Download Fever in Ectotherms: Evolutionary Implications Fever results when

AMER. ZOOL..1 9:295-304 (1979).
Fever in Ectotherms: Evolutionary Implications
MATTHEW J. KLUGER
Department of Physiology, University of Michigan Medical School,
Ann Arbor, Michigan 48109
SYNOPSIS Fever, an elevated thermoregulatory "set-point," occurs in vertebrates from
fishes through mammals in response to infection with appropriate pathogens. The long
phylogenetic history of fever supports the hypothesis that fever has an adaptive or beneficial role (i.e., fever is a component of the host's immunological defenses). Besides providing
insight into determining the role of fever in disease, ectothermic vertebrates have also
served as excellent animal models to specifically answer many questions relating to fever
and disease. For example, survival studies using goldfishes, lizards, and newborn mammals
(which are also virtually ectothermic) have shown that an elevated body temperature increases the survival rate of the infected organism. Furthermore, by using ectotherms it has
been possible to demonstrate that the reduction in serum iron which accompanies most
infections is not directly attributable to an elevation in body temperature. Nevertheless, a
rise in body temperature, coupled with a fall in serum iron, appears to constitute a coordinated host defense mechanism in response to at least some bacterial infections in reptiles
and mammals, and perhaps other groups of vertebrates.
INTRODUCTION
There is, occasionally, some misunderstanding
concerning fever and hyperFever results when the thermoregulais not equivalent to hyperthermia.
Fever
tory "set-point" becomes elevated. While
thermia.
During
hyperthermia, the ormany of the details of the pathways leading
ganism's
body
temperature
is raised above
to a raised thermoregulatory "set-point"
the
thermoregulatory
"set-point."
This
are still unknown, it is currently believed
the
result
of
exercise
(particularly
might
be
that in response to some activator or stimulating agent (bacteria, viruses, etc.) the on a warm day), or in response to some
host organism produces pyrogenic pro- drug, or could be induced by some other
teins collectively known as endogenous disturbance. The hyperthermic organism
pyrogens (see review in Dinarello and actively attempts to return its body tempWolff, 1978). These proteins, by some erature toward the thermoregulatory
poorly-defined mechanism, raise the ther- "set-point." In a human being, this is acmoregulatory "set-point" resulting in the complished by reducing metabolic heat
initiation of both physiological and be- production, increasing skin blood How,
havioral responses which lead to a rise in sweating, increasing the exposed surface
body temperature. In a mammal such as a area (stretching out, removing clothing,
human being this is accomplished by in- etc.), drinking cool liquids, and by other
creasing metabolic heat production, de- physiological and behavioral means.
creasing skin blood flow, decreasing the Clearly the effector responses during fever
exposed surface area (huddling, adding and hyperthermia are diametrically oppoextra blankets, etc.), drinking warm liquids site.
This distinction between fever and hyand by other physiological and behavioral
perthermia is most striking when one
means.
studies fevers in ectotherms. This is because any substantial elevation in body
Supported by NIH Al 13878. I thank W. W. temperature in an ectothermic organism
Reynolds for organizing, and inviting me to, this (which is permitted to select its "preferred"
symposium. Page charges for publication of this
paper were supported by NSF Grant PCM78-05691 body temperature) must be caused by
some change in its thermoregulatory "setto W. W. Reynolds.
295
296
MATTHEW J. KLUGER
point." For example, if one places a lizard
or a fish in a warm (above their thermal
preference) environment, the ectotherm
soon attempts to move to a cooler microclimate. In contrast, following an injection of some fever-inducing (pyrogenic)
agent, these ectotherms will actively seek
out this warm environment, and as a result
their body temperature will rise.
Within the last few years research from
many laboratories has shown that both endotherms and ectotherms develop fevers
in response to infection. The work on
fever in ectotherms began when Vaughn et
at. (1974) demonstrated that the desert
Based on the many similarities between
mammalian and non-mammalian fever, it
is likely that fever in the vertebrates had a
common origin. In other words, it is probable that the ability to increase the thermoregulatory "set-point" in response to
some pyrogenic stimulus has existed in the
vertebrate central nervous system for
hundreds of millions of years. This is not
particularly surprising since the area generally thought to be largely responsible
for integrating thermal information, the
hypothalamus, is phylogenetically conservative. For example, studies involving
vertebrates from fishes through mammals
have
shown that the hypothalamus is
iguana (Dipsosaurus dorsalis) would select a
warmer environmental temperature fol- thermally sensitive in all classes of vertelowing inoculation with the Gram-negative brates (see reviews in Bligh, 1973 and in
bacteria Aeromonas hydrophila. This work Kluger, 1979). Since it is generally believed
was followed by a series of studies from that pyrogens exert their effects largely at
several laboratories which showed that the level of the hypothalamus (Cooper et
many non-mammalian vertebrates also ai, 1976) it seems reasonable to speculate
developed fevers in response to various that the hypothalamic neurons capable of
stimuli. In fact, it has recently been shown responding to pyrogens by changing their
that even crayfish develop fevers in re- firing rate, patterns, etc., have had a long
sponse to injection with bacteria (Casterlin phylogeny.
