FeverPathophysiolo

By Lynn BabcockCimpello,MD,
DavidL. Goldman,MD,and Hnin Khine,MD
BRONX,NEWYORK

T HE ELEVATION of body temperature in association with

infection is a primitive host response that is shown by animals
separated from humans by millions of years of evolution. A febrile
response to infection is observed even in “cold-blooded” animals such
as fish that swim in warm water and
lizards that linger out in the sun to elevate their body tempera-tures in
response to infection. 1 In humans, the febrile response is a complex,
dynamically regulated process that is just beginning to be understood.
Fever is part of an integrated, nonspecific response to a variety of
insults to the human body including
infection, inflammatory disorders, neoplastic diseases or im-
mune-mediated illnesses. Pediatricians frequently evaluate and
manage children with fever, often with little regard to the mech-
anisms of fever. In this review, the authors present an overview
of the current understanding of the pathogenesis of fever with an
emphasis on its clinical relevance.

Normothermia

The human body has the remarkable ability to maintain a

relatively constant temperature, despite wide fluctuations in sev-
eral variables, including ambient temperature, energy expendi-
ture, and energyintake. Thermoregulation is actively controlled
by the thermoregulatory center within the hypothalamus. This
center receives input from peripheral receptors and the temper-
ature of the blood bathing the hypothalamus. Specialized neu-
rons in the thermoregulatory center respond to various stimuli,
including cold and warm temperatures, by altering their firing
rates, This center can in turn act on autonomic, endocrine, and
behavioral mechanisms to maintain body temperature at a par-
ticular set point. When this set point is elevated, the result is
fever. The maintenance of normothermia is a balance between
heat production and heat loss (Table 1). Under normal condi-
tions, metabolic activity generally produces more than sufficient
heat to reach this set point, therefore, the maintenance of normal
body temperature involves the regulation of heat loss. This is

