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Fever

Fever or pyrexia in humans is a body temperature above the normal range due to an increase in the body's temperature set point in the hypothalamus.[5][6][12][7] There is no single agreed-upon upper limit for normal temperature: sources use values ranging between 37.2 and 38.3 °C (99.0 and 100.9 °F) in humans.[1][7][8] The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills.[2] This results in greater heat production and efforts to conserve heat.[3] When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat.[3] Rarely a fever may trigger a febrile seizure, with this being more common in young children.[4] Fevers do not typically go higher than 41 to 42 °C (106 to 108 °F).[6]

Fever
Other namesPyrexia, febrile response, febrile[1]
"The Sick Girl", 1882, National Gallery of Denmark
SpecialtyInfectious disease, pediatrics
SymptomsInitially: shivering, feeling cold, chills[2]
Later: flushed, sweating[3]
ComplicationsFebrile seizure[4]
CausesVirus, bacteria, increase in the body's temperature set point[5][6]
Diagnostic methodTemperature higher than the normal range of 37.2 and 38.3 °C (99.0 and 100.9 °F)[1][7][8]
Differential diagnosisHyperthermia[1]
TreatmentBased on underlying cause, not required for fever itself[2][9]
MedicationIbuprofen, paracetamol (acetaminophen)[9][10]
FrequencyCommon[2][11]

A fever can be caused by many medical conditions ranging from non-serious to life-threatening.[13] This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, Lassa, COVID-19, and malaria.[13][14] Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication or vaccination, and cancer.[13][15] It differs from hyperthermia, in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss.[1]

Treatment to reduce fever is generally not required.[2][9] Treatment of associated pain and inflammation, however, may be useful and help a person rest.[9] Medications such as ibuprofen or paracetamol (acetaminophen) may help with this as well as lower temperature.[9][10] Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms.[16] Hyperthermia requires treatment.[2]

Fever is one of the most common medical signs.[2] It is part of about 30% of healthcare visits by children[2] and occurs in up to 75% of adults who are seriously sick.[11] While fever evolved as a defense mechanism, treating a fever does not appear to improve or worsen outcomes.[17][18][19] Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as "fever phobia."[2][20]

Associated symptoms edit

A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, dehydration,[21][22] and the inability to concentrate. Sleeping with a fever can often cause intense or confusing nightmares, commonly called "fever dreams".[23] Mild to severe delirium (which can also cause hallucinations) may also present itself during high fevers.[24]

Diagnosis edit

A range for normal temperatures has been found.[8] Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures.[30] Fever is generally agreed to be present if the elevated temperature[31] is caused by a raised set point and:

  • Temperature in the anus (rectum/rectal) is at or over 37.5–38.3 °C (99.5–100.9 °F)[1][8] An ear (tympanic) or forehead (temporal) temperature may also be used.[32][33]
  • Temperature in the mouth (oral) is at or over 37.2 °C (99.0 °F) in the morning or over 37.7 °C (99.9 °F) in the afternoon[7][34]
  • Temperature under the arm (axillary) is usually about 0.6 °C (1.1 °F) below core body temperature.[35]

In adults, the normal range of oral temperatures in healthy individuals is 35.7–37.7 °C (96.3–99.9 °F) among men and 33.2–38.1 °C (91.8–100.6 °F) among women, while when taken rectally it is 36.7–37.5 °C (98.1–99.5 °F) among men and 36.8–37.1 °C (98.2–98.8 °F) among women, and for ear measurement it is 35.5–37.5 °C (95.9–99.5 °F) among men and 35.7–37.5 °C (96.3–99.5 °F) among women.[36]

Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more.[37][38] Normal daily temperature variation has been described as 0.5 °C (0.9 °F).[7]: 4012  A raised temperature is not always a fever.[37] For example, the temperature rises in healthy people when they exercise, but this is not considered a fever, as the set point is normal.[37] On the other hand, a "normal" temperature may be a fever, if it is unusually high for that person; for example, medically frail elderly people have a decreased ability to generate body heat, so a "normal" temperature of 37.3 °C (99.1 °F) may represent a clinically significant fever.[37][39]

Hyperthermia edit

Hyperthermia is an elevation of body temperature over the temperature set point, due to either too much heat production or not enough heat loss.[1][7] Hyperthermia is thus not considered fever.[7]: 103 [40] Hyperthermia should not be confused with hyperpyrexia (which is a very high fever).[7]: 102 

