Faculty Bibliography

While exploring the effects of aerosol IFN-gamma treatment in HIV-1/tuberculosis co-infected patients, we observed A to G mutations in HIV-1 envelope sequences derived from bronchoalveolar lavage (BAL) of aerosol IFN-gamma-treated patients and induction of adenosine deaminase acting on RNA 1 (ADAR1) in the BAL cells. IFN-gamma induced ADAR1 expression in monocyte-derived macrophages (MDM) but not T cells. ADAR1 siRNA knockdown induced HIV-1 expression in BAL cells of four HIV-1 infected patients on antiretroviral therapy. Similar results were obtained in MDM that were HIV-1 infected in vitro. Over-expression of ADAR1 in transformed macrophages inhibited HIV-1 viral replication but not viral transcription measured by nuclear run-on, suggesting that ADAR1 acts post-transcriptionally. The A to G hyper-mutation pattern observed in ADAR1 over-expressing cells in vitro was similar to that found in the lungs of HIV-1 infected patients treated with aerosol IFN-gamma suggesting the model accurately represented alveolar macrophages. Together, these results indicate that ADAR1 restricts HIV-1 replication post-transcriptionally in macrophages harboring HIV-1 provirus. ADAR1 may therefore contribute to viral latency in macrophages.

OBJECTIVES: We hypothesise that there is an association between an elevated pulmonary artery/aorta (PA/A) and World Trade Center-Lung Injury (WTC-LI). We assessed if serum vascular disease biomarkers were predictive of an elevated PA/A. DESIGN: Retrospective case-cohort analysis of thoracic CT scans of WTC-exposed firefighters who were symptomatic between 9/12/2001 and 3/10/2008. Quantification of vascular-associated biomarkers from serum collected within 200 days of exposure. SETTING: Urban tertiary care centre and occupational healthcare centre. PARTICIPANTS: Male never-smoking firefighters with accurate pre-9/11 forced expiratory volume in 1 s (FEV1) >/=75%, serum sampled /=0.92 (n=38) and PA/A<0.92(n=59) to determine serum vascular biomarkers that were predictive of this vasculopathy. OUTCOME MEASURES: The primary outcome of this study was to identify a PA/A ratio in a cohort of individuals exposed to WTC dust that was associated with WTC-LI. The secondary outcome was to identify serum biomarkers predictive of the PA/A ratio using logistic regression. RESULTS: PA/A>/=0.92 was associated with WTC-LI, OR of 4.02 (95% CI 1.21 to 13.41; p=0.023) when adjusted for exposure, body mass index and age at CT. Elevated macrophage derived chemokine and soluble endothelial selectin were predictive of PA/A>/=0.92, (OR, 95% CI 2.08, 1.05 to 4.11, p=0.036; 1.33, 1.06 to 1.68, p=0.016, respectively), while the increased total plasminogen activator inhibitor 1 was predictive of not having PA/A>/=0.92 (OR 0.88, 0.79 to 0.98; p=0.024). CONCLUSIONS: Elevated PA/A was associated with WTC-LI. Development of an elevated PA/A was predicted by biomarkers of vascular disease found in serum drawn within 6 months of WTC exposure. Increased PA/A is a potentially useful non-invasive biomarker of WTC-LI and warrants further study.

Respiratory disorders are associated with occupational and environmental exposures. The latency period between exposure and disease onset remains uncertain. The World Trade Center (WTC) disaster presents a unique opportunity to describe the latency period for obstructive airway disease (OAD) diagnoses. This prospective cohort study of New York City firefighters compared the timing and incidence of physician-diagnosed OAD relative to WTC exposure. Exposure was categorized by WTC arrival time as high (on the morning of September 11, 2001), moderate (after noon on September 11, 2001, or on September 12, 2001), or low (during September 13-24, 2001). We modeled relative rates and 95% confidence intervals of OAD incidence by exposure over the first 5 years after September 11, 2001, estimating the times of change in the relative rate with change point models. We observed a change point at 15 months after September 11, 2001. Before 15 months, the relative rate for the high- versus low-exposure group was 3.96 (95% confidence interval: 2.51, 6.26) and thereafter, it was 1.76 (95% confidence interval: 1.26, 2.46). Incident OAD was associated with WTC exposure for at least 5 years after September 11, 2001. There were higher rates of new-onset OAD among the high-exposure group during the first 15 months and, to a lesser extent, throughout follow-up. This difference in relative rate by exposure occurred despite full and free access to health care for all WTC-exposed firefighters, demonstrating the persistence of WTC-associated OAD risk.

