Walter et al. Critical Care (2016) 20:200 DOI 10.1186/s13054-016-1375-5 REVIEW Open Access The pathophysiological basis and consequences of fever Edward James Walter*, Sameer Hanna-Jumma, Mike Carraretto and Lui Forni of the cause [1]. Fever has its etymological basis in Latin, Abstract meaning simply ‘heat,’ and pyrexia comes from the Greek There are numerous causes of a raised core ‘pyr,’ meaning fire or fever. Some sources use the terms temperature. A fever occurring in sepsis may be interchangeably, whereas others preserve ‘fever’ to mean a associated with a survival benefit. However, this is not raised temperature caused by the action of thermoregula- the case for non-infective triggers. Where heat tory pyrogens on the hypothalamus; for instance, in sepsis generation exceeds heat loss and the core and inflammatory conditions [3]. temperature rises above that set by the Hyperthermia also has no agreed definition; it has been hypothalamus, a combination of cellular, local, defined as a core temperature above 38.2 °C, irrespective organ-specific, and systemic effects occurs and puts of the cause [3]. Others use it for the classification of those the individual at risk of both short-term and long-term conditions that increase the body’s temperature above that dysfunction which, if severe or sustained, may lead to set by the hypothalamus, and therefore specifically exclude death. This narrative review is part of a series that will those where fever is caused by pyrogens [4], being due to outline the pathophysiology of pyrogenic and heat exposure or unregulated heat production in excess of non-pyrogenic fever, concentrating primarily on the heat loss. Common causes include classical and exertional pathophysiology of non-septic causes. heatstroke, and drug-related illnesses (for example, malig- nant hyperthermia and neuroleptic syndrome). Keywords: Hyperthermia, Fever, Organ failure, There is, however, increasing evidence that many Physiopathology, Heatstroke conditions considered non-pyrogenic may stimulate an in- flammatory response, and the division into pyrogenic and Background non-pyrogenic may therefore be less clear-cut than previ- ously understood. “Humanity has but three great enemies: fever, famine, and war, and of these by far the greatest, by far the Generation of fever ” most terrible, is fever. (William Osler) Sepsis accounts for up to 74 % of fever in hospitalised patients [5] and, of the remainder, malignancy, tissue is- The normal human temperature is considered to be chaemia, and drug reactions account for the majority 37 °C, but may vary by up to 1 °C in healthy individuals [6]. Neurogenic fever, and fevers associated with endo- [1]. Elevated core temperature is a common finding in crinopathy, are rarer. intensive care, affecting up to 70 % of patients [2]. Despite the general usage of the terms ‘pyrexia’, ‘fever’, Sepsis and ‘hyperthermia,’ they are not yet universally defined. The American College of Critical Care Medicine, the Pyrogenicfeverisacommonresponsetosepsisincritically International Statistical Classification of Diseases, and the ill patients, and the generation of fever occurs through sev- Infectious Diseases Society of America define fever as a eral mechanisms. The interaction of exogenous pyrogens (e.g. micro-organisms) or endogenous pyrogens (e.g. inter- core temperature of 38.3 °C or higher, i.e. just above the α upper limit of a normal human temperature, irrespective leukin (IL)-1, IL-6, tumour necrosis factor (TNF)- )with the organum vasculosum of the lamina terminalis (OVLT) leads to the production of fever. Exogenous pyrogens may * Correspondence: [email protected] Department of Intensive Care Medicine, Royal Surrey County Hospital, stimulate cytokine production, or may act directly on the Egerton Road, Guildford, Surrey GU2 7XX, UK OVLT. The OVLT is one of seven predominantly cellular © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Walter et al. Critical Care (2016) 20:200 Page 2 of 10 structures in the anterior hypothalamus within the lamina The febrile response is well preserved across the animal terminalis, located in the optic recess at the anteroventral kingdom, with some experimental evidence suggesting it end of the third ventricle. Being a circumventricular may be a beneficial response to infection. Retrospective organ it is highly vascular and lacks a blood–brain bar- data analysis shows that a raised temperature in patients rier (BBB), permitting it to be stimulated directly by with