Fever

Akkadian cuneiform inscriptions from the sixth century BC were the first to refer to fever in writing [1]. Only a couple of centuries later the ancient Greeks, including Hippocrates, developed the first theoretical concepts about the pathophysiology of fever. Fever then was believed to be a beneficial sign during infection [2]. This concept was maintained even into the seventeenth century. The English physician Thomas Sydenham (1624-1689) claimed that “Fever is Nature’s engine which she brings into the field to remove her enemy” [3]. Nevertheless, starting from the late nineteenth century the beneficial effect of fever was questioned. Writings by the German physician Carl von Liebermeister were the first to claim that fevers were dangerous if they were too high or persisted for too long [4]. If in fact fever in itself is beneficial or destructive (and thus an adaptive or maladaptive response) is not yet decided. From an evolutionary point of view, Mackowiak stated that “the febrile response and its mediators may have evolved both as a mechanism for accelerating the recovery of infected individuals with localized or mild to moderately severe systemic infections and for hastening the demise of hopelessly infected individuals, who pose a threat of epidemic disease to the species” [5]. Since the central mechanism for the regulation of body temperature is hosted by the brain, almost all illnesses that cause fever must interact with the central nervous system (CNS). In the CNS, circumventricular organs (CVOs) located around the third and fourth ventricles are vascularized structures characterized by the lack of a blood–brain barrier (BBB). Blood, the brain parenchyma, and the cerebrospinal fluid (CSF) are able to communicate here. Sodium and water balance, cardiovascular regulation, energy metabolism, immunomodulation, and, last but not least, the fever response are regulated via interconnections with the hypothalamus and brainstem.