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Fever, also referred to as pyrexia, is defined as having a temperature above the
normal range In medicine and health-related fields, a reference range or reference interval is the range (statistics), range or the interval (mathematics), interval of values that is deemed normal for a physiology, physiological measurement in healthy persons ...
due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between in humans. The increase in set point triggers increased muscle contractions and causes a feeling of cold or
chills Chills is a feeling of coldness occurring during a high fever, but sometimes is also a common symptom which occurs alone in specific people. It occurs during fever due to the release of cytokines and prostaglandins as part of the inflammatory r ...
. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes
flushed Flushing is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, gene ...
, and may begin to sweat. Rarely a fever may trigger a febrile seizure, with this being more common in young children. Fevers do not typically go higher than . A fever can be caused by many medical conditions ranging from non-serious to
life-threatening Lethality (also called deadliness or perniciousness) is how capable something is of causing death. Most often it is used when referring to diseases, chemical weapons, biological weapons, or their toxic chemical components. The use of this ter ...
. This includes
viral Viral means "relating to viruses" (small infectious agents). Viral may also refer to: Viral behavior, or virality Memetic behavior likened that of a virus, for example: * Viral marketing, the use of existing social networks to spread a marke ...
, bacterial, and parasitic infectionssuch as
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
, the
common cold The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...
,
meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...
, urinary tract infections, appendicitis, Lassa, COVID-19, and malaria. Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication or vaccination, and cancer. 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. Treatment to reduce fever is generally not required. Treatment of associated pain and inflammation, however, may be useful and help a person rest. Medications such as
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
or
paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
(acetaminophen) may help with this as well as lower temperature. Children younger than three months require medical attention, as might people with serious medical problems such as a
compromised immune system Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
or people with other symptoms. Hyperthermia requires treatment. Fever is one of the most common
medical signs Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
. It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick. While fever evolved as a defense mechanism, treating a fever does not appear to improve or worsen outcomes. Abstract alone is in German and in English. Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as fever phobia.


Associated symptoms

A fever is usually accompanied by
sickness behavior 350px, Ancher, Michael, "The Sick Girl", 1882, Statens Museum for Kunst Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection. They usually, but not always, accom ...
, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, dehydration, and the inability to concentrate. Sleeping with a fever can often cause intense or confusing nightmares, commonly called "fever dreams". Mild to severe
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...
(which can also cause
hallucinations A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
) may also present itself during high fevers.


Diagnosis

A range for normal temperatures has been found. Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures. Fever is generally agreed to be present if the elevated temperature is caused by a raised set point and: * Temperature in the
anus The anus (Latin, 'ring' or 'circle') is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, the residual semi-solid waste that remains after food digestion, which, d ...
(rectum/rectal) is at or over An ear (tympanic) or
forehead In human anatomy, the forehead is an area of the head bounded by three features, two of the skull and one of the scalp. The top of the forehead is marked by the hairline, the edge of the area where hair on the scalp grows. The bottom of the fore ...
(temporal) temperature may also be used. * Temperature in the mouth (oral) is at or over in the morning or over in the afternoon * Temperature under the arm (axillary) is usually about below core body temperature. In adults, the
normal range In medicine and health-related fields, a reference range or reference interval is the range (statistics), range or the interval (mathematics), interval of values that is deemed normal for a physiology, physiological measurement in healthy persons ...
of oral temperatures in healthy individuals is among men and among women, while when taken rectally it is among men and among women, and for ear measurement it is among men and among women. Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more. Normal daily temperature variation has been described as 0.5 簞C (0.9 簞F). A raised temperature is not always a fever. For example, the temperature rises in healthy people when they exercise, 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 Frailty is a common geriatric syndrome that embodies an elevated risk of catastrophic declines in health and function among older adults. Frailty is a condition associated with ageing, and it has been recognized for centuries. It is also a marke ...
elderly people have a decreased ability to generate body heat, so a "normal" temperature of may represent a clinically significant fever.