Clinically, it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications. The distinction may however be difficult to make in an emergency setting, and is often established by identifying possible causes.[7]: 103 

Types edit

 
Different fever patterns observed in Plasmodium infections

Various patterns of measured patient temperatures have been observed, some of which may be indicative of a particular medical diagnosis:

Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are:[48][49]

In addition, there is disagreement regarding whether a specific fever pattern is associated with Hodgkin's lymphoma—the Pel–Ebstein fever, with patients argued to present high temperature for one week, followed by low for the next week, and so on, where the generality of this pattern is debated.[52][53]

Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin.[7][54] A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal immune system function.[55] Because of the lack of infection-fighting neutrophils, a bacterial infection can spread rapidly; this fever is, therefore, usually considered to require urgent medical attention.[56] This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people.[55][57]

Hyperpyrexia edit

Hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to 40 or 41 °C (104 or 106 °F); the range of hyperpyrexias includes cases considered severe (≥ 40 °C) and extreme (≥ 42 °C).[7][58][59] It differs from hyperthermia in that one's thermoregulatory system's set point for body temperature is set above normal, then heat is generated to achieve it. In contrast, hyperthermia involves body temperature rising above its set point due to outside factors.[7][60] The high temperatures of hyperpyrexia are considered medical emergencies, as they may indicate a serious underlying condition or lead to severe morbidity (including permanent brain damage), or to death.[61] A common cause of hyperpyrexia is an intracranial hemorrhage.[7] Other causes in emergency room settings include sepsis, Kawasaki syndrome,[62] neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.[61]

Differential diagnosis edit

Fever is a common symptom of many medical conditions:

Adult and pediatric manifestations for the same disease may differ; for instance, in COVID-19, one metastudy describes 92.8% of adults versus 43.9% of children presenting with fever.[14]

In addition, fever can result from a reaction to an incompatible blood product.[75]

Teething is not a cause of fever.[76]

Function edit

 
Hyperthermia: Characterized on the left. Normal body temperature (thermoregulatory set point) is shown in green, while the hyperthermic temperature is shown in red. As can be seen, hyperthermia can be conceptualized as an increase above the thermoregulatory set point.
Hypothermia: Characterized in the center: Normal body temperature is shown in green, while the hypothermic temperature is shown in blue. As can be seen, hypothermia can be conceptualized as a decrease below the thermoregulatory set point.
Fever: Characterized on the right: Normal body temperature is shown in green. It reads "New Normal" because the thermoregulatory set point has risen. This has caused what was the normal body temperature (in blue) to be considered hypothermic.

Immune function edit

Fever is thought to contribute to host defense,[17] as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions are increased by temperature.[77] Fever has been described in teaching texts as assisting the healing process in various ways, including:

Advantages and disadvantages edit

A fever response to an infectious disease is generally regarded as protective, whereas fever in non-infections may be maladaptive.[80][81] Studies have not been consistent on whether treating fever generally worsens or improves mortality risk.[82] Benefits or harms may depend on the type of infection, health status of the patient and other factors.[80] Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever.[83] In sepsis, fever is associated with reduced mortality.[84]

Pathophysiology of fever induction edit

Hypothalamus edit

Temperature is regulated in the hypothalamus. The trigger of a fever, called a pyrogen, results in the release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind (EP1-4), with a previous study showing the EP3 subtype is what mediates the fever response.[85] Hence, the hypothalamus can be seen as working like a thermostat.[7] When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue, and muscle contraction through shivering raises the metabolic rate.[86]

If 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 surrounding it and its response to anti-pyretic medications.[7][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]

Pyrogens edit

A pyrogen is a substance that induces fever.[87] 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.[88] The types of pyrogens include internal (endogenous) and external (exogenous) to the body.[citation needed]

The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers.[89]

Endogenous edit

Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system).[90] 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 molecular patterns such as cases like rheumatoid arthritis or lupus.[91]

Major endogenous pyrogens are interleukin 1 (α and β)[92]: 1237–1248  and interleukin 6 (IL-6).[93] 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.[92]: 1237–1248  Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release.[94] 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.[95]

Exogenous edit

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.[96]

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.[97]

PGE2 release edit

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.[citation needed]

PGE2 is the ultimate mediator of the febrile response. The setpoint 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.[citation needed]

