BASIC REVIEW

Fever: Pathogenesis, Pathophysiology, and Purpose

H. A. BERNHEIM, Ph.D.; L H. BLOCK, M.D.; and E. ATKINS, M.D.; New Haven, Connecticut

Fever appears to have evolved in vertebrate hosts as an the body appears to have a thermostatic mechanism in
adaptive mechanism for controlling infection. This the anterior hypothalamus that receives thermal informa-
phenomenon is produced by certain exogenous (largely tion from both peripheral and central receptors. When
microbial) stimuli that activate bone-marrow-derived
phagocytes to release a fever-inducing hormone ambient or internal temperature increases or decreases,
(endogenous pyrogen). Endogenous pyrogen, in turn, these receptors relay the information to this thermostat
circulates to the thermoregulatory center of the brain which, in turn, makes appropriate adjustments along ef-
(preoptic area of the anterior hypothalamus) where it ferent tracts that modify heat production or loss so that
causes an elevation in the "set-point" for normal body
central temperature is maintained at or near normal
temperature. Warm blooded animals produce fever by
increasing heat production (through shivering) or levels.
reducing heat loss (by peripheral vasoconstriction), At times, however, body temperature may change sig-
whereas cold blooded animals do so only by behavioral nificantly despite the homeostatic mechanisms that at-
mechanisms (seeking a warmer environment). This paper tempt to return it to 37 °C. For instance, exposure to
discusses current concepts that involve the mechanism of
endogenous pyrogen production, the role of central extremely low temperatures with inadequate shelter or
transmittors, and the probable function of fever in clothing eventually produces a fall in body temperature
combating disease. (hypothermia) despite vasoconstriction and violent shiv-
ering. On the other hand, violent exercising or exposure
FEVER remains a fascinating problem for both clinicians to high ambient temperatures and humidity increases
and basic scientists. Although there have been several body temperature (hyperthermia) despite vasodilation
reviews on fever in the past 10 years, recent research in and profuse sweating. As air becomes more humid it is
this area provides an opportunity to survey the current increasingly difficult for sweat to evaporate from the skin.
knowledge of the pathogenesis and the pathophysiology As a result, the heat normally lost when water evaporates
of this universal response of warm-blooded animals. This remains in the body. During these extremes of induced
review deals with both cellular and neurophysiologic hypothermia and hyperthermia, the "set-point" in the
aspects of fever and discusses the recent discovery that anterior hypothalamus is not altered; instead there is a
fever is developed adaptively in experimentally infected failure of regulating mechanisms to compensate for the
poikilotherms and plays a dramatic beneficial role in mo- loss or gain of heat.
bilizing host defenses against infection. On the other hand, " t r u e " fever is a disorder of therm-
For centuries man has recognized fever as a sign of oregulation in which there appears to be an upward dis-
inflammation, but only within the last few decades have placement of set-point so that the body actively seeks to
scientists begun to understand its pathogenesis and func- raise its temperature. This is accomplished physiological-
tion. In essence, fever represents a disturbance in normal ly by vasoconstriction and shivering and behaviorally by,
thermoregulation. Body temperature in health is main- for example, curling up in bed under layers of blankets.
tained over a narrow range in homeotherms (warm- In contrast, with the hyperthermia that follows exercise,
blooded species) by both behavioral and physiologic the body attempts to bring its temperature back to nor-
mechanisms. The behavioral mechanisms are familiar, as mal by vasodilation and sweating or adaptively by seek-
when we turn up the thermostat or put on more clothing ing a cooler environment. In clinical fevers the rise in
when the environmental temperature feels too cold, or body temperature is regulated by negative feedback
turn on the air conditioning or take off clothing when the mechanisms in such a fashion that temperatures rarely
temperature becomes warm. Physiologic mechanisms in- exceed 41 °C (1, 2), whereas in some hyperthermic states
volve increasing heat loss (vasodilation, sweating) when it such as heat stroke or malignant hyperthermia after ad-
is hot or conserving and producing more heat (vasocon- ministration of anesthesia, the central controlling mecha-
striction and shivering) when it is cold. In humans, this nism appears to be lost and temperatures may reach
balance is precisely maintained so that body temperature lethal levels. Body temperatures higher than 41 °C are
is usually 37 ± 1 °C, with values usually lowest in the occasionally seen during fevers but this is usually a result
early morning and highest in the late afternoon. of superimposed activity such as convulsions.
