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
adaptive mechanism for controlling infection. This
phenomenon is produced by certain exogenous (largely
microbial) stimuli that activate bone-marrow-derived
phagocytes to release a fever-inducing hormone
(endogenous pyrogen). Endogenous pyrogen, in turn,
circulates to the thermoregulatory center of the brain
(preoptic area of the anterior hypothalamus) where it
causes an elevation in the "set-point" for normal body
temperature. Warm blooded animals produce fever by
increasing heat production (through shivering) or
reducing heat loss (by peripheral vasoconstriction),
whereas cold blooded animals do so only by behavioral
mechanisms (seeking a warmer environment). This paper
discusses current concepts that involve the mechanism of
endogenous pyrogen production, the role of central
transmittors, and the probable function of fever in
combating disease.
FEVER remains a fascinating problem for both clinicians
and basic scientists. Although there have been several
reviews on fever in the past 10 years, recent research in
this area provides an opportunity to survey the current
knowledge of the pathogenesis and the pathophysiology
of this universal response of warm-blooded animals. This
review deals with both cellular and neurophysiologic
aspects of fever and discusses the recent discovery that
fever is developed adaptively in experimentally infected
poikilotherms and plays a dramatic beneficial role in mo-
bilizing host defenses against infection.
For centuries man has recognized fever as a sign of
inflammation, but only within the last few decades have
scientists begun to understand its pathogenesis and func-
tion. In essence, fever represents a disturbance in normal
thermoregulation. Body temperature in health is main-
tained over a narrow range in homeotherms (warm-
blooded species) by both behavioral and physiologic
mechanisms. The behavioral mechanisms are familiar, as
when we turn up the thermostat or put on more clothing
when the environmental temperature feels too cold, or
turn on the air conditioning or take off clothing when the
temperature becomes warm. Physiologic mechanisms in-
volve increasing heat loss (vasodilation, sweating) when it
is hot or conserving and producing more heat (vasocon-
striction and shivering) when it is cold. In humans, this
balance is precisely maintained so that body temperature
is usually 37 ± 1 °C, with values usually lowest in the
early morning and highest in the late afternoon.
The mechanisms involved in temperature regulation
are discussed below, but we may simply note here that
• F r o m the Department of Internal Medicine, Yale University School of Medi-
cine; New Haven, Connecticut.
Annals of Internal Medicine. 1979;91:261-270.
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the body appears to have a thermostatic mechanism in
the anterior hypothalamus that receives thermal informa-
tion from both peripheral and central receptors. When
ambient or internal temperature increases or decreases,
these receptors relay the information to this thermostat
which, in turn, makes appropriate adjustments along ef-
ferent tracts that modify heat production or loss so that
central temperature is maintained at or near normal
levels.
At times, however, body temperature may change sig-
nificantly despite the homeostatic mechanisms that at-
tempt to return it to 37 °C. For instance, exposure to
extremely low temperatures with inadequate shelter or
clothing eventually produces a fall in body temperature
(hypothermia) despite vasoconstriction and violent shiv-
ering. On the other hand, violent exercising or exposure
to high ambient temperatures and humidity increases
body temperature (hyperthermia) despite vasodilation
and profuse sweating. As air becomes more humid it is
increasingly difficult for sweat to evaporate from the skin.
As a result, the heat normally lost when water evaporates
remains in the body. During these extremes of induced
hypothermia and hyperthermia, the "set-point" in the
anterior hypothalamus is not altered; instead there is a
failure of regulating mechanisms to compensate for the
loss or gain of heat.
On the other hand, " t r u e " fever is a disorder of therm-
oregulation in which there appears to be an upward dis-
placement of set-point so that the body actively seeks to
raise its temperature. This is accomplished physiological-
ly by vasoconstriction and shivering and behaviorally by,
for example, curling up in bed under layers of blankets.
In contrast, with the hyperthermia that follows exercise,
the body attempts to bring its temperature back to nor-
mal by vasodilation and sweating or adaptively by seek-
ing a cooler environment. In clinical fevers the rise in
body temperature is regulated by negative feedback
mechanisms in such a fashion that temperatures rarely
exceed 41 °C (1, 2), whereas in some hyperthermic states
such as heat stroke or malignant hyperthermia after ad-
ministration of anesthesia, the central controlling mecha-
nism appears to be lost and temperatures may reach
lethal levels. Body temperatures higher than 41 °C are
occasionally seen during fevers but this is usually a result
of superimposed activity such as convulsions.
Until very recently, fever was thought to occur only in
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
fever thus arose early in evolution and was maintained
© 1 9 7 9 American College of Physicians 261

Figure 1 . Postulated pathway for the pathogenesis of fever (see
text for details). Adapted from Rosendorff ( 1 1 5 ) . Ag = antigen;
Ag-Ab = antigen-antibody complexes; Compl = complement;
cAMP = cyclic adenosine-3',5' monophosphate; DHS = delayed hy-
persensitivity; EP = endogenous pyrogen; 5HT = serotonin;
LK = lymphokine; NE = norepinephrine; PO/AH = preoptic area of
anterior hypothalamus; RES = reticuloendothelial s y s t e m , ^ * inhib-
itors; - activators.
throughout the vertebrate classes. This suggests an adap-
tive or defensive role for this physiologic phenomenon.
Fever-Inducing Agents
There are numerous substances, collectively known as
"pyrogens," that have been found to cause fever experi-
mentally. Among these are microbial agents such as vi-
ruses (9-11), gram-positive bacteria (12) and some of
their exotoxins (13-16), gram-negative bacterial endotox-
ins (17-19), and pathogenic fungi (20, 21), as well as cer-
tain steroids (22), antigen-antibody complexes (23-26),
antigens producing states of delayed hypersensitivity
(27), and a number of nonorganic substances (28). The
characteristics of the fevers induced by these different
agents vary with respect to time of onset (latency) and
duration, but the mechanisms involved in the production
of fever appear to be quite similar in most instances. Each
so-called "exogenous" pyrogen evokes an apparently
common mediator, endogenous pyrogen, a protein pro-
duced by host leukocytes (29) (Figure 1). The pyrogen
used in most early models of experimental fever was en-
dotoxin, a complex lipopolysaccharide found in cell walls
of all gram-negative bacteria. The active moiety of endo-
toxin consists of lipid A, a beta 1-6 linked diglucosamine
backbone containing both ester- and amide-linked long-
chain fatty acids, as well as 2-keto-3-deoxyoctonate and
pyrophosphate groups (30). In doses of several nano-
grams or less intravenously, endotoxin produces brief
fever in rabbits (31). In higher doses, endotoxin causes
biphasic fevers lasting several hours. Gram-positive bac-
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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.
Studies are in progress with endogenous substances at
sites of inflammation and necrosis to determine whether
they are activators of endogenous pyrogen production
and hence may be responsible for fever in those diseases
in which no infectious agents can be isolated. Such acti-
vators may account for the presence of endogenous pyro-
gen in exudate fluids from joints of patients with nonmi-
crobial arthritis (43).
Endogenous Pyrogen
In 1943, Menkin isolated a substance ("pyrexin") from
inflammatory exudates that caused fevers when injected
intravenously into rabbits (44). Others demonstrated that
the pyrogenic effects of pyrexin could be accounted for by
contaminating endotoxin (45). In 1948 however, Beeson
(46) extracted from rabbit polymorphonuclear leukocytes
a fever-producing substance that was later shown to be
distinct from endotoxin in that it produced fevers of short
latency and duration, was heat labile, and produced no
pyrogenic tolerance after repeated injection (45). Since
that time, this substance has been shown to be released
from the leukocytes of many species, both mammalian
and nonmammalian, and to have some cross-species and
even cross-class reactivity (47-49).
In the last few years, human and rabbit endogenous
pyrogens have been highly purified. Both are proteins
with a molecular weight range of 13 000 to 15 000 dal-
tons (50-53). As little as 35 ng of rabbit and human en-
dogenous pyrogen will produce fevers of 0.6 °C or more
when injected intravenously into rabbits (50-54). Rabbit
endogenous pyrogen is inactivated at alkaline p H and has
a requirement for free S-H groups, since its biological
activities are destroyed or restored, respectively, by S-H
oxidizing or reducing agents (55). Rabbit and human en-
dogenous pyrogen seem to be equally effective in produc-
ing fevers in rabbits when injected intravenously (56).