Management edit

Fever does not necessarily need to be treated,[98] and most people with a fever recover without specific medical attention.[99] Although it is unpleasant, fever rarely rises to a dangerous level even if untreated.[100] Damage to the brain generally does not occur until temperatures reach 42.0 °C (107.6 °F), and it is rare for an untreated fever to exceed 40.6 °C (105.1 °F).[101] Treating fever in people with sepsis does not affect outcomes.[102] Small trials have shown no benefit of treating fevers of 38.5 °C (101.3 °F) or higher of critically ill patients in ICUs, and one trial was terminated early because patients receiving aggressive fever treatment were dying more often.[19]

According to the NIH, the two assumptions which are generally used to argue in favor of treating fevers have not been experimentally validated. These are that (1) a fever is noxious, and (2) suppression of a fever will reduce its noxious effect. Most of the other studies supporting the association of fever with poorer outcomes have been observational in nature. In theory, these critically ill patients and those faced with additional physiologic stress may benefit from fever reduction, but the evidence on both sides of the argument appears to be mostly equivocal.[19]

Conservative measures edit

Limited evidence supports sponging or bathing feverish children with tepid water.[103] The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort. If the temperature reaches the extremely high level of hyperpyrexia, aggressive cooling is required (generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water).[61] In general, people are advised to keep adequately hydrated.[104] Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known.[105]

Medications edit

Medications that lower fevers are called antipyretics.[106] The antipyretic ibuprofen is effective in reducing fevers in children.[107] It is more effective than acetaminophen (paracetamol) in children.[107] Ibuprofen and acetaminophen may be safely used together in children with fevers.[108][109] The efficacy of acetaminophen by itself in children with fevers has been questioned.[110] Ibuprofen is also superior to aspirin in children with fevers.[111] 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.[112]

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.[113] It is not clear if it increases child comfort.[113] Response or nonresponse to medications does not predict whether or not a child has a serious illness.[114]

With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019.[115] Animal models have found increased mortality with the use of antipyretics in influenza but as of 2010 there have been no randomized placebo-controlled trials in humans that gave data on mortality.[116]

Epidemiology edit

Fever is one of the most common medical signs.[2] It is part of about 30% of healthcare visits by children,[2] 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.[117]

History edit

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).[118] It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.[118]

Infections presenting with fever 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 infections before the age of fifteen.[119]

An older term, febricula (a diminutive form of the Latin word for fever), was once used to refer to a low-grade fever lasting only a few days. This term fell out of use in the early 20th century, and the symptoms it referred to are now thought to have been caused mainly by various minor viral respiratory infections.[120]

Society and culture edit

Mythology edit

 
Febris

Paediatrics edit

Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia,[2][122] 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.[122] They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers.[122] The underlying problem, according to professor of pediatrics Barton D. Schmitt, is that "as parents we tend to suspect that our children's brains may melt."[123] 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.[122]

Other species edit

Fever is an important metric 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).[124] In species that allow the body to have a wide range of "normal" temperatures, such as camels,[125] whose body temperature varies as the environmental temperature varies,[126] the body temperature which constitutes a febrile state differs depending on the environmental temperature.[127] 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.[128] Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis.[128]

References edit

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Further reading edit

  • Rhoades R, Pflanzer RG (1996). "Chapter 27: Regulation of Body Temperature (Clinical Focus: Pathogenesis of Fever)". Human Physiology (3rd ed.). Philadelphia, PA: Saunders College. ISBN 9780030051593. Retrieved 2 April 2020.

External links edit

  • Fever and Taking Your Child's Temperature
  • US National Institute of Health factsheet
  • Drugs most commonly associated with the adverse event Pyrexia (Fever) as reported the FDA 9 March 2012 at the Wayback Machine
  • Fever at MedlinePlus
  • Why are We So Afraid of Fevers? at The New York Times

