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]

A fever can be caused by many

• 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

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

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

• typhoid, infective endocarditis, tuberculosis, or typhus).^[42][43]
• 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]
• 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

• boils.^{[63][64][65][66][67][68]}
• 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

Immune function

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
  T cells.^{[78]: 1030 [79]}
  ^: 212

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. 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
  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

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

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

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

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

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

Limited evidence supports sponging or bathing feverish children with tepid water.

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

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

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,

respiratory infections.^[120]

Society and culture

Mythology

• Febris (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

Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia,

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

Main article: Thermoregulation

Fever is an important metric for the

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

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.

External links

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