Hyperthermia

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


Types

Various patterns of measured patient temperatures have been observed, some of which may be indicative of a particular medical diagnosis: *
Continuous fever Continuous fever is a type or pattern of fever in which temperature does not touch the baseline and remains above normal throughout the day. The variation between maximum and minimum temperature in 24 hours is less than 1簞C (1.5簞F). It usually o ...
, where temperature remains above normal and does not fluctuate more than in 24 hours (e.g. in bacterial pneumonia, typhoid, infective endocarditis, tuberculosis, or typhus. *
Intermittent fever Intermittent fever is a type or pattern of fever in which there is an interval where temperature is elevated for several hours followed by an interval when temperature drops back to normal. This type of fever usually occurs during the course of an ...
is present only for a certain period, later cycling back to normal (e.g., in malaria,
leishmaniasis Leishmaniasis is a wide array of clinical manifestations caused by parasites of the trypanosome genus ''Leishmania''. It is generally spread through the bite of phlebotomine sandflies, ''Phlebotomus'' and ''Lutzomyia'', and occurs most freq ...
,
pyemia Pyaemia (or pyemia) is a type of sepsis that leads to widespread abscesses of a metastatic nature. It is usually caused by the staphylococcus bacteria by pus-forming organisms in the blood. Apart from the distinctive abscesses, pyaemia exhibits ...
, sepsis, or
African trypanosomiasis African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species ''Trypanosoma brucei''. Humans are infected by two typ ...
. *
Remittent fever Remittent fever is a type or pattern of fever in which temperature does not touch the baseline and remains above normal throughout the day. Daily variation in temperature is more than 1簞C in 24 hours, which is also the main difference as compared ...
, where the temperature remains above normal throughout the day and fluctuates more than in 24 hours (e.g., in infective endocarditis or brucellosis). *
PelEbstein fever PelEbstein fever is a rarely seen condition noted in patients with Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated R ...
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 Continuous fever is a type or pattern of fever in which temperature does not touch the baseline and remains above normal throughout the day. The variation between maximum and minimum temperature in 24 hours is less than 1簞C (1.5簞F). It usually o ...
showing a characteristic ''step-ladder pattern,'' a step-wise increase in temperature with a high plateau. Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are: * Quotidian fever, with a 24-hour periodicity, typical of malaria caused by '' Plasmodium knowlesi'' (''P. knowlesi''); *
Tertian fever Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects humans and other animals. Malaria causes Signs and symptoms, symptoms that typically include fever, fatigue (medical), tiredness, vomiting, and headaches. In se ...
, with a 48-hour periodicity, typical of later course malaria caused by ''
P. falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'', '' P. vivax'', or ''
P. ovale ''Plasmodium ovale'' is a species of parasitic protozoon that causes tertian malaria in humans. It is one of several species of ''Plasmodium'' parasites that infect humans, including ''Plasmodium falciparum'' and ''Plasmodium vivax'' which are ...
''; *
Quartan fever Quartan fever is one of the four types of malaria which can be contracted by humans. It is specifically caused by the ''Plasmodium malariae'' species, one of the six species of the protozoan genus ''Plasmodium''. Quartan fever is a form of malaria ...
, with a 72-hour periodicity, typical of later course malaria caused by '' P. malariae''. In addition, there is disagreement regarding whether a specific fever pattern is associated with Hodgkin's lymphomathe
PelEbstein fever PelEbstein fever is a rarely seen condition noted in patients with Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated R ...
, 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. Persistent fever that cannot be explained after repeated routine clinical inquiries is called
fever of unknown origin Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (fever) but, despite investigations by a physician, no explanation has been found.
. A
neutropenic fever Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood. The term neutropenic sepsis is also ...
, 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.


Hyperpyrexia

Hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a
core body temperature Normal human body-temperature (normothermia, euthermia) is the typical temperature range found in humans. The normal human body temperature range is typically stated as . Human body temperature varies. It depends on sex, age, time of day, exert ...
greater than or equal to ; the range of hyperpyrexias includes cases considered severe ( 40 簞C) and extreme ( 42 簞C). 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. 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 Neurotrauma, brain damage or brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating t ...
), or to death. A common cause of hyperpyrexia is an intracranial hemorrhage. Other causes in emergency room settings include sepsis, Kawasaki syndrome,Marx (2006), p. 2506. neuroleptic malignant syndrome,
drug overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.
, serotonin syndrome, and thyroid storm.