The mechanisms involved in temperature regulation Until very recently, fever was thought to occur only in
are discussed below, but we may simply note here that mammalian species, but crustaceans, fish, amphibians,
reptiles, and birds are also capable of developing fevers in
response to infectious agents (3-8). The ability to develop
• F r o m the Department of Internal Medicine, Yale University School of Medi-
cine; New Haven, Connecticut. fever thus arose early in evolution and was maintained

Annals of Internal Medicine. 1979;91:261-270. © 1 9 7 9 American College of Physicians 261

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 teria and viruses produce similar biphasic febrile respons-
es but with longer latency and duration than those from
lipopolysaccharide (10, 12). Certain experimental infec-
tions caused by microbial agents may also be accompa-
nied by fever and the presence of endogenous pyrogen at
the local site and in the circulation (32-34).
Fevers due to hypersensitivity can be produced in spe-
cifically immunized rabbits by intravenous injection of
antigen (23, 35). In some of these instances, serum anti-
bodies appear to be responsible for fever, since passive
transfer of serum from a sensitized animal enables a non-
sensitized recipient to develop a fever when challenged
intravenously with the same antigen (36). In addition,
injection of antigen-antibody complexes prepared in vitro
will produce fever in unsensitized animals (25). In some
situations (antigen excess), complement appears to play a
role in the pyrogenicity of these injected complexes (37,
38). Atkins and co-workers (27, 39-41) have shown that
lymphocytes from rabbits or guinea pigs with delayed
hypersensitivity to various vertebrate proteins produce
nonpyrogenic soluble factor(s) ("lymphokines") (42)
which, in turn, stimulate mononuclear and perhaps other
phagocytic cells to produce and release endogenous pyro-
gen.
Figure 1 . Postulated pathway for the pathogenesis of fever (see
text for details). Adapted from Rosendorff ( 1 1 5 ) . Ag = antigen; Studies are in progress with endogenous substances at
Ag-Ab = antigen-antibody complexes; Compl = complement; sites of inflammation and necrosis to determine whether
cAMP = cyclic adenosine-3',5' monophosphate; DHS = delayed hy-
persensitivity; EP = endogenous pyrogen; 5HT = serotonin; they are activators of endogenous pyrogen production
LK = lymphokine; NE = norepinephrine; PO/AH = preoptic area of and hence may be responsible for fever in those diseases
anterior hypothalamus; RES = reticuloendothelial s y s t e m , ^ * inhib- in which no infectious agents can be isolated. Such acti-
itors; - activators.
vators may account for the presence of endogenous pyro-
gen in exudate fluids from joints of patients with nonmi-
throughout the vertebrate classes. This suggests an adap-
crobial arthritis (43).
tive or defensive role for this physiologic phenomenon.

Fever-Inducing Agents Endogenous Pyrogen

There are numerous substances, collectively known as In 1943, Menkin isolated a substance ("pyrexin") from
"pyrogens," that have been found to cause fever experi- inflammatory exudates that caused fevers when injected
mentally. Among these are microbial agents such as vi- intravenously into rabbits (44). Others demonstrated that
ruses (9-11), gram-positive bacteria (12) and some of the pyrogenic effects of pyrexin could be accounted for by
their exotoxins (13-16), gram-negative bacterial endotox- contaminating endotoxin (45). In 1948 however, Beeson
ins (17-19), and pathogenic fungi (20, 21), as well as cer- (46) extracted from rabbit polymorphonuclear leukocytes
tain steroids (22), antigen-antibody complexes (23-26), a fever-producing substance that was later shown to be
antigens producing states of delayed hypersensitivity distinct from endotoxin in that it produced fevers of short
(27), and a number of nonorganic substances (28). The latency and duration, was heat labile, and produced no
characteristics of the fevers induced by these different pyrogenic tolerance after repeated injection (45). Since
agents vary with respect to time of onset (latency) and that time, this substance has been shown to be released
duration, but the mechanisms involved in the production from the leukocytes of many species, both mammalian
of fever appear to be quite similar in most instances. Each and nonmammalian, and to have some cross-species and
so-called "exogenous" pyrogen evokes an apparently even cross-class reactivity (47-49).
