Matt Harmon

11 Chapter one interacting with immune cells through toll-like receptors (TLRs). This interaction induces the synthesis of endogenous pyrogenic cytokines, including interleukin (IL)-1 β , tumor necrosis factor (TNF) α , and IL-6. In turn, these pyrogens elicit the release of prostaglandins, mainly type E2, from the brain. Prostaglandin E2 interacts with the pre-optic area of the hypothalamus, activating several post- hypothalamic heat generating and heat conserving mechanisms. These include warmth seeking behavior and shivering as well as autonomic reactions such as decreased sweating and vasoconstriction of superficial vessels in an attempt to conserve heat. 11 The body also initiates several hormonal and metabolic mechanisms including a decrease in vasopressin, which decreases the amount of fluid in the body that needs to be heated, and increased heat thermogenesis from brown adipose tissue. Fever is tightly regulated by glucocorticoids, neuropeptides and anti-inflammatory cytokines. 12 These mechanisms are highlighted in figure 1. There are also other fever pathways, including a pathway that acts independently of pyrogenic cytokines. 13 The effects of fever Fever has both beneficial effects and adverse effects. These beneficial effects mostly relate to the body’s ability to fight an infection. During an infection, fever enhances components of both the innate and adaptive immune response 10 For the innate immunity these include improved neutrophil taxation and phagocytosis. 14,15 Regarding the adaptive immunity, fever promotes lymphocyte trafficking, increasing the chance that rare antigen specific T-cells come into contact with activating dendritic cells. 10 In addition, fever promotes and stabilizes binding to antigen presenting cells and increase CD-8 T-cell differentiation. Immune cell adhesion to the endothelium via L-selectin is also improved. 16 Fever also promotes the expression of heat shock proteins, which are important for cellular protection and can potentially reduce endothelial and organ damage during proteotoxic stress such as infection. 10 Finally, fever inhibits the growth of pathogens such as s. pneumoniae in experimental study designs. 17 However, to inhibit the growth of some pathogens, the bodies temperature has to rise to supraphysiologic temperatures, so this mechanism may not always be viable. Taken together, fever augments several important aspects of the immune response to a pathogen. Fever can also harm patients. Patients with an injured brain subjected to fever have unfavorable outcome. 18 The mechanism for increased brain injury may include increased circulation of free radicals 19 and also increased metabolism. Increasing body temperature from 38°C to 41°C in anesthetized and mechanically ventilated dogs results in a 20% increase in oxygen consumption. 20 The increased cerebral oxygen consumption augments ischemic injury and can increase cerebral