 However, these proteins have different antigenic moieties,
since a specific antibody raised in rabbits against human
endogenous pyrogen blocks its pyrogenic activity but not
that of rabbit endogenous pyrogen (57). Although inflam-
matory exudates are a potent source of human endoge-
nous pyrogen (58), it has been difficult to detect endoge-
nous pyrogen in plasma from febrile patients by bioassay
(59). This may be due to the difficulty of obtaining
enough blood for a single pyrogenic dose (60). With the
recent development of a radioimmunoassay for human
endogenous pyrogen by Dinarello and co-workers (61), it
seems likely that detectable levels of circulating endoge-
nous pyrogen will be found in the plasma of febrile pa-
tients.
Only bone marrow-derived phagocytes are capable of
producing and secreting endogenous pyrogen, since
"non-professional" phagocytes, such as HeLa cells and
fibroblasts do not produce endogenous pyrogen after
stimulation (62). Endogenous-pyrogen-producing cells
include blood and exudate granulocytes (45, 63) and
monocytes (64, 65) as well as macrophages from the lung
(66) and liver (67, 68). Human eosinophils release en-
dogenous pyrogen but in significantly less amounts than
those released from polymorphonuclear leukocytes (69).
In 1974, Bodel (70) showed that tissues from several
human tumors produce endogenous pyrogen "spontane-
ously" in vitro, without additional stimuli, unlike normal
phagocytic cells that require a stimulus to do so. These
initial studies did not define the cell type(s) responsible
for this activity. In subsequent studies, however, mouse
histiocytic and myelomonocytic tumor cells (71) as well
as human histiocytic lymphoma and Hodgkin's disease
cell lines (unpublished observations) have been shown to
produce endogenous pyrogen spontaneously.
Endogenous pyrogen released from the human tumor
cell lines appears to be antigenically similar to endoge-
nous pyrogen from normal human leukocytes since the
activity of both is blocked by antibody to normal leuko-
cytes. Endogenous pyrogen derived from both sources is
similarly susceptible to heat and pronase inactivation.
However, both human and mouse tumor cells appear to
produce several pyrogenic substances with different mo-
lecular weights, which may represent dimer- or trimer-
ization of tumor pyrogen. Similarly, human monocytes
release two molecular types of endogenous pyrogen (52),
one of which occurs in much smaller amounts and is
apparently a trimer of the other (54). Thus, fevers ob-
served in patients with various malignancies—acute leu-
kemias, histiocytic lymphomas, and Hodgkin's disease—
may, in some instances, be due to endogenous pyrogen
production by tumor cells themselves. These findings
may also provide a way of determining whether a tumor
cell is of lymphocytic or histiocytic origin, since lympho-
cytes seem to be incapable of producing endogenous py-
rogen (39, 72, 73).
A C T I V A T I O N , PRODUCTION, A N D RELEASE
The mechanisms involved in release of endogenous py-
rogen in vitro have been most extensively studied with
leukocytes from blood and sterile exudates. Endogenous
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pyrogen produced by these cells appears to have the same
properties, but the steps involved in its production differ
in the two cell populations. Because exudate leukocytes
are more numerous and easily obtained than blood leuko-
cytes, most early studies involving mechanisms of release
or purification of endogenous pyrogen done by Wood and
colleagues were conducted with these cells (29).
Exudate polymorphonuclear leukocytes are believed to
be activated in vivo by a heat-labile macromolecule in the
exudate fluid (74). This substance has only been partially
characterized (75), and possibly endotoxin escaping from
the intestinal tract may contribute to the accumulation
and activation of polymorphonuclear leukocytes in peri-
toneal exudate fluid, the source of cells in most experi-
mental studies (74). When the peritoneal exudate cells
are placed in physiologic saline at 37 °C, they release
most of the endogenous pyrogen over a 1-h period (76).
Neither Na+ nor CI- appears to be essential in this proc-
ess since endogenous pyrogen release will take place in
certain other media from which Na+ and CI- are omitted
(77). Incubation, however, with physiologic concentra-
tions of K+ or Ca++ or cations other than Na+ inhibits
the release of endogenous pyrogen as well as that of aldo-
lase, a cytoplasmic enzyme (77, 78). This suppression can
be reversed by ouabain, an inhibitor of the adenosine tri-
phosphotase involved in the Na+-K+ pump (77). Taken
together, these data suggest that release of endogenous
pyrogen is associated with changes in the intracellular
ionic composition normally maintained by the Na+-K+
pump.
Preformed endogenous pyrogen cannot be maintained
in any significant quantities from distrupted exudate leu-
kocytes (76). This observation, along with the fact that
no protein synthesis is needed for the release of endoge-
nous pyrogen from these cells (76, 79), suggests that en-
dogenous pyrogen exists in an inactive form in the cell
and is enzymatically converted to endogenous pyrogen
shortly before it crosses the cell membrane. This convert-
ing enzyme may have an active sulfhydryl moiety, since
incubation of exudate granulocytes with sulfhydryl-
reactive enzyme inhibitors (in concentrations that do not
inactivate endogenous pyrogen itself) prevents the release
of endogenous pyrogen (55). It is not known at present
where endogenous pyrogen is stored in these cells. How-
ever, degranulation of leukocytes does not appear to be
essential for endogenous pyrogen release, since colchi-
cine, which reduces degranulation, does not suppress re-
lease of endogenous pyrogen from rabbit leukocytes (79)
and, in fact, stimulates human monocytes to synthesize
and release endogenous pyrogen (80). In addition, no en-
dogenous pyrogen is detectable in granule portions of ex-
udate granulocytes (79). On the other hand, endogenous
pyrogen is released along with cytoplasmic enzymes (al-
dolase) but not with granule enzymes such as acid phos-
phatase (79). These results indicate that endogenous py-
rogen is stored in the cytoplasm rather than in granules.
To date, however, experiments attempting to extract en-
dogenous pyrogen in vitro from isolated cell fractions
have been unsuccessful (79). The release of endogenous
pyrogen from exudate cells may be an active process
Bernheim et al. • Fever 263
 because incubation of these cells with sodium fluoride, or
other metabolic inhibitors that block production of ade-
nosine triphosphate (ATP), prevents its release (76).
Unlike exudate cells, blood leukocytes do not release
endogenous pyrogen spontaneously. The production of
endogenous pyrogen by blood leukocytes involves three
steps: activation, production, and release.
Activation: The initial process by which leukocytes
are activated to produce endogenous pyrogen is un-
known. Activators such as endotoxin or certain phagocy-
tizable particles may combine with specific receptor sites
on the cell membrane to initiate protein synthesis. Cer-
tain particles may have to be engulfed to activate cells
because, when phagocytosis is blocked, blood leukocytes
incubated with heat-killed pneumococci will not release
endogenous pyrogen (81). Phagocytosis per se is not al-
ways a sufficient stimulus, however, because phagocytosis
of latex particles by granulocytes does not lead to endoge-
nous pyrogen production (81). On the other hand, ma-
crophages will release endogenous pyrogen after inges-
tion of latex particles (62). A potential second "messen-
ger," cyclic adenosine-3'5' monophosphate (cAMP), does
not seem to play a part in the activation process since
agents that increase intracellular levels of cAMP (phos-
phodiesterase inhibitors) do not modify the amount of
endogenous pyrogen produced when monocytes are acti-
vated by endotoxin (82). The possible role of cyclic guan-
idine monophosphate has not yet been investigated.
Production: During the production of endogenous
pyrogen (or its inactive precursor) by blood cells, there is
believed to be increased protein synthesis. When protein
inhibitors such as puromycin and dactinomycin are add-
ed early during incubation, little or no pyrogen is pro-
duced. If these agents are added 2-4 hours after incuba-
tion, however, there is no inhibition of endogenous pyro-
gen (83, 84). Thus synthesis of endogenous pyrogen (or a
critical protein precursor) occurs within 2 h after addi-
tion of the activator. In confirmation of this hypothesis,
leukocytes incubated with radioactively labeled amino
acids incorporate these agents into newly synthesized
endogenous pyrogen (85). The synthesis of endogenous
pyrogen in blood leukocytes is an energy-requiring mech-
anism since NaF (an inhibitor of glycolysis) prevents pro-
duction of endogenous pyrogen if added to cells early
after stimulation (83, 84). Presumably as in the case of
exudate cells, the synthesis and storage of endogenous
pyrogen occur in the cytoplasm rather than in the gran-
ules of blood cells.