common mediator, endogenous pyrogen, a protein pro- In the last few years, human and rabbit endogenous
duced by host leukocytes (29) (Figure 1). The pyrogen pyrogens have been highly purified. Both are proteins
used in most early models of experimental fever was en- with a molecular weight range of 13 000 to 15 000 dal-
dotoxin, a complex lipopolysaccharide found in cell walls tons (50-53). As little as 35 ng of rabbit and human en-
of all gram-negative bacteria. The active moiety of endo- dogenous pyrogen will produce fevers of 0.6 °C or more
toxin consists of lipid A, a beta 1-6 linked diglucosamine when injected intravenously into rabbits (50-54). Rabbit
backbone containing both ester- and amide-linked long- endogenous pyrogen is inactivated at alkaline p H and has
chain fatty acids, as well as 2-keto-3-deoxyoctonate and a requirement for free S-H groups, since its biological
pyrophosphate groups (30). In doses of several nano- activities are destroyed or restored, respectively, by S-H
grams or less intravenously, endotoxin produces brief oxidizing or reducing agents (55). Rabbit and human en-
fever in rabbits (31). In higher doses, endotoxin causes dogenous pyrogen seem to be equally effective in produc-
biphasic fevers lasting several hours. Gram-positive bac- ing fevers in rabbits when injected intravenously (56).
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 However, these proteins have different antigenic moieties, pyrogen produced by these cells appears to have the same
since a specific antibody raised in rabbits against human properties, but the steps involved in its production differ
endogenous pyrogen blocks its pyrogenic activity but not in the two cell populations. Because exudate leukocytes
that of rabbit endogenous pyrogen (57). Although inflam- are more numerous and easily obtained than blood leuko-
matory exudates are a potent source of human endoge- cytes, most early studies involving mechanisms of release
nous pyrogen (58), it has been difficult to detect endoge- or purification of endogenous pyrogen done by Wood and
nous pyrogen in plasma from febrile patients by bioassay colleagues were conducted with these cells (29).
(59). This may be due to the difficulty of obtaining Exudate polymorphonuclear leukocytes are believed to
enough blood for a single pyrogenic dose (60). With the be activated in vivo by a heat-labile macromolecule in the
recent development of a radioimmunoassay for human exudate fluid (74). This substance has only been partially
endogenous pyrogen by Dinarello and co-workers (61), it characterized (75), and possibly endotoxin escaping from
seems likely that detectable levels of circulating endoge- the intestinal tract may contribute to the accumulation
nous pyrogen will be found in the plasma of febrile pa- and activation of polymorphonuclear leukocytes in peri-
tients. toneal exudate fluid, the source of cells in most experi-
Only bone marrow-derived phagocytes are capable of mental studies (74). When the peritoneal exudate cells
producing and secreting endogenous pyrogen, since are placed in physiologic saline at 37 °C, they release
"non-professional" phagocytes, such as HeLa cells and most of the endogenous pyrogen over a 1-h period (76).
fibroblasts do not produce endogenous pyrogen after Neither Na+ nor CI- appears to be essential in this proc-
stimulation (62). Endogenous-pyrogen-producing cells ess since endogenous pyrogen release will take place in
include blood and exudate granulocytes (45, 63) and certain other media from which Na+ and CI- are omitted
monocytes (64, 65) as well as macrophages from the lung (77). Incubation, however, with physiologic concentra-
(66) and liver (67, 68). Human eosinophils release en- tions of K+ or Ca++ or cations other than Na+ inhibits
dogenous pyrogen but in significantly less amounts than the release of endogenous pyrogen as well as that of aldo-
those released from polymorphonuclear leukocytes (69). lase, a cytoplasmic enzyme (77, 78). This suppression can
In 1974, Bodel (70) showed that tissues from several be reversed by ouabain, an inhibitor of the adenosine tri-
human tumors produce endogenous pyrogen "spontane- phosphotase involved in the Na+-K+ pump (77). Taken
ously" in vitro, without additional stimuli, unlike normal together, these data suggest that release of endogenous
phagocytic cells that require a stimulus to do so. These pyrogen is associated with changes in the intracellular
initial studies did not define the cell type(s) responsible ionic composition normally maintained by the Na+-K+
for this activity. In subsequent studies, however, mouse pump.