fever, this, article, about, medical, condition, other, uses, disambiguation, redirects, here, pure, album, pure, canadian, band, pyrexia, humans, body, temperature, above, normal, range, increase, body, temperature, point, hypothalamus, there, single, agreed,. This article is about the medical condition For other uses see Fever disambiguation Feverish redirects here For the Pure album see Pure Canadian band Feverish Fever or pyrexia in humans is a body temperature above the normal range due to an increase in the body s temperature set point in the hypothalamus 5 6 12 7 There is no single agreed upon upper limit for normal temperature sources use values ranging between 37 2 and 38 3 C 99 0 and 100 9 F in humans 1 7 8 The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills 2 This results in greater heat production and efforts to conserve heat 3 When the set point temperature returns to normal a person feels hot becomes flushed and may begin to sweat 3 Rarely a fever may trigger a febrile seizure with this being more common in young children 4 Fevers do not typically go higher than 41 to 42 C 106 to 108 F 6 FeverOther namesPyrexia febrile response febrile 1 The Sick Girl 1882 National Gallery of DenmarkSpecialtyInfectious disease pediatricsSymptomsInitially shivering feeling cold chills 2 Later flushed sweating 3 ComplicationsFebrile seizure 4 CausesVirus bacteria increase in the body s temperature set point 5 6 Diagnostic methodTemperature higher than the normal range of 37 2 and 38 3 C 99 0 and 100 9 F 1 7 8 Differential diagnosisHyperthermia 1 TreatmentBased on underlying cause not required for fever itself 2 9 MedicationIbuprofen paracetamol acetaminophen 9 10 FrequencyCommon 2 11 A fever can be caused by many medical conditions ranging from non serious to life threatening 13 This includes viral bacterial and parasitic infections such as influenza the common cold meningitis urinary tract infections appendicitis Lassa COVID 19 and malaria 13 14 Non infectious causes include vasculitis deep vein thrombosis connective tissue disease side effects of medication or vaccination and cancer 13 15 It differs from hyperthermia in that hyperthermia is an increase in body temperature over the temperature set point due to either too much heat production or not enough heat loss 1 Treatment to reduce fever is generally not required 2 9 Treatment of associated pain and inflammation however may be useful and help a person rest 9 Medications such as ibuprofen or paracetamol acetaminophen may help with this as well as lower temperature 9 10 Children younger than three months require medical attention as might people with serious medical problems such as a compromised immune system or people with other symptoms 16 Hyperthermia requires treatment 2 Fever is one of the most common medical signs 2 It is part of about 30 of healthcare visits by children 2 and occurs in up to 75 of adults who are seriously sick 11 While fever evolved as a defense mechanism treating a fever does not appear to improve or worsen outcomes 17 18 19 Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved a phenomenon known as fever phobia 2 20 Contents 1 Associated symptoms 2 Diagnosis 2 1 Hyperthermia 3 Types 3 1 Hyperpyrexia 4 Differential diagnosis 5 Function 5 1 Immune function 5 2 Advantages and disadvantages 6 Pathophysiology of fever induction 6 1 Hypothalamus 6 2 Pyrogens 6 2 1 Endogenous 6 2 2 Exogenous 6 3 PGE2 release 7 Management 7 1 Conservative measures 7 2 Medications 8 Epidemiology 9 History 10 Society and culture 10 1 Mythology 10 2 Paediatrics 11 Other species 12 References 13 Further reading 14 External linksAssociated symptoms editA fever is usually accompanied by sickness behavior which consists of lethargy depression loss of appetite sleepiness hyperalgesia dehydration 21 22 and the inability to concentrate Sleeping with a fever can often cause intense or confusing nightmares commonly called fever dreams 23 Mild to severe delirium which can also cause hallucinations may also present itself during high fevers 24 Diagnosis editA range for normal temperatures has been found 8 Central temperatures such as rectal temperatures are more accurate than peripheral temperatures 30 Fever is generally agreed to be present if the elevated temperature 31 is caused by a raised set point and Temperature in the anus rectum rectal is at or over 37 5 38 3 C 99 5 100 9 F 1 8 An ear tympanic or forehead temporal temperature may also be used 32 33 Temperature in the mouth oral is at or over 37 2 C 99 0 F in the morning or over 37 7 C 99 9 F in the afternoon 7 34 Temperature under the arm axillary is usually about 0 6 C 1 1 F below core body temperature 35 In adults the normal range of oral temperatures in healthy individuals is 35 7 37 7 C 96 3 99 9 F among men and 33 2 38 1 C 91 8 100 6 F among women while when taken rectally it is 36 7 37 5 C 98 1 99 5 F among men and 36 8 37 1 C 98 2 98 8 F among women and for ear measurement it is 35 5 37 5 C 95 9 99 5 F among men and 35 7 37 5 C 96 3 99 5 F among women 36 Normal body temperatures vary depending on many factors including age sex time of day ambient temperature activity level and more 37 38 Normal daily temperature variation has been described as 0 5 C 0 9 F 7 4012 A raised temperature is not always a fever 37 For example the temperature rises in healthy people when they exercise but this is not considered a fever as the set point is normal 