Release: The pyrogen formed by blood leukocytes is
released over a 3- to 16-h period (74, 83, 84). In contrast
with its effect on exudate cells, potassium does not inhibit
the release of endogenous pyrogen from activated blood
leukocytes (81). During this phase, endogenous pyrogen
may be enzymatically converted from an inactive to an
active form (83). At present, however, no converting en-
zyme has been isolated. The release of endogenous pyro-
gen from blood leukocytes, as opposed to exudate cells, is
an energy-independent process, as the addition at this
phase of agents that block the normal pathways of cell
respiration do not interfere with secretion of endogenous
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pyrogen (83), an activity that appears to stop only with
death or disruption of the cell.
The release of pyrogen from blood monocytes has also
been studied. These cells release more endogenous pyro-
gen than do granulocytes and for longer periods of time
(24 to 72 h) (65). There is also an active stage of protein
synthesis that occurs before and during endogenous pyro-
gen release into the incubating medium (65), in contrast
to polymorphonuclear leukocytes, which only have an
active stage of protein synthesis before endogenous pyro-
gen release.
The circulating blood leukocytes used in the studies
described above as a source of endogenous pyrogen are
presumably not the cells activated in vivo, because they
do not spontaneously release endogenous pyrogen in vi-
tro as exudate cells do when removed during either clini-
cal or experimentally induced fevers and placed in saline
(86). Instead, monocytes and granulocytes at inflamma-
tory sites or marginated in vasculature, as well as fixed
tissue histiocytes, seem more likely to be the main source
of circulating endogenous pyrogen during both experi-
mental and clinical fevers. In addition, intravenously
injected viruses or bacteria probably cause fever by stim-
ulating Kupffer cells, which rapidly phagocytize these
particles to release endogenous pyrogen (68).
Chemical Mediators in the Central Nervous System of the
Febrile Response
Endogenous pyrogen appears to cause fever by altering
the activity of temperature-sensitive neurons in the
preoptic area of the anterior hypothalamus that presum-
ably determine the "set point" for normal body tempera-
ture (see below). Endogenous pyrogen, however, may not
act directly on these neurons but may work through oth-
er intermediates such as monoamines, Na+ or Ca++ ions,
prostaglandins, or cyclic nucleotides.
MONOAMINES
The changes in body temperature induced by injecting
serotonin and norepinephrine into the lateral ventricles
or anterior hypothalamus are variable, depending on the
animal species. In some species, serotonin causes a de-
crease in body temperature while norepinephrine causes
an increase (87, 88); in others, the opposite results occur
(89, 90). The amount of monoamines used in these exper-
iments, however, is large when compared with that found
normally in the anterior hypothalamus, and these experi-
ments may not indicate what is occurring under normal
conditions. More recent experiments have involved alter-
ing the endogenous stores of monoamines with various
pharmacologic agents such as 6-hydroxydopamine,
which destroys norepinephrine nerve terminals, and p-
chlorophenylalanine, which depletes brain stores of sero-
tonin. Using these drugs, Woolf and colleagues (91, 92)
showed that norepinephrine and serotonin may be impor-
tant in normal temperature regulation. Pretreatment with
p-chlorophenylalanine, however, did not alter the ability
of rabbits to develop a fever in response to pyrogens. On
the other hand, 6-hydroxydopamine and the alpha block-
er phenoxybenzamine attenuated the febrile response to
 various pyrogens. Propranolol, a beta blocker, was with-
out effect (93). The results indicate that pyrogens may
activate fever-producing pathways via alpha-adrenergic
(but not serotonergic) receptors in the anterior hypothal-
amus. Reserpine, however, which depletes both serotonin
and norepinephrine levels, did not alter the febrile re-
sponse of rabbits to endogenous pyrogen (91, 94). In ad-
dition, Giarman and co-workers (95) have shown that
hypothalamic levels of serotonin and norepinephrine
were not significantly changed after intravenous injection
of endogenous pyrogen. However, rabbits pretreated with
various agents that selectively decrease intracerebral lev-
els of either norepinephrine or serotonin had significantly
modified fevers (reduced or augmented, respectively) in
response to endogenous pyrogen. In view of these results,
it is uncertain whether monoamines play an essential role
in the febrile response.
SODIUM A N D CALCIUM
An infusion of sodium into the cerebral ventricles pro-
duces a high fever in unanesthesized cats (96). Alterna-
tively, an infusion of calcium ions leads to a decrease in
body temperature. Myers and Veale (97) concluded that
the body's set-point is controlled by a balance between
these two ions in the hypothalamus. Later, by using ra-
dioactive isotopes of sodium and calcium, Myers and Ty-
tell (98) showed that there was an increase in the N a + /
Ca++ ratio in the brain during fever. It is not known at
this time, however, how these cations bring about altera-
tions in body temperature and what precise role they play
in the normal induction of fever.
PROSTAGLANDINS
Injection of prostaglandin E, (PGE,) into the anterior
hypothalamus of several species of animals produces a
rapid rise in body temperature (99-102). In addition an
infusion of PGE, into the lateral ventricles of unanesthe-
tized cats causes a fever, which ceases as soon as the
infusion is stopped (99). When fever is induced by an
injection of endotoxin, there is a rise of PGE, in the cere-
bral spinal fluid of cats (103). Antipyretics such as sodi-
um salicylate, which prevent the synthesis of PGE, from
arachidonic acid (104), can attenuate fevers induced by
endotoxin with a concomitant decrease in cerebral spinal
fluid-PGE, levels (105).
Recent evidence, however, raises some questions about
the postulated role of prostaglandins as intermediates in
the development of endogenous pyrogen-induced fever.
Local application of PGE, and endogenous pyrogen did
not lead to an increase in body temperature in animals
with lesions of the anterior hypothalamus; however, infu-
sion of endogenous pyrogen into the lateral ventricles of
such animals resulted in a febrile response, whereas PGE,
was ineffective (106). This finding suggests that endoge-
nous pyrogen can stimulate other neuronal sites to pro-
duce fever without release of PGE,. Later, Cranston and
co-workers (107) showed that sodium salicylate given af-
ter injection of endotoxin led to a decrease in fever height
without corresponding decrease in cerebral spinal fluid
levels of PGE,. In addition, two prostaglandin antago-
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nists, SC 19220 and HR 546, prevented fever after an
injection of PGE, but not after an injection of endoge-
nous pyrogen (108). Injection of arachidonic acid into the
cerebral ventricles, however, will produce a fever even
after an infusion of these prostaglandin antagonists, sug-
gesting that some metabolite of arachidonic acid other
than PGE, may be involved as a mediator in the produc-
tion of fever (109).
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
An intracerebral injection of dibutyryl cAMP in rab-
bits and cats (110, 111) results in a rapid rise in body
temperature that is unaffected by an injection of sodium
salicylate. In addition, after injection of endotoxin, myxo-
viruses, endogenous pyrogen, or PGE,, there is a signifi-
cant increase in levels of cAMP in the cerebral spinal
fluid (112, 113). Theophylline, which inhibits phosphodi-
esterase activity and hence the breakdown of cAMP,
potentiates PGE,- and endotoxin-induced fevers, while
nicotinic acid, which potentiates the action of phosphodi-
esterase, causes a decrease in the febrile response to PGE,
(114).
The precise role of these various mediators in the fe-
brile response has not been ascertained. Rosendorff (115)
has developed an interesting model for the pathogenesis
of fever that postulates a sequential involvement of most
of the intermediate agents discussed above. (Figure 1) In
essence, his model states that endogenous pyrogen circu-
lates to the hypothalamus, where it induces the produc-
tion of a metabolite of arachidonic acid. This substance,
in turn, increases the synthesis of norepinephrine, an al-
pha adrenergic agonist that increases the production of
cAMP. This cyclonucleotide then directly causes altera-
tions in the activity of temperature-sensitive neurons that
bring about the increase in heat conservation or produc-
tion, or both. Because of the conflicting evidence summa-
rized above, however, there remains the possibility that
endogenous pyrogen acts directly or via some other as yet
unidentified intermediate which, in turn, alters the set-
point of temperature-regulating neurons to produce
fever.
Neuronal Mechanisms During Fever
Although the spinal cord is capable of initiating ther-
moregulatory responses (116, 117), the preoptic area of
the hypothalamus is primarily responsible for integrating
thermal stimuli and initiating homeostatic thermal mech-
anisms when warm or cold stimuli are applied locally
(118-120). Moreover, a great deal of evidence indicates
that an area in the hypothalamus is similarly responsible
for the development of fever. Injection of pyrogens into
the anterior hypothalamus and brain stem (121) but not
other areas of the brain produces a rapid increase in body
temperature (122-124). In addition, sectioning the brain
between the midbrain and the pons eliminates an ani-
mal's febrile response to an intravenous dose of endotox-
in (125).
