Relationship between bilirubin levels and risk of asthma severity and frequency of exacerbation

    Relationship between bilirubin levels and risk of asthma severity and frequency of exacerbation Mildly higher bilirubin or upper level bilirubin has shown be protective against different diseases including lung diseases. Bilirubin has antioxidant effect(1). Among patients with normal-range bilirubin levels in primary care practices, relatively higher levels of bilirubin were associated with a lower risk of respiratory disease and all-cause mortality (2). Genetically raised unconjugated serum bilirubin as in Gilbert's syndrome is associated with higher adult respiratory function and protection from respiratory disease (3). In rat model study Bilirubin was shown to be able to promote the reconstruction of extracellular matrix by decreasing the expression of Laminin and epidermal growth factor in lung tissue and in type II Pneumocyte in the development of emphysema (4).Another rate model study found Bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema (5). Bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin concentration was associated with a higher FEV1 and less annual decline in FEV1 (6). Bilirubin was also associated with less coronary heart disease mortality(6). literature shows that higher TBili levels correlate with a reduced risk of stroke, atherosclerosis, Coronary artery disease, renal perfusion injuries, Rheumatoid arthritis and angiotensin-mediated hypertension(7-12). To our knowledge, no study was done to see correlation between asthma patients and bilirubin in term of prevalence , severity and exacerbation . our study to look for asthma patients and see if they have low bilirubin and correlate asthma severity to bilirubin level and see if more reduced bilirubin can increase exacerbation. Objective to examine the relationship between bilirubin levels and risk of asthma severity and frequency of exacerbationStud design:Retrospective study from EVMS pulmonary clinic and Sentra Norfolk general hospital electronic records with serum bilirubin levels recorded.Data between January 2011 and December 2016Inclusion criteria:Patients with diagnosis of ICD code diagnosis of asthma, Have PFT or MCT show air way limitation with reversibility Age > 18 years’ old Exclusion criteria:PregnancyHepatobiliary diseasehemolytic disease diseasesCHFCOPD or other underling lung diseases / cancer Primary outcomes:low or low normal bilirubin associated with less severe asthma Secondary outcomes:Frequency of exacerbation Mortality Variables:AgeSexRaceBMIFEV1FVCTLCDLCOMethacholine challenge test Bilirubin Level Smoking status (former, current, Pack year history)Comorbidities: CAD, DM, HTN, Stroke, Hyperlipidemia, OSA diagnosis, allergic rhinitis, seasonal allergy, Immunization status (flu and pneumonia vaccine) Inhaler use ( SABA,SAMA,ICS,LABA,LAMA,singulair, oral prednisone, Monoclonal antibodies) Statistical analysis:Continuous data will expressed as mean ± standard deviation (SD) or median and interquartile rang according to the data distribution; categorical data will be presented as proportions and 95%CIs. For evaluation of differences at the univariate level, the one-way ANOVA test and the difference of means will be used to compare with the Tukey-Kramer post hoc test, the Wilcoxon-Kruskal-Wallis test for nonnormally distributed data, or the chi-square test or Fisher exact test for proportions. The association between PaO2 variable and ICU mortality and in hospital mortality will be evaluated by logistic regression analysis.  P value of 0.05 will be considered the cut off value below which data will be deemed significant. The analyses will be carried out by SPSS version 14.0 (SPSS Inc., Chicago, IL, USA) and S- plus version 7.0 (Insightful Corp., Seattle, WA, USA).REFERENCE LIST 1. Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci U S A. 1987;84(16):5918-22.2. Horsfall LJ, Rait G, Walters K, et al. Serum bilirubin and risk of respiratory disease and death. JAMA. 2011;305(7):691-7.3. Horsfall LJ, Hardy R, Wong A, et al. Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert's syndrome) and respiratory health in the 1946 British birth cohort. J Hepatol. 2014;61(6):1344-51.4. Li JQ, Wen Y, Zhao H, et al. [The effects of bilirubin concentration on laminin and epidermal growth factor expression in lung tissue and type II pneumocytes in smoking rats model]. Zhonghua Nei Ke Za Zhi. 2005;44(2):129-32.5. Wei J, Zhao H, Fan G, et al. Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema. Biochem Biophys Res Commun. 2015;465(2):180-7.6. Apperley S, Park HY, Holmes DT, et al. Serum Bilirubin and Disease Progression in Mild COPD. Chest. 2015;148(1):169-75.7. Adin CA, Croker BP, Agarwal A. Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney. Am J Physiol Renal Physiol. 2005;288(4):F778-84.8. Ghem C, Sarmento-Leite RE, de Quadros AS, et al. Serum bilirubin concentration in patients with an established coronary artery disease. Int Heart J. 2010;51 (2):86-91.9. Kawamoto R, Ninomiya D, Hasegawa Y, et al. Mildly elevated serum total bilirubin levels are negatively associated with carotid atherosclerosis among elderly persons with type 2 diabetes. Clin Exp Hypertens. 2016;38(1):107-12.10. Kang SJ, Kim D, Park HE, et al. Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. Atherosclerosis. 2013;230 (2):242-8.11. Juping D, Yuan Y, Shiyong C, et al. Serum bilirubin and the risk of rheumatoid arthritis. J Clin Lab Anal. 2017.12. Fischman D, Valluri A, Gorrepati VS, et al. Bilirubin as a Protective Factor for Rheumatoid Arthritis: An NHANES Study of 2003 - 2006 Data. J Clin Med Res. 2010;2(6):256-60.