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There are numerous causes of a raised core temperature. A fever occurring in sepsis may be associated with a survival benefit. However, this is not the case for non-infective triggers. Where heat generation exceeds heat loss and the core temperature rises above that set by the hypothalamus, a combination of cellular, local, organ-specific, and systemic effects occurs and puts the individual at risk of both short-term and long-term dysfunction which, if severe or sustained, may lead to death.

This narrative review is part of a series that will outline the pathophysiology of pyrogenic and non-pyrogenic fever, concentrating primarily on the pathophysiology of non-septic causes. Hyperthermia also has no agreed definition; it has been defined as a core temperature above Common causes include classical and exertional heatstroke, and drug-related illnesses for example, malignant hyperthermia and neuroleptic syndrome. There is, however, increasing evidence that many conditions considered non-pyrogenic may stimulate an inflammatory response, and the division into pyrogenic and non-pyrogenic may therefore be less clear-cut than previously understood.

Neurogenic fever, and fevers associated with endocrinopathy, are rarer. Pyrogenic fever is a common response to sepsis in critically ill patients, and the generation of fever occurs through several mechanisms. The interaction of exogenous pyrogens e.

Exogenous pyrogens may stimulate cytokine production, or may act directly on the OVLT. The OVLT is one of seven predominantly cellular structures in the anterior hypothalamus within the lamina terminalis, located in the optic recess at the anteroventral end of the third ventricle.

Being a circumventricular organ it is highly vascular and lacks a blood—brain barrier BBB , permitting it to be stimulated directly by pyrogenic substances.

Its stimulation leads to increased synthesis of prostanoids including prostaglandin PG E 2 , which acts in the pre-optic nucleus of the hypothalamus slowing the firing rate of the warm sensitive neurons and resulting in an increase in body temperature.

The bioactive lipid derivative, ceramide, which has a proapoptotic as well as a cell signalling role, may act as a second messenger independent of PGE 2 , and may be of particular importance in the early stages of fever generation [ 7 ].

LPS-stimulated fever may also be neurally mediated [ 10 ]. Neural pathways may account for the rapid onset of fever, with cytokine production responsible for the maintenance, rather than the initiation, of fever [ 11 ].

Fever generation is also thought to occur by signalling via the Toll-like receptor cascade, which may be independent of the cytokine cascade [ 12 ] Fig. 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 E 2 PGE 2 , and ceramide. PGE 2 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. The febrile response is well preserved across the animal kingdom, with some experimental evidence suggesting it may be a beneficial response to infection.

A temperature greater than The raised temperature may provide protection by several mechanisms. Thirdly, a rise in temperature may also be associated with an increase in innate immunity associated with microbial destruction [ 19 ]. In contrast with a fever in response to sepsis, a non-pyrogenic fever is not of any perceived teleological benefit. A temperature of In critically ill patients, inflammation is commonly observed to aid repair after traumatic or infective insults.

Fever is a ubiquitous component of inflammation across the animal kingdom, and enhances the host response. A large number of both the cell-derived and plasma-derived inflammatory mediators are pyrogenic; fever associated with inflammation is probably mediated in a similar way to sepsis as described above.

Chronic inflammation is deleterious; the recently described compensatory anti-inflammatory response syndrome CARS restores homeostasis, and it is likely that the magnitude and relative timings of the inflammatory and anti-inflammatory responses are both important in determining the host outcome.

Fever in patients with malignancy is reported to be sepsis related in around two thirds of cases [ 21 ]. Regulated autoimmunity is considered to be a natural physiological reaction; however, pathological autoimmunity occurs because of higher titres of more antigen-specific antibodies, often of the IgG isoform, and a reduction in self-tolerance. There are five pathogenic processes associated with autoimmune disease development, and in excess of 80 diseases have been described; fever is considered to be cytokine mediated in the majority of cases [ 22 ].