37 On the other hand a normal temperature may be a fever if it is unusually high for that person for example medically frail elderly people have a decreased ability to generate body heat so a normal temperature of 37 3 C 99 1 F may represent a clinically significant fever 37 39 Hyperthermia edit Hyperthermia is an elevation of body temperature over the temperature set point due to either too much heat production or not enough heat loss 1 7 Hyperthermia is thus not considered fever 7 103 40 Hyperthermia should not be confused with hyperpyrexia which is a very high fever 7 102 Clinically it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications The distinction may however be difficult to make in an emergency setting and is often established by identifying possible causes 7 103 Types edit nbsp Different fever patterns observed in Plasmodium infectionsVarious patterns of measured patient temperatures have been observed some of which may be indicative of a particular medical diagnosis Continuous fever where temperature remains above normal and does not fluctuate more than 1 C in 24 hours 41 e g in bacterial pneumonia typhoid infective endocarditis tuberculosis or typhus 42 43 Intermittent fever is present only for a certain period later cycling back to normal e g in malaria leishmaniasis pyemia sepsis 44 or African trypanosomiasis 45 Remittent fever where the temperature remains above normal throughout the day and fluctuates more than 1 C in 24 hours e g in infective endocarditis or brucellosis 46 Pel Ebstein fever is a cyclic fever that is rarely seen in patients with Hodgkin s lymphoma Undulant fever seen in brucellosis Typhoid fever is a continuous fever showing a characteristic step ladder pattern a step wise increase in temperature with a high plateau 47 Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens These are 48 49 Quotidian fever with a 24 hour periodicity typical of malaria caused by Plasmodium knowlesi P knowlesi 50 51 Tertian fever with a 48 hour periodicity typical of later course malaria caused by P falciparum P vivax or P ovale 48 Quartan fever with a 72 hour periodicity typical of later course malaria caused by P malariae 48 In addition there is disagreement regarding whether a specific fever pattern is associated with Hodgkin s lymphoma the Pel Ebstein fever with patients argued to present high temperature for one week followed by low for the next week and so on where the generality of this pattern is debated 52 53 Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin 7 54 A neutropenic fever also called febrile neutropenia is a fever in the absence of normal immune system function 55 Because of the lack of infection fighting neutrophils a bacterial infection can spread rapidly this fever is therefore usually considered to require urgent medical attention 56 This kind of fever is more commonly seen in people receiving immune suppressing chemotherapy than in apparently healthy people 55 57 Hyperpyrexia edit Hyperpyrexia is an extreme elevation of body temperature which depending upon the source is classified as a core body temperature greater than or equal to 40 or 41 C 104 or 106 F the range of hyperpyrexias includes cases considered severe 40 C and extreme 42 C 7 58 59 It differs from hyperthermia in that one s thermoregulatory system s set point for body temperature is set above normal then heat is generated to achieve it In contrast hyperthermia involves body temperature rising above its set point due to outside factors 7 60 The high temperatures of hyperpyrexia are considered medical emergencies as they may indicate a serious underlying condition or lead to severe morbidity including permanent brain damage or to death 61 A common cause of hyperpyrexia is an intracranial hemorrhage 7 Other causes in emergency room settings include sepsis Kawasaki syndrome 62 neuroleptic malignant syndrome drug overdose serotonin syndrome and thyroid storm 61 Differential diagnosis editFever is a common symptom of many medical conditions Infectious disease e g COVID 19 14 dengue Ebola gastroenteritis HIV influenza Lyme disease rocky mountain spotted fever secondary syphilis malaria mononucleosis as well as infections of the skin e g abscesses and boils 63 64 65 66 67 68 Immunological diseases e g relapsing polychondritis 69 autoimmune hepatitis granulomatosis with polyangiitis Horton disease inflammatory bowel diseases Kawasaki disease lupus erythematosus sarcoidosis Still s disease Rheumatoid arthritis Lymphoproliferative disorders and Psoriasis citation needed Tissue destruction as a result of cerebral bleeding crush syndrome hemolysis infarction rhabdomyolysis surgery etc 70 71 Cancers particularly blood cancers such as leukemia and lymphomas 72 Metabolic disorders e g gout and porphyria 73 and 74 Inherited metabolic disorder e g Fabry disease 7 Adult and pediatric manifestations for the same disease may differ for instance in COVID 19 one metastudy describes 92 8 of adults versus 43 9 of children presenting with fever 14 In addition fever can result from a reaction to an incompatible blood product 75 Teething is not a cause of fever 76 Function edit nbsp Hyperthermia Characterized on the left Normal body temperature thermoregulatory set point is shown in green while the hyperthermic temperature is shown in red As can be seen hyperthermia can be conceptualized as an increase above the thermoregulatory set point Hypothermia Characterized