Fever

Fever, also known as pyrexia and febrile response,[6] is defined as

Fever
having a temperature above the normal range due to an increase in the
body's temperature set point.[4][5] There is not a single agreed-upon Other names Pyrexia, febrile response
upper limit for normal temperature with sources using values between
37.5 and 38.3 °C (99.5 and 100.9 °F).[6][7] The increase in set point
triggers increased muscle contractions and causes a feeling of cold.[1]
This results in greater heat production and efforts to conserve heat.[2]
When the set point temperature returns to normal, a person feels hot,
becomes flushed, and may begin to sweat.[2] Rarely a fever may
trigger a febrile seizure.[3] This is more common in young children.[3]
Fevers do not typically go higher than 41 to 42 °C (105.8 to
107.6 °F).[5]
An analog medical thermometer showing a
A fever can be caused by many medical conditions ranging from non
temperature of 38.7 °C or 101.7 °F
serious to life-threatening.[11] This includes viral, bacterial and
parasitic infections such as the common cold, urinary tract infections,
Specialty Infectious disease, pediatrics
meningitis, malaria and appendicitis among others.[11] Non-infectious Symptoms Initially: shivering, feeling
causes include vasculitis, deep vein thrombosis, side effects of cold[1]
medication, and cancer among others.[11] It differs from hyperthermia, Later: flushed, sweating[2]
in that hyperthermia is an increase in body temperature over the Complications Febrile seizure[3]
temperature set point, due to either too much heat production or not
Causes Increase in the body's
enough heat loss.[6]
temperature set point[4][5]
Treatment to reduce fever is generally not required.[1][8] Treatment of Diagnostic Temperature > between 37.5
associated pain and inflammation, however, may be useful and help a method and 38.3 °C (99.5 and
person rest.[8] Medications such as ibuprofen or paracetamol 100.9 °F)[6][7]
(acetaminophen) may help with this as well as lower temperature.[8][9] Differential Hyperthermia[6]
Measures such as putting a cool damp cloth on the forehead and diagnosis
having a slightly warm bath are not useful and may simply make a
Treatment Based on underlying cause,
person more uncomfortable.[8] Children younger than three months
not required for fever itself[1][8]
require medical attention, as might people with serious medical
problems such as a compromised immune system or people with other
Medication Ibuprofen, paracetamol
symptoms.[12] Hyperthermia does require treatment.[1]
(acetaminophen)[8][9]
Frequency Common[1][10]
Fever is one of the most common medical signs.[1] It is part of about
30% of healthcare visits by children[1] and occurs in up to 75% of adults who are seriously sick.[10] While fever is a useful defense
mechanism, treating fever does not appear to worsen outcomes.[13][14] Fever is viewed with greater concern by parents and
healthcare professionals than it usually deserves, a phenomenon known asfever phobia.[1]

Contents
Signs and symptoms
Diagnosis
Types
Hyperpyrexia
 Hyperthermia
Differential diagnosis
Pathophysiology
Pyrogens
PGE2 release
Hypothalamus
Usefulness
Management
Conservative measures
Medications
Epidemiology
History
Society and culture
Etymology
Fever phobia
Other animals
References
Further reading
External links

Signs and symptoms

A fever is usually accompanied bysickness behavior, which consists of
lethargy, depression, anorexia, sleepiness, hyperalgesia, and the
inability to concentrate.[15][16][17]

Diagnosis
A wide range for normal temperatures has been found.[7] Central
temperatures, such as rectal temperatures, are more accurate than
peripheral temperatures.[23] 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)[6][7]
Temperature in the mouth (oral) is at or over37.7 °C
(99.9 °F)[24]
Michael Ancher, "The Sick Girl", 1882,Statens Temperature under the arm (axillary) or in theear (tympanic) is
Museum for Kunst at or over 37.2 °C (99.0 °F)
In healthy adults, the range of normal, healthy temperatures for oral
temperature is 33.2–38.2 °C (91.8–100.8 °F), for rectal it is 34.4–
37.8 °C (93.9–100.0 °F), for tympanic membrane (the ear drum) it is 35.4–37.8 °C (95.7–100.0 °F), and for axillary (the armpit) it is
35.5–37.0 °C (95.9–98.6 °F).[25] Harrison's Principles of Internal Medicinedefines 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) while the normal daily temperature variation is typically 0.5 °C
(0.9 °F).[26]

Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and
more. 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
.