Differential diagnosis

Fever is a common
symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
of many medical conditions: * Infectious disease, e.g., COVID-19, dengue,
Ebola Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...
,
gastroenteritis Gastroenteritis, also known as infectious diarrhea and gastro, is an inflammation of the gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of energy, and dehydra ...
, HIV,
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
, Lyme disease, rocky mountain spotted fever, secondary syphilis, malaria, mononucleosis, as well as infections of the skin, e.g.,
abscess An abscess is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pressed. The area of redness often extends b ...
es and boils. *
Immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
diseases, e.g.,
relapsing polychondritis Relapsing polychondritis is a multi-systemic condition characterized by repeated episodes of inflammation and deterioration of cartilage. The often painful disease can cause joint deformity and be life-threatening if the respiratory tract, heart v ...
, autoimmune hepatitis, granulomatosis with polyangiitis,
Horton disease Giant cell arteritis (GCA), also called temporal arteritis, is an inflammatory autoimmune disease of large blood vessels. Symptoms may include headache, pain over the temples, flu-like symptoms, double vision, and difficulty opening the mouth. ...
,
inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
s, Kawasaki disease, lupus erythematosus, sarcoidosis, and Still's disease; * Tissue destruction, as a result of cerebral bleeding, crush syndrome, hemolysis, infarction,
rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...
,
surgery Surgery ''cheirourgik'' (composed of 庰巹, "hand", and 廒帠怷彖, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
, etc.; * Cancers, particularly blood cancers such as leukemia and lymphomas; * Metabolic disorders, e.g., gout, and porphyria; and * Inherited metabolic disorder, e.g.,
Fabry disease Fabry disease, also known as AndersonFabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
. 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. In addition, fever can result from a reaction to an incompatible blood product. Teething is not a cause of fever.


Function


Immune function

Fever is thought to contribute to host defense, as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions are increased by temperature. Fever has been described in teaching texts as assisting the healing process in various ways, including: :* increased mobility of leukocytes; :* enhanced leukocyte phagocytosis; :* decreased endotoxin effects; and :* increased
proliferation Proliferation may refer to: Weapons *Nuclear proliferation, the spread of nuclear weapons, material, and technology *Chemical weapon proliferation, the spread of chemical weapons, material, and technology * Small arms proliferation, the spread of ...
of T cells.


Advantages and disadvantages

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


Pathophysiology of fever induction


Hypothalamus

Temperature is regulated in the hypothalamus. The trigger of a fever, called a pyrogen, results in the release of
prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...
(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. Hence, the hypothalamus can be seen as working like a
thermostat A thermostat is a regulating device component which senses the temperature of a physical system and performs actions so that the system's temperature is maintained near a desired setpoint. Thermostats are used in any device or system tha ...
. 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. 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 The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
or primary motor center for shivering. These may be: * Increased heat production by increased
muscle tone In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial muscle contraction, contraction of the muscles, or the muscle's resistance to passive stretch during resting state.OSull ...
, shivering (muscle movements to produce heat) and release of hormones like
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
; and * Prevention of heat loss, e.g., through vasoconstriction. When the hypothalamic set point moves back to baselineeither spontaneously or via medicationnormal 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 An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which r ...
medications. 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 Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
in fever.


Pyrogens

A pyrogen is a substance that induces fever. 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 ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
.'' But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well. 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). 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. Major endogenous pyrogens are interleukin 1 (帢 and 帣) and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-帣, macrophage inflammatory protein-帢 and macrophage inflammatory protein-帣 as well as interferon-帢, interferon-帣, and interferon-帠.
Tumor necrosis factor-帢 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-帢) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release. 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
bloodbrain barrier The bloodbrain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the
arachidonic acid pathway Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupua癟u butter. Its name derives from the New Latin word ''arachi ...
. Of these, IL-1帣, 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.


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. 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 LBPLPS complex then binds to a
CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). C ...
receptor on a
macrophage Macrophages (abbreviated as M , M峖 or MP) ( el, large eaters, from Greek ''弮帢庥'' (') = large, ''帢帠庰彃彖'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
. 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 (TNF帢). A further downstream event is activation of the
arachidonic acid pathway Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupua癟u butter. Its name derives from the New Latin word ''arachi ...
.


PGE2 release

PGE2 release comes from the
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupua癟u butter. Its name derives from the New Latin word ''arachi ...
pathway. This pathway (as it relates to fever), is mediated by the enzymes
phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid tail and the glyce ...
(PLA2), cyclooxygenase-2 (COX-2), and
prostaglandin E2 synthase Prostaglandin E synthase (, or PGE synthase) is an enzyme involved in eicosanoid and glutathione metabolism, a member of MAPEG family. It generates prostaglandin E (PGE) from prostaglandin H2. The synthase generating PGE2 is a membrane-associated ...
. These enzymes ultimately mediate the synthesis and release of PGE2. 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 Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind wi ...
(EP3). EP3-expressing neurons in the POA innervate the
dorsomedial hypothalamus The dorsomedial hypothalamic nucleus is a nucleus of the hypothalamus. It is involved in feeding, drinking, body-weight regulation and circadian activity. More specifically, it is a necessary component for the expression of numerous behavioral a ...
(DMH), the rostral raphe pallidus nucleus in the
medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...
(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 The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
.