and Reynolds, 1977a), and PGE, (prostaThe assumption of a common phyloglandin E,) (Casterlin and Reynolds, 1978). genetic origin for the febrile mechanism
Much of the work on fevers in non- allows the investigator to utilize various
mammalian vertebrates is summarized in species of ectotherms as animal models
Table 1. (For more detail, see reviews in to study various characteristics of fever
Kluger, 1978a,b).
and disease. The ectotherm has at least one
major advantage in studies concerning
fever and disease: an easily manipulated
EVOLUTIONARY IMPLICATIONS
body temperature. It is virtually impossible
to substantially alter the body temperature
Origin ojjever
of an adult mammal for any considerable
There are many similarities between the length of time; however, the body temperfebrile responses in mammals and in other ature of the temperature-labile ectotherm
vertebrates. Table 1 summarizes the ex- can be raised oi lowered simply by placing
periments which have shown that non- the ectotherm in a constant-temperature
mammalian vertebrates respond to various chambei or bath set at a warm oi cool
stimuli by developing fevers. These are temperature. The manipulation of the
precisely the kind of stimuli which induce bod) temperature of the ectotherm allows
fevers in mammals. Another similarity the investigator to determine whether the
concerns the effects of antipyretic drug response under stud)' is attributable to
therapy. Many drugs, such as sodium temperature or to some other factor. Foi
salicylate and acetaminophen, are known example, during infection it is known that
to reduce or attenuate fevers in mammals. serum iron levels fall in human beings and
These drugs are also effective antipyretics other mammals (see review in W'einberg.
1974). It has recentl\ been shown that this
in non-mammalian sei lebiates (D'Alccv
and Kluger, 1975; Bernheim and Klugei, fall in serum iron is induced In a piotein
bc'!ie\t'(l to be endogenous pyrogen (\Iei
/; Reynolds, 1977).
297
FEVER AND DISEASE
TABLE 1. Febrile responses of the non-mammalian vertebrates.
Species
Callus domesticus
Gallus domesticus
E. coli endotoxin (iv)
Salmonella abortus equi
Investigators
van Miert and Frens (1968)
Pittman <•< a/. (1976)
Gallus domesticus
endotoxin (ant. hypolhal.)
Prostaglandin E, (ant.
hypothal.)
Pittman etal. (1976)
Columba hvia
Pasteurella multocida (iv, ip)
D'Alecyand Kluger(1975)
Dipsosaurus dorsalis
Aeromonas hydrophila
Vaughn rt al. (1974)
2
UJ
-J
Activator of fever*
(intracardiac, [ic])
Dipsosaurus dorsalis
Dipsosaurus dorsalis
Dipsosaurus dorsalis
Pasteurella haemolytica (ic)
Citrobacter diversus (ic)
Iguana iguana
Aeromonas hydrophila (ic)
Kluger(1978a)
Aeromonas hydrophila (sc)
Aeromonas hydrophila (ip)
Aeromonas hydrophila (ip)
Mycobacterium sp. (ip)
i
Hyla cmerea
Rana pipiens
Rana catesbeiana
Rana esculenta
Rana esculenta
Kluger (1977)
Casterlin and Reynolds (19776)
Casterlin and Reynolds (19776)
Myhreetal. (1977)
Myhreetal. (1977)
i
<
Rana esculenta
I
Micropterus salmoides
Lepomis macrochirus
Lepomis macrochinus
Lepomis macrochirus
Carassius auratus
Carassius auratus
u
a.
oi
If)
z<
3
r
vi
u>
lizard or rabbit-derived
endogenous pyrogen (ic)
frog-derived endogenous
pyrogen (ip)
Prostaglandin E,
(diencephalon)
Aeromonas hydrophila (ip)
Aeromonas hydrophila (ip)
E. coli endotoxin (ip)
Staphylococcus aureus (ip)
Aeromonas hydrophila (ip)
E. coli endotoxin (ip)
Kluger (1978a)
Kluger (19786)
Bernheim and Kluger (1977)
Myhre et al. (1977)
Reynolds et al. (1976)
Reynolds et al. (1976)
Reynolds etal. (1978a)
Reynolds et al. (1978a)
Reynolds and Covert (1977)
Reynolds et al. (19786)
Stimulus used by investigators to induce fever.