Types
The pattern of temperature changes may occasionally hint at the
diagnosis:

Continuous fever: Temperature remains above normal

throughout the day and does not fluctuate more than1 °C in
24 hours, e.g. lobar pneumonia, typhoid, meningitis, urinary
tract infection, or typhus. Typhoid fever may show a specific
fever pattern (Wunderlich curve of typhoid fever), with a
slow stepwise increase and a high plateau.(Drops due to
fever-reducing drugs are excluded.)
Intermittent fever: The temperature elevation is present only
for a certain period, later cycling back to normal,e.g.
malaria, kala-azar, pyaemia, or septicemia. Following are its
types:[27]

Quotidian fever, with a periodicity of 24 hours, typical of

Plasmodium knowlesi malaria
Tertian fever (48-hour periodicity), typical of later in the
course of Plasmodium falciparum, Plasmodium vivax, or
Plasmodium ovale malaria[28]
Quartan fever (72-hour periodicity), typical of later in the
course of Plasmodium malariae malaria.[28] Performance of the various types of fever
Remittent fever: Temperature remains above normal a) Fever continues
throughout the day and fluctuates more than1 °C in 24 b) Fever continues to abrupt onset and remission
hours, e.g., infective endocarditis, brucellosis.
c) Remittent fever
Pel-Ebstein fever: A specific kind of fever associated with
d) Intermittent fever
Hodgkin's lymphoma, being high for one week and low for
the next week and so on. However, there is some debate as e) Undulant fever
to whether this pattern truly exists.[29] f) Relapsing fever

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.

Febricula is an old term for a low-grade fever, especially if the cause is Different fever patterns observed in Plasmodium
unknown, no other symptoms are present, and the patient recovers fully infections.
in less than a week.[30]

Hyperpyrexia
Hyperpyrexia is an extreme elevation ofbody temperature which, depending upon the source, is classified as a core body temperature
greater than or equal to 40.0 or 41.5 °C (104.0 or 106.7 °F).[31][32][33] Such a high temperature is considered a medical emergency,
as it may indicate a serious underlying condition or lead to problems including permanent brain damage, or death.[34] The most
common cause of hyperpyrexia is an intracranial hemorrhage.[35][33] Other possible causes include sepsis, Kawasaki syndrome,[36]
neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.[34]
Infections are the most common cause of fevers, but as the temperature rises other causes become more common.[34] Infections
commonly associated with hyperpyrexia include roseola, measles and enteroviral infections.[36] Immediate aggressive cooling to less
than 38.9 °C (102.0 °F) has been found to improve survival.[34] Hyperpyrexia differs from hyperthermia in that in hyperpyrexia the
body's temperature regulation mechanism sets the body temperature above the normal temperature, then generates heat to achieve this
temperature, while in hyperthermia the body temperature rises above itsset point due to an outside source.[35]

Hyperthermia
Hyperthermia is an example of a high temperature that is not a fever. It occurs from a number of causes including heatstroke,
neuroleptic malignant syndrome, malignant hyperthermia, stimulants such as substituted amphetamines and cocaine, idiosyncratic
drug reactions, and serotonin syndrome.[37][38]

Differential diagnosis
Fever is a common symptom of many medical conditions:

Infectious disease, e.g., influenza, primary HIV infection, malaria, Ebola, infectious mononucleosis, gastroenteritis,
Lyme disease, Dengue
Various skin inflammations, e.g., boils, abscess
Immunological diseases, e.g., lupus erythematosus, sarcoidosis, inflammatory bowel diseases, Kawasaki disease,
Still disease, Horton disease, granulomatosis with polyangiitis, autoimmune hepatitis, relapsing polychondritis[39]
Tissue destruction, which can occur inhemolysis, surgery, infarction, crush syndrome, rhabdomyolysis, cerebral
bleeding, etc.
Reaction to incompatible blood products
Cancers, most commonly kidney cancer and leukemia and lymphomas
Metabolic disorders: gout, porphyria
Inherited metabolic disorder:Fabry disease[40]
Persistent fever that cannot be explained after repeated routine clinical inquiries is called
fever of unknown origin.

Teething is not a cause.[41]

Pathophysiology
Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes 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.

In many respects, the hypothalamus works like a thermostat.[42] 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.[43] If these measures are insufficient to make the blood temperature in the brain match the new set
point in the hypothalamus, thenshivering begins in order to use muscle movements to produce more heat.When the hypothalamic set
point moves back to baseline either spontaneously or with medication, the reverse of these processes (vasodilation, end of shivering
and nonshivering heat production) and sweating 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.[42] 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.

Pyrogens
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 ofgram-negative bacteria,[44] 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.