in the center Normal body temperature is shown in green while the hypothermic temperature is shown in blue As can be seen hypothermia can be conceptualized as a decrease below the thermoregulatory set point Fever Characterized on the right Normal body temperature is shown in green It reads New Normal because the thermoregulatory set point has risen This has caused what was the normal body temperature in blue to be considered hypothermic Immune function edit Fever is thought to contribute to host defense 17 as the reproduction of pathogens with strict temperature requirements can be hindered and the rates of some important immunological reactions are increased by temperature 77 Fever has been described in teaching texts as assisting the healing process in various ways including increased mobility of leukocytes 78 1044 enhanced leukocyte phagocytosis 78 1030 decreased endotoxin effects 78 1029 and increased proliferation of T cells 78 1030 79 212 Advantages and disadvantages edit A fever response to an infectious disease is generally regarded as protective whereas fever in non infections may be maladaptive 80 81 Studies have not been consistent on whether treating fever generally worsens or improves mortality risk 82 Benefits or harms may depend on the type of infection health status of the patient and other factors 80 Studies using warm blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever 83 In sepsis fever is associated with reduced mortality 84 Pathophysiology of fever induction editSee also Thermoregulation in humans Hypothalamus edit Temperature is regulated in the hypothalamus The trigger of a fever called a pyrogen results in the release of prostaglandin E2 PGE2 PGE2 in turn acts on the hypothalamus which creates a systemic response in the body causing heat generating effects to match a new higher temperature set point There are four receptors in which PGE2 can bind EP1 4 with a previous study showing the EP3 subtype is what mediates the fever response 85 Hence the hypothalamus can be seen as working like a thermostat 7 When the set point is raised the body increases its temperature through both active generation of heat and retention of heat Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold Norepinephrine increases thermogenesis in brown adipose tissue and muscle contraction through shivering raises the metabolic rate 86 If 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 Increased heat production by increased muscle tone shivering muscle movements to produce heat and release of hormones like epinephrine and Prevention of heat loss e g through vasoconstriction 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 surrounding it and its response to anti pyretic medications 7 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 Pyrogens edit A pyrogen is a substance that induces fever 87 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 88 The types of pyrogens include internal endogenous and external exogenous to the body citation needed The pyrogenicity of given pyrogens varies in extreme cases bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers 89 Endogenous edit Endogenous pyrogens are cytokines released from monocytes which are part of the immune system 90 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 molecular patterns such as cases like rheumatoid arthritis or lupus 91 Major endogenous pyrogens are interleukin 1 a and b 92 1237 1248 and interleukin 6 IL 6 93 Minor endogenous pyrogens include interleukin 8 tumor necrosis factor b macrophage inflammatory protein a and macrophage inflammatory protein b as well as interferon a interferon b and interferon g 92 1237 1248 Tumor necrosis factor a TNF also acts as a pyrogen mediated by interleukin 1 IL 1 release 94 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 1b 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 95 Exogenous edit 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 96 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 TNFa A further downstream event is activation of the arachidonic acid pathway 97 PGE2 release edit 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 citation needed PGE2 is the ultimate mediator of the febrile response The setpoint 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 citation needed Management editFever does not necessarily need to be treated 98 and most people with a fever recover without specific medical attention 99 Although it is unpleasant fever rarely rises to a dangerous level even if untreated 100 Damage to the brain generally does not occur until temperatures reach 42 0 C 107 6 F and it is rare for an untreated fever to exceed 40 6 C 105 1 F 101 Treating fever in people with sepsis does not affect outcomes 102 Small trials have shown no benefit of treating fevers of 38 5 C 101 3 F or higher of critically ill patients in ICUs and one trial was terminated early because patients receiving aggressive fever treatment were dying more often 19 According to the NIH the two assumptions which are generally used to argue in favor of treating fevers have not been experimentally validated These are that 1 a fever is noxious and 2 suppression of a fever will reduce its noxious effect Most of the other studies supporting the association of fever with poorer outcomes have been observational in nature In theory these critically ill patients and those faced with additional physiologic stress may benefit