PyrogeIf these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be:[citation needed]
When the hypothalamic set point moves back to baseline—either spontaneously or via medication—normal functions such as sweating, and the reverse of the foregoing processes (e.g., vasodilation, end of shivering, and nonshivering heat production) are used to cool the body to the new, lower setting.[citation needed]
This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances sur
This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications.[1][verification needed]
In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis, also known as non-shivering thermogenesis).[citation needed]
Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.[citation needed]
A pyrogen is a substance that induces fever.[56] In the presence of an infectious agent, such as bacteria, viruses, viroids, etc., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides (LPS) produced by Gram-negative bacteria such as E. coli. But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well.[57] The types of pyrogens include internal (endogenous) and external (exogenous) to the body.
The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers.superantigens and cause rapid and dangerous fevers.[citation needed]
Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system).[58] In general, they stimulate chemical responses, often in the presence of an antigen, leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated from molecular patterns such as cases like rheumatoid arthritis or lupus.[59]
Major endogenous pyrogens are interleukin 1 (α and β)[60]:1237âMajor endogenous pyrogens are interleukin 1 (α and β)[60]:1237–1248 and interleukin 6 (IL-6).[61] Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ.[60]:1237–1248 Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release.[62] These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier.[citation needed] The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the arachidonic acid pathway.[citation needed]
Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature.[63]
Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint.[64]
An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria. According to one mech
An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria. According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage. The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines, e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the arachidonic acid pathway.[65]
PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2.
PGE2 is the ultimate mediator of the febrile response. The set point temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the PGE2 is the ultimate mediator of the febrile response. The set point temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa), and the paraventricular nucleus (PVN) of the hypothalamus . Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs.
Fever does not necessarily need to be treated,[66] and most febrile cases recover without specific medical attention.[67] Although it is unpleasant, fever rarely rises to a dangerous level even if untreated. Damage to the brain generally does not occur until temperatures reach 42 °C (107.6 °F), and it is rare for an untreated fever to exceed 40.6 °C (105 °F).[68] Treating fever in people with sepsis does not affect outcomes.[69]
Conservative measures
Medications that lower feve
Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in reducing fevers in children.[73] It is more effective than acetaminophen (paracetamol) in children.[73] Ibuprofen and acetaminophen may be safely used together in children with fevers.[74][75] The efficacy of acetaminophen by itself in children with fevers has been questioned.[76] Ibuprofen is also superior to aspirin in children with fevers.[77] Additionally, aspirin is not recommended in children and young adults (those under the age of 16 or 19 depending on the country) due to the risk of Reye's syndrome.[78]
Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen.[79] It is not clear if it increases
Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen.[79] It is not clear if it increases child comfort.[79] Response or nonresponse to medications does not predict whether or not a child has a serious illness.[80]
With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019.[81] Animal models have found worsened outcomes with the use of antipyretics in influenza as of 2010 but they have not been studied for this use in humans.[82]
Fever is one of the most common medical signs.[3] It is part of about 30% of healthcare visits by children,[3] and occurs in up to 75% of adults who are seriously sick.[11] About 5% of people who go to an emergency room have a fever.[83]
History
A number of
A number of types of fever were known as early as 460 BC to 370 BC when Hippocrates was practicing medicine including that due to malaria (tertian or every 2 days and quartan or every 3 days).[84] It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.[84]
Fevers were a major source of mortality in humans for about 200,000 years. Until the late nineteenth century, approximately half of all humans died from fever before the age of fifteen.[85]
Fevers were a major source of mortality in humans for about 200,000 years. Until the late nineteenth century, approximately half of all humans died from fever before the age of fifteen.[85]
Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia,[3][86] which is based in both caregiver's and parents' misconceptions about fever in children. Among them, many parents incorrectly believe that fever is a disease rather than a medical sign, that even low fevers are harmful, and that any temperature even briefly or slightly above the oversimplified "normal" number marked on a thermometer is a clinically significant fever.[86] They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers.[86] The underlying problem, according to professor of pediatrics Barton D. Schmitt, is "as parents we tend to suspect that our children’s brains may melt."[87] As a result of these misconceptions parents are anxious, give the child fever-reducing medicine when the temperature is technically normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine.[86]
Other species
Fever is an important feature for the
diagnosis of
disease in domestic animals. The body temperature of animals, which is taken rectally, is different from one species to another. For example, a
horse is said to have a fever above
101 °F (
38.3 °C).
[88] In species that allow the body to have a wide range of "normal" temperatures, such as
camels,
[89] it is sometimes difficult to determine a febrile stage.
[citation needed] Fever can also be behaviorally induced by invertebrates that do not have immune-system based fever. For instance, some species of grasshopper will thermoregulate to achieve body temperatures that are 2–5 °C higher than normal in order to inhibit the growth of fungal pathogens such as
Beauveria bassiana and
Metarhizium acridum.
[90] Honeybee colonies are also able to induce a fever in response to a fungal parasite
Ascosphaera apis.
[90]
References