BACKGROUND: We investigated early post 9/11 factors that could predict rhinosinusitis healthcare utilization costs up to 11 years later in 8,079 World Trade Center-exposed rescue/recovery workers. METHODS: We used bivariate and multivariate analytic techniques to investigate utilization outcomes; we also used a pyramid framework to describe rhinosinusitis healthcare groups at early (by 9/11/2005) and late (by 9/11/2012) time points. RESULTS: Multivariate models showed that pre-9/11/2005 chronic rhinosinusitis diagnoses and nasal symptoms predicted final year healthcare utilization outcomes more than a decade after WTC exposure. The relative proportion of workers on each pyramid level changed significantly during the study period. CONCLUSIONS: Diagnoses of chronic rhinosinusitis within 4 years of a major inhalation event only partially explain future healthcare utilization. Exposure intensity, early symptoms and other factors must also be considered when anticipating future healthcare needs. Am. J. Ind. Med. (c) 2014 Wiley Periodicals, Inc.

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

Microbes are readily cultured from epithelial surfaces of the skin, mouth, and colon. In the last 10 years, culture-independent DNA-based techniques demonstrated that much more complex microbial communities reside on most epithelial surfaces; this includes the lower airways, where bacterial culture had failed to reliably demonstrate resident bacteria. Exposure to a diverse bacterial environment is important for adequate immunological development. The most common microbes found in the lower airways are also found in the upper airways. Increasing abundance of oral characteristic taxa is associated with increased inflammatory cells and exhaled nitric oxide, suggesting that the airway microbiome induces an immunological response in the lung. Furthermore, rhinovirus infection leads to outgrowth of Haemophilus in patients with chronic obstructive pulmonary disease, and human immunodeficiency virus-infected subjects have more Tropheryma whipplei in the lower airway, suggesting a bidirectional interaction in which the host immune defenses also influence the microbial niche. Quantitative and/or qualitative changes in the lung microbiome may be relevant for disease progression and exacerbations in a number of pulmonary diseases. Future investigations with longitudinal follow-up to understand the dynamics of the lung microbiome may lead to the development of new therapeutic targets.

RATIONALE: After 9/11/2001, most FDNY workers had persistent lung function decline but some exposed workers recovered. We hypothesized that the protease/anti-protease balance in serum soon after exposure predicts subsequent recovery. METHOD: S: We performed a nested case-control study measuring biomarkers in serum drawn before 3/2002 and subsequent forced expiratory volume at one second (FEV1) on repeat spirometry before 3/2008. Serum was assayed for matrix metalloproteinases (MMP-1,2,3,7,8,9,12 and 13) and tissue inhibitors of metalloproteinases (TIMP-1,2,3,4). The representative sub-cohort defined analyte distribution and a concentration above 75th percentile defined elevated biomarker expression. Having an FEV1 one standard deviation above the mean defined resistance to airway injury. Logistic regression was adjusted for pre-9/11 FEV1, BMI, age and exposure intensity modeled the association between elevated biomarker expression and above average FEV1. RESULTS:: FEV1 in cases and controls declined 10% of after 9/11/2001. Cases subsequently returned to 99% of their pre-exposure FEV1 while decline persisted in controls. Elevated TIMP-1 and MMP-2 increased the odds of resistance by 5.4 and 4.2 fold while elevated MMP-1 decreased it by 0.27 fold. CONCLUSIONS:: Resistant cases displayed healing, returning to 99% of pre-exposure values. High TIMP-1 and MMP-2 predict healing. MMP/TIMP balance reflects independent pathways to airway injury and repair after WTC exposure.

BACKGROUND: Firefighters exposed to World Trade Center (WTC) dust have developed chronic rhinosinusitis (CRS) and abnormal forced expiratory volume in 1 s (FEV1). Overlapping but distinct immune responses may be responsible for the clinical manifestations of upper and lower airway injury. We investigated whether a panel of inflammatory cytokines, either associated or not associated with WTC-LI, can predict future chronic rhinosinusitis disease and its severity. METHODS: Serum obtained within six months of 9/11/2001 from 179 WTC exposed firefighters presenting for subspecialty evaluation prior to 3/2008 was assayed for 39 cytokines. The main outcomes were medically managed CRS (N = 62) and more severe CRS cases requiring sinus surgery (N = 14). We tested biomarker-CRS severity association using ordinal logistic regression analysis. RESULTS: Increasing serum IL-6, IL-8, GRO and neutrophil concentration reduced the risk of CRS progression. Conversely, increasing TNF-alpha increased the risk of progression. In a multivariable model adjusted for exposure intensity, increasing IL-6, TNF-alpha and neutrophil concentration remained significant predictors of progression. Elevated IL-6 levels and neutrophil counts also reduced the risk of abnormal FEV1 but in contrast to CRS, increased TNF-alpha did not increase the risk of abnormal FEV1. CONCLUSIONS: Our study demonstrates both independent and overlapping biomarker associations with upper and lower respiratory injury, and suggests that the innate immune response may play a protective role against CRS and abnormal lung function in those with WTC exposure.