The anterior hypothalamus, along with the skin and
spinal cord (126), contains two populations of thermally
sensitive neurons that respond to either warm or cold
Bernheim et al. • Fever 265
 stimuli and presumably initiate the appropriate ther-
moregulatory responses to local changes in temperature.
Units studies of warm receptors that are more numerous
than cold receptors in the anterior hypothalamus (127)
have shown that as local temperatures increase, the re-
ceptors increase their spontaneous discharge with a cor-
responding Q10 of 5-15. (Q 10 is denned as the increase in
physiologic activity for every 10 °C rise in temperature.
This relation is expressed by the equation
Q,o = K, 10
K2 T, - T 2 ,
where Kj and K2 are physiologic activities [such as meta-
bolic rate] at temperatures of T{ and T2, respectively.
Thus, if a physiologic activity increases 1.5 times over a
5 °C range, the Q10 is 2.25.) As local temperatures de-
crease, cold receptors increase their rate of discharge
with a resultant Q10 of less than one (127-129). Neurons
with a Q10 between one and two are thermally insensitive.
Both warm- and cold-sensitive neurons consist of two
distinct types, one of which has a continuous increase in
unit activity and one a discontinuous response to changes
in hypothalamic temperature (129). The former, located
mainly in the preoptic and septal areas, are presumably
primary detectors, while the latter, distributed through-
out the hypothalamus, are interneurons. The relative role
of each of these types of neurons in thermal integration is
not known.
Some neurons in the anterior hypothalamus respond
only to local temperature changes; others respond only to
temperature changes evoked elsewhere in the midbrain,
spinal cord, or skin, or some combination of these (129-
133). Although the variation in these neuronal types im-
plies an integrative function for the anterior hypothala-
mus, the precise afferent and efferent pathways remain to
be defined.
Unit studies of the activity of thermally sensitive neu-
rons after systemic injection of endotoxin or endogenous
pyrogen show that warm-sensitive neurons decrease their
activity (heat loss mechanisms are depressed) while cold-
sensitive neurons increase theirs. Thermally insensitive
neurons are unaffected. These changes are associated
with an increase in heat-conserving mechanisms and, as a
result, fever (134, 135). Additional studies have shown
that an infusion of an antipyretic, such as sodium salicy-
late, reverses the alteration in unit activity brought about
by endotoxin or endogenous pyrogen (135, 136), thus
confirming the correlation between the activity of these
specialized neurons and the physiologic changes associat-
ed with thermoregulation and fever.
During a fever there appears to be an increase in the
thermostatic "set-point" so that the anterior hypothala-
mus "senses" a lower-than-normal body temperature and
initiates heat-conserving mechanisms until the internal
temperature reaches the new level, much as the increased
setting of a thermostat activates the furnace until the de-
sired temperature is achieved (137). If, however, the hy-
pothalamus is heated during the latent period after an
injection of pyrogen, the animal fails to develop a fever,
presumably because the heat supplied locally, as in other
negative feedback systems, has decreased the "error-sig-
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nal" between the febrile set-point and the temperature of
the anterior hypothalamus (138). The way in which this
set-point is regulated, and indeed the whole concept of a
set-point, both in health as well as in fever, is uncertain,
although several theoretical models have been proposed
(126, 137, 139-143). Alternatively, the temperature of the
body in health or in fever may simply be the resultant of
all those stimuli (biochemical, neurologic, or physical)
that tend to increase or decrease body temperature by
local effects on temperature-sensitive neurons in the ante-
rior hypothalamus (144). That body temperature is, how-
ever, regulated at a higher level during fever has been
clearly shown in a study of febrile patients during exer-
cise. Temperatures rose above the febrile level with exer-
cise but fell promptly afterwards to the pre-existing fe-
brile level, not to normal, as with healthy persons (145,
146).
In the initial stages of fever in a thermally neutral envi-
ronment (20 °C), the anterior hypothalamus activates
physiologic responses to cold, such as shivering and pe-
ripheral vasoconstriction, so that the body temperature
rises. When fever is constant, heat conservation and loss
are again balanced as in health, but at a somewhat higher
level due to the elevation of basal metabolism that occurs
with increased body temperature (7% for each degree
Fahrenheit) (147). During defervescence, the physiologic
responses to heat—vasodilation and increase of evapora-
tive water loss—are activated and the body temperature
returns to normal. The temperature rise evoked by a py-
rogen remains the same regardless of the environmental
temperature. However, the means by which this elevation
is achieved varies with the ambient temperature, an in-
creased metabolic rate being the major mechanism in
cold, vasoconstriction and a decrease in evaporative wa-
ter loss in the heat (148). In poikilotherms, a similar ele-
vation in body temperature is achieved by behavioral
changes that make an animal seek a higher environmen-
tal temperature (3-7) (see below). Behavioral changes
during onset and subsidence of fever also occur in ho-
meotherms including man, as in the familiar example
where patients "feel cold" and bundle up during the chill
phase of fever (thus conserving heat) and, conversely,
"feel hot" and fling off bed clothes during defervescence.
Interestingly, in this regard, newborn rabbits, though un-
able to develop a fever by physiologic means, raise their
body temperature behaviorly after an injection of endo-
toxin, as do poikilotherms (149).
Experimental findings in lambs and guinea pigs con-
firm the clinical observation that newborns do not nor-
mally develop fever with infections or when injected with
either endotoxin or endogenous pyrogen. Evidence sug-
gests that this failure may be due in some instances to
lack of sensitization (to exogenous pyrogens) (150) or im-
maturity of thermoregulatory responses, or both (151). A
possibility that should be investigated is that leukocytes
of newborns have a decreased ability to generate endo-
genous pyrogen.
Effects of Fever on Host-Defense Systems
The value of fever in host defense has never been satis-
 factorily established in mammals. Some heat-sensitive
microorganisms that produce disease, such as those caus-
ing syphilis and gonorrhea, can be killed in vivo by arti-
fically induced fever, but natural infections with these
organisms almost never produce high fevers (152). In
rabbits, rats, and mice (153-155) there is a decrease in the
median lethal dose of endotoxin when these animals are
made hyperthermic by physical or pharmacologic means.
Data from these experiments do not show whether natu-
rally acquired fevers benefit the host, particularly during
infectious states. Although fever in experimental infec-
tions can be suppressed by antipyretic drugs or by low
ambient temperatures, these measures also alter other as-
pects of host resistance besides body temperature.
As already mentioned, lower vertebrates such as liz-
ards, amphibians, and fish normally develop fever during
infections (4-7). Unlike mammals, these animals lack the
capacity to conserve or generate body heat by intrinsic
mechanisms. Instead, they regulate body temperature
normally and, when infected, develop fever in response to
their own circulating endogenous pyrogen by seeking ap-
propriate environmental temperatures (49). Thus, fever
in lizards can be prevented by simply altering the exter-
nal temperature available to the animals. Using this mod-
el, Kluger and colleagues (156) have shown the survival
value of fever in the desert iguana. Animals infected with
Aeromonas hydrophila, a natural gram-negative patho-
gen for lizards, were placed at environmental tempera-
tures between 35 °C and 42 °C. Almost all animals kept
at 40 °C or 42 °C survived, whereas most infected ani-
mals kept at lower temperatures died. Drug-induced anti-
pyresis, which modified the tendency of these animals to
seek elevated environmental temperature, also increased
the mortality caused by this pathogen (157). Similar re-
sults have been obtained wth infected fish (158).
Higher body temperatures encountered during a fever
may aid an infected host by increasing the activity of
their defense system. For example, human lymphocytes
incubated in vitro at 39 °C show a higher uptake of thy-
midine than lymphocytes incubated at 37 °C (159). In
addition, leukocytes from humans and guinea pigs dem-
onstrated maximum phagocytic activity between 38 to
40 °C and 39 to 41 °C, respectively (160). Recently,
Bernheim and co-workers (161) have shown that fever in
lizards enhances some aspect of the early inflammatory
response, which leads to increased leukocyte emigration
and containment of the infection at the local site.
The role of iron in host-defense systems has been ex-
tensively reviewed by Weinberg (162). Many microbes
need iron for their normal growth and reproduction.