Management

Fever does not necessarily need to be treated, and most people with a fever recover without specific medical attention. 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 , and it is rare for an untreated fever to exceed . Treating fever in people with sepsis does not affect outcomes. Small trials have shown no benefit of treating fevers of or higher of critical ill patients in ICUs, and one trial was terminated early because patients receiving aggressive fever treatment were dying more often. 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.


Conservative measures

Limited evidence supports sponging or bathing feverish children with tepid water. 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 Conductor or conduction may refer to: Music * Conductor (music), a person who leads a musical ensemble, such as an orchestra. * Conductor (album), ''Conductor'' (album), an album by indie rock band The Comas * Conduction, a type of structured f ...
by applying numerous ice packs across most of the body or direct submersion in ice water). In general, people are advised to keep adequately hydrated. Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the
common cold The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...
is not known.


Medications

Medications that lower fevers are called '' antipyretics''. The antipyretic
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
is effective in reducing fevers in children. It is more effective than
acetaminophen Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
(paracetamol) in children. Ibuprofen and acetaminophen may be safely used together in children with fevers. The efficacy of acetaminophen by itself in children with fevers has been questioned. Ibuprofen is also superior to aspirin in children with fevers. 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. 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. It is not clear if it increases child comfort. Response or nonresponse to medications does not predict whether or not a child has a serious illness. With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019. 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.


Epidemiology

Fever is one of the most common
medical signs Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
. It is part of about 30% of healthcare visits by children, and occurs in up to 75% of adults who are seriously sick. About 5% of people who go to an emergency room have a fever.


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). It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself. 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. An older term, febricula (a
diminutive A diminutive is a root word that has been modified to convey a slighter degree of its root meaning, either to convey the smallness of the object or quality named, or to convey a sense of intimacy or endearment. A (abbreviated ) is a word-formati ...
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 Viral means "relating to viruses" (small infectious agents). Viral may also refer to: Viral behavior, or virality Memetic behavior likened that of a virus, for example: * Viral marketing, the use of existing social networks to spread a marke ...
respiratory infections.


Society and culture


Mythology

*
Febris Febris (), or Dea Febris (), is the Roman goddess of fevers, who embodied, but also protected people from fever and malaria. Because of this, Febris was a feared goddess whom people wanted the favour of. She does not have a myth of her own. Among ...
(''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. * Jvarasura (''fever-demon'' in Hindi) is the personification of fever and disease in
Hindu Hindus (; ) are people who religiously adhere to Hinduism.Jeffery D. Long (2007), A Vision for Hinduism, IB Tauris, , pages 3537 Historically, the term has also been used as a geographical, cultural, and later religious identifier for ...
and
Buddhist mythology The Buddhist traditions have created and maintained a vast body of mythological literature. The central myth of Buddhism is the life of the Buddha. This is told in relatively realistic terms in the earliest texts, and was soon elaborated into ...
.


Paediatrics

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


Other species

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 (). In species that allow the body to have a wide range of "normal" temperatures, such as
camel A camel (from: la, camelus and grc-gre, 庥峎弮庢弇怷 (''kamlos'') from Hebrew or Phoenician: 硌硌 ''gml''.) is an even-toed ungulate in the genus ''Camelus'' that bears distinctive fatty deposits known as "humps" on its back. C ...
s, whose body temperature varies as the environmental temperature varies, the body temperature which constitutes a febrile state differs depending on the environmental temperature. 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 25 簞C higher than normal in order to inhibit the growth of fungal pathogens such as ''
Beauveria bassiana ''Beauveria bassiana'' is a fungus that grows naturally in soils throughout the world and acts as a parasite on various arthropod species, causing white muscardine disease; it thus belongs to the entomopathogenic fungi. It is used as a biological ...
'' and ''
Metarhizium acridum ''Metarhizium acridum'' is the new name given to a group of fungal isolates that are known to be virulent and specific to the Acrididea (grasshoppers). Previously, this species has had variety status in ''Metarhizium anisopliae'' (var. ''acridu ...
''. Honeybee colonies are also able to induce a fever in response to a fungal parasite ''Ascosphaera apis''.


References


Further reading

*


External links


Fever and Taking Your Child's Temperature



Drugs most commonly associated with the adverse event Pyrexia (Fever) as reported the FDA


at MedlinePlus

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