Center, 111 East 210th St., Bronx, NY 10467, or taldrich@montefiore.orgFunding/Support:This work was supported by the National Institutes of Health [Grants K23HL084191, K24A1080298, RO1HL057879, HL090316, U01CA008617, U10-OH008243, U10-OH008242].