from fever reduction but the evidence on both sides of the argument appears to be mostly equivocal 19 Conservative measures edit Limited evidence supports sponging or bathing feverish children with tepid water 103 The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort If the temperature reaches the extremely high level of hyperpyrexia aggressive cooling is required generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water 61 In general people are advised to keep adequately hydrated 104 Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known 105 Medications edit Medications that lower fevers are called antipyretics 106 The antipyretic ibuprofen is effective in reducing fevers in children 107 It is more effective than acetaminophen paracetamol in children 107 Ibuprofen and acetaminophen may be safely used together in children with fevers 108 109 The efficacy of acetaminophen by itself in children with fevers has been questioned 110 Ibuprofen is also superior to aspirin in children with fevers 111 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 112 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 113 It is not clear if it increases child comfort 113 Response or nonresponse to medications does not predict whether or not a child has a serious illness 114 With respect to the effect of antipyretics on the risk of death in those with infection studies have found mixed results as of 2019 115 Animal models have found increased mortality with the use of antipyretics in influenza but as of 2010 there have been no randomized placebo controlled trials in humans that gave data on mortality 116 Epidemiology editFever is one of the most common medical signs 2 It is part of about 30 of healthcare visits by children 2 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 117 History editA 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 118 It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself 118 Infections presenting with fever 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 infections before the age of fifteen 119 An older term febricula a diminutive form of the Latin word for fever was once used to refer to a low grade fever lasting only a few days This term fell out of use in the early 20th century and the symptoms it referred to are now thought to have been caused mainly by various minor viral respiratory infections 120 Society and culture editMythology edit nbsp FebrisFebris fever in Latin is the goddess of fever in Roman mythology People with fevers would visit her temples Tertiana and Quartana are the goddesses of tertian and quartan fevers of malaria in Roman mythology 121 Jvarasura fever demon in Hindi is the personification of fever and disease in Hindu and Buddhist mythology Paediatrics edit Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved a phenomenon known as fever phobia 2 122 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 122 They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers 122 The underlying problem according to professor of pediatrics Barton D Schmitt is that as parents we tend to suspect that our children s brains may melt 123 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 122 Other species editMain article Thermoregulation Fever is an important metric 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 124 In species that allow the body to have a wide range of normal temperatures such as camels 125 whose body temperature varies as the environmental temperature varies 126 the body temperature which constitutes a febrile state differs depending on the environmental temperature 127 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 128 Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis 128 References edit a b c d e f g h i Axelrod YK Diringer MN May 2008 Temperature management in acute 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the original on 26 March 2010 Retrieved 22 March 2010 Schmidt Nielsen K Schmidt Nielsen B Jarnum SA Houpt TR January 1957 Body temperature of the camel and its relation to water economy The American Journal of Physiology 188 1 103 12 doi 10 1152 ajplegacy 1956 188 1 103 PMID 13402948 Leese A March 1917 Tips on camels for veterinary surgeons on active service The British Veterinary Journal 73 81 via Google Books Tefera M July 2004 Observations on the clinical examination of the camel Camelus dromedarius in the field Tropical Animal Health and Production 36 5 435 49 doi 10 1023 b trop 0000035006 37928 cf PMID 15449833 S2CID 26358556 a b Thomas MB Blanford S July 2003 Thermal biology in insect parasite interactions Trends in Ecology amp Evolution 18 7 344 50 doi 10 1016 S0169 5347 03 00069 7 Further reading editRhoades R Pflanzer RG 1996 Chapter 27 Regulation of Body Temperature Clinical Focus Pathogenesis of Fever Human Physiology 3rd ed Philadelphia PA Saunders College ISBN 9780030051593 Retrieved 2 April 2020 External links edit nbsp Wikimedia Commons has media related to Fever Fever and Taking Your Child s Temperature US National Institute of Health factsheet Drugs most commonly associated with the adverse event Pyrexia Fever as reported the FDA Archived 9 March 2012 at the Wayback Machine Fever at MedlinePlus Why are We So Afraid of Fevers at The New York Times Retrieved from https en wikipedia org w index php title Fever amp oldid 1200981944, wikipedia, wiki, book, books, library,

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