Holguín, Fernando

Abstract Rationale Asthma and obesity are common comorbidities, both driven by inflammation and oxidative stress. Oxylipins are derivatives of polyunsaturated fatty acids that regulate the onset and resolution of inflammation. Oxylipin profiles are altered in obesity and have been shown to differentiate asthma from non-asthma; however, the association between oxylipins and asthma outcomes and the impact of obesity is not known. This study aims to identify differences in serum oxylipins associated with asthma morbidity and evaluate the effect modification by BMI. Methods We analyzed 150 participants in the Best African American Response to Asthma Drugs (BARD) clinical trial. Ninety oxylipins were quantified using liquid chromatography tandem mass spectroscopy from serum obtained at the time of randomization. Oxylipins found to be above the limit of detection in > 80% of samples were log-transformed and included in the analysis. Asthma severity measures included past 12-month systemic corticosteroid use for asthma exacerbation, spirometry, asthma control and asthma quality of life questionnaires (AQLQ). The associations between oxylipins and asthma outcomes were tested using multivariable regression models adjusted for sex, age, BMI, absolute eosinophil count, percent African ancestry, and child vs adult/adolescent cohort. A false discovery rate (FDR) of < 0.1 is used to determine statistical significance. Results Of the 90 oxylipins measured, 42 (46.7%) were detected in > 80% of all samples and included in the analysis. In multivariable models, the pro-inflammatory arachidonic acid (AA) derivative 5,6-DiHETrE was associated with decreased odds of past 12-month systemic corticosteroid use (FDR-adjusted p-value 0.0628). AA derivatives TXB2, PGF2a, and 6-α-prostaglandin were associated with increased FEV1/FVC (FDR-adjusted p-values=0.0925). Thirteen oxylipins were associated with decreased asthma-related quality of life in multivariable models, including AA metabolites 5S-HETE, 5-KETE, 14,15-EET, LTB4, and Lipoxin A4; dihomo-gamma-linoleic acid metabolites 5-HETrE and 15-HETrE; linoleic acid metabolites 3-OxoODE and 9-OxoODE; and eicosapentaenoic acid metabolites 15-HEPE and 17,18-EpETE, all with FDR-adjusted p-values<0.05. Oxylipin-BMI interaction was significant only in the AQLQ models. In all but LTE4, increased concentrations of oxylipins were associated with a decreased quality of life in individuals with higher BMI (Figure). Six of these oxylipins are products of lipoxygenase activity. Conclusions In this study, we find decreased quality of life with increasing concentrations of pro-inflammatory and resolving oxylipins among those with obesity. These oxylipins are primarily produced via lipoxygenases and may represent an important inflammatory pathway in obesity-associated asthma. Quantification of sputum oxylipins and correlation with serum levels will be important in understanding potential mechanisms and is forthcoming. This abstract is funded by: K12TR004412, R01HL123385, U10HL098075, Parker B. Francis Fellowship, 2L30HL159725

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is mixed. Whether asthma–COPD overlap (ACO) is associated with lung cancer has not been studied. Objectives We aimed to compare lung cancer risk among patients with ACO versus COPD and other conditions associated with airway obstruction. Methods We studied 13,939 smokers from the National Lung Cancer Screening Trial who had baseline spirometry and used spirometric indices and history of childhood asthma to categorize participants into five specific airway disease subgroups. We used Poisson regression to compare unadjusted and adjusted lung cancer risk. Results The incidence rate of lung cancer per 1,000 person-years was as follows: ACO, 13.2 (95% confidence interval [CI], 8.1–21.5); COPD, 11.7 (95% CI, 10.5–13.1); asthmatic smokers, 1.8 (95% CI, 0.6–5.4); Global Initiative for Chronic Obstructive Lung Disease–Unclassified, 7.7 (95% CI, 6.4–9.2); and normal spirometry smokers, 4.1 (95% CI, 3.5–4.8). Patients with ACO had increased adjusted risk of lung cancer compared with patients with asthma (incidence rate ratio [IRR], 4.5; 95% CI, 1.3–15.8) and normal spirometry smokers (IRR, 2.3; 95% CI, 1.3–4.2) in models adjusting for other risk factors. Adjusted lung cancer incidence in patients with ACO and COPD were not found to be different (IRR, 1.2; 95% CI, 0.7–2.1). Conclusions The risk of lung cancer among patients with ACO is similar to those with COPD and higher than other groups of smokers. These results provide further evidence that COPD, with or without a history of childhood asthma, is an independent risk factor for lung cancer.