84 FEVER PATHOPHYSlOLOGY/ CIMPELLO, GOLDMAN, AND KHINE

 FEVER PATHOPHYSlOLOGY / CIMPELLO, GOLDMAN,
TABLEI. Physiologicand BehavioralMechanism atricians. Of note, infants (especially those younger
of BodyTemperatureRegulation
Elevation of Body Reduction of Body
Temperature Temperature
Heat generation Heat loss
Increased cell metabolism Obligate heat loss
Muscle activity Vasodilation
Involuntary shivering Sweating
Heat conservation Cold preference behavior
Vasoconstriction
Heat preference behavior
achieved primarily by altering blood flow to the skin
through the control of the autonomic system. A
decrease in sympathetic tone in the arterioles of
the skin results in vasodilation and increased blood
flow to the skin where heat loss can occur by either
conduction, convection, or radiation. In addition,
increasing perspiration, which is also under control
of the autonomic system, can augment heat loss
through the skin.
The hypothalamic set point normally maintains
body temperature at about 37°C. Nevertheless
“normal” temperature is best represented as a
range of temperatures because there can be signif-
icant variation in temperature between individuals.
Confusion regarding the definition of “normal” tem-
perature in the literature is compounded by differ-
ences in observational techniques used in various
studies, including methods of measurement, sites
of measurement, and the time of day temperature
was taken. Children, especially those younger than
1 year of age have been reported to have a slightly
higher range of “normal” temperature.2 Body tem-
perature varies during the day (circadian rhythm)
with the peak occurring in the late afternoon (5:00
PM to 7:00 PM) and the trough early in the morning (2:00
AM to 6:00 AM).~ This circadian variation can differ
significantly between individuals and can be as much
as 1.3”C (2.4”F) or as little as O.l”C (0.2”F).3 This
rhythm is less prominent during the first few months of
life, and becomes established by the second year of
life. The mechanisms of circa-dian variation are
unclear, but this pattern appears to be a tightly
regulated process. Circadian varia-tion in body
temperature can persist even during febrile illnesses,
although it is absent in patients with hyperthermia.2
A working definition of fever as a rectal temper-
AND
KHINE 85
ature of 38°C (100.4”F) is commonly used by pedi-
than 2 months) may have a blunted febrile
response to infection and the absence of fever
should not be taken as a criterion to exclude
infection. In con-trast, toddlers typically have a very
labile response to infection and may show
exaggerated febrile re-sponses to infection.
The Functionof Feverin Infection
The beneficial effects of fever have been sug-
gested by physicians as far back as the ancient
Greeks. Hippocrates hypothesized that fever was
the result of an imbalance of the four humors and
that fever plays a role in burning off the excessive
humor.4 At various times in history, physicians
have attempted to exploit the beneficial effects of
fever therapeutically. For example, before the de-
velopment of antibiotics, fever therapy (induced by
infecting patients with malaria or injecting killed typhoid
bacilli) was used to treat syphilis.5 The fact that fever
occurs in response to infection in many animal types (eg,
insects, fish, amphibians, reptiles, birds, and mammals)
has been used to support the argument that fever must
be beneficial to the host.6 Furthermore, the production of
fever in response to bacterial and viral infections in
various animal models improves survival rates,7-9
whereas the sup-pression of the fever results in
increased mortal-
ity. 10.12
Recently, a number of studies have shown that
moderate increases in temperature can directly en-
hance both the specific and nonspecific arms of the
immune response.13 Neutrophils are the first line of
defense against a variety of pathogens. Fever en-
hances neutrophil function by improving chemo-tactic
responses14 and increasing microbial killing ability by
increasing the production of superox-ide.15 Fever also
increases the production of inter-ferons by
lymphocytes16 and enhances their func-tion.17
Interferons have important antibacterial and antiviral
activity and are now being used therapeu-tically for the
treatment of certain infections. Fever augments T cell
proliferative responses and B-cell antibody production by
the action of T helper cells, and thereby enhances both
cellular and humoral immune responses.18 The
beneficial effects of tem-perature on the immune
response are generally lost when the elevation in
temperature is excessive, ie, greater than 4O”C.19
Fever can also have direct antimicrobial activity and
can inhibit the growth of certain bacterial (in-cluding
treponemes and neisseria), viral and fungal
 86 FEVER PATHOPHYSlOLOGY/ CIMPELLO, GOLDMAN, AND KHINE
pathogens2 The antimicrobial action of fever ap-