Endogenous Hyperthermia: Characterized on the

left. Normal body temperature
In essence, all endogenous pyrogens are cytokines, molecules that are a part of the (thermoregulatory set point) is shown
immune system. They are produced by activated immune cells and cause the in green, while the hyperthermic
increase in the thermoregulatory set point in the hypothalamus. Major endogenous temperature is shown in red. As can
pyrogens are interleukin 1 (α and β)[45] and interleukin 6 (IL-6). Minor endogenous be seen, hyperthermia can be
conceptualized as an increase above
pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory
the thermoregulatory set point.
protein-α and macrophage inflammatory protein-β as well as interferon-α,
Hypothermia: Characterized in the
interferon-β, and interferon-γ.[45] Tumor necrosis factor-α also acts as a pyrogen. It center: Normal body temperature is
is mediated by interleukin 1 (IL-1) release.[46] shown in green, while the
hypothermic temperature is shown in
These cytokine factors are released into general circulation, where they migrate to blue. As can be seen, hypothermia
the circumventricular organs of the brain due to easier absorption caused by the can be conceptualized as a decrease
blood–brain barrier's reduced filtration action there. The cytokine factors then bind below the thermoregulatory set point.
with endothelial receptors on vessel walls, or interact with local microglial cells. Fever: Characterized on the right:
Normal body temperature is shown in
When these cytokine factors bind, thearachidonic acid pathwayis then activated.
green. It reads "New Normal"
because the thermoregulatory set
Exogenous point has risen. This has caused
what was the normal body
One model for the mechanism of fever caused by exogenous pyrogens includes LPS, temperature (in blue) to be
which is a cell wall component ofgram-negative bacteria. An immunological protein considered hypothermic.
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.[47] The highly toxic metabolism-boosting supplement2,4-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.[48]

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 involvingpituitary gland and various endocrine organs.
Hypothalamus
The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering.
These may be:

Increased heat production by increasedmuscle tone, shivering and hormones like epinephrine (adrenaline)
Prevention of heat loss, such asvasoconstriction.
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.

Usefulness
There are arguments for and against the usefulness of fever, and the issue is controversial.[49][50][51] There are studies using warm-
blooded vertebrates with some suggesting that they recover more rapidly from infections or critical illness due to fever.[52] Studies
[53]
suggest reduced mortality in bacterial infections when fever was present.

In theory, fever can aid in host defense.[49] There are certainly some important immunological reactions that are sped up by
[54]
temperature, and somepathogens with strict temperature preferences could be hindered.

Research[55] has demonstrated that fever assists the healing process in several important ways:

Increased mobility of leukocytes

Enhanced leukocyte phagocytosis
Endotoxin effects decreased
Increased proliferation of T cells[56]

Management
Fever should not necessarily be treated.[57] Most people recover without specific medical attention.[58] 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).[57] Treating fever in people with sepsis does not affect
outcomes.[59]

Conservative measures
Some limited evidence supports sponging or bathing feverish children with tepid water.[60] 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).[34] In general, people are advised to keep adequately hydrated.[61] Whether increased fluid
intake improves symptoms or shortens respiratory illnesses such as thecommon cold is not known.[62]

Medications
Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in reducing fevers in children.[63] It is
more effective than acetaminophen (paracetamol) in children.[63] Ibuprofen and acetaminophen may be safely used together in
children with fevers.[64][65] The efficacy of acetaminophen by itself in children with fevers has been questioned.[66] Ibuprofen is also
superior to aspirin in children with fevers.[67] 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 ofReye's syndrome.[68]
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.[69] It is not clear if it increases child comfort.[69] Response or nonresponse to medications does
[70]
not predict whether or not a child has a serious illness.

Epidemiology
About 5% of people who go to an emergency room have a fever.[71]

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).[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

Etymology
Pyrexia is from the Greekpyr meaning fire. Febrile is from the Latin word febris, meaning fever, and archaically known asague.

Fever phobia
Fever phobia is the name given by medical experts to parents' misconceptions about fever in their 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.[73] They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent
damage from typical fevers.[73] 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."[74]

As a result of these misconceptions parents are anxious, give the child fever-reducing medicine when the temperature is technically
[73]
normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine.

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

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Further reading
Rhoades, R. and Pflanzer, R. Human physiology, third edition, chapter 27Regulation of body temperature, p. 820
Clinical focus: pathogenesis of fever. ISBN 0-03-005159-2

External links
Fever and Taking Your Child's Temperature Classification ICD-10: R50 · D
US National Institute of Health factsheet ICD-9-CM: 780.6 ·
Drugs most commonly associated with the adverse event Pyrexia (Fever) MeSH: D005334 ·
as reported the FDA
DiseasesDB:
18924
External MedlinePlus:
resources 003090 ·
eMedicine:
med/785

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