During fever, however, there is a decrease in circulating
levels of iron due to increased uptake by reticuloendothe-
lial cells in the liver and spleen and decreased absorption
from the gut. Kampschmidt and co-workers (163, 164)
have shown that endogenous pyrogen itself lowers serum
iron in rats and produces other effects that may increase
host resistance to infection. Some infections produce in-
creased plasma levels of transferrin and lactoferrin (non-
heme-binding glycoproteins). The release of lactoferrin
from secondary granules of polymorphonuclear leuko-
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cytes is increased, at least in vitro, by endogenous pyro-
gen (165). In addition, the production of siderophores,
bacterial iron-binding proteins, is suppressed by higher
temperatures such as occur in fever, so that a microbe's
ability to sequester sufficient quantities of iron is de-
creased. The survival value of fever-induced hypoferre-
mia has been recently shown by Grieger and Kluger
(166). Infected febrile lizards became hypoferremic and
had low mortality, but when they were injected with
exogenous sources of iron their mortality rate increased
significantly.
Conclusion
Nearly all known exogenous pyrogens produce fever
by acting through a common intermediate, endogenous
pyrogen. This substance is a low molecular weight pro-
tein released by activated bone marrow-derived phago-
cytes at various sites in the body. Endogenous pyrogen
appears to act on specialized temperature-sensitive neu-
rons localized in the anterior hypothalamus, where it
causes an upward displacement of the body's temperature
set-point. In this review, we have summarized present
knowledge and indicated areas where further research is
needed. These include the endogenous agents and steps
involved in activating phagocytes to produce and release
endogenous pyrogen; the central role of mediators such
as prostaglandins and catecholamines in the pathogenesis
of fever; the relation of neuronal events to the physiologic
changes that take place during fever; and mechanisms by
which fever benefits an infected host. Current investiga-
tions should help to shed light on some of these still unre-
solved issues in our understanding of this ancient evolu-
tionary mechanism to combat infection.
A C K N O W L E D G M E N T : This review is dedicated to the memory of our
colleague, mentor, and friend, Phyllis Tuck Bodel, whose work has contrib-
uted so much to our understanding of fever. The authors thank Richard K.
Root for critically reviewing the manuscript.
• Requests for reprints should be addressed to H.A. Bernheim, Ph.D.; De-
partment of Biology, Tufts University; Medford, MA 02155.
Received 15 December 1978; revision accepted 1 May 1979.
References
1. D u Bois EF. Why are fever temperatures over 106 °F rare? Am J Med
Sci. 1949;217:361-8.
2. H A R D Y JD. Fever and thermogenesis. Isr J Med Sci. 1976;12:942-50.
3. CASTERLIN ME, REYNOLDS WW. Behavioral fever in crayfish. Hydro-
biologia. 1977;56:99-101.
4. R E Y N O L D S WW, C A S T E R L I N ME, C O V E R T JB. Behavioral fever in
teleost fishes. Nature. 1976;259:41-2.
5. CASTERLIN ME, REYNOLDS WW. Behavioral fever in anuran amphib-
ian larvae. Life Sci. 1977;20:593-6.
6. K L U G E R MJ. Fever in the frog Hyla cincrea. J Thermal Biol
1977;2:79-81.
7. V A U G H N LK, B E R N H E I M HA, K L U G E R MJ. Fever in the lizard Dip-
sosaurus dorsalis. Nature. 1974;252:473-4.
8. D ' A L E C Y L, K L U G E R MJ. Avian febrile response. / Physiol (Lond).
1975;253:223-32.
9. W A G N E R RR, B E N N E T T IL J R , L E Q U I R E VS. The production of fever
by influenzal viruses: I. Factors influencing the febrile response to sin-
gle injections of virus. J Exp Med. 1949;90:321-34.
10. ATKINS E, H U A N G WC. Studies on the pathogenesis of fever with
influenzal viruses: I. The appearance of an endogenous pyrogen in the
blood following intravenous injection of virus. / Exp Med.
1958;107:383-401.
11. K I N G MK. Production of fever in rabbits with extracts of tissue culture
cells infected with coxsackie virus. J Lab Clin Med. 1962;59:986-92.
12. ATKINS E, F R E E D M A N LR. Studies in staphylococcal fever: I. Re-
sponses to bacterial cells. Yale J Biol Med. 1963;35:451-71.
Bernheim et al. • Fever 267
 13. WESLEY CG, PAGE JS. Pyrogenic responses to staphylococcal entero-
toxins A and B in cats. J Bactehol. 1968;96:1940-6.
14. STETSON CA JR. The endotoxic properties of lysates of group A hemo-
lytic streptococci J Exp Med. 1956;104:921-34.
15. SCHUH V, HRIBALOVA V. The pyrogenic effect of scarlet fever toxin:
II. Leukocytic pyrogen formation induced by scarlet fever toxin or
Salmonella paratyphi B endotoxin. Folia Microbiol (Praha).
1966;11:112-22.
16. C U N N I N G H A M CM, BARSUMIAN EL, W A T S O N DW. Further purifica-
tion of group A streptococcal pyrogenic exotoxin and characterization
of the purified toxin. Infect Immun. 1976;14:767-75.
17. A T K I N S E, W O O D WB J R . Studies on the pathogenesis of fever: II.
Identification of an endogenous pyrogen in the blood stream following
the injection of typhoid vaccine. J Exp Med. 1955;102:499-516.
18. C R A N S T O N WI, G O O D A L E F J R , S N E L L ES, W E N D T F. The role of
leukocytes in the initial action of bacterial pyrogens in man. Clin Sci.
1956;15:217-26.
19. S H E A G R E N JN, W O L F F SM, S H U L M A N NR. Febrile and hematologic
responses of rhesus monkeys to bacterial endotoxin. Am J Physiol.
1967;212:884-90.
20. BRAUDE AI, M C C O N N E L L J, DOUGLAS H. Fever from pathogenic
fungi. J Clin Invest. 1960;39:1266-76.
21. BRIGGS RS, ATKINS E. Studies in cryptococcal fever: I. Responses to
intact organisms and to a soluble agent derived from cryptococci. Yale
J Biol Med. 1966;38:431 -48.
22. BODEL P, DILLARD M. Studies on steroid fever: I. Production of leu-
kocyte pyrogen in vitro by etiocholanolone. J Clin Invest. 1968;47:107-
17.
23. FARR RS. Fever as a manifestation of an experimental allergy. J Aller-
gy. 1959;30:268-9.
24. MoTT PD, W O L F F SM. The association of fever and antibody response
in rabbits immunized with human serum albumin. / Clin Invest.
1966;45:372-9.
25. R O O T RK, W O L F F SM. Pathogenetic mechanisms in experimental im-
mune fever. J Exp Med. 1968;128:309-23.
26. CHUSID MJ, ATKINS E. Studies on the mechanism of penicillin-in-
duced fever. J Exp Med. 1972;136:227-40.
27. A T K I N S E, F E L D M A N J D , F R A N C I S L, H U R S C H E. Studies on the
mechanism of fever accompanying delayed hypersensitivity: the role of
the sensitized lymphocyte. J Exp Med. 1972; 135:1113-32.
28. PETERSDORF RG, B E N N E T T IL JR. Studies on the pathogenesis of
fever: VIII. Fever-producing substance in the serum of dogs. / Exp
Med. 1957;106:293-314.
29. ATKINS E, BODEL PT. Fever. In: ZWEIFACH BW, GRANT L,
MCCLUSKEY RT, eds. The Inflammatory Process, vol. 3. 2nd ed. New
York: Academic Press; 1974:467-514.
30. G M E I N E R J, LUDERITZ O, WESTPHAL O. Biochemical studies on lipo-
polysaccharides of Salmonella R mutans: 6. Investigations on the struc-
ture of the lipid A component. Eur J Biochem. 1969;7:370-9.
31. K I M YB, WATSON DW. Biologically active endotoxins from Salmonel-
la mutants deficient in O- and R-polysaccharides and heptose. / Bacte-
riol. 1967;94:1320-6.
32. B E N N E T T IL J R . Studies on the pathogenesis of fever: V. The fever
accompanying pneumococcal infection in the rabbit. Bull Johns Hop-
kins Hosp. 1956;98:216-35.
33. K I N G MK, W O O D WB JR. Studies on the pathogenesis of fever: V. The
relation of circulating endogenous pyrogen to the fever of acute bacteri-
al infections. J Exp Med. 1958;107:305-18.
34. B E R E N D T RF, H A L L WC. Reaction of squirrel monkeys to intratra-
cheal inoculation with influenza/A/ New Jersey/76 (swine) virus. In-
fect Immun. 1977;16:476-9.
35. H A L L CH J R , ATKINS E. Studies on tuberculin fever: I. The mecha-
nism of fever in tuberculin hypersensitivity. J Exp Med. 1959;109:339-
59.