pears to be in part related to its effects on iron
metabolism. Iron is an essential cofactor for many
metabolic processes for both humans and patho-
gens. To this end, pathogens have evolved
elaborate mechanisms to obtain iron from the host.
Fever can increase the iron requirements of certain
pathogens and at the same time inhibit their ability
to obtain iron from the host20 Fever decreases the
produc-tion of siderophores by bacteria.
Siderophores are molecules secreted by bacteria
that act as iron scavengers. In addition, the febrile
response in-volves the production of acute phase
reactants that decrease the availability of free iron
to the invading microbe.
Despite these observations, clinical evidence to
support the hypotheses that fever is beneficial dur-ing
infection and that fever reduction is harmful remain
elusive. There are several possible explana-tions for this.
Fever is only part of a complex re-sponse that has a
variety of redundant mechanisms, therefore, the clinical
effects associated with elim-ination of fever may not be
significant. Further-more, certain pathogens are more
susceptible to temperature elevation than others. Fever
may be especially beneficial in infections caused by
these pathogens. On the other hand, fever may actually
be detrimental to the hosts in certain circum-stances.
Sustained increases in body temperature result in a
dramatic increase (10% to 12% percent per degree
centigrade) in metabolic activity that is associated with
increases in oxygen consumption and carbon dioxide
production. Fever is also asso-ciated with a substantial
increase in heart rate (ap-proximately 10 to 15 beats per
minute/degree cen-tigrade).*iJ2 These physiologic
changes could be potentially detrimental to patients with
pre-existing pulmonary or cardiac conditions or patients
that are in extremis.
AcutePhaseChanges
In addition to the production of an elevation in body
temperature, the febrile response is associ-ated with a
cascade of physiologic changes known as acute phase
changes. These changes occur in response to a variety
of stressful situations, includ-ing infection, burns,
inflammatory conditions, and neoplasia. The role of
these changes remains to be clearly defined.
Nevertheless, evidence suggests that this response can
enhance the host’s ability to eradicate infection. These
changes include the pro-duction of acute phase
reactants, alterations in me-tabolism, and alterations in
endocrine function.23
Acute phase reactants consist of a series of pro-
teins that are synthesized during infection and in
response to other injuries to the body. Increased
synthesis of acute phase reactants occurs in the
liver within 8 to 12 hours of infection. Acute phase
proteins (APP) include ceruloplasmin, haptoglobin,
C-reactive protein (CRP), amyloid A, complement,
and fibrinogen. Concomitant with an increase in
the production of APP is a decrease in the
synthesis of certain proteins, such as albumin. The
synthesis of APP is regulated by hormones and
cytokines, some of which are endogenous
pyrogens, (eg, inter-leukin-6 [IL-61 and tumor
necrosis factor [TNF]). During the febrile response,
serum levels of some APP are increased by only
several-fold (haptoglobin and ceruloplasmin),
whereas other APP serum lev-els can be
increased by l,OOO-fold (CRP and amy-loids A).
The functions of APP are incompletely under-stood.
CRP was initially identified for its ability to bind the
polysaccharide capsule of pneumococcus and can act as
an opsonin. CRP can be easily mea-sured in most
laboratories and is often used as a marker of disease
process. Another marker of dis-ease processes, the
erythrocyte sedimentation rate,
is a result of increased plasma concentration of
APP, glycoproteins, and globulins. APP help the
body to destroy damaged tissue structures, control
infection, and aid in wound healing. APP also prob-
ably help contain pathogens and their toxins, inac-
tivate both microbial proteases, and highly reactive
oxygen metabolites. Some APP bind to divalent
cat-ions, such as zinc and iron, and lead to
decreased levels of the cations in the plasma.
During the febrile response, organs such as
mus-cle and bone undergo catabolism. The overall
pro-cess results in a negative nitrogen balance and
weight loss. Amino acids liberated from proteolysis
are channeled toward gluconeogenesis, and the
synthesis of APP and reparative proteins. In addi-
tion to these metabolic changes, the acute phase
response is often accompanied by glucose intoler-
ance and the reduction of lipolysis as a result of a
reduction in lipoprotein lipase synthesis in the liver.
Fever also increases oxygen consumption and
carbon dioxide production, along with increases in
requirements of fluids and calories.
The activation of stress responses by the host
organism is also part of the febrile response. This
is associated with an increase in corticotropin
releas-ing hormone secretion, which in turn
increases corticotropin and subsequently
glucocorticoid se-cretion. Increases in secretion of
growth hormone and aldosterone occur, along with
decreases in se-cretion of vasopressin.
 FEVER PATHOPHYSIOLOGY
The FebrileResponse
Fever results when the thermoregulatory set point is
elevated above the normal set point. The hypothalamus
sensing that the current temperature is below the new
set point, produces physiological changes designed to
elevate the body temperature. These changes involve
endocrine, metabolic, auto-nomic, and behavioral
processes that in turn pro-duce the signs and symptoms
associated with fever (Table 1). For example, the
diversion of blood from vessels supplying the skin to
more central vessels produces cool extremities, but
helps to elevate core temperature, by decreasing heat
loss. Shivering in-creases metabolic activity and
increases heat pro-duction. The affected person may feel
cold and display behavioral changes (eg, putting on
more clothing, seeking a warmer environment and curl-
ing up in a fetal position) which prevent heat loss. Once
these processes have resulted in an increase in core
temperature to approximate the elevated set
point, the thermoregulatory center acts to maintain this
temperature as it does during normothermia.
When the thermoregulatory point is reset in as-
sociation with the resolution of an infection, the
hypothalamus senses that the current temperature is
above the set point and produces physiological changes
designed to decrease the core temperature. These
changes can include an increase in perspira-tion that
results in heat loss. For example, the resolution of
pneumococcal pneumonia in the pre-antibiotic era was
typically associated with a crisis characterized by
increased perspiration and a rapid decline in fever. Other
physiological changes that decrease core temperature
include dilation of cuta-neous vessels and the sensation
of feeling hot which may produce behavioral changes
such as the re-moval of clothes.
Hyperthermia
Pediatricians may occasionally encounter a pa-
tient with an elevated body temperature that is due
to hyperthermia. Hyperthemia must be distin-
guished from fever because the pathophysiology
and management of these two entities differs
greatly. In contrast to fever, hyperthermia results
from an unregulated rise in body temperature to a
level above the hypothalamic set point. Hyper-
themia can result from an excessive production of
heat (eg, thyroid storm) or a reduced ability to
dissipate heat (eg, anhidrotic ectodermal dyspla-
sia). A combination of these two mechanisms may
also result in hyperthermia (eg, exercise in hot,
CIMPELLO, GOLDMAN, AND KHINE 87
humid environment). In patients with hyperther-
mia, body temperature can reach extreme heights
(eg, 45.6%) and can produce multiorgan dysfunc-
tion leading to death.
Overviewof ProposedPathway
The febrile response is a dynamically regulated
process, controlled by a central thermostat (ther-
moregulatory center) within the hypothalamus (Fig
1). During infection, microbial products (exogenous
pyrogens) induce the production of certain cyto-
kines (endogenous pyrogens), which through the
action of prostaglandins, turn up the thermostat. In
addition to providing the signal to raise the ther-
mostat, EPs play an essential role in regulating the
inflammatory and acute phase responses. Once
raised, the thermostat produces fever through a
variety of mechanisms, involving the following sys-
tems: autonomic, behavioral, metabolic, and endo-
crine. Concomitant with the production of EPs, the
body produces substances known as endogenous
cryogens that counteract the effect of EPs and pre-
vent extreme and potentially harmful elevations of
the core body temperature.
ExogenousPvroeens
Any substance that causes fever is termed a py-
rogen. Exogenous pyrogens come from outside the body
and can be viruses, microbes, microbial prod-ucts, or
toxins. Examples of exogenous pyrogens include the
endotoxin found in cell membrane of Gram-negative
bacteria, and the toxins from cer-tain bacteria, such as
Staphylococcus aureus and Groups A and B
streptococci. Following phagocyto-sis of exogenous
pyrogens, host cells, especially
monocyteslmacrophages, produce numerous
cyto-kines, including endogenous pyrogens (EPs).
EndogenousPvroeens
EPs are cytokines that are induced in response to a
variety of exogenous pyrogens. Production of EPs can
also be induced by endogenously produced
molecules such as antigen-antibody complexes,
certain androgenic steroid metabolites, inflamma-
tory bile acids, and complement components. EPs
are virtually undetectable in the circulation of healthy
subjects. EPs can induce fever by their action on the
hypothalamus (through prostaglan-dins) and do not
require intermediary cytokines. In addition to their
pyrogenic properties, EPs have many
88 FEVER PATHOPHYSIOLOGY CIMPELLO, GOLDMAN, AND KHINE