histiocytic and myelomonocytic tumor cells (71) as well Preformed endogenous pyrogen cannot be maintained
as human histiocytic lymphoma and Hodgkin's disease in any significant quantities from distrupted exudate leu-
cell lines (unpublished observations) have been shown to kocytes (76). This observation, along with the fact that
produce endogenous pyrogen spontaneously. no protein synthesis is needed for the release of endoge-
Endogenous pyrogen released from the human tumor nous pyrogen from these cells (76, 79), suggests that en-
cell lines appears to be antigenically similar to endoge- dogenous pyrogen exists in an inactive form in the cell
nous pyrogen from normal human leukocytes since the and is enzymatically converted to endogenous pyrogen
activity of both is blocked by antibody to normal leuko- shortly before it crosses the cell membrane. This convert-
cytes. Endogenous pyrogen derived from both sources is ing enzyme may have an active sulfhydryl moiety, since
similarly susceptible to heat and pronase inactivation. incubation of exudate granulocytes with sulfhydryl-
However, both human and mouse tumor cells appear to reactive enzyme inhibitors (in concentrations that do not
produce several pyrogenic substances with different mo- inactivate endogenous pyrogen itself) prevents the release
lecular weights, which may represent dimer- or trimer- of endogenous pyrogen (55). It is not known at present
ization of tumor pyrogen. Similarly, human monocytes where endogenous pyrogen is stored in these cells. How-
release two molecular types of endogenous pyrogen (52), ever, degranulation of leukocytes does not appear to be
one of which occurs in much smaller amounts and is essential for endogenous pyrogen release, since colchi-
apparently a trimer of the other (54). Thus, fevers ob- cine, which reduces degranulation, does not suppress re-
served in patients with various malignancies—acute leu- lease of endogenous pyrogen from rabbit leukocytes (79)
kemias, histiocytic lymphomas, and Hodgkin's disease— and, in fact, stimulates human monocytes to synthesize
may, in some instances, be due to endogenous pyrogen and release endogenous pyrogen (80). In addition, no en-
production by tumor cells themselves. These findings dogenous pyrogen is detectable in granule portions of ex-
may also provide a way of determining whether a tumor udate granulocytes (79). On the other hand, endogenous
cell is of lymphocytic or histiocytic origin, since lympho- pyrogen is released along with cytoplasmic enzymes (al-
cytes seem to be incapable of producing endogenous py- dolase) but not with granule enzymes such as acid phos-
rogen (39, 72, 73). phatase (79). These results indicate that endogenous py-
rogen is stored in the cytoplasm rather than in granules.
A C T I V A T I O N , PRODUCTION, A N D RELEASE To date, however, experiments attempting to extract en-
The mechanisms involved in release of endogenous py- dogenous pyrogen in vitro from isolated cell fractions
rogen in vitro have been most extensively studied with have been unsuccessful (79). The release of endogenous
leukocytes from blood and sterile exudates. Endogenous pyrogen from exudate cells may be an active process

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 because incubation of these cells with sodium fluoride, or pyrogen (83), an activity that appears to stop only with
other metabolic inhibitors that block production of ade- death or disruption of the cell.
nosine triphosphate (ATP), prevents its release (76). The release of pyrogen from blood monocytes has also
Unlike exudate cells, blood leukocytes do not release been studied. These cells release more endogenous pyro-
endogenous pyrogen spontaneously. The production of gen than do granulocytes and for longer periods of time
endogenous pyrogen by blood leukocytes involves three (24 to 72 h) (65). There is also an active stage of protein
steps: activation, production, and release. synthesis that occurs before and during endogenous pyro-
Activation: The initial process by which leukocytes gen release into the incubating medium (65), in contrast
are activated to produce endogenous pyrogen is un- to polymorphonuclear leukocytes, which only have an
known. Activators such as endotoxin or certain phagocy- active stage of protein synthesis before endogenous pyro-
tizable particles may combine with specific receptor sites gen release.
on the cell membrane to initiate protein synthesis. Cer- The circulating blood leukocytes used in the studies
tain particles may have to be engulfed to activate cells described above as a source of endogenous pyrogen are
because, when phagocytosis is blocked, blood leukocytes presumably not the cells activated in vivo, because they
incubated with heat-killed pneumococci will not release do not spontaneously release endogenous pyrogen in vi-
endogenous pyrogen (81). Phagocytosis per se is not al- tro as exudate cells do when removed during either clini-
ways a sufficient stimulus, however, because phagocytosis cal or experimentally induced fevers and placed in saline
of latex particles by granulocytes does not lead to endoge- (86). Instead, monocytes and granulocytes at inflamma-
nous pyrogen production (81). On the other hand, ma- tory sites or marginated in vasculature, as well as fixed
crophages will release endogenous pyrogen after inges- tissue histiocytes, seem more likely to be the main source
tion of latex particles (62). A potential second "messen- of circulating endogenous pyrogen during both experi-
ger," cyclic adenosine-3'5' monophosphate (cAMP), does mental and clinical fevers. In addition, intravenously
not seem to play a part in the activation process since injected viruses or bacteria probably cause fever by stim-
agents that increase intracellular levels of cAMP (phos- ulating Kupffer cells, which rapidly phagocytize these
phodiesterase inhibitors) do not modify the amount of particles to release endogenous pyrogen (68).
