Fever

Fever (also known as pyrexia

[1]
or febrile response) is one of the most common medical
signs and is characterized by an elevation of body temperature above the normal range of 36.5
37.5 C (97.799.5 F) due to an increase in the temperature regulatory set-point.
[2]
This
increase in set-point triggers increased muscle tone and chills.
As a person's temperature increases, there is, in general, a feeling of cold despite an increase in
body temperature. Once body temperature has increased to the new set-point temperature, there
is a feeling of warmth.
A fever can be caused by many medical conditions ranging from benign to potentially serious.
Some studies suggest that fever is useful as a defense mechanism as the body's immune
response can be strengthened at higher temperatures; however, there are arguments for and
against the usefulness of fever, and the issue is controversial. With the exception of very high
temperatures, treatment to reduce fever is often not necessary; however, antipyretic medications
can be effective at lowering the temperature, which may improve the affected person's comfort.
Fever differs from uncontrolled hyperthermia,
[1]
in that hyperthermia is an increase in body
temperature over the body's thermoregulatory set-point, due to excessive heat production or
insufficient thermoregulation.
Definition[edit]
Temperature classification

Core (rectal, esophageal, etc.)
Hypothermia <35.0 C (95.0 F)
[3]

Normal 36.537.5 C (97.799.5 F)
[2]

Fever >37.538.3 C (99.5100.9 F)
[1][4]

Hyperthermia >37.538.3 C (99.5100.9 F)
[1][4]

Hyperpyrexia >40.041.5 C (104.0106.7 F)
[5][6]

Note: The difference between fever and hyperthermia is the underlying mechanism.
A wide range for normal temperatures has been found.
[4]
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 37.538.3 C (99.5100.9 F)
[1][4]

Temperature in the mouth (oral) is at or over 37.7 C (99.9 F)
[7]

Temperature under the arm (axillary) or in the ear (otic) is at or over 37.2 C (99.0 F)
In healthy adult men and women, the range of normal, healthy temperatures for oral temperature
is 33.238.2 C (91.8100.8 F), for rectal it is 34.437.8 C (93.9100.0 F), for tympanic
membrane(the ear drum) it is 35.437.8 C (95.7100.0 F), and for axillary (the armpit) it is
35.537.0 C (95.998.6 F).
[8]
Harrison's textbook 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) while the normal daily temperature variation is typically 0.5 C (0.9 F).
[9]

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[edit]

Performance of the various types of fever
a) Fever continues
b) Fever continues to abrupt onset and remission
c) Fever remittent
d) Intermittent fever
e) Undulant fever
f) Relapsing fever
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 than 1 C in 24 hours, e.g.lobar pneumonia, typhoid, urinary tract
infection, brucellosis, 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
[10]

Quotidian fever, with a periodicity of 24 hours, typical of Plasmodium
falciparum or Plasmodium knowlesi malaria
Tertian fever (48 hour periodicity), typical of Plasmodium vivax or Plasmodium
ovale malaria
Quartan fever (72 hour periodicity), typical of Plasmodium malariae malaria.
Remittent fever: Temperature remains above normal throughout the day and fluctuates more
than 1 C in 24 hours, e.g., infective endocarditis.
Pel-Ebstein fever: A specific kind of fever associated with Hodgkin's lymphoma, being high
for one week and low for the next week and so on. However, there is some debate as to
whether this pattern truly exists.
[11]

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 unknown, no other
symptoms are present, and the patient recovers fully in less than a week.
[12]

Hyperpyrexia[edit]
Hyperpyrexia is a fever with an extreme elevation of body temperature greater than or equal to
41.5 C (106.7 F).
[13]
Such a high temperature is considered a medical emergencyas it may
indicate a serious underlying condition or lead to significant side effects.
[14]
The most common
cause is an intracranial hemorrhage.
[13]
Other possible causes includesepsis, Kawasaki
syndrome,
[15]
neuroleptic malignant syndrome, drug effects, serotonin syndrome, and thyroid
storm.
[14]
Infections are the most common cause of fevers, however as the temperature rises
other causes become more common.
[14]
Infections commonly associated with hyperpyrexia
include: roseola, rubeola and enteroviralinfections.
[15]
Immediate aggressive cooling to less than
38.9 C (102.0 F) has been found to improve survival.
[14]
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 its set point due to an
outside source.
[13]

Hyperthermia[edit]
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 amphetamines and cocaine, idiosyncratic drug reactions, and serotonin
syndrome
Signs and symptoms[edit]
A fever is usually accompanied by sickness behavior, which consists
of lethargy, depression, anorexia, sleepiness, hyperalgesia, and the inability to
concentrate.
[16][17][18]

Differential diagnosis[edit]
Fever is a common symptom of many medical conditions:
Infectious disease, e.g., influenza, HIV, malaria, infectious mononucleosis,
or gastroenteritis, Lyme disease
Various skin inflammations, e.g., boils, or abscess
Immunological diseases, e.g., lupus erythematosus, sarcoidosis, inflammatory bowel
diseases, Kawasaki disease, Still disease, Horton disease, Wegener disease, Hepatitis
autoimmune
Tissue destruction, which can occur in hemolysis, surgery, infarction, crush
syndrome, rhabdomyolysis, cerebral hemorrhage, etc.
Reaction to incompatible blood products
Cancers, most commonly kidney cancer and leukemia and lymphomas
Metabolic disorders, e.g., gout or porphyria
Thrombo-embolic processes, e.g., pulmonary embolism or deep venous thrombosis
Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of
unknown origin.
Pathophysiology[edit]

