Pathophysiology and Treatment of Fever-1

Pathophysiology and treatment of fever in adults
Reuven Porat, MD
Charles A Dinarello, MD

UpToDate performs a continuous review of over 330 journals and other resources. Updates are
added as important new information is published. The literature review for version 12.3 is current
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UpToDate (13.1) will be released in February 2005.
Fever is a characteristic feature of most infectious diseases but is also found in a number of non-
infectious processes. Definitions of normal body temperature, the pathophysiology of fever, the
role of cytokines, and the treatment of fever in adults will be reviewed here. Fever of unknown
origin in adults, drug fever, and the treatment of fever in infants and children are discussed
separately. (See "Approach to the adult with fever of unknown origin", see "Etiologies of fever of
unknown origin in adults"see "Drug fever" and see "Pathophysiology and treatment of fever in
infants and children").
NORMAL BODY TEMPERATURE - Normal body temperature varies over the course of the day,
controlled in the thermoregulatory center located in the anterior hypothalamus. Fever is an
elevation of body temperature above this normal daily variation. The body is normally able to
maintain a fairly steady temperature because the hypothalamic thermoregulatory center balances
the excess heat production, derived from metabolic activity in muscle and the liver, with heat
dissipation from the skin and lungs. However, faced with environmental extremes, humans cannot
maintain the narrow daily variation of body temperature without the aid of clothing and protective
environments [1].
In healthy individuals, the mean oral temperature for those aged 18 to 40 years is 36.8 0.4 C
(98.2 0.7 F) with low levels at 6 AM and higher levels at 4 to 6 PM [2]. The maximum normal
oral temperature at 6 AM is 37.2 C (98.9 F), and the maximum level at 4 PM is 37.7 C (99.9
F), both values defining the 99th percentile for healthy subjects. From these studies, a morning
reading >37.2 C (98.9 F) or an afternoon temperature of >37.7 C (99.9 F) would be
considered a fever. Rectal temperatures are generally 0.6 C (1.0 F) higher than oral readings.
Oral readings are lower probably because of mouth breathing, which is particularly important in
patients with respiratory infections and rapid breathing. Lower esophageal temperature reflects
core temperature, and tympanic membrane temperature readings are also close to core
temperature.
The normal daily temperature variation is typically 0.5 C (0.9 F). However, in some individuals
recovering from a febrile illness, this daily variation can be as high as 1.0 C. During a febrile
illness, daily lows and highs temperature readings are maintained but clearly at higher levels.
However, in patients with hyperthermia (see below), the daily temperature swings are not present.
In menstruating women, the morning temperature is generally lower during the two weeks prior to
ovulation, rising by about 0.6 C (1.0 F) with ovulation and remaining at that level until menses
occur. Seasonal variation in body temperature has been described, but this may reflect a metabolic
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change and is not a common observation. Elevation in body temperature occurs during the
postprandial state, but this is not fever. Pregnancy and endocrinologic dysfunction also affect body
temperature. The daily temperature variation appears to be fixed in early childhood. On the other
hand, it is well-established that the ability to develop fever in the elderly is impaired. Thus, elderly
patients with severe infections may only display a modest fever.
FEVER, HYPERTHERMIA, AND HYPERPYREXIA - Fever, hyperthermia, and hyperpyrexia are
not synonymous terms.
Fever - Fever is regulated at the level of the hypothalamus. The thermostat which regulates the
temperature in a home can be considered comparable to the hypothalamus for the control of body
temperature. The thermostat setting in the hypothalamic center shifts upwards during a fever, for
example, from 37 to 39C. During fever there is a shift of the "set-point" in the hypothalamus from
the "normothermia" setting to febrile levels, similar to the way the home thermostat is reset to a
higher level in order to raise the ambient temperature in a room. Once the hypothalamic set-point
is raised, this activates neurons in the vasomotor center to commence vasoconstriction.
This vasoconstriction produces a noticeable cold sensation in the hands and feet. Blood is shunted
away from the periphery to the internal organs, essentially decreasing heat loss from the skin, and
the patient feels cold. For most fevers, this is sufficient to raise body temperatures 1 to 2C.
Shivering is also initiated at this time in order to increase heat production from the muscles, but
shivering is not required if heat conservation mechanisms sufficiently raise blood temperature to
the required level. There is also increased heat production from the liver.