endogenous pyrogen produced when monocytes are acti-
vated by endotoxin (82). The possible role of cyclic guan- Chemical Mediators in the Central Nervous System of the
idine monophosphate has not yet been investigated. Febrile Response
Production: During the production of endogenous Endogenous pyrogen appears to cause fever by altering
pyrogen (or its inactive precursor) by blood cells, there is the activity of temperature-sensitive neurons in the
believed to be increased protein synthesis. When protein preoptic area of the anterior hypothalamus that presum-
inhibitors such as puromycin and dactinomycin are add- ably determine the "set point" for normal body tempera-
ed early during incubation, little or no pyrogen is pro- ture (see below). Endogenous pyrogen, however, may not
duced. If these agents are added 2-4 hours after incuba- act directly on these neurons but may work through oth-
tion, however, there is no inhibition of endogenous pyro- er intermediates such as monoamines, Na+ or Ca++ ions,
gen (83, 84). Thus synthesis of endogenous pyrogen (or a prostaglandins, or cyclic nucleotides.
critical protein precursor) occurs within 2 h after addi-
tion of the activator. In confirmation of this hypothesis, MONOAMINES
leukocytes incubated with radioactively labeled amino The changes in body temperature induced by injecting
acids incorporate these agents into newly synthesized serotonin and norepinephrine into the lateral ventricles
endogenous pyrogen (85). The synthesis of endogenous or anterior hypothalamus are variable, depending on the
pyrogen in blood leukocytes is an energy-requiring mech- animal species. In some species, serotonin causes a de-
anism since NaF (an inhibitor of glycolysis) prevents pro- crease in body temperature while norepinephrine causes
duction of endogenous pyrogen if added to cells early an increase (87, 88); in others, the opposite results occur
after stimulation (83, 84). Presumably as in the case of (89, 90). The amount of monoamines used in these exper-
exudate cells, the synthesis and storage of endogenous iments, however, is large when compared with that found
pyrogen occur in the cytoplasm rather than in the gran- normally in the anterior hypothalamus, and these experi-
ules of blood cells. ments may not indicate what is occurring under normal
Release: The pyrogen formed by blood leukocytes is conditions. More recent experiments have involved alter-
released over a 3- to 16-h period (74, 83, 84). In contrast ing the endogenous stores of monoamines with various
with its effect on exudate cells, potassium does not inhibit pharmacologic agents such as 6-hydroxydopamine,
the release of endogenous pyrogen from activated blood which destroys norepinephrine nerve terminals, and p-
leukocytes (81). During this phase, endogenous pyrogen chlorophenylalanine, which depletes brain stores of sero-
may be enzymatically converted from an inactive to an tonin. Using these drugs, Woolf and colleagues (91, 92)
active form (83). At present, however, no converting en- showed that norepinephrine and serotonin may be impor-
zyme has been isolated. The release of endogenous pyro- tant in normal temperature regulation. Pretreatment with
gen from blood leukocytes, as opposed to exudate cells, is p-chlorophenylalanine, however, did not alter the ability
an energy-independent process, as the addition at this of rabbits to develop a fever in response to pyrogens. On
phase of agents that block the normal pathways of cell the other hand, 6-hydroxydopamine and the alpha block-
respiration do not interfere with secretion of endogenous er phenoxybenzamine attenuated the febrile response to

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 various pyrogens. Propranolol, a beta blocker, was with- nists, SC 19220 and HR 546, prevented fever after an
out effect (93). The results indicate that pyrogens may injection of PGE, but not after an injection of endoge-
activate fever-producing pathways via alpha-adrenergic nous pyrogen (108). Injection of arachidonic acid into the
(but not serotonergic) receptors in the anterior hypothal- cerebral ventricles, however, will produce a fever even
amus. Reserpine, however, which depletes both serotonin after an infusion of these prostaglandin antagonists, sug-
and norepinephrine levels, did not alter the febrile re- gesting that some metabolite of arachidonic acid other
sponse of rabbits to endogenous pyrogen (91, 94). In ad- than PGE, may be involved as a mediator in the produc-
dition, Giarman and co-workers (95) have shown that tion of fever (109).
hypothalamic levels of serotonin and norepinephrine
were not significantly changed after intravenous injection CYCLIC A D E N O S I N E - 3 ' , 5' M O N O P H O S P H A T E
of endogenous pyrogen. However, rabbits pretreated with An intracerebral injection of dibutyryl cAMP in rab-
various agents that selectively decrease intracerebral lev- bits and cats (110, 111) results in a rapid rise in body
els of either norepinephrine or serotonin had significantly temperature that is unaffected by an injection of sodium
modified fevers (reduced or augmented, respectively) in salicylate. In addition, after injection of endotoxin, myxo-
response to endogenous pyrogen. In view of these results, viruses, endogenous pyrogen, or PGE,, there is a signifi-
it is uncertain whether monoamines play an essential role cant increase in levels of cAMP in the cerebral spinal
in the febrile response. fluid (112, 113). Theophylline, which inhibits phosphodi-
esterase activity and hence the breakdown of cAMP,
SODIUM A N D CALCIUM potentiates PGE,- and endotoxin-induced fevers, while
An infusion of sodium into the cerebral ventricles pro- nicotinic acid, which potentiates the action of phosphodi-
duces a high fever in unanesthesized cats (96). Alterna- esterase, causes a decrease in the febrile response to PGE,
tively, an infusion of calcium ions leads to a decrease in (114).
body temperature. Myers and Veale (97) concluded that The precise role of these various mediators in the fe-
the body's set-point is controlled by a balance between brile response has not been ascertained. Rosendorff (115)
these two ions in the hypothalamus. Later, by using ra- has developed an interesting model for the pathogenesis
dioactive isotopes of sodium and calcium, Myers and Ty- of fever that postulates a sequential involvement of most
tell (98) showed that there was an increase in the N a + / of the intermediate agents discussed above. (Figure 1) In
Ca++ ratio in the brain during fever. It is not known at essence, his model states that endogenous pyrogen circu-
this time, however, how these cations bring about altera- lates to the hypothalamus, where it induces the produc-
tions in body temperature and what precise role they play tion of a metabolite of arachidonic acid. This substance,
in the normal induction of fever. in turn, increases the synthesis of norepinephrine, an al-
pha adrenergic agonist that increases the production of
PROSTAGLANDINS cAMP. This cyclonucleotide then directly causes altera-
Injection of prostaglandin E, (PGE,) into the anterior tions in the activity of temperature-sensitive neurons that
hypothalamus of several species of animals produces a bring about the increase in heat conservation or produc-
rapid rise in body temperature (99-102). In addition an tion, or both. Because of the conflicting evidence summa-
infusion of PGE, into the lateral ventricles of unanesthe- rized above, however, there remains the possibility that
tized cats causes a fever, which ceases as soon as the endogenous pyrogen acts directly or via some other as yet
infusion is stopped (99). When fever is induced by an unidentified intermediate which, in turn, alters the set-
injection of endotoxin, there is a rise of PGE, in the cere- point of temperature-regulating neurons to produce
bral spinal fluid of cats (103). Antipyretics such as sodi- fever.
um salicylate, which prevent the synthesis of PGE, from
arachidonic acid (104), can attenuate fevers induced by Neuronal Mechanisms During Fever
endotoxin with a concomitant decrease in cerebral spinal Although the spinal cord is capable of initiating ther-
fluid-PGE, levels (105). moregulatory responses (116, 117), the preoptic area of
Recent evidence, however, raises some questions about the hypothalamus is primarily responsible for integrating
the postulated role of prostaglandins as intermediates in thermal stimuli and initiating homeostatic thermal mech-
the development of endogenous pyrogen-induced fever. anisms when warm or cold stimuli are applied locally
Local application of PGE, and endogenous pyrogen did (118-120). Moreover, a great deal of evidence indicates
not lead to an increase in body temperature in animals that an area in the hypothalamus is similarly responsible
with lesions of the anterior hypothalamus; however, infu- for the development of fever. Injection of pyrogens into
sion of endogenous pyrogen into the lateral ventricles of the anterior hypothalamus and brain stem (121) but not
such animals resulted in a febrile response, whereas PGE, other areas of the brain produces a rapid increase in body
was ineffective (106). This finding suggests that endoge- temperature (122-124). In addition, sectioning the brain
nous pyrogen can stimulate other neuronal sites to pro- between the midbrain and the pons eliminates an ani-
duce fever without release of PGE,. Later, Cranston and mal's febrile response to an intravenous dose of endotox-
co-workers (107) showed that sodium salicylate given af- in (125).
ter injection of endotoxin led to a decrease in fever height The anterior hypothalamus, along with the skin and
without corresponding decrease in cerebral spinal fluid spinal cord (126), contains two populations of thermally
levels of PGE,. In addition, two prostaglandin antago- sensitive neurons that respond to either warm or cold
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 stimuli and presumably initiate the appropriate ther- nal" between the febrile set-point and the temperature of
moregulatory responses to local changes in temperature. the anterior hypothalamus (138). The way in which this
Units studies of warm receptors that are more numerous set-point is regulated, and indeed the whole concept of a
than cold receptors in the anterior hypothalamus (127) set-point, both in health as well as in fever, is uncertain,
have shown that as local temperatures increase, the re- although several theoretical models have been proposed
ceptors increase their spontaneous discharge with a cor- (126, 137, 139-143). Alternatively, the temperature of the
responding Q10 of 5-15. (Q 10 is denned as the increase in body in health or in fever may simply be the resultant of
physiologic activity for every 10 °C rise in temperature. all those stimuli (biochemical, neurologic, or physical)
This relation is expressed by the equation that tend to increase or decrease body temperature by
Q,o = K, 10 local effects on temperature-sensitive neurons in the ante-
K2 T, - T 2 , rior hypothalamus (144). That body temperature is, how-
where Kj and K2 are physiologic activities [such as meta- ever, regulated at a higher level during fever has been
bolic rate] at temperatures of T{ and T2, respectively. clearly shown in a study of febrile patients during exer-
Thus, if a physiologic activity increases 1.5 times over a cise. Temperatures rose above the febrile level with exer-
5 °C range, the Q10 is 2.25.) As local temperatures de- cise but fell promptly afterwards to the pre-existing fe-
crease, cold receptors increase their rate of discharge brile level, not to normal, as with healthy persons (145,
with a resultant Q10 of less than one (127-129). Neurons 146).
with a Q10 between one and two are thermally insensitive. In the initial stages of fever in a thermally neutral envi-
Both warm- and cold-sensitive neurons consist of two ronment (20 °C), the anterior hypothalamus activates
distinct types, one of which has a continuous increase in physiologic responses to cold, such as shivering and pe-
unit activity and one a discontinuous response to changes ripheral vasoconstriction, so that the body temperature
in hypothalamic temperature (129). The former, located rises. When fever is constant, heat conservation and loss
mainly in the preoptic and septal areas, are presumably are again balanced as in health, but at a somewhat higher
primary detectors, while the latter, distributed through- level due to the elevation of basal metabolism that occurs
out the hypothalamus, are interneurons. The relative role with increased body temperature (7% for each degree
of each of these types of neurons in thermal integration is Fahrenheit) (147). During defervescence, the physiologic
not known. responses to heat—vasodilation and increase of evapora-
Some neurons in the anterior hypothalamus respond tive water loss—are activated and the body temperature
only to local temperature changes; others respond only to returns to normal. The temperature rise evoked by a py-
temperature changes evoked elsewhere in the midbrain, rogen remains the same regardless of the environmental
spinal cord, or skin, or some combination of these (129- temperature. However, the means by which this elevation
133). Although the variation in these neuronal types im- is achieved varies with the ambient temperature, an in-
plies an integrative function for the anterior hypothala- creased metabolic rate being the major mechanism in
mus, the precise afferent and efferent pathways remain to cold, vasoconstriction and a decrease in evaporative wa-
be defined. ter loss in the heat (148). In poikilotherms, a similar ele-
Unit studies of the activity of thermally sensitive neu- vation in body temperature is achieved by behavioral
rons after systemic injection of endotoxin or endogenous changes that make an animal seek a higher environmen-
pyrogen show that warm-sensitive neurons decrease their tal temperature (3-7) (see below). Behavioral changes
activity (heat loss mechanisms are depressed) while cold- during onset and subsidence of fever also occur in ho-
sensitive neurons increase theirs. Thermally insensitive meotherms including man, as in the familiar example
neurons are unaffected. These changes are associated where patients "feel cold" and bundle up during the chill
with an increase in heat-conserving mechanisms and, as a phase of fever (thus conserving heat) and, conversely,
result, fever (134, 135). Additional studies have shown "feel hot" and fling off bed clothes during defervescence.
that an infusion of an antipyretic, such as sodium salicy- Interestingly, in this regard, newborn rabbits, though un-
late, reverses the alteration in unit activity brought about able to develop a fever by physiologic means, raise their
by endotoxin or endogenous pyrogen (135, 136), thus body temperature behaviorly after an injection of endo-
confirming the correlation between the activity of these toxin, as do poikilotherms (149).
specialized neurons and the physiologic changes associat- Experimental findings in lambs and guinea pigs con-
ed with thermoregulation and fever. firm the clinical observation that newborns do not nor-
During a fever there appears to be an increase in the mally develop fever with infections or when injected with
thermostatic "set-point" so that the anterior hypothala- either endotoxin or endogenous pyrogen. Evidence sug-
mus "senses" a lower-than-normal body temperature and gests that this failure may be due in some instances to
initiates heat-conserving mechanisms until the internal lack of sensitization (to exogenous pyrogens) (150) or im-
temperature reaches the new level, much as the increased maturity of thermoregulatory responses, or both (151). A
setting of a thermostat activates the furnace until the de- possibility that should be investigated is that leukocytes
sired temperature is achieved (137). If, however, the hy- of newborns have a decreased ability to generate endo-
pothalamus is heated during the latent period after an genous pyrogen.
injection of pyrogen, the animal fails to develop a fever,
presumably because the heat supplied locally, as in other Effects of Fever on Host-Defense Systems
negative feedback systems, has decreased the "error-sig- The value of fever in host defense has never been satis-
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 factorily established in mammals. Some heat-sensitive cytes is increased, at least in vitro, by endogenous pyro-
microorganisms that produce disease, such as those caus- gen (165). In addition, the production of siderophores,
ing syphilis and gonorrhea, can be killed in vivo by arti- bacterial iron-binding proteins, is suppressed by higher
fically induced fever, but natural infections with these temperatures such as occur in fever, so that a microbe's
organisms almost never produce high fevers (152). In ability to sequester sufficient quantities of iron is de-
rabbits, rats, and mice (153-155) there is a decrease in the creased. The survival value of fever-induced hypoferre-
median lethal dose of endotoxin when these animals are mia has been recently shown by Grieger and Kluger
made hyperthermic by physical or pharmacologic means. (166). Infected febrile lizards became hypoferremic and
Data from these experiments do not show whether natu- had low mortality, but when they were injected with
rally acquired fevers benefit the host, particularly during exogenous sources of iron their mortality rate increased
infectious states. Although fever in experimental infec- significantly.
tions can be suppressed by antipyretic drugs or by low
ambient temperatures, these measures also alter other as- Conclusion
pects of host resistance besides body temperature. Nearly all known exogenous pyrogens produce fever
As already mentioned, lower vertebrates such as liz- by acting through a common intermediate, endogenous
ards, amphibians, and fish normally develop fever during pyrogen. This substance is a low molecular weight pro-
infections (4-7). Unlike mammals, these animals lack the tein released by activated bone marrow-derived phago-
capacity to conserve or generate body heat by intrinsic cytes at various sites in the body. Endogenous pyrogen
mechanisms. Instead, they regulate body temperature appears to act on specialized temperature-sensitive neu-
normally and, when infected, develop fever in response to rons localized in the anterior hypothalamus, where it
their own circulating endogenous pyrogen by seeking ap- causes an upward displacement of the body's temperature
propriate environmental temperatures (49). Thus, fever set-point. In this review, we have summarized present
in lizards can be prevented by simply altering the exter- knowledge and indicated areas where further research is
nal temperature available to the animals. Using this mod- needed. These include the endogenous agents and steps
el, Kluger and colleagues (156) have shown the survival involved in activating phagocytes to produce and release
value of fever in the desert iguana. Animals infected with endogenous pyrogen; the central role of mediators such
Aeromonas hydrophila, a natural gram-negative patho- as prostaglandins and catecholamines in the pathogenesis
gen for lizards, were placed at environmental tempera- of fever; the relation of neuronal events to the physiologic
tures between 35 °C and 42 °C. Almost all animals kept changes that take place during fever; and mechanisms by
at 40 °C or 42 °C survived, whereas most infected ani- which fever benefits an infected host. Current investiga-
mals kept at lower temperatures died. Drug-induced anti- tions should help to shed light on some of these still unre-
pyresis, which modified the tendency of these animals to solved issues in our understanding of this ancient evolu-
seek elevated environmental temperature, also increased tionary mechanism to combat infection.
the mortality caused by this pathogen (157). Similar re- A C K N O W L E D G M E N T : This review is dedicated to the memory of our
sults have been obtained wth infected fish (158). colleague, mentor, and friend, Phyllis Tuck Bodel, whose work has contrib-
uted so much to our understanding of fever. The authors thank Richard K.
Higher body temperatures encountered during a fever Root for critically reviewing the manuscript.
may aid an infected host by increasing the activity of
• Requests for reprints should be addressed to H.A. Bernheim, Ph.D.; De-
their defense system. For example, human lymphocytes partment of Biology, Tufts University; Medford, MA 02155.
incubated in vitro at 39 °C show a higher uptake of thy-
Received 15 December 1978; revision accepted 1 May 1979.
midine than lymphocytes incubated at 37 °C (159). In
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