\\m<xn etal., 1977). Is this fall in serum iron
induced by the elevation in body temperature, or is the endogenous pyrogen independently inducing both a fever and a fall
in serum iron? We have been able to answer this question using the lizard Dipsosaurus dorsalis (Grieger and Kluger,
1978). Elevating the body temperature of
the uninfected lizards led to no changes in
serum iron concentrations. However, in
response to infection, serum iron levels fell
regardless of whether body temperature
was elevated to the febrile level or maintained at the afebrile level. Clearly, the fall
in serum iron is the result of the inducer
protein, and not of the rise in body temperature.
Function oj fever
For thousands of years, the question of
whether fever is beneficial or harmful has
been debated. According to the humoral
theory of disease, a person became ill when
one of the bodily "humors" was produced
in excess (Yost, 1950). The response of the
infected organism to this imbalance was
first to "cook" the "raw" humor (i.e.,
develop a fever) and then to evacuate the
cooked humor by sweating, vomiting, or
defecating. This view of fever as a host defense mechanism was espoused by Hippocrates and other ancient physicians, and
persisted until the latter part of the 19th
century (Kluger, 1979). For some reason
(perhaps related to the advent of antipyretic drugs), the view of fever as an adaptive
response changed, so that it is now fairly
common for physicians or laymen to prescribe antipyretic drugs, such as aspirin,
for any febrile episode.
In 1960 Bennett and Xicastri reviewed
298
MATTHEW J. KLUGER
the experimental evidence concerning the
function of fever and, based on the information available to them, were unable to
conclude whether fever was beneficial or
harmful. It has been very difficult to resolve the question of fever's function in
mammals. Consequently, the simplest experiment would involve infecting a group
of mammals with live bacteria or viruses,
and then allowing some to develop the elevated body temperature and preventing
others from developing an elevated temperature. Differences in survival rate could
then be compared between the two groups.
The problem with this experimental design is that, in order to manipulate the
body temperature of most adult mammals
(particularly those commonly used in laboratory investigations), one has to use fairly
drastic procedures. These could entail infusing drugs, subjecting the animals to extremely high or low environmental temperatures, heating or cooling their hypothalami, etc. All of these experimental manipulations would make the interpretation
of the survival data difficult.
I believe that the results of the investigations on the evolution of fever have helped
to resolve the question of fever's function.
This is because fever is energetically very
expensive. Whether an organism is an endotherm or an ectotherm, a rise in body
temperature results in substantial increases
in metabolic heat production and therefore energy expenditure. For example, assuming a Q10 of 2.5 for most biochemical
reactions, a rise in body temperature of 2
or 3°C will result in an increase in energy
expenditure of approximately 25%. While
it is possible that fever arose dp novn as a
harmful trait, linked genetically to some
beneficial immunological effect, the widespread nature of the phenomenon, and
the substantial metabolic costs of small elevations in body temperature argue against
this. There is obviously no selective pressure for maladaptations. Since fever has
apparently existed for millions of years in
numerous vertebrate orders and classes
without diminishing in magnitude, the
comparative or phylogenetic approach argues strongly for fever being adaptive; that
is, fe\er is likely a component of the host
organism's immunological defense repertoire.
ECTOTHERMS AS ANIMAL MODELS TO STUDY
FEVER AND DISEASE
As described above, ectotherms provide
excellent animals to investigate various
questions concerning fever and disease.
One of the areas in which ectotherms have
been used extensively has been to resolve
the question of fever's adaptive value.
Fever and survival
We have used the lizard (D. dorsalis) to
resolve the question of fever's adaptive
value. Lizards were infected with live A.
hydrophila and placed in constant-temperature chambers set at 34, 36, 38, 40,
or 42°C. (Kluger e< ai, 1975). These represented temperatures ranging from afebrile (34-38°C) to febrile (40-42°C). The results of this study are shown in Figure 1.
Lizards maintained at a febrile temperature had a higher percent survival than
those maintained at the normal afebrile
temperature of 38°C, or at temperatures
below (36 or 34°C) their preferred body
temperature. To determine whether this
increased survival at febrile temperatures
was related specifically to decreased bacterial growth, bacteria were grown in vitro at
temperatures ranging from 34 to 42°C. We
found no relationship between temperature and the growth rate of these bacteria
from 34-40°C; however, at 42°C the bacteria grew more slowly. The fact that moderate fevers (40°C) did not diminish the
growth of these bacteria has been confirmed
in a later study by Bernheim et ai (1978).