EXOGENOUS PYROGENS OTHER INDUCERS OF

Bacteria,virus, tingi, endotoxins ENDOGENOUS PYROGENS
Toxins, antibody-antigen complexes,
complement components, inflammatory bile acids,
lymphocyte products, certain androgenic steroids

HOST INFLAMMATORY CELL

Monocyte, macrophage, endothelial cells,
B-lymphocytes, mesangial cells, keratinocytes,
epithelialcells, astrocytes, glial cells

4
ENDOGENOUS PYROGENS
IL-l, IL-6, TNF, IFN

+
CIRCULATION

f
PREOPTIC AREA OF THE
ANTERIOR HYPOTHALAMUS

INCREASED PROSTOGLANDIN SYNTHESIS

PGE2

I”:“““:“”
Via physiological and behavioral responses

Figure I. Proposed pathway

by which exogenous pyro-
gens produce fever.

biological activities, including the regulation of the acute
phase and inflammatory responses.24 The pro-tean
effects of EPs highlights the intricate connection
between fever and the host immune response. A va-riety
of inflammatory cells, in particular circulating monocytes
and tissue macrophages, produce EPs. In the brain,
astrocytes and microglia are responsible for the
production of EPs. The regulation of EP produc-tion is
complex and contains both positive and nega-tive
feedback systems. Individual EPs can regulate their own
expression as well as the expression of other EPs. EPs
exert their effects through interactions with their own
specific receptor. Recently, a common receptor known
as gp 130 has been described to in-teract with a group
of EPs.
The first EP to be identified, IL-l, was initially isolated
from activated leukocytes in a rabbit model of sterile
peritonitis.25 More recently, two forms of interleukin-1
(IL-la and IL-l@ have been identi-
fied. Both of these cytokines show extensive biolog-ical
activities and possess considerable proinflam-matory
properties. Early investigators were unclear as to
whether the pyrogenic properties of IL-l were related to
impurities, but the availability of recom-binant IL-1 has
helped resolve this issue. When human subjects are
injected with either form of recombinant IL-l, fever and
chills occur in nearly all subjects.26 IL-1 is an extremely
potent pyrogen, producing fever in humans at a dose as
low as 1 rig/kg. The febrile response to IL-1 is dose-
related and at high doses, significant hypotension can
oc-cur.27,2s Some of the other physiological responses
seen after injection with IL-1 include increases in
cortisol, adrenocorticotropic hormone and thyroid-
stimulating hormone levels, and decreases in
serum glucose and testosterone level.28 Table 2
shows some of the immunologic properties of IL-l.
TNF is also a productof activated macrophages
 FEVER PATHOPHYSlOLOGYI
TABLE2. BiologicActivitiesof the CurrentlyRecognizedPyrogenicCytokines
and was initially identified for its direct toxic effects
on certain tumor cells and its ability to induce
cachexia. TNF shares many of the biological/proin-
flammatory properties of IL-l (Table 2) including the
ability to induce fever. Nevertheless, TNF and IL-l
do not share significant amino acid sequence
homology and bind to different receptors. The fever
pattern produced by injection of recombinant TNF
is indistinguishable from that of IL-1.29 Both in vitro
and in vivo studies indicate that TNF can induce IL-
1 production and that IL-l can induce TNF
production, leading some to suggest that these
cytokines work synergistically to produce fever.30
Interferons were initially recognized for their an-tiviral
activities31 and were the first cytokines to be used
therapeutically in humans. Fever is noted con-
sistently with the administration of recombinant
interferon (IFN) to humans. All subtypes of IFN, (a,
p, -y) have been shown to possess varying
degrees of pyrogenic activities.z2 The fever pattern
induced by IFN (eg, rate of rise and time of peak
temperature elevation) differ from that of IL-l and
TNF, but all are considered EPs.
Numerous other cytokines have been implicated
in fever production. Recently, a common receptor,
gp 130, which can bind a group of pyrogenic cyto-
kines has been discovered.33 The gp 130 receptor
triggering cytokines include IL-6, IL-2, leukemic
inhibitory factor, ciliary neurotropic factor, car-
CIMPELLO, GOLDMAN, AND KHINE 89
diotropin, and oncostatin M. Among these cyto-
kines, the greatest amount of data exists for IL-6.
IL-6 injection produces fever in rabbits but at much
higher concentration than IL-l. IL-6 expression is
greatly enhanced by TNF and IL-l. Elevated levels
of IL-6 have been found in various body fluids,
including plasma, cerebrospinal fluid, and joint fluid
of patients with arthritis, septic shock, infec-tious
diseases, kidney transplants, and burns.34335 In
contrast to IL-l and TNF, IL-6 does not appear to
possess proinflammatory properties. Nevertheless,
IL-6 appears to play a central role in inducing the
production of acute phase reactants.35,36
IL-2 has also been implicated as an EP. Admin-
istration of recombinant IL-2 causes fever in
humans,37 as well as increases in levels of
adreno-corticotropic hormone, prolactin, and
growth hor-mone.3s The half-life of IL-2 is very
