Fever

Fever
Other names: Pyrexia, febrile response, febrile[1][2]
An analog medical thermometer showing a temperature of 38.7 °C or 101.7 °F
SpecialtyInfectious 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)[1][2][8]
Differential diagnosisHyperthermia[2]
TreatmentBased on underlying cause, not required for fever itself[3][9]
MedicationIbuprofen, paracetamol (acetaminophen)[9][10]
FrequencyCommon[3][11]

Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point.[1][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.[1][2][8] 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] Rarely a 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 non-serious to life-threatening.[12] This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, COVID-19, and malaria.[12][13] Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication, and cancer.[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 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] While fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes.[16][17] Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as fever phobia.[3][18]

Associated symptoms

Michael Ancher, "The Sick Girl", 1882, Statens Museum for Kunst

A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, and the inability to concentrate. [19]

Diagnosis

Temperature classification
Core (rectal, esophageal, etc.)
Hypothermia <35.0 °C (95.0 °F)[20]
Normal 36.5–37.5 °C (97.7–99.5 °F)[21][22]
Fever >37.5 or 38.3 °C (99.5 or 100.9 °F)[2][8]
Hyperthermia >37.5 or 38.3 °C (99.5 or 100.9 °F)[2][8]
Hyperpyrexia >40.0 or 41.0 °C (104.0 or 105.8 °F)[23][24]
Note: The difference between fever and hyperthermia is the underlying mechanism. Different sources have different cut-offs.

A range for normal temperatures has been found.[8] Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures.[25] 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.[26][27]
  • 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[1][28]
  • 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).[29] 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  Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more.[30][31] 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. 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.

Hyperthermia

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.[32][1]: 117–121  Hyperthermia differs from hyperpyrexia, see section following.

Types

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:[34][35]

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.[36]

Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin.[1] A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal immune system function. 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. This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people.

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.[37]

Hyperpyrexia

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).[1][38][39] 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.[1][40] 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.[41] A common cause of hyperpyrexia is an intracranial hemorrhage.[1] Other causes in emergency room settings include sepsis, Kawasaki syndrome,[42] neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.[41]

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 describes 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.[45]

Teething is not a cause of fever.[46]

Pathophysiology

See also: Thermoregulation in humans

Hypothalamus

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] 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.[47]

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:

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.

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]

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).

Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.

Pyrogens

A pyrogen is a substance that induces fever.[48] 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.[49] 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.

Endogenous

Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system).[50] 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.[51]

Major endogenous pyrogens are interleukin 1 (α and β)[52]: 1237–1248  and interleukin 6 (IL-6).[53] 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]: 1237–1248  Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release.[54] 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. The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the arachidonic acid pathway.

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.[55]

Exogenous

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.[56]

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.[57]

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.

Selective advantage

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.

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.[16][58][59] On the other hand, while fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes.[16][17] Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever.[60] Other studies suggest reduced mortality in bacterial infections when fever was present.[61] Fever is thought to contribute to host defense,[16] as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions are increased by temperature.[62] Fever has been described in teaching texts as assisting the healing process in various ways, including:

Management

Fever does not necessarily need to be treated,[65] and most febrile cases recover without specific medical attention.[66] 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).[67] Treating fever in people with sepsis does not affect outcomes.[68]

Conservative measures

Limited evidence supports sponging or bathing feverish children with tepid water.[69] 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).[41] In general, people are advised to keep adequately hydrated.[70] Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known.[71]

Medications

Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in reducing fevers in children.[72] It is more effective than acetaminophen (paracetamol) in children.[72] Ibuprofen and acetaminophen may be safely used together in children with fevers.[73][74] The efficacy of acetaminophen by itself in children with fevers has been questioned.[75] Ibuprofen is also superior to aspirin in children with fevers.[76] 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.[77]

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.[78] It is not clear if it increases child comfort.[78] Response or nonresponse to medications does not predict whether or not a child has a serious illness.[79]

With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019.[80] 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.[81]

Epidemiology

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.[82]

History

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).[83] It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.[83]

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,[3][84] 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.[84] They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers.[84] 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."[85] 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.[84]

Other species

Main article: thermoregulation

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).[86] In species that allow the body to have a wide range of "normal" temperatures, such as camels,[87] it is sometimes difficult to determine a febrile stage. 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.[88] Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis.[88]

References

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  15. ↑ "Fever". MedlinePlus. 30 August 2014. Archived from the original on 11 May 2009.
  16. 1 2 3 4 Schaffner A (March 2006). "Fieber – nützliches oder schädliches, zu behandelndes Symptom?" [Fever–useful or noxious symptom that should be treated?]. Therapeutische Umschau (in Deutsch). 63 (3): 185–88. doi:10.1024/0040-5930.63.3.185. PMID 16613288. Abstract alone is in German and in English.
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  19. ↑ Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, Broussard SR (February 2003). "Cytokine-induced sickness behavior". Brain, Behavior, and Immunity. 17 Suppl 1 (1): S112–18. doi:10.1016/S0889-1591(02)00077-6. PMID 12615196. S2CID 25400611.
  20. ↑ Marx, John (2006). Rosen's emergency medicine : concepts and clinical practice (6th ed.). Philadelphia: Mosby/Elsevier. p. 2239. ISBN 978-0-323-02845-5. OCLC 58533794.{{cite book}}: CS1 maint: date and year (link)
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  33. ↑ Typhoid fever may show a specific fever pattern, a Wunderlich curve, with a slow stepwise increase and a high plateau (drops due to fever-reducing drugs are excluded).
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Further reading

  • 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.{{cite book}}: CS1 maint: uses authors parameter (link)
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