From Wikipedia, the free encyclopedia

Other namesPyrexia, febrile response[1][2]
Clinical thermometer 38.7.JPG
An analog medical thermometer showing a temperature of 38.7 °C or 101.7 °F
SpecialtyInternal medicine,[1] Infectious disease, pediatrics
SymptomsInitially: shivering, feeling cold[3]
Later: flushed, sweating[4]
ComplicationsFebrile seizure[5]
CausesIncrease in the body's temperature set point[6][7]
Diagnostic methodTemperature > between 37.2 and 38.3 °C (99.0 and 100.9 °F)[2][8][1][page needed]
Differential diagnosisHyperthermia[2]
TreatmentBased on underlying cause, not required for fever itself[3][9]
MedicationIbuprofen, paracetamol (acetaminophen)[9][10]

Fever, also known as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point.[1][page needed][6][7] There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.2 and 38.3 °C (99.0 and 100.9 °F) in humans.[2][8][1][page needed] The increase in set point triggers increased muscle contractions and causes a feeling of cold.[3] This results in greater heat production and efforts to conserve heat.[4] When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat.[4] As the CDC states, in rare casesa fever may trigger a febrile seizure, with this being more common in young children.[5] Fevers do not typically go higher than 41 to 42 °C (105.8 to 107.6 °F).[7]

A fever can be caused by many medical conditions ranging from life-threatening to non-serious.[12] This includes viral, bacterial, and parasitic infections—such as influenza, COVID-19, the common cold, meningitis, urinary tract infections, appendicitis, and malaria (among others).[12][13] Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication, and cancer among others.[12][14] 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.[2]

Treatment to reduce fever is generally not required.[3][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] Measures such as putting a cool damp cloth on the forehead and having a slightly warm bath are not useful and may simply make a person more uncomfortable.[9] 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.[15] Hyperthermia does require treatment.[3]

Fever is one of the most common presenting medical symptoms, for instance with its presence reported in about three in four of adults who are seriously ill, in about one in three children in healthcare visits, and in about one in twenty individuals presenting in emergency rooms. From an organismal and evolutionary perspective, the fever response is believed to be of value, in particular as a defense mechanism in response to infectious disease; despite this being the case, treating fever for the comfort of the patient does not appear to worsen outcomes. Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as fever phobia.

Diagnosis and epidemiology

A range for normal temperatures has been found.[8] Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures.[21] Fever is generally agreed to be present if the elevated temperature 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)[2][8] An ear (tympanic) or forehead (temporal) temperature may also be used.[22][23]
  • 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[24][1][page needed]
  • Temperature under the arm (axillary) is at or over 37.2 °C (99.0 °F)

In adults, the normal range of oral temperatures in healthy individuals is 33.2–38.2 °C (91.8–100.8 °F), while when taken rectally it is 34.4–37.8 °C (93.9–100.0 °F), for ear measurement it is 35.4–37.8 °C (95.7–100.0 °F), and for armpit (axillary) measurement it is 35.5–37.0 °C (95.9–98.6 °F).[25] Harrison's Principles of Internal Medicine defines a fever as a morning oral temperature of >37.2 °C (>98.9 °F) or an afternoon oral temperature of >37.7 °C (>99.9 °F) although normal daily temperature variation has been described as 0.5 °C (0.9 °F).[1]:4012[verification needed] Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more.[citation needed] A raised temperature is not always a fever; for example, the temperature of a healthy person rises when he or she exercises, but this is not considered a fever, as the set point is normal.[citation needed] 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.[citation needed]

Epidemiologically, 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.[26]


Hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss.[2] It is an example of a high temperature phenomenon that is not a fever; rather, it occurs from a number of causes including heatstroke, neuroleptic malignant syndrome, malignant hyperthermia, as well as in response to stimulants such as substituted amphetamines and cocaine, and in idiosyncratic drug reactions, and serotonin syndrome.[27][1]:117-121[verification needed] Hyperthermia differs from hyperpyrexia, see section following.

Accompanying symptoms

A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, and the inability to concentrate.[28][better source needed]

Purpose and value

Scholars viewing fever from an organismal and evolutionary perspective note the value to an organism of having a fever response, in particular in response to infective disease.[29][30][31] On the other hand, while fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes.[29][32] Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever.[33] Other studies suggest reduced mortality in bacterial infections when fever was present.[34] Fever is thought to contribute to host defense,[29] as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions[clarification needed] are increased by temperature.[35] Fever has been described in teaching texts as assisting the healing process in various ways, including:


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

Different fever patterns observed in Plasmodium infections.

Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are:[39][40][page needed][better source needed]

In addition, there is disagreement regarding whether a specific fever pattern is associated with Hodgkin's lymphoma—the Pel–Ebstein fever, with patient's 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.[41][needs update]

A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal immune system function.[citation needed] 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.[citation needed] This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people.[citation needed]

An old term, febricula, has been used to refer to low-grade fever, especially if the cause is unknown, no other symptoms are present, and the patient recovers fully in less than a week.[42][better source needed]

Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin.[citation needed]


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 40.0 or 41.0 °C (104.0 or 105.8 °F); the range of hyperpyrexias include cases considered severe (≥ 40 °C) and extreme (≥ 42 °C).[43][44][1][page needed] It differs from hyperthermia in that ones thermoregulatory system's set point for body temperature is set above normal, then heat is generated to achieve it (versus body temperature rising above its set point due to outside factors.[1][45][page needed] 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 mortality.[46] A common cause of hyperpyrexia is an intracranial hemorrhage.[1][page needed] Other causes in emergency room settings include sepsis, Kawasaki syndrome,[47] neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.[46]

Differential diagnosis

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 decribes 92.8% of adults versus 43.9% of children presenting with fever.[13]

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

Teething is not a cause of fever.[49]


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.


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. Hence, the hypothalamus can be seen as working like a thermostat.[1]:117–121[verification needed] 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.[50]

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.[1][page needed][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. These can be either internal (endogenous) or external (exogenous) to the body. The bacterial substance lipopolysaccharide (LPS), present in the cell wall of gram-negative bacteria,[51] is an example of an exogenous pyrogen. Pyrogenicity can vary: In extreme examples, some bacterial pyrogens known as superantigens can cause rapid and dangerous fevers. Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.


In essence, all endogenous pyrogens are cytokines, molecules that are a part of the immune system. They are produced by activated immune cells and cause the increase in the thermoregulatory set point in the hypothalamus. Major endogenous pyrogens are interleukin 1 (α and β)[52] and interleukin 6 (IL-6). 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.[52] Tumor necrosis factor-α also acts as a pyrogen. It is mediated by interleukin 1 (IL-1) release.[53]

These cytokine factors are released into general circulation, where they migrate to the circumventricular organs of the brain due to easier absorption caused by the blood–brain barrier's reduced filtration action there. The cytokine factors then bind with endothelial receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid pathway is then activated.


One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which is a cell wall component of gram-negative bacteria. An immunological protein called lipopolysaccharide-binding protein (LBP) binds to LPS. The LBP–LPS complex then binds to the CD14 receptor of a nearby macrophage. This binding results in the synthesis and release of various endogenous cytokine factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis factor-alpha. In other words, exogenous factors cause release of endogenous factors, which, in turn, activate the arachidonic acid pathway.[54] The highly toxic metabolism-boosting supplement 2,4-dinitrophenol induces high body temperature via the inhibition of ATP production by mitochondria, resulting in impairment of cellular respiration. Instead of producing ATP, the energy of the proton gradient is lost as heat.[55]

PGE2 release

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 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 should not necessarily be treated.[56] Most people recover without specific medical attention.[57] 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).[56] Treating fever in people with sepsis does not affect outcomes.[58]

Conservative measures

Some limited evidence supports sponging or bathing feverish children with tepid water.[59] 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).[46] In general, people are advised to keep adequately hydrated.[60] Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known.[61]


Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in reducing fevers in children.[62] It is more effective than acetaminophen (paracetamol) in children.[62] Ibuprofen and acetaminophen may be safely used together in children with fevers.[63][64] The efficacy of acetaminophen by itself in children with fevers has been questioned.[65] Ibuprofen is also superior to aspirin in children with fevers.[66] 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.[67]

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.[68] It is not clear if it increases child comfort.[68] Response or nonresponse to medications does not predict whether or not a child has a serious illness.[69]

With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019.[70] Animals 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.[71]


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).[72] It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.[72]

Society and culture

Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia,[73][3] 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.[74] They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers.[74] 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."[75] 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.[74]

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).[76] In species that allow the body to have a wide range of "normal" temperatures, such as camels,[77] 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.[78] Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis. [78]


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Further reading

  • Rhoades R, Pflanzer R. "Chapter 27: Regulation of body temperature (Clinical focus: pathogenesis of fever)". Human physiology (3rd ed.). Unspecified location: Unspecified publisher. p. 820. ISBN 0030051592.CS1 maint: uses authors parameter (link)[full citation needed]

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