short and serum levels may be very low and are
generally undetect-able by the time the fever is
present. IL-2 may induce fevers indirectly, possibly
through other cy-tokines such as IL-l and TNF.
The Hypothalamusin FeverProduction
Circulating EPs do not readily cross the blood-
brain barrier. Instead, EPs are believed to act indi-
rectly on the thermoregulatory set point by their
90 FEVER PATHOPHYSlOLOGYI CIMPELLO, GOLDMAN, AND KHINE
actions within the organum vasculosum of the lam-
ina terminalis (OVLT).39-40 This region of the hy-
pothalamus is located near the preoptic area and is
a circumventricular organ. Fenestrated capillaries
that supply blood to this area of the brain allow the
neurons of this region to be in close contact with
cytokines in the circulation. Injection of EPs into
the OVLT of cats and rabbits produced fever.41,4*
Ablation of this area reduced the ability of these
animals to produce fever after injection with endo-
toxin or EPs.43~44
Within the OVLT, arachidonic acid metabolites
especially prostaglandin E, (PGE,), have been
impli-cated for their role in producing fever (Fig 2).
PGE, levels are consistently elevated in the brains
of ani-mals injected with EPs.45 Glial cells and
neurons around the site of OVLT produce the
enzyme cyclo-oxygenase which is involved in the
production of PGE2.46 The greatest number of
PGE, receptors within the brain is found near the
OVLT.47 Additional evidence supporting the role
of PGE, in producing fever comes from the
observation that inhibition of cyclooxygenase by
the administration of agents such as aspirin and
acetominophen result in the reduction of fever.
The exact mechanism by which PGE, produc-
tion results in fever is uncertain. It is believed that
PGE, probably modifies the activity of the thermo-
sensitive neurons in the OVLT to raise the set
point. It is not clear if PGE, acts directly or through
another neurotransmitter such as cyclic adenosine
monophosphate, which is induced by PGEa.48 Once the
set point is raised, the hypothalamus is respon-sible for
coordinating the autonomic, endocrine, and behavioral
components of the febrile response. This requires
sending signals to different parts of
Membrane Phospholipids
jLipoxygenase[
\ reduction of endo-toxin-induced fever.54 Conversely,
Leukotrienes
Prostacyclins
*m--es
Figure 2. Pathway describing the production of
prostaglandins by endogenous pyrogens.
the hypothalamus and the brain stem to achieve
an integrated response. The rapid speed at which
fever occurs after injection of cytokines suggests
that it occurs by intrinsic neuronal pathways rather
than diffusion of PGE, or other mediators.49
The UpperLimit of Fever
Although mild to moderate elevations in body
temperature can be beneficial to the host, severe
elevations are likely to be detrimental. It is not
surprising that the body possesses mechanisms to
down-modulate fever and to limit the maximal tem-
perature associated with the febrile response. Sev-
eral clinical and laboratory observations support
the notion of an upper limit to the febrile response,
however the exact limit in humans has not been
precisely defined. In the preantibiotic era, it was
rare to see a patient’s temperature rise above 42”C.j’J
Today, with the advent of antimicrobial therapies and
antipyretic agents it is rare to see a patient’s temperature
persist above 41°C with most febrile illnesses. Most of
the clinician’s understand-ing of the effect of extreme
temperature elevations in humans has been
extrapolated from fatal cases of heatstroke. In patients
with heatstroke, tempera-tures can rise as high as 45°C
due to a failure of the
thermoregulatory center and heat loss mecha-
nisms. Temperature elevations of this extreme pro-
duce widespread organ dysfunction and damage
including acid-base disturbances, disseminated in-
travascular coagulation, thrombocytopenia,
hemor-rhage, and organ congestion.51
Several mechanisms of maintaining an upper limit to
the febrile response have been proposed including the
production of antipyretics, also known as endog-enous
cryogens. The existence of endogenous cryo-gens was
initially suggested by studies with pregnant ewe and their
offspring. 52 These animals were found to have blunted
febrile responses to endotoxin in as-sociation with high
levels of circulating arginine vaso-pressin (AVP).j3
Subsequent studies support the role of AVP as an
endogenous cryogen, although the mechanism of action
of this peptide remains un-known. Microinjections of AVP
into the ventral septal area of sheep’s brain results in a
conditions that cause decreased levels of AVP are
associated with increased fevers.55
Another proposed endogenous cryogen is a-MSH, a
small peptide which is found in various regions of the
brain. Injections of (-w-MSHattenuate the pyrogen-
induced febrile response in animals.56 Furthermore,
injection of rabbits with antiserum to
 FEVER PATHOPHYSIOLOGY/
a-MSH results in significantly higher and longer
temperature elevations after pyrogen injections