Autoinflammatory conditions differ from autoimmune diseases. In the former, the innate immune system directly causes inflammation without a significant T-cell response, whereas in the latter the innate immune system activates the adaptive immune system, which is in itself responsible for the inflammatory process. The former are also known as periodic fever syndromes, highlighting the intermittent febrile nature of these conditions. Most autoinflammatory conditions are genetic, and a large number are related to abnormalities in pro-inflammatory cytokine handling, for example IL-1 or interferon IFN signalling, or constitutive NF-kB activation, offering therapeutic targets.

Pharmacological agents may cause fever by a number of pathophysiological mechanisms. These include interference with the physiological mechanisms of heat loss from the peripheries, interference with central temperature regulation, direct damage to tissues, stimulation of an immune response, or pyrogenic properties of the drug.

Taken from [ 23 ] with permission. A common mechanism in many of these drugs is considered to be stimulation of non-shivering thermogenesis NST , primarily in brown adipose tissue and skeletal muscle.

Under normal conditions, cellular oxidative phosphorylation allows the synthesis of ATP from ADP for cellular metabolism. NST uncouples the proton movement from this pathway, allowing the energy to be dissipated as heat, under the control of uncoupling proteins, ultimately influenced by thyroid hormones and catecholamines. A number of agents, including sympathomimetics and those which act via the serotonin pathway, are thought to cause fever by modifying the NST pathway at a central, peripheral, or cellular level [ 24 ].

Fever after acute brain damage, from trauma or a vascular event, is common, and is independently associated with a worse outcome. Alterations in cellular metabolism, a shift to anaerobic metabolism, and ischaemic—reperfusion injury are all associated with thermogenesis [ 26 ]. The cerebral production of a large number of inflammatory and pyrogenic cytokines is increased acutely [ 27 ]; IL-6 in particular is associated with fever production after a stroke, and with a worse outcome.

After cerebral haemorrhage, both the presence of blood and the presence of its degradation products are associated with heat production [ 28 ]. Recent work suggests a protective role for uncoupling of mitochondrial oxidative phosphorylation following neurotrauma under the regulation of uncoupling proteins [ 29 ]; the dissipation of the proton gradient produces heat.

Brain injury following a cardiac arrest is well recognised, but the pathology is complex and probably involves multiple mechanisms, including cell death, excitotoxicity, cell signalling changes, ischaemia—reperfusion, and alterations in cellular metabolism [ 30 ]; this is very similar to those described following brain injury from other causes, and, as such, the mechanisms of thermogenesis are likely to be similar.

The teleological benefit of pyrexia following brain injury is uncertain. Thyroid hormones are essential for regulation of energy metabolism. Hyperthyroidism is associated with hyperthermia; patients with thyroid storm have an average body temperature of The mechanism of thermogenesis is not clear; the classical view is that metabolism of peripheral tissues increases through a peripherally mediated pathway.

The levels of T4 and thyroid-stimulating hormone TSH are unchanged with changes in body temperature [ 33 ]. Adrenal insufficiency is rarely associated with fever, but the hyperthermia may be related to the underlying pathology; autoimmunity accounts for the majority of primary insufficiency. A malignant process, or an infectious process, account for a proportion of the remainder; all of the patients in the original description had adrenal tuberculosis [ 34 ].

There are a number of pathophysiological mechanisms for the deleterious effects of a fever, classified as follows Fig. Hyperthermia is directly cytotoxic, affecting membrane stability and transmembrane transport protein function.

Consequently, ionic transport is disrupted leading to increased intracellular sodium and calcium with a reduced intracellular potassium concentration. Protein and DNA synthesis is disrupted at various stages in the pathway; while RNA and protein synthesis may recover quickly after cessation of hyperthermia, DNA synthesis remains disrupted for longer [ 36 ].

The thermal energy required for cell death is similar to that required for protein denaturation, suggesting that hyperthermic cell death may occur primarily through its effect on protein structure, although cell death occurs primarily through necrosis or from apoptosis depending on the cell line and the temperature [ 36 ].