infection in the first 24 h following admission to pyrogenic substances. Its stimulation leads to increased the intensive care unit (ICU) is associated with a better synthesis of prostanoids including prostaglandin outcome compared with normothermia or hyperther- (PG)E2, which acts in the pre-optic nucleus of the mia above 40 °C [13], and that a temperature between hypothalamus slowing the firing rate of the warm sensi- 37.5 °C and 39.4 °C trends towards improved outcome tive neurons and resulting in an increase in body compared with normothermia [14]. In elderly patients temperature. The bioactive lipid derivative, ceramide, with community-acquired pneumonia, the observed which has a proapoptotic as well as a cell signalling mortalityratewassignificantlyhigherinpatientswho role, may act as a second messenger independent of lacked fever (29 %) when compared with patients who PGE2, and may be of particular importance in the early developed a febrile response (4 %) [15]. A temperature stages of fever generation [7]. Lipopolysaccharides (LPS) greater than 38.2 °C has also been found to have a pro- from gram-negative bacteria may stimulate peripheral tective role against invasive fungal infections in the production of PGE2 from hepatic Kupffer cells [8, 9]. ICU [16]. The raised temperature may provide protec- LPS-stimulated fever may also be neurally mediated tion by several mechanisms. Firstly, human infective [10]. Neural pathways may account for the rapid onset pathogens often demonstrate optimal replication at of fever, with cytokine production responsible for the temperatures below 37 °C; thus an elevated host maintenance, rather than the initiation, of fever [11]. temperature inhibits reproduction [17]. Secondly, in- Fever generation is also thought to occur by signal- creasing the temperature in vitro from 35 °C to 41.5 °C ling via the Toll-like receptor cascade, which may be increases the antimicrobial activity of many classes of independent of the cytokine cascade [12] (Fig. 1). antibiotics [18]. Thirdly, a rise in temperature may also Fig. 1 Proposed mechanisms for the generation of fever in sepsis. Stimulation of sentinel cells by exogenous pyrogens produces endogenous pyrogens which stimulate fever production in the pre-optic area (POA) of the hypothalamus by the second messengers prostaglandin E2 (PGE2), and ceramide. PGE2 is also produced from Kupffer cells in the liver in response to stimulation from lipopolysaccharide (LPS), which additionally stimulates the POA via the vagus nerve. OVLT organum vasculosum of the lamina terminalis Walter et al. Critical Care (2016) 20:200 Page 3 of 10 be associated with an increase in innate immunity asso- activates the adaptive immune system, which is in itself ciated with microbial destruction [19]. Interestingly, at responsible for the inflammatory process. The former temperatures above around 40 °C there is a further are also known as periodic fever syndromes, highlighting mortality increase [13, 14], suggesting that at this stage the intermittent febrile nature of these conditions. the deleterious effects of hyperthermia on organ and Examples include familial Mediterranean fever and cellular function outweigh any benefit conferred from some arthopathies, including adult-onset Still’s disease. hyperpyrexia in acute sepsis. These potential benefits of Most autoinflammatory conditions are genetic, and a large fever in sepsis may not be well recognised; in one survey number are related to abnormalities in pro-inflammatory of fever monitoring in sepsis from UK ICUs, 76 % of ICU cytokine handling, for example IL-1 or interferon (IFN) physicians would be concerned about a temperature of signalling, or constitutive NF-kB activation, offering thera- 38–39 °C, and 66 % would initiate active cooling at that peutic targets. point [20]. In contrast with a fever in response to sepsis, a Drug-induced fever non-pyrogenic fever is not of any perceived teleological The causes of drug-induced fever are shown in Table 1 benefit. A temperature of 37.5 °C or greater at any point [23]. Pharmacological agents may cause fever by a num- during an ICU admission trends towards a worse out- ber of pathophysiological mechanisms. These include come, and becomes significant at temperatures greater interference with the physiological mechanisms of heat than 38.5 °C [14]. loss from the peripheries, interference with central temperature regulation, direct damage to tissues, stimu- Fever associated with inflammation lation of an