To determine whether drug-induced
antipyresis would adversely affect the survival rate of these lizards, we infected additional lizards with live bacteria, as well as
with a non-toxic dose of sodium salicylate.
The dose of salicylate used was selected because an earlier study (Bernheim and
Kluger, 1976«) had shown that this dose of
antipyretic led to an attenuation of the
fever in some, but not all lizards. It was
found that in those lizards in which the
fever failed to develop, the mortality rate
299
FEVER AND DISEASE
100 m
*%
^^ "• —
^ ^ *
80 -
* •
^k^
^
"-vx
^
•
•
40<'0(12)
-h
60 oc
z>
CO
A \
- \\
20 \\
38C '0(36)
40 -
1
K
1
3 6 C > r* /JO]
34 £ > Q(\O)
1
1
1
1
0
TIME (days)
FIG. 1. Percentage survival of D. dorsalis injected 34° to 42°C. The number of lizards in each group is
with A. hydrophila and maintained at temperatures of given in parenthesis, (from Kluger et al., 1975)
was 100%, while in those lizards in which enced no mortality (Fig. 2). The goldfish
the sodium salicylate failed to attenuate or maintained at 30.5°C had a survival rate of
reduce the fever, their survival rate was 84%, while those at 28°C had a survival
100% (Bernheim and Kluger, 1976ft). rate of 64%, and those at 25.5°C had a surThese studies demonstrated that prevent- vival rate of only 24% (Fig. 2).
Overall, the studies using ectothermic
ing the development of an elevated body
temperature by physical means (Kluger et vertebrates to determine fever's function
al., 1975) or by pharmacological means indicate that the prevention of an elevated
(Bernheim and Kluger, 1976ft) was harm- temperature during bacterial infection is
harmful. Whether this is a general pheful to the infected animals.
Covert and Reynolds (1977) have found nomenon throughout the vertebrates is as
that fever also has survival value in fishes. yet unknown; however, similar studies
They infected goldfish (Carassim auratus) resulting in virtually the same conclusion
with live bacteria (A. hydrophila) and main- have been performed using newborn
tained these animals at either afebrile mammals infected with viruses. Newborn
temperatures (25-28°C) or at the moder- mammals tend to be fairly thermolabile
ate febrile temperature of 30.5°C. In addi- (Pembrey, 1895), and as a result one can
tion, ten goldfish were allowed to thermo- manipulate their body temperatures in
regulate behaviorally following infection much the way that one can manipulate the
with live bacteria; these fish selected a mean body temperature of ectotherms. In one
body temperature of 32.7°C, and experi- study, newborn mice were infected with
300
MATTHEW J. KLUGER
100
*32.7°c no;
80
*30.5°C (25)
60
*28.0° C (25)
40
20
0
25.5° C (25?
i
i
i
4 8 12
24
48
72
Time (hours)
FIG. 2. Percent survival of goldfish infected with A.
hydrophila and maintained at temperatures of 25.5°C,
28.0°C, and 30.5°C; 10 goldfish were allowed to behaviorally thermoregulate and selected a mean body
temperature of 32.7°C. The numbers of fishes in each
group is given in parenthesis. (From Covert and
Reynolds, 1977)
Coxsacki B, virus (Teisner and Haahr,
1974). One group was held at 34°C, and as
a result had a mean body temperature
close to 36°C (some 2 to 3°C higher than
control mice held at normal room temperature), similar to the body temperature of
adult mice. The mice held at 34°C had a
lower mortality rate than did the control
mice. Similar results were found by Carmichael et al. (1969) for 2-5-day-old dog
pups which were inoculated with canine
herpesvirus. Based on these results, Haahr
and Mogensen (1977) suggested that one
of the reasons that generalized herpes infections are greatly over-represented in
premature babies might be attributable to
their restricted temperature regulation
and poor febrile responses.
and indirect effects. There are many
examples of the direct effects of temperature on both viral and bacterial growth.
One such example is the effects of temperature on the growth of poliomyelitis virus
(Lwoff, 1969). The yield of these viruses
when grown at 37°C was 250 times greater
than when grown at 40°C. The mechanism
behind the inhibitory effects of temperature on the growth of viruses is not known.
The effect of temperature on bacterial
growth is illustrated by the adverse effects
of temperatures as low as 40—41°C on the
gonorrhea gonococci (Carpenter et al.,
1933). Neurosyphilis spirochetes are also
killed by temperature elevations (Bruetsch,
1949), and it is this effect of elevated temperature which has provided the rationale
for fever therapy, a practice dating back
thousands of years (Kluger, 1979).
One component of the immune response which is thought to be increased by
temperature elevation is leucocyte function. There is considerable evidence that
the leucocyte mobility increases with temperature