36. G R E Y HM, BRIGGS W, FARR RS. The passive transfer of sensitivity to
antigen-induced fever. J Clin Invest. 1961;40:703-6.
37. M I C K E N B E R G ID, S N Y D E R M A N R, R O O T RK, M E R G E N H A G E N SE,
W O L F F SM. Immune fever in the rabbit: responses of the hematologic
and complement systems. J Immunol. 1971;107:1437-65.
38. M I C K E N B E R G ID, S N Y D E R M A N R, R O O T RK, M E R G E N H A G E N SE,
W O L F F SM. The relationship of complement consumption to immune
fever. J Immunol. 1971;107:1466-76.
39. C H A O PL, FRANCIS L, ATKINS E. The release of an endogenous pyro-
gen from guinea pig leukocytes in vitro: a new model for investigating
the role f^f lymphocytes in fevers induced by antigen in hosts with
delayed hypersensitivity. J Exp Med. 1977;145:1288-98.
40. ATKINS E, FRANCIS L. Pathogenesis of fever in delayed hypersensitivi-
ty: factors influencing release of pyrogen inducing lymphokines. Infect
Immun. 1978;21:806-12.
41. A T K I N S E, FRANCIS L, B E R N H E I M HA. Pathogenesis of fever in de-
layed hypersensitivity: role of monocytes. Infect Immun. 1978;21:813-
20.
42. D U M O N D E DC, W O L S T E N C R O F T RA, P A N A Y I GS, M A T T H E W M,
268 August 1979 • Annals of Internal Medicine • Volume 91 • Number 2
Downloaded From: http://annals.org/ by a University of Otago User on 12/12/2016
MORLEY J, HOVVSON WT. "Lymphokines": non-antibody mediators of
cellular immunity generated by lymphocyte activation. Nature
1969;224:38-42.
43. BODEL PT, HOLLINGSWORTH JW. Pyrogen release for human synovi-
al exudate cells. Br J Exp Pathol. 1968;49:11-9.
44. M E N K I N V. Chemical basis of injury in inflammation. Arch Pathol.
1943;36:269-88.
45. B E N N E T T IL JR, BEESON PB. Studies on the pathogenesis of fever: II.
Characterization of fever-producing substances from polymorphonu-
clear leukocytes and from the fluid of sterile exudates. / Exp Med.
1953;98:493-508.
46. BEESON PB. Temperature-elevating effect of a substance obtained from
polymorphonuclear leukocytes. / Clin Invest. 1948;27:524.
47. BORNSTEIN DL, WOODS JW. Species specificity of leukocytic pyro-
gens. J Exp Med. 1969;130:707-21.
48. PETERSDORF R G , B E N N E T T IL J R . Studies on the pathogenesis of
fever: VII. Comparative observations on the production of fever by
inflammatory exudates in rabbits and dogs. Bull Johns Hopkins Hosp.
1957;100:277-86.
49. BERNHEIM HA, K L U G E R MJ. Endogenous pyrogen-like substance
produced by reptiles. J Physiol (Lond). 1977;267:659-66.
50. M U R P H Y PA, C H E S N E Y PJ, W O O D WB J R . Purification of an endoge-
nous pyrogen, with an appendix on assay methods. In: Ciba Founda-
tion Symposium on Pyrogens and Fever. London: Churchill Living-
stone; 1971:59-79.
51. M U R P H Y PA, C H E S N E Y PJ, W O O D WB J R . Further purification of
rabbit leukocyte pyrogen. J Lab Clin Med. 1974;83:310-22.
52. D I N A R E L L O CA, G O L D I N NP, W O L F F SM. Demonstration and char-
acterization of two distinct human leucocytic pyrogens. / Exp Med.
1974;139:1369-81.
53. B O D E L PT, W E C H S L E R A, A T K I N S E. Comparison of endogenous py-
rogens from human and rabbit leucocytes utilizing sephadex filtration.
Yale J Biol Med. 1969;41:376-87.
54. DINARELLO CA, W O L F F SM. Partial purification of human leukocytic
pyrogen. Inflammation. 1977;2:179-89.
55. KAISER HK, W O O D WB J R . Studies on the pathogenesis of fever: X.
The effect of certain enzyme inhibitors on the production and activity
of leucocytic pyrogen. J Exp Med. 1962;115:37-47.
56. BODEL PT, ATKINS E. Human leukocyte pyrogen producing fever in
rabbits. Proc Soc Exp Biol Med. 1966;121:943-6.
57. D I N A R E L L O CA, R E N F E R L, W O L F F SM. The production of antibody
against human leukocytic pyrogen. J Clin Invest. 1977;60:456-72.
58. SNELL ES. Pyrogenic properties of human pathological fluids. Clin Sci.
1962;23:141-50.
59. SNELL ES. An examination of the blood of febrile subjects for pyrogen-
ic properties. Clin Sci. 1961;21:115-24.
60. GREISMAN SE, HORNICK RB. On the demonstration of circulating
human endogenous pyrogen. Proc Soc Exp Biol Med. 1972;139:690-2.
61. DINARELLO CA, R E N F E R L, W O L F F SM. Human leukocytic pyrogen:
purification and development of a radioimmunoassay. Proc Natl Acad
Sci USA. 1977;74:4624-7.
62. BODEL PT, M I L L E R H. Differences in pyrogen production by mononu-
clear phagocytes and by fibroblasts on HeLa cells. / Exp Med.
1977;145:607-17.
63. COLLINS RD, W O O D WB JR. Studies on the pathogenesis of fever: VI.
The interaction of leukocytes and endotoxin in vitro. / Exp Med.
1959;110:1005-16.
64. H A H N H H , C H A R DC, POSTEL WB, W O O D WB J R . Studies on the
pathogenesis of fever: XV. The production of endogenous pyrogen by
peritoneal macrophages. J Exp Med. 1967;126:385-94.
65. BODEL PT. Studies on the mechanism of endogenous pyrogen produc-
tion: III. Human blood monocytes. J Exp Med. 1974;140:954-65.
66. ATKINS E, BODEL P, FRANCIS L. Release of an endogenous pyrogen in
vitro from rabbit mononuclear cells. J Exp Med. 1967;126:357-83.
67. D I N A R E L L O CA, BODEL P, ATKINS E. The role of the liver in produc-
tion of fever and in pyrogenic tolerance. Trans Assoc Am Physicians.
1968;81:334-43.
68. HAESELER F, BODEL PT, A T K I N S E. Characteristics of pyrogen pro-
duction by isolated rabbit Kupffer cells in vitro. J Reticuloendothel
Soc. 1977;22:569-81.
69. M I C K E N B E R G ID, R O O T RK, W O L F F SM. Bactericidal and metabolic
properties of human eosinophils. Blood. 1972;39:67-80.
70. BODEL PT. Tumors and fever. Ann NY Acad Sci. 1974;230:6-13.
71. BODEL P. Spontaneous pyrogen production by mouse histiocytic and
myelomonocytic tumor cell lines in vitro. J Exp Med. 1978;147:1503-
16.
72. SNELL ES, ATKINS E. Interactions of gram-negative bacterial endotox-
in with rabbit blood in vitro. Am J Physiol. 1967;212:1103-12.
73. R O O T RK, N O R D L U N D JJ, W O L F F SM. Factors affecting the quantita-
tive production and assay of human leukocytic pyrogen. / Lab Clin
Med. 1970;75:679-93.
74. M O O R E DM, C H E U K SF, M O R T O N J D , B E R L I N R D , W O O D WB J R .
Studies on the pathogenesis of fever: XVIII. Activation of leukocytes
 for pyrogen production. J Exp Med. 1970;131:179-88.
75. G A N D E R GW, K E N N Y M. Characteristics of a leukocyte activator for
pyrogen production isolated from rabbit peritoneal exudate fluid. In:
COOPER KE, LOMAX P, SCHONBAUM E, eds. Drugs, Biogenic Amines
and Body Temperature. Basel: S. Karger; 1977:111-7.
76. H A H N H H , C H E U K SF, M O O R E D M , W O O D WB J R . Studies on the
pathogenesis of fever: XVII. The cationic control of pyrogen release
from exudate granulocytes in vitro. J Exp Med. 1970;131:165-78.
77. BERLIN RD, W O O D WB JR. Studies on the pathogenesis of fever: XII.
Electrolytic factors in influencing the release of endogenous pyrogen
from polymorphonuclear leukocytes. J Exp Med. 1964;119:697-714.
