Matt Harmon

Chapter four 86 Discussion In this study of canonical pathways in blood leukocytes in septic patients we found that hypothermic septic patients have a unique gene expression profile compared to sepsis patient presenting with fever. After correcting for disease severity hypothermic septic patients showed a surprisingly similar gene expression profile compared patients with febrile sepsis. However, there were distinct upregulated signaling pathways related to degradation of amino acids and (poly)amines were strongly associated with hypothermia, both in uncorrected analyses and analyses corrected for disease severity. Patients with hypothermic sepsis show significant alterations in genomic pathways compared to febrile patients. These included downregulated pathways related to protein catabolism and translation, cell growth proliferation and mobility, cardiovascular signaling, pattern recognition receptor and cytokine signaling and lymphocyte pathways. In addition, pathways relating to amino acid and (poly)amine degradation were significantly upregulated. In a different sepsis cohort similar defects in metabolic and immunologic signaling pathways have been associated with underlying immunoparalysis. 23 In line with this finding, a recent retrospective analysis of hypothermic septic patients found increased incidence of lymphopenia associated with hypothermia compared to nonhypothermic septic patients. 10 However, other studies focusing on the host response have revealed remarkably few differences between hypothermic and nonhypothermic or febrile patients regarding typical pro- and anti-inflammatory cytokine responses and thereby signal that hypothermic patients are initially able to mount an adequate host response. 7,8 Subsequently, to address confounding due to increased disease severity in hypothermic patients, we adjusted our model for illness severity by matching of patients on APACHE IV score and presence of shock. In this analysis, many of the identified genetic pathways found in the unmatched cohort were no longer present in the matched cohort, suggesting that these pathways may be related to disease severity. CIRBP expression, which encodes cold-induced RNA binding protein was significantly elevated in patients discordant for hypothermia sepsis, importantly, after matching patients for disease severity. Altered CIRBP expression in several different species in response to lower temperatures, suggesting that CIRBP is a conserved response to cold stress. 24 CIRPB expression is upregulated during hypoxia, hypothermia, and oxidative stress. 25 It plays a role in cold induced cell suppression. In addition, it can trigger an inflammatory response in sepsis 26 and may be a critical mediator in organ failure during sepsis. 25 Interestingly,