Hyperthermia: Characterized on the left. Normal body temperature (thermoregulatory set point) is shown in
green, while the hyperthermic temperature is shown in red. As can be seen, hyperthermia can be conceptualized
as an increase above the thermoregulatory set point.
Hypothermia: Characterized in the center: Normal body temperature is shown in green, while the hypothermic
temperature is shown in blue. As can be seen, hypothermia can be conceptualized as a decrease below the
thermoregulatory set point.
Fever: Characterized on the right: Normal body temperature is shown in green. It reads "New Normal" because
the thermoregulatory set point has risen. This has caused what was the normal body temperature (in blue) to be
considered hypothermic.
Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen,
causes a release of prostaglandin E2(PGE2). PGE2 then in turn acts on the hypothalamus,
which generates a systemic response back to the rest of the body, causing heat-creating effects
to match a new temperature level.
In many respects, the hypothalamus works like a thermostat.
[19]
When the set point is raised, the
body increases its temperature through both active generation of heat and retaining
heat. Vasoconstriction both reduces heat loss through the skin and causes the person to feel
cold. If these measures are insufficient to make the blood temperature in the brain match the new
setting in the hypothalamus, thenshivering begins in order to use muscle movements to produce
more heat. When the fever stops, and the hypothalamic setting is set lower; 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.
[19]
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-pyreticmedications.
Pyrogens[edit]
A pyrogen is a substance that induces fever. These can be either internal (endogenous)
or external (exogenous) to the body. The bacterial substance lipopolysaccharide (LPS), present
in the cell wall of some bacteria, 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[edit]
In essence, all endogenous pyrogens are cytokines, molecules that are a part of the immune
system. They are produced by activatedimmune cells and cause the increase in the
thermoregulatory set point in the hypothalamus. Major endogenous pyrogens are interleukin 1(
and ),
[20]
interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8, tumor necrosis
factor-, macrophage inflammatory protein- and macrophage inflammatory protein- as well
as interferon-, interferon-, and interferon-.
[20]
Tumor necrosis factor- also acts as a pyrogen.
It is mediated by interleukin 1 (IL-1) release.
[21]

These cytokine factors are released into general circulation, where they migrate to
the circumventricular organs of the brain due to easier absorption caused by the bloodbrain
barrier's reduced filtration action there. The cytokine factors then bind with endothelial
receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind,
the arachidonic acid pathway is then activated.
Exogenous[edit]
One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which is a
cell wall component of gram-negative bacteria. An immunological protein
calledlipopolysaccharide-binding protein (LBP) binds to LPS. The LBPLPS 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.
PGE2 release[edit]
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 thepreoptic
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 thesympathetic 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.
Hypothalamus[edit]
The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system.
These may be:
Increased heat production by increased muscle tone, shivering and hormones
like epinephrine (adrenaline)
Prevention of heat loss, such as vasoconstriction.
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[edit]
There are arguments for and against the usefulness of fever, and the issue is
controversial.
[22][23]
There are studies using warm-blooded vertebrates
[24]
and humans
[25]
in vivo,
with some suggesting that they recover more rapidly from infections or critical illness due to
fever. A Finnish study suggested reduced mortality in bacterial infections when fever was
present.
[26]

In theory, fever can aid in host defense.
[22]
There are certainly some important immunological
reactions that are sped up by temperature, and some pathogens with strict temperature
preferences could be hindered.
[27]

Research
[28]
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
[29]

Management[edit]
Fever should not necessarily be treated.
[30]
Most people recover without specific medical
attention.
[31]
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).
[30]

Conservative measures[edit]
Some limited evidence supports sponging or bathing feverish children with tepid water.
[32]
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.
[14]
In general, people are advised to keep adequately hydrated.
[33]
Whether increased
fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not
known.
[34]

Medications[edit]
Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in
reducing fevers in children.
[35]
It is more effective than acetaminophen (paracetamol) in children.
Ibuprofen and acetaminophen may be safely used together in children with fevers.
[36][37]
The
efficacy of acetaminophen by itself in children with fevers has been questioned.
[38]
Ibuprofen is
also superior to aspirin in children with fevers.
[39]
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.
[40]

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.
[41]
It is not clear if it
increases child comfort.
[41]

Epidemiology[edit]
About 5% of people who go to an emergency room have a fever.
[42]

History[edit]
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).
[43]
It also became clear around this time that fevers were a symptom of a disease rather
than a disease in and of itself.
[43]

Society and culture[edit]
Etymology[edit]
Pyrexia is from the Greek pyr meaning fire. Febrile is from the Latin word febris, meaning fever,
and archaically known as ague.
Fever phobia[edit]
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 diseaserather 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.
[44]
They are also afraid of harmless side effects like febrile seizures and dramatically
overestimate the likelihood of permanent damage from typical fevers.
[44]
The underlying problem,
according to professor of pediatrics Barton D. Schmitt, is "as parents we tend to suspect that our
childrens brains may melt."
[45]

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.
[44]

Other animals[edit]
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).
[46]
In species that allow the
body to have a wide range of "normal" temperatures, such as camels,
[47]
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.
[48]
Honeybee colonies are also
able to induce a fever in response to a fungal parasite Ascosphaera apis.
[48]

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