78. C H E U K SF, H A H N HH, M O O R E DM, K R A U S E D N , T O M A S U L O PA,
W O O D WB J R . Studies on the pathogenesis of fever: XX. Suppression
and regeneration of pyrogen-producing capacity of exudate granulo-
cytes. J Exp Med. 1976;132:127-33.
79. H A H N H H , C H E U K SF, E L F E N B E I N CDS, W O O D WB J R . Studies on
the pathogenesis of fever: XIX. Localization of pyrogen in granulo-
cytes. / Exp Med. 1970;131:701-10.
80. BODEL P. Colchicine stimulation of pyrogen production by human
blood leukocytes. J Exp Med. 1976;143:1015-26.
81. BERLIN RD, W O O D WB JR. Studies on the pathogenesis of fever: XIII.
The effect of phagocytosis on the release of endogenous pyrogen by
polymorphonuclear leukocytes. J Exp Med. 1964;119:715-26.
82. B E R N H E I M HA, W E N C K, B O D E L PT. C A M P and the release of en-
dogenous pyrogen. Clin Res. 1978;26:625A. Abstract.
83. BODEL P. Studies on the mechanism of endogenous pyrogen produc-
tion: I. Investigation of new protein synthesis in stimulated human
blood leucocytes. Yale J Biol Med. 1970;43:145-63.
84. N O R D L U N D JJ, R O O T RK, W O L F F SM. Studies on the origin of human
leukocytic pyrogen. J Exp Med. 1970;131:727-43.
85. M O O R E D M , M U R P H Y PA, C H E S N E Y PJ, W O O D WB J R . Synthesis of
endogenous pyrogen by rabbit leukocytes. J Exp Med. 1973;137:1263-
74.
86. ATKINS E, BODEL P. Fever. N Engl J Med. 1972;286:27-34.
87. FELDBERG W, MYERS RD. Changes in temperature produced by mi-
cro injection of amines into the anterior hypothalamus of the cat. /
Physiol (Lond). 1965;177:230-45.
88. FELDBERG W, LOLTI VJ. Temperature responses to monoamines and
an inhibitor of MAO injected into the cerebral ventricles of rats. Br J
Pharmacol Chemother. 1967;31:152-61.
89. COOPER KE, C R A N S T O N WI, H O N O U R AJ. Effects of intraventricular
and intrahypothalamic injection of noradrenaline and 5-HT on body
temperature in conscious rabbits. J Physiol (Lond). 1965;181:852-64.
90. BLIGH J, C O T T E WH, MASKREY N. Influence of ambient temperature
on the thermoregulatory responses to 5-hydroxytryptamine, noradre-
naline and acetylcholine injected into the lateral cerebral ventricles of
sheep, goats and rabbits. J Physiol (Lond). 1971;212:377-92.
91. W O O L F CJ, LABURN HP, W I L L I E S G H , R O S E N D O R F F C. Hypothalam-
ic heating and cooling in monoamine depleted rabbits. Am J Physiol.
1975;228:569-74.
92. BORSOOK D, LABURN HP, R O S E N D O R F F C, W I L L I E S G H , W O O L F CJ.
A dissociation between temperature regulation and fever in the rabbit.
J Physiol (Lond). 1977;266:423-33.
93. LABURN H, W O O L F CJ, W I L L I E S G H , R O S E N D O R F F C. Pyrogen and
prostaglandin fever in the rabbit: II. Effects of noradrenaline depletion
and adrenergic receptor blockade. Neuropharmacology. 1975; 14:405-
11.
94. LIPTON JM, TRZCINKA GP. Persistence of febrile response to pyrogens
after P O / A H lesions in squirrel monkeys. Am J Physiol.
1976;231:1638-48.
95. G I A R M A N NJ, T A N A K A C, M O O N E Y J, A T K I N S E. Serotonin, norepi-
nephrine, and fever. In: GAROTTINI S, SHORE PA, eds. Advances in
Pharmacology, vol. 6. New York: Academic Press; 1968:307-17.
96. FELDBERG W, MYERS RD, VEALE WL. Perfusion from cerebral ven-
tricle to cisterna magna in the unanesthetized cat: effect of calcium on
body temperature. J Physiol (Lond). 1970;207:403-16.
97. MYERS RD, VEALE WL. The role of sodium and calcium ions in the
hypothalamus in the control of body temperature of the unanesthetized
cat. J Physiol (Lond). 1971;212:411-30.
98. MYERS R D , TYTELL M. Fevers: reciprocal shift in brain sodium to
calcium ratio as the set-point temperature rises. Science. 1972; 178:765-
7.
99. FELDBERG W, SAXHNA PN. Fever produced by prostaglandin E,. J
Physiol (Lond). 1971;217:547-56.
100. STITT JT. Prostaglandin E, fever induced in rabbits. J Physiol (Lond).
1973;232:163-79.
101. BLIGH J, M I L T O N AS. The thermoregulatory effects of prostaglandin
E, when infused into a lateral cerebral ventricle of the Welsh Mountain
Sheep at different ambient temperatures. / Physiol (Lond).
1973;229:30-1. Abstract.
102. MILTON AS, W E N D L A N D T S. Effects on body temperature of prosta-
glandins of the A, E and F series on injection into the third ventricle of
unanesthetized cats and rabbits. J Physiol (Lond). 1971;218:325-36.
Downloaded From: http://annals.org/ by a University of Otago User on 12/12/2016
103. FELDBERG W, G U P T A KP. Pyrogen fever and prostaglandin-like activ-
ity in cerebrospinal fluid. J Physiol (Lond). 1973;228:41-53.
104. V A N E JR. Inhibition of prostaglandin synthesis as a mechanism of
action for aspirin-like drugs. Nature. 1971;231:232-5.
105. F E L D B E R G W, G U P T A K P , M I L T O N AS, W E N D L A N D T S. Effect of
pyrogen and antipyretics on prostaglandin activity in cisternal C.S.F.
of unanesthetized cats. J Physiol (Lond). 1973;234:270-303.
106. VEALE WL, COOPER KE. Comparison of site of action of prostaglan-
din E and leucocyte pyrogen in brain. In: LOMAX P, SCHONBAUM E,
JACOB J, eds. Temperature Regulation and Drug Action. Basel: S. Kar-
ger; 1975:218-26.
107. C R A N S T O N WI, H E L L O N RF, M I T C H E L L D. A dissociation between
fever and prostaglandin concentration in cerebrospinal fluid. J Physiol
(Lond). 1975;253:583-92.
108. C R A N S T O N WI, D U F F GW, H E L L O N RF, M I T C H E L L D, T O W N S E N D
Y. Evidence that brain prostaglandin synthesis is not essential in fever.
J Physiol (Lond). 1976;259:239-49.
109. LABURN H, M I T C H E L L D, R O S E N D O R F F C. Effects of prostaglandin
antagonism on sodium arachidonate fever in rabbits. / Physiol (Lond).
1977;267:559-70.
110. WILLIES GH, W O O L F CJ, ROSENDORFF C. The effect of sodium salicy-
late on dibutyryl cyclic AMP fever in the conscious rabbit. Neurophar-
macology. 1976;15:9-10.
111. DASCOMBE MJ, M I L T O N AS. The effects of cyclic adenosine 3',5' mon-
ophosphatr and other adenine nucleotides on body temperature. J
Physiol (Lond). 1975;250:143-60.
112. PHILIPP-DORMSTON WK. Evidence for the involvement of adenosine
3',5'-cyclic monophosphate in fever genesis. Pfluegers Arch.
1976;362:232-7.
113. DASCOMBE MJ, M I L T O N AS. Cyclic adenosine-3',5' monophosphate in
cerebrospinal fluid during thermoregulation and fever. J Physiol
(Lond). 1976;263:441-63.
114. W O O L F CJ, W I L L I E S G H , LABURN H, R O S E N D O R F F C. Pyrogen and
prostaglandin fever in the rabbit: I. Effects of salicylate and the role of
cyclic AMP. Neuropharmacology. 1975;14:397-403.
115. ROSENDORFF C. Neurochemistry of fever. S Afr J Med Sci.
1976;41:23-48.
116. T H A U E R R. Thermosensitivity of the spinal cord. In: H A R D Y J D ,
G A G G E AP, STOLWIJK J A J, eds. Physiological and Behavioral Tem-
perature Regulation. Springfield, Illinois: Charles C Thomas; 1970:472-
9.
117. M C C O O K RD, R A N D A L L WC, HASSLER CR, M I H A L D Z I C N, W U R -
STEN RD. The role of cutaneous thermal receptors in sudomotor con-
trol. See Reference 116, pp. 627-33.