Cells in mitosis are more thermosensitive than cells in other phases of replication. Given that organ dysfunction occurs at temperatures lower than that required for in-vitro cell death, milder degrees of hyperthermia are also likely to affect cell structure and function with a degree of reversibility.

The role of cytokines in heat stress is unclear, with an inconsistent response to thermal stress. The levels of a number of pro-inflammatory and anti-inflammatory cytokines are elevated at the time of hyperthermia from heatstroke.

Acute phase reactants may also increase. Furthermore, there is some correlation with outcome; the rise in IL-6 and the duration of the increased expression is related to mortality, independent of the maximum core temperature obtained [ 40 ]. Mice pre-treated with IL-6 before exposure to heat take longer to reach Antagonism of IL-1 also improves survival [ 42 ]. The cytokine profile of the two forms of heatstroke, classical and exertional, show similarities, and mirrors that produced by exercise [ 43 ].

The profile also shows similarities to that produced by endotoxaemia, which is considered to be of importance in the cytokine expression—abolition of endotoxaemia significantly reduces cytokine production [ 43 ]. Development of other hyperthermic states may also be associated with inflammatory mediators. Conversely, levels of anti-inflammatory agents such as serum iron and albumin initially decline then return to the normal range, coinciding with clinical improvement [ 44 ].

It is proposed that the acute phase response may be triggered by the heat stress per se, or by muscle breakdown, or by interaction between a virus and the drug, or the immune system [ 45 ]. Heat shock proteins HSP are a family of cell-derived proteins that offer protection against a range of insults, including heat. They are expressed in response to the insult, and their effect may depend on their location.

Intracellularly located HSPs have a protective role, including correcting misfolded proteins, preventing protein aggregation, transport of proteins, and supporting antigen processing and presentation, and limiting apoptosis. In contrast, membrane-bound or extracellular HSPs may be immunostimulatory, and appear to induce cytokine release or provide recognition sites for natural killer cells. HSPs may also have both pro-apoptotic and anti-apoptotic actions [ 48 , 49 ].

Non-pyrogenic hyperthermia increases gut bacterial translocation and the gastrointestinal GI tract and BBB appear to be more permeable to toxins than during normothermia [ 51 , 52 ]. Bacterial and endotoxin translocation are also implicated in the development of multi-organ dysfunction in non-pyrogenic hyperthermia.

For example, antibiotic administration to dogs with heatstroke appears to improve their survival, suggesting that bacteraemia may have a role even in non-pyrogenic conditions [ 53 ]. In a similar study, raising the core temperature in monkeys from In the animals pre-treated with oral kanamycin, which is very poorly absorbed, and heated to However, microbiological and clinical evidence of infection was not significantly higher in this group, and therefore it is unclear whether this represents undiagnosed bacteraemia or procalcitonin elevated in the absence of infection.

Genotypic and phenotypic differences may account for how tolerant a particular individual is to heat exposure. Individuals who demonstrate heat-intolerance may show a reduction in HSP levels and, in addition, their vasculature may be less reactive to heat stress [ 57 ]. Well-described genotypic differences are seen in particular conditions.

MH affects up to 1 in patients, and is more common in males and in young people, although it can affect all age groups including neonates [ 58 ]. It has also been observed in other species, such as dogs, cats, horses and pigs.

RYRs in the sarcoplasmic reticulum of skeletal muscle form calcium channels and are the main mediators of calcium-induced calcium release in animal cells. In MH, the RYR functions abnormally such that calcium is released in a greater than normal amount and heat is generated during the processing of this excess calcium.

The first documented survivor of MH was in Australia in ; a young man required surgery for a fractured tibia. Ten of his family members had previously developed uncontrolled hyperthermia and died during general anaesthesia with ether [ 60 ]. Exertional heatstroke EHS is increasingly observed in endurance athletes [ 61 ].

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Saab, et al. Mycobacterium tuberculosis-induced activation accelerates apoptosis in peripheral blood neutrophils from patients with active tuberculosis. Aliprantis, A. Yang, M. Mark, et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor Science

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