compared with control rabbits.57 a-MSH
production appears to be enhanced by IL-1 and IL-
2 in vitro58 suggesting the possibility of a negative
feedback system to regulate the febrile response.
In addition to enhancing the production of en-
dogenous cryogens, EPs may also down-modulate fever
by inhibiting the production of pyrogenic cy-tokines at
high temperatures and eliminating pyro-genie cytokines
via a negative feedback system.59,60 For example,
induction of IL-1 production by the
endotoxin lipopolysaccharide is also associated
with the production of a soluble receptor antago-
nist. This is known as IL-1 receptor antagonist,
which inhibits the action of IL-l.60 TNF, another
EP, may also act as an endogenous cryogen under
certain circumstances. In rats, pretreatment with
anti-TNF antibodies as compared with controls re-
sulted in significantly higher fevers with lipopoly-
saccharide challenge.6l
Numerous other neurochemicals are believed to have
a role in limiting the febrile response. Cortico-tropin-
releasing hormone and glucocorticoids limit fever by
their inhibitory effects on both prostaglandin synthesis
and on EP production.62,63 Thyrotropin-re-leasing
hormone, gastric inhibitory peptide, neu-ropeptide Y and
bombesin are other neuropeptides shown to have an
inhibitory effect on febrile response under certain
conditions5r
In addition to these mechanisms, some investi-
gators have proposed that the thermoregulatory
neurons in the hypothalamus possess special prop-
erties that limit the febrile response.51 Above 42”C,
the thermosensitive neurons may be incapable of
providing additional neural signals to regulate the
body temperature, thus limiting the response.
Summary
In summary, the production of fever involves a
cascade of events that can be initiated by a variety of
insults. The febrile response is a dynamic process which
is part of a larger host response designed to assist the
host in limiting infections. The febrile response involves
the production of a variety of endogenous pyrogens
which, through actions on
hypothalamus, are primarily responsible for the
production of fever. This process is actively regu-
lated and is limited by intrinsic processes including
the production of endogenous cryogens to avoid
detrimental effects associated with extreme tem-
perature elevation.
CIMPELLO, GOLDMAN, AND KHINE 91
References
1. Vaughn LK, Bernheim HA, Kluger MJ: Fever in the
lizard LXpsosaurus dorsalis. Nature 252:473-474,1974.
2. Lorin MI: Fever: Pathogenesis and treatment, in
Feigin RD, Cherry JD (eds): Textbook of Pediatric Infec-
tious Diseases. (3rd ed, ~011) Philadelphia, PA, WB
Saun-ders, pp 130-136, 1992.
3. Mackowiak PA, Wasserman SS, Levine MM: A
crit-ical appraisal of 986”F, the upper limit of the normal
body temperature,and other legacies of Carl Reinhold
August Wunderlich.JAMA. 268:1578-1580,1992.
4. Yost RM: Sydenham’s philosophy of science.
Osiris. 9:84-104, 19.50.
5. Austin SC, Stolley PD, Lasky T: The history of
malariotherapyof neurosyphilis:Modern parallels. JAMA.
268516-519,1992.
6. Kluger MJ, Ringler DH, Anver MR: Fever and sur-
vival. Science 166:166-168,1980.
7. Covert JB, Reynold WW: Survival value of fever
in fish. Nature Lond 267:43-45, 1977.
8. Kluger MJ: The evolution and adaptive value of
fever. American scientist 66:38-43, 1978.
9. Carmichael LE, Barnes FD, Percy DH: Tempera-
ture as a factor in resistance of young puppies. J Infect
Dis 120:669-678,1969.
10. Kluger MJ, Kozak W, Conn CA, et al: Role of fever
in disease. Ann NY Acad Sci 856:224-233,1998.
11. Husseini RH, Sweet C, Collie MH, Smith H: Ele-
vation of nasal viral levels by suppression of fever in
ferrets infected with influenza viruses of differing viru-
lence. J Infect Dis 145:520-524,1982.
12. Vaughn LK, Veale WL, Cooper KE:
Antipyresis:Its
effect on mortality rate of bacterially infected rabbits.
Brain Res Bull 5:69-73, 1980.
13. Roberts NJ Jr: Impact of temperatureelevation
on
immunologicdefenses. Rev Infect Dis 13:462-472,1991
14. Nahas GG, Tannieres ML, Lennon JF: Direct mea-
surement of leukocyte motility: Effects of pH and tem-
perature. Proc Sot Exp Biol Med 138:350-352,1981.
15. van Oss CJ, Absolom DR, et al: Effect of temper-
ature on chemotaxis,phagocyticengulfment,digestion
and 0, consumptionof human polymorphonuclearleu-
kocytes. J ReticulendothelSot 27:561-565,1980.
16. Downing JF, Martinez-ValdezH, Elizondo RS, et
al: Hyperthermiain humans enhances interferon-asyn-
thesis and alters the peripheral lymphocyte
population. J Interferon Res 8:143-150, 1988.
17. Hirai N, Hill NO, Osther K: Temperature influ-
ences on different human alpha interferon activities. J
In-terferon Res 4:507-516, 1984.
18. Jampel HD, Duff GW, Gershon RK, et al: Fever and
immunoregulation. III. Hyperthermia augments the pri-
mary in vitro humoral immune response. J Exp Med
157:1229-1238, 1983.
19. Austin TW, Truant G: Hyperthermia,antipyretics
and function of polymorphonuclearleukocytes. Can Med
Assoc J 118:493-495,1978.
20. Kluger MJ, RothenbergBA: Fever and reduced