118. BLIGH J. The thermosensitivity of the hypothalamus and thermoregu-
lation in mammals. Biol Rev. 1966;41:317-67.
119. ANDERSSON B, G R A N T R, LARSSON C. Central control of heat loss
mechanisms in the goat. Acta Physiol Scand. 1956;37:261-80.
120. H A M M E L HT, H A R D Y JD, F u s c o MM. Thermoregulatory responses
to hypothalamic cooling in unanesthetized dogs. Am J Physiol.
1960;198:481-6.
121. ROSENDORFF C, MOONEY JJ. Central nervous system sites of action of
purified leucocyte pyrogen. Am J Physiol. 1971;220:597-603.
122. COOPER KE, C R A N S T O N WI, H O N O U R J. Observations on the site and
mode of action of pyrogens in the rabbit brain. / Physiol (Lond).
1967;191:325-37.
123. JACKSON DL. A hypothalamic region responsive to localized injection
of pyrogens. J Neurophysiol. 1967;30:586-602.
124. VILLABLANCA J, MYERS RD. Fever produced by microinjection of
typhoid vaccine into hypothalamus of cats. Am J Physiol.
1965;208:703-7.
125. BARD P, WOODS J. Central nervous region essential for endotoxin fe-
ver. Trans Am Neurol Assoc. 1962;87:37-9.
126. H E N S E L H. Neural process in thermoregulation. Physiol Rev.
1973;53:948-1017.
127. N A K A Y A M A T, H A M M E L HT, H A R D Y JD, EISENMAN JS. Thermal
stimulation of electrical activity of single units of the preoptic region.
Am J Physiol. 1963;204:1122-6.
128. HARDY JD, HELLON RF, S U T H E R L A N D K. Temperature-sensitive
neurons in the dog's hypothalamus. / Physiol (Lond). 1964; 173:242-
53.
129. EISENMAN JS, JACKSON DC. Thermal response patterns of septal and
preoptic neurons in cats. Exp Neurol. 1967;19:33-45.
130. W I T A, W A N G SC. Temperature-sensitive neurons in preoptic/anterior
hypothalamus region: effects of increasing ambient temperature. Am J
Physiol. 1968;215:1151-9.
131. NAKAYAMA T, H A R D Y JD. Unit responses in the rabbit's brain stem to
changes in brain and cutaneous temperature. / Appl Physiol.
1969;27:848-57.
132. H E L L O N RF. Hypothalamic neurons responding to changes in hypoth-
alamic and ambient temperatures. See Reference 116, pp. 463-71.
133. G U I E U JD, H A R D Y J D . Effects of heating and cooling of the spinal
cord on preoptic unit activity. J Appl Physiol. 1970;29:673-83.
Bernheim et al. • Fever 269
 134. C A B A N A C M, S T O L W I J K JAJ, H A R D Y J D . Effect of temperature and
pyrogens on single-mnit activity in the rabbit's brain stem. J AppI Phys-
iol. 1968;24:645-52.
135. W I T A, W A N G SC. Temperature-sensitive neurons in preoptic/anterior
hypothalamic region: action of pyrogen and acetylsalicylate. Am J
Physiol. 1968;215:1160-9.
136. SCHOENER EP, W A N G SC. Leukocytic pyrogen and sodium acetylsali-
cylate on hypothalamic neurons in the cat. Am J Physiol.
1975;229:185-90.
137. S T I T T JT, H A R D Y JD, STOLWIJK JA. PGE, fever: its effect on therm-
oregulation at different low ambient temperatures. Am J Physiol.
1974;227:622-9.
138. A N D E R S E N HT, H A M M E L H T , H A R D Y J D . Modifications of the re-
sponse to pyrogen by hypothalamic heating and cooling in the unan-
esthetized dog. Acta Physiol Scand. 1961;53:247-54.
139. H A M M E L HT. The set-point in temperature regulation: analogy or re-
ality. In: BLIGH J, MOORE RE, eds. Essays On Temperature Regula-
tion. Amsterdam:North-Holland; 1972:121-37.
140. COOPER KE. The body temperature "set-point" in fever. See Reference
139, pp. 149-62.
141. CABANC M. Thermoregulatory behavior. See Reference 139, pp. 19-32.
142. EISENMAN JS. Depression of preoptic thermosensitivity by bacterial
pyrogen in rabbits. Am J Physiol. 1974;227:1067-73.
143. M I T C H E L L D, S N E L L E N JW, A T K I N S AR. Thermoregulation during
fever: change of set-point or change of gain. Pfluegers Arch.
1970;321:293-302.
144. BLIGH J. Neuronal models of mammalian temperature regulation. See
Reference 139, pp. 105-20.
145. MACPHERSON RK. The effect of fever on temperature regulation in
man. Clin Sci. 1959;18:281-7.
146. COOPER KE, CRANSTON WI, SNELL ES. Temperature regulation dur-
ing fever in man. Clin Sci. 1964;27:345-56.
147. A T K I N S E. Fever. In: M A C B R Y D E CM, B L A C K L O W RS, eds. Signs and
Symptoms. 5th ed. Philadelphia: J. B. Lippincott; 1970:451-75.
148. PALMES ED, PARK CR. The regulation of body temperature during
fever. Arch Environ Health 1965;11:749-59.
149. S A T I N O F F E, M C E W E N G N J R , W I L L I A M S BA. Behavioral fever in
newborn rabbits. Science. 1976;193:1139-40.
150. P I T T M A N QJ, C O O P E R K E , V E A L E HL, VAN P E T T E N FR. Observa-
270 August 1979 • Annals of Internal Medicine • Volume 91 • Number 2
Downloaded From: http://annals.org/ by a University of Otago User on 12/12/2016
tions on the development of the febrile response to pyrogens in sheep.
Clin Sci Mol Med. 1974;46:591-602.
151. BLATTEIS CM. Postnatal development of pyrogenic sensitivity in guin-
ea pigs. J Appl Physiol. 1975;39:251-7.
152. B E N N E T T IL J R , NICASTRI A. Fever as a mechanism of resistance.
Bacteriol Rev. 1960;24:16-34.
153. A T W O O D RP, KASS EH. Relationship of body temperature to the le-
thal action of bacterial endotoxin. J Clin Invest. 1964;43:151-9.
154. PORTER PJ, K A S S EH. Mediation by the central nervous system of the
lethal action of bacterial endotoxin. Clin Res. 1962;10:185. Abstract.
155. CONNOR DG, K A S S EH. Effect of artificial fever in increasing suscepti-
bility to bacterial endotoxin. Nature. 1961;190:453-4.
156. K L U G E R MJ, R I N G L E R DH, A N V E R MR. Fever and survival. Science.
1975;11:166-8.
157. BERNHEIM HA, K L U G E R MJ. Effect of drug-induced antipyresis on
survival. Science. 1976;16:237-9.
158. COVERT JB, REYNOLDS WW. Survival value of fever in fish. Nature.
1977;267:43-5.
159. A S H M A N RB, G O M E Z - B A R R I E T O JW, N A H A M I A S AJ. The effect of
temperature on the in vitro transformation of human peripheral blood
lymphocytes. Fed Proc. 1976;35:821. Abstract.
160. ELLINGSON HV, CLARK PF. The influence of artificial fever on mecha-
nisms of resistance. J Immunol. 1942;43:65-83.
161. B E R N H E I M HA, B O D E L PT, A S K E N A S E PW, A T K I N S E. Effects of
fever on host defence mechanisms after infection in the lizard Dipso-
saurus dorsalis. Br J Exp Pathol. 1978;59:76-84.
162. WEINBERG ED. Iron and infection. Microbiol Rev. 1978;42:45-66.
163. K A M P S C H M I D T R F , L O N G R D , U P C H U R C H H F . Neutrophil releasing
activity in rats injected with endogenous pyrogen. Proc Soc Exp Biol
Med. 1972;139:1224-6.
164. K A M P S C H M I D T R F , U P C H U R C H H F , E D D I N G T O N CL, P U L L I A M LA.
Multiple biological activities of a partially purified leukocytic endoge-
nous mediator. Am J Physiol. 1973;224:530-3.
165. K L E M P N E R MS, D I N A R E L L O CA, G A L L I N JI. Human leukocytic py-
rogen induces release of specific granule contents from human neutro-
phils. / Clin Invest. 1978;61:1330-6.
166. G R I E G E R TA, K L U G E R MJ. Fever and survival: the role of serum iron.
J Physiol (Lond). 1978;279:187-96.