In humans, behavioral instincts assist in raising body temperature with reduction of exposed
surfaces. Subjects seek warm rooms, add extra clothing and reduce activity. The processes of heat
conservation (vasoconstriction) and heat production (shivering and increased metabolic activity)
continue until the temperature of the blood bathing the hypothalamic neurons matches the new
setting. When that point is reached, the hypothalamus now maintains the new setting at the febrile
level temperature, just as it does at the normothermic level. In fact, studies have shown that the
mechanisms of heat balance in fever are the same as in the afebrile state.
When the hypothalamic set-point is reset downwards, the processes of heat loss through
vasodilation and sweating are initiated. The resetting of the set-point downwards can be due to
either a reduction in the concentration of pyrogens (see below) or the use of antipyretics.
Behavioral changes are also triggered at this time and removal of insulating clothing or bedding
takes place. Loss of heat by sweating and vasodilation continue until the temperature of the blood
supplying the hypothalamus matches the lower setting.
In some rare patients the hypothalamic set-point is elevated owing to local trauma, hemorrhage,
tumor, or intrinsic hypothalamic malfunction. The term "hypothalamic fever" is sometimes used to
describe elevated temperature caused by abnormal hypothalamic function. However, the majority
of patients with hypothalamic damage have hypo not hyperthermia. These patients do not respond
properly to minor environmental temperature changes; in this condition, core temperature falls
upon exposure to slight drops in temperature, whereas normal hypothalamic function can maintain
core temperature for a few hours. In those very few patients in whom elevated core temperature is
suspected to be due to hypothalamic damage, the diagnosis depends upon the demonstration of
other abnormal hypothalamic functions, such as production of hypothalamic releasing factors,
abnormal response to cold, and absence of circadian temperature and hormonal rhythms.
Hyperthermia - Although the vast majority of patients with elevated body temperature have
fever, there are a few instances in which an elevated temperature represents hyperthermia. These
include heat stroke syndromes, certain metabolic diseases, and the effects of pharmacologic agents
that interfere with thermoregulation. (See "Severe hyperthermia: Heat stroke; neuroleptic
malignant syndrome; and malignant hyperthermia"). In contradistinction to fever, the setting of
the thermoregulatory center during hyperthermia remains unchanged at normothermic levels,
while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat.
Exogenous heat exposure and endogenous heat production are two mechanisms by which
hyperthermia can result in dangerously high internal temperatures.
It is important to make the distinction between fever and hyperthermia. Hyperthermia can be
rapidly fatal, and its treatment differs from that of fever. Despite physiologic and behavioral control
of body temperature, excessive heat production can easily occur. As an example, overinsulating
clothing can result in elevated core temperature. Hyperthermia is also observed in persons who
work or exercise in hot environments and produce heat faster than the peripheral mechanisms can
lose it.
Certain metabolic diseases such as hyperthyroidism can result in mild elevations of core
temperature. The effects of some pharmacologic agents (atropine) that interfere with
thermoregulation by blocking sweating or vasodilation can also raise core temperature. Once again,
these syndromes represent hyperthermia because they take place in the presence of a normal
hypothalamic set-point.
A diagnosis of hyperthermia is often made because of a preceding history of heat exposure or use
of certain drugs that interfere with normal thermoregulation. There is no rapid way to differentiate
elevated core temperature due to fever from hyperthermia. The immediate events prior to the
onset of hyperthermia usually play an important role in determining its cause. However, physical
examination can assist the clinician in some forms of hyperthermia; for example, the skin is hot
but dry in heat stroke syndromes and in patients taking drugs that block sweating. Antipyretics do
not reduce the elevated temperature in hyperthermia whereas there is usually some decrease in
body temperature in patients with fever or even "hyperpyrexia" (see below) after adequate doses
of either aspirin or acetaminophen.
Hyperthermia can also occur when certain anesthetics produce a rapid uncoupling of oxidative
phosphorylation in susceptible individuals [3]. This is known as malignant hyperthermia and is
often fatal. Another form of hyperthermia results in patients taking certain neuroleptic drugs and is
called "neuroleptic malignant syndrome" [4,5]. (See "Severe hyperthermia: Heat stroke;
neuroleptic malignant syndrome; and malignant hyperthermia").
Hyperpyrexia - Hyperpyrexia is the term for an extraordinarily high fever (>41.5 C), which can
be observed in patients with severe infections but most commonly occurs in patients with central
nervous system (CNS) hemorrhages. Although antipyretics reduce the body temperature in
hyperpyrexic fever, cooling blankets and cool water sponging are recommended to accelerate
peripheral heat losses. However, peripheral cooling with cooling blankets can be counterproductive
in the absence of antipyretics since cold receptors in the skin trigger reactive vasoconstriction, thus
reducing heat loss mechanisms.
PYROGENS - The term pyrogen is used to describe any substance that causes fever. Pyrogens
are either exogenous or endogenous. Endogenous pyrogens are more precisely termed pyrogenic
cytokines.
Exogenous pyrogens - Exogenous pyrogens, derived from outside the host, are mainly microbes
or their products, such as toxins. The classic example of an exogenous pyrogen is the
lipopolysaccharide endotoxin produced by all Gram negative bacteria. Endotoxins are potent
substances not only as pyrogens but also as inducers of various pathologic changes observed in
Gram negative infections [6].
Another group of bacterial substances which are potent pyrogens are produced by Gram positive
organisms. The toxic shock syndrome toxin (TSST-1) is associated with strains of Staphylococcus
aureus isolated from patients with the toxic shock syndrome (TSS) [7,8]. TSST-1 and other
enterotoxins from S. aureus and exotoxins from group A streptococcus act both as direct toxins but
also serve as "superantigens" [9,10]. Superantigens appear to play a role in the pathogenesis of
severe Gram positive infections by interacting with the major histocompatibility complex (MHC) II
and a number of T cell subsets [11,12] to release pyrogenic cytokines (see below). Like the
endotoxins from Gram negative bacteria, the toxins produced by staphylococci and streptococci
produce fever in experimental animals when injected intravenously in the submicrogram/kg range.
Of considerable importance is the fact that endotoxin is a highly pyrogenic molecule in humans
since 2 to 3 ng/kg produces fever and generalized symptoms of malaise in volunteers [13].
Pyrogenic cytokines - Pyrogenic cytokines are specific endogenous pyrogens which are released
in response to exogenous pyrogens [14,15]. Cytokines are small proteins (molecular weight 10 to
20,000 daltons) which regulate immune, inflammatory and hematopoietic processes. (See "Role of
cytokines in the immune system"). As an example, stimulation of lymphocyte proliferation during
an immune response to vaccination is the result of various cytokines including interleukin (IL)-2,
IL-4 and IL-6. A cytokine called granulocyte colony stimulating factor (G-CSF) stimulates
granulocytopoiesis in the bone marrow. (See "Introduction to recombinant hematopoietic growth
factors"). Some cytokines cause fever and hence are called pyrogenic cytokines.
From a historical point of view, the field of "cytokine biology" began with laboratory investigations
into the cause of fever by products of activated leukocytes in the 1940s. These fever producing
molecules were called "endogenous pyrogens" [16]. When endogenous pyrogens were purified
from activated leukocytes, they were shown to possess various biological activities, now properties
of various cytokines.
There are several pyrogenic cytokines, namely IL-1, IL-6, tumor necrosis factor (TNF) and ciliary
neurotrophic factor (CNTF) [14,17]. Others likely exist. Interferon (IFN)-alpha can also be
considered a pyrogenic cytokine since it produces fever. In fact, IL-1, IL-6 and TNF have each been
injected into humans and have produced fever. IL-1 and TNF are particularly pyrogenic, resulting in
fever at doses as low as 10 ng/kg (either subcutaneously or intravenously) [14]. IL-6 is also
pyrogenic but microgram/kg rather than nanogram/kg doses of IL-6 are needed to produce fever in
humans. Nevertheless, large amounts of IL-6 circulate in nearly all febrile diseases and IL-6
induced by IL-1 or the combination of IL-1 plus TNF likely accounts for the clinical fever most often
measured. Mice without the gene for IL-6 do not develop fever during bacterial infection. Thus, in
most inflammatory and infectious diseases, low concentrations of IL-1 and TNF induce large
amounts of IL-6 and it is the IL-6 which likely triggers the hypothalamic centers for control of body
temperature. Thus, in addition to exogenous pyrogens from microbial sources, endogenous
pyrogenic cytokines cause fever. Each cytokine is coded by a separate gene and each pyrogenic
cytokine has been shown to cause fever not only in laboratory animals but also when injected into
humans.
A wide spectrum of exogenous pyrogens induce the synthesis and release of endogenous pyrogenic
cytokines. Most of the exogenous pyrogenic substances can be recognized from their bacterial or
fungal sources. Viruses induce pyrogenic cytokines by infecting cells. However, in the absence of
microbial infection, fever is present in a variety of diseases. Inflammation, trauma or antigen-
antibody complexes induce the production of IL-1, TNF and IL-6, and each or all three cytokines
trigger the hypothalamus to raise the set-point to febrile levels [18]. The cellular sources of
pyrogenic cytokines are primarily monocytes, neutrophils and lymphocytes, although many
different cells can synthesize these molecules, when stimulated.
ELEVATION OF THE HYPOTHALAMIC SET-POINT BY CYTOKINES - During fever,
hypothalamic tissue and third cerebral ventricle levels of prostaglandin (PG)E2 are elevated [19-
21]. The highest concentrations of PGE2 are near the circumventricular vascular organs (organ
vasculosum lamina terminalis, OVLT) which are networks of enlarged capillaries surrounding the
hypothalamic regulatory centers [22]. Destruction of these organs reduces the ability of pyrogens
to produce fever. However, most studies in animals have not been able to show that pyrogenic
cytokines pass from the circulation into the brain substance itself [14]. Thus, it appears that both
exogenous and endogenous pyrogens interact with the endothelium of these capillaries which is
probably the first step in initiating fever (show figure 1).
The interaction of pyrogens with the hypothalamic circumventricular vascular endothelium is the
first step in raising the set-point to febrile levels. Figure 1 illustrates the key events in the
production of fever (show figure 1). As shown, several cells have the potential to produce
pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6 and TNF then are released from the cell
and enter the systemic circulation. Although the systemic effects of these circulating cytokines
initiate fever by their ability to induce the synthesis of PGE2, they also induce PGE2 in peripheral
tissues [14]. The increase in PGE2 in the periphery accounts for the non-specific myalgias and
arthralgias which often accompany fever. However, it is the induction of PGE2 in the brain which
starts the process of raising the hypothalamic set-point for core temperature.
There are four receptors for PGE2, and each signals the cell in different ways. Studies in mice
demonstrated that the third PGE2 receptor (EP-3) is essential for the production of fever; mice
deficient in the gene for this receptor do not develop fever following the injection of IL-1 or
endotoxin [23]. Deletion of the other PGE2 receptor genes leave the fever mechanism intact.
Although PGE2 is essential for fever, PGE2 is not a neurotransmitter. However, release of PGE2
from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and
this results in the rapid release of cyclic AMP (cAMP) which is a neurotransmitter [14].
As shown in Figure 1, release of cAMP from the glial cells activates neuronal endings from the
thermoregulatory center which extend into the area (show figure 1). The elevation of cAMP is
thought to account for changes in the hypothalamic set-point either directly or indirectly by
inducing the release of monoamine neurotransmitters. Receptors for endotoxin share many
similarities to those of IL-1, and hence, activation of endotoxin receptors on the hypothalamic
endothelium also results in PGE2 production and fever [24].
Production of cytokines in the central nervous system - Several viral diseases produce
active infection in the brain. Glial and possibly neuronal cells synthesize IL-1, TNF, and IL-6 [25].
CNTF is also synthesized by neural as well as neuronal cells. These cytokines produced within the
brain itself appear to play a role in the production of fever. When a cytokine is injected directly into
the brain of experimental animals, the dose required to cause fever is several orders of magnitude
lower compared to intravenous injection. Thus, it appears that CNS production of these cytokines
can raise the hypothalamic set-point, bypassing the circumventricular organs involved in the fever
which results from circulating cytokines. Local production of cytokines in the CNS may account for
the hyperpyrexia of CNS hemorrhage noted above.
MECHANISMS OF ANTIPYRETIC AGENTS - The synthesis of PGE2 depends upon the
constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic
acid released from the cell membrane, and this release is the rate limiting step in the synthesis of
PGE2. Inhibitors of cyclooxygenase are potent antipyretics [26]. There is a direct correlation of
antipyretic potency of various drugs and the inhibition of brain cyclooxygenase [27]. (See
"NSAIDs: Mechanism of action"). Acetaminophen is a poor cyclooxygenase inhibitor in peripheral
tissue and does not display noteworthy antiinflammatory activity; however, acetaminophen is
oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits
cyclooxygenase activity.
There is no difference between oral aspirin and acetaminophen in reducing fever in humans.
Nonsteroidal antiinflammatory agents (NSAIDs), such as indomethacin or ibuprofen, are also
excellent antipyretics and can be used for this purpose. (See "NSAIDs: Mechanism of action").
There appears to be no role for PGE2 in normal thermoregulation based upon observations that
chronic use of aspirin or NSAIDs in arthritis does not reduce normal core body temperature.
Corticosteroids are also effective antipyretics, which act at two levels [28,29]:
Similar to the cyclooxygenase inhibitors, corticosteroids reduce PGE2 synthesis by inhibiting the
activity of phospholipase A2 which is needed to release arachidonic acid from the membrane.

Corticosteroids block the transcription of the mRNA for the pyrogenic cytokines.

Drugs that interfere with vasoconstriction (eg, phenothiazines) can also act as antipyretics as can
drugs that block muscle contractions. However, these are not true antipyretics since they can also
reduce core temperature independently of hypothalamic control.
TREATMENT OF FEVER AND HYPERTHERMIA - Fever increases the demand for oxygen and
can aggravate preexisting cardiac or pulmonary insufficiency. For every increase of one degree
above 37C, there is a 13 percent increase in O2 consumption. In addition, elevated temperature
can induce mental changes in patients with organic brain disease. Thus, treatment of fever in some
patient groups is recommended.
Decision to treat fever - The vast majority of fevers are associated with self-limited infections,
most commonly of a viral origin, where the cause of the fever is easily identified. The decision to
reduce fever with antipyretics assumes that there is no diagnostic benefit of allowing the fever to
persist. However, there are clinical situations in which observation of the pattern of fever can be
helpful diagnostically. As an example, the daily highs and lows of normal temperature are
exaggerated in most fevers, but these fluctuations may be reversed in typhoid fever and
disseminated tuberculosis. Temperature-pulse dissociation (relative bradycardia) is seen in typhoid
fever, brucellosis, leptospirosis, some drug-induced fevers and factitious fever. Fever may not be
present during infection in newborns, the elderly, patients with chronic renal failure, and in patients
taking corticosteroids; hypothermia, in fact, can occur. Hypothermia can also be observed in
patients with septic shock.
Some febrile diseases have characteristic patterns. Among these are malaria and cyclic
neutropenia. However, most of the febrile illnesses which are thought to exhibit a specific time-
related pattern (eg, Hodgkin's disease) are in fact, upon close examination, not reliable indicators
or of no diagnostic value. As an example, there is no periodicity of fever in patients with Familial
Mediterranean Fever. (See "Clinical manifestations and diagnosis of familial Mediterranean fever").
Patients infected with the human immunodeficiency virus (HIV) can experience recurrent daily
fevers which do not necessarily indicate mycobacterial infection.
There is no evidence that fever itself facilitates the recovery from infection or acts as an adjuvant
to the immune system. In fact, peripheral PGE2 production is a potent immunosuppressant. Hence,
treating fever and its symptoms does no harm and does not slow the resolution of common viral
and bacterial infections.
Treating fever - Reducing fever with antipyretics also reduces systemic symptoms of headache,
myalgias and arthralgias. Aspirin and NSAIDs are excellent oral agents but cause unwanted side
effects on platelets and the gastrointestinal tract. Thus, acetaminophen is generally the preferred
antipyretic.
In cases of hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature, but
cooling blankets should not be used without antipyretics. The objectives in treating fever are to
first reduce the elevated set-point of the hypothalamus and then to facilitate heat loss. If the
patient cannot take oral antipyretics, parenteral preparations of NSAIDs or rectal suppositories of
various antipyretics can be used. Since hyperpyrexia may occur in patients with CNS disease or
trauma, reducing core temperature helps to reduce the ill-effect of high temperature on the brain.
Treating hyperthermia - The treatment of hyperthermia is primarily targeted at rapid reduction
of body temperature by physical means. (See "Severe hyperthermia: Heat stroke; neuroleptic
malignant syndrome; and malignant hyperthermia"). Antipyretics are of no use. Rapid reduction in
body temperature can be accomplished by cool or tepid (20 C), not cold, bathing, preferably using
damp sponges. Submersion should be avoided, so that body heat loss by evaporation can occur.
Alcohol adds nothing to tepid or cool water sponging. Cooling blankets are of potential danger
because of excess vasoconstriction. Intravenous fluids can also be administered for dehydration,
but cool fluids through a central line close to the heart are not advisable.

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