Using Syndromic Surveillance to Assess the Impact of Environmental Factors on Asthma- and COPD- Related ED Visits in Douglas County, Nebraska

Background: Asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases associated with health disparities in Douglas County, Nebraska and in the United States. Currently there is a lack of information describing the impact of environmental factors in Nebraska on the burden of emergency department (ED) visits or hospitalizations related to these chronic respiratory (CR) diseases. The aim of this study was to determine if there is an association between the numbers of seasonal viral respiratory (SVR)- related ED visits, outdoor air pollutants, aeroallergens, or meteorological factors on the number of CR- related ED visits in Douglas County, Nebraska. Methods: We analyzed electronic health record (EHR) data from 8 of 9 hospitals in Douglas County, NE for ED visits from February 28, 2016 to December 29, 2018. Syndromic surveillance definitions were used to identify CR- and SVR- related ED visits in EHR ED data. Aeroallergen, outdoor air pollutant and temperature data were obtained. Descriptive statistics were performed on EHR and environmental data. Negative binomial models were used to determine the association between the number of CR- related weekly ED visits and the environmental factors of interest. These models were stratified to account for possible cofounding effect of patient age and season. Patient age was stratified into 3 age groups: \u3c 18 yrs., 18-39 yrs., ≥ 40 yrs. Results: Significant associations were observed between the number of CR- related weekly ED visits and the weekly number of SVR-related ED visits, mean weed pollen counts, mean mold spore counts, mean minimum temperature, mean carbon monoxide levels and mean fine particulate matter (PM2.5) levels. Discrepancies in significant associations between the CR- related weekly ED visits and the environmental variables were observed after stratifying the model by season and age groups. For instance, SVR-related weekly ED visits were significantly associated with an increase in CR-related weekly ED visits among the \u3c 18 yrs. and 18 to 39 yrs. age groups in the summer, the ≥ 40 yrs. age group in the fall, and the 18 to 39 yrs. and the ≥ 40 yrs. age groups in the winter. Minimum temperature was significantly associated with the increase in CR- related weekly ED visits among the \u3c 18 yrs. and 18 to 39 yrs. age groups in the fall. Significant associations with an increase in CR- related weekly ED visits were also observed for PM2.5 among the 18 to 39 yrs. and ≥ 40 yrs. age groups in the spring, and the \u3c 18 yrs. and ≥ 40 yrs. age groups in the fall. Weed pollen and mold spores were also significantly associated with an increase in CR- related weekly ED visits. While significant associations were observed for weed pollen during the summer among the \u3c 18 yrs. age group, significant associations were observed for mold spores among all age groups during spring, and among the ≥ 40 yrs. age group during summer. Carbon monoxide was associated with a decrease in CR-related weekly ED visits for the 18 to 39 yrs. age group in the fall. Conclusions: Results of this study indicate the association between environmental factors and CR- related ED visits in Douglas County, Nebraska could be affected by not only by SVR disease cycles, temperature and other environmental factors, but also by age. Additional analyses may be needed to further explore these associations

Fatty Acids, Amphiregulin Production, and Lung Function in a Cohort of Midwestern Veterans

RationaleThe relationship between many fatty acids and respiratory outcomes remains unclear, especially with regard to mechanistic actions. Altered regulation of the process of lung repair is a key feature of chronic lung disease and may impact the potential for pulmonary rehabilitation, but underlying mechanisms of lung repair following injury or inflammation are not well-studied. The epidermal growth factor receptor agonist amphiregulin (AREG) has been demonstrated to promote lung repair following occupational dust exposure in animals. Studies suggest the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) may enhance the production of AREG. The objective of this study was to determine the relationship between fatty acids and lung function in a population of veterans and determine if fatty acid status is associated with concentrations of AREG.Materials and MethodsData were collected from a cross-sectional study of veterans within the Nebraska-Western Iowa Health Care System. Whole blood assays were performed to quantify AREG concentrations via a commercially available ELISA kit. Fatty acids from plasma samples from the same patients were measured using gas-liquid chromatography. Intakes of fatty acids were quantified with a validated food frequency questionnaire. Linear regression models were used to determine whether plasma fatty acids or intakes of fatty acids predicted lung function or AREG concentrations. A p < 0.05 was considered statistically significant.ResultsNinety participants were included in this analysis. In fully adjusted models, plasma fatty acids were associated with AREG production, including the PUFA eicosapentaenoic acid (EPA) (β = 0.33, p = 0.03) and the monounsaturated fatty acid octadecenoic acid: (β = −0.56, p = 0.02). The omega-3 PUFA docosapentaenoic acid (DPA) was positively associated with lung function (β = 0.28, p = 0.01; β = 26.5, p = 0.05 for FEV1/FVC ratio and FEV1 % predicted, respectively), as were the omega-6 PUFAs eicosadienoic acid (β = 1.13, p < 0.001; β = 91.2, p = 0.005 for FEV1/FVC ratio and FEV1 % predicted, respectively) and docosadienoic acid (β = 0.29, p = 0.01 for FEV1/FVC ratio). Plasma monounsaturated and saturated fatty acids were inversely associated with lung function.ConclusionOpposing anti- and pro-inflammatory properties of different fatty acids may be associated with lung function in this population, in part by regulating AREG induction

Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust

BACKGROUND: Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation. METHODS: As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0–200 nM MaR1, followed by 1–24 hour treatment with 5% hog confinement facility-derived organic dust extract (HDE). Alternatively, a mouse lung slice model was utilized in supportive cytokine studies. Supernatants were harvested and cytokine levels determined via enzyme-linked immunosorbent assays. Epithelial cell protein kinase C (PKC) isoforms α and ϵ, and PKA activities were assessed via radioactivity assays, and NFκB and MAPK-related signaling mechanisms were investigated using luciferase vector reporters. RESULTS: MaR1 dose-dependently reduced IL-6 and IL-8 production following HDE treatment of BECs. MaR1 also reduced HDE-stimulated cytokine release including TNF-α in a mouse lung slice model when given before or following HDE treatment. Previous studies have established that HDE sequentially activates epithelial PKCα and PKCϵ at 1 and 6 hours, respectively that regulated TNF-α, IL-6, and IL-8 release. MaR1 pretreatment abrogated these HDE-induced PKC activities. Furthermore, HDE treatment over a 24-hour period revealed temporal increases in NFκB, AP-1, SP-1, and SRE DNA binding activities, using luciferase reporter assays. MaR1 pretreatment did not alter the activation of NFκB, AP-1, or SP-1, but did reduce the activation of DNA binding at SRE. CONCLUSIONS: These observations indicate a role for MaR1 in attenuating the pro-inflammatory responses of BECs to organic dust extract, through a mechanism that does not appear to rely on reduced NFκB, AP-1, or SP-1-related signaling, but may be mediated partly through SRE-related signaling. These data offer insights for a novel mechanistic action of MaR1 in bronchial epithelial cells, and support future in vivo studies to test MaR1’s utility in reducing the deleterious inflammatory effects of environmental dust exposures

Saturated Fat Intake Is Associated with Lung Function in Individuals with Airflow Obstruction: Results from NHANES 2007⁻2012

Nutritional status is a well-recognized prognostic indicator in chronic obstructive pulmonary disease (COPD); however, very little is known about the relationship between lung function and saturated fat intake. We used data from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) to assess the relationship between saturated fatty acid (SFA) intake and lung function in the general US adult population. Adults in NHANES (2007⁻2012) with pre-bronchodilator spirometry measurements and dietary SFA intake were included. Primary outcomes were lung function including forced expiratory volume in one second (FEV₁

Short term dynamics of the sputum microbiome among COPD patients.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction. The complexity of the lung microbial community in COPD patients has been highlighted in recent years. Evidence suggests that transplantation, medications, age, and disease severity influence microbial community membership. However, the dynamics of the lung microbiome in stable COPD patients remain poorly understood. In this study, we completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on replicate sputum samples collected from 4 former smokers with COPD (Stage 2) within a 2-day time period. Samples from each individual over the two-day period were similar based on α-diversity, principle component analysis and taxonomy at the phyla and genera level. Sputum samples from COPD patients were also collected between 2-9 months of follow-up. Data suggest an increased variability of the sputum microbiota when comparing samples collected ≤ 3 months compared to those collected ≥ 4 months; however, no statistically significant shifts in the abundance (\u3e2-fold) of taxa between the two time points was observed. Bacterial composition and the number of operational taxonomic units (OTUs) remained similar over time. Results from this study suggest that the sputum microbiome is relatively stable in clinically stable COPD patients (Stage 2). This study furthers our understanding of the dynamics of the lung microbiome in COPD patients

Relationships of Serum CC16 Levels with Smoking Status and Lung Function in COPD

Background: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects, and low CC16 serum levels have been associated with both risk and progression of COPD, yet the interaction between smoking and CC16 on lung function outcomes remains unknown. Methods: Utilizing cross-sectional data on United States veterans, CC16 serum concentrations were measured by ELISA and log transformed for analyses. Spirometry was conducted and COPD status was defined by post-bronchodilator FEV1/FVC ratio \u3c 0.7. Smoking measures were self-reported on questionnaire. Multivariable logistic and linear regression were employed to examine associations between CC16 levels and COPD, and lung function with adjustment for covariates. Unadjusted Pearson correlations described relationships between CC16 level and lung function measures, pack-years smoked, and years since smoking cessation. Results: The study population (N = 351) was mostly male, white, with an average age over 60 years. An interaction between CC16 and smoking status on FEV1/FVC ratio was demonstrated among subjects with COPD (N = 245, p = 0.01). There was a positive correlation among former smokers and negative correlation among current or never smokers with COPD. Among former smokers with COPD, CC16 levels were also positively correlated with years since smoking cessation, and inversely related with pack-years smoked. Increasing CC16 levels were associated with lower odds of COPD (ORadj = 0.36, 95% CI 0.22-0.57, Padj \u3c 0.0001). Conclusions: Smoking status is an important effect modifier of CC16 relationships with lung function. Increasing serum CC16 corresponded to increases in FEV1/FVC ratio in former smokers with COPD versus opposite relationships in current or never smokers. Additional longitudinal studies may be warranted to assess relationship of CC16 with smoking cessation on lung function among subjects with COPD

Relationship of Systemic IL-10 Levels With Proinflammatory Cytokine Responsiveness and Lung Function in Agriculture Workers

BACKGROUND: Agriculture workers are exposed to microbial component- and particulate matter-enriched organic dust aerosols. Whereas it is clear that exposure to these aerosols can lead to lung inflammation, it is not known how inflammatory responses are resolved in some individuals while others develop chronic lung disease. Interleukin (IL)-10 is an immunomodulatory cytokine that is recognized as a potent anti-inflammatory and pro-resolving factor. The objective of this study was to determine whether there is a relationship of systemic IL-10 and proinflammatory responses and/or respiratory health effects in humans with prior agriculture exposure. METHODS: This is a cross sectional study of 625 veterans with \u3e 2 years of farming experience. Whole blood was stimulated with or without organic dust and measured for IL-6, TNFα and IL-10. Participants underwent spirometry and respiratory symptoms were assessed by questionnaire. RESULTS: We found that baseline IL-10 concentration from the whole blood assay was inversely associated with ΔTNF-α (r = - 0.63) and ΔIL-6 (r = - 0.37) levels. Results remained highly significant in the linear regression model after adjusting for age, sex, BMI, race, education, smoking status, and white blood cell count (ΔTNF-α, p \u3c 0.0001; ΔIL-6, p \u3c 0.0001). We found no association between chronic cough (p = 0.18), chronic phlegm (p = 0.31) and chronic bronchitis (p = 0.06) and baseline IL-10 levels using univariate logistic regression models. However, we did find that higher FEV CONCLUSIONS: Collectively, these studies support a potential role for IL-10 in modulating an inflammatory response and lung function in agriculture-exposed persons

A principal factor analysis to characterize agricultural exposures among Nebraska veterans

Agricultural workers are at an increased risk of developing chronic respiratory disorders. Accurate estimation of long-term agricultural exposures based on questionnaires has been used to improve the validity of epidemiologic investigations and subsequent evaluation of the association between agricultural exposures and chronic diseases. Our aim was to use principal factor analysis (PFA) to distill exposure data into essential variables characterizing long-term agricultural exposures. This is a crosssectional study of veterans between the ages of 40 and 80 years and who worked on a farm for ≥ 2 years. Participant characteristics were: 98.1% were white males with a mean age 65 ± 8 (SD) years and 39.8% had chronic obstructive pulmonary disease. The final model included four factors and explained 16.6% of the variance in the exposure data. Factor 1 was a heterogeneous factor; however, Factor 2 was exclusively composed of exposure to livestock such as hogs, dairy and poultry. Factor 3 included exposures from jobs on or off the farm such as wood dust, mineral dust, asbestos and spray paint. Crop exposure loaded exclusively in Factor 4 and included lifetime hours of exposure and maximum number of acres farmed in the participants’ lifetime. The factors in the final model were interpretable and consistent with farming practices

Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study

Abstract Introduction A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE). Methods Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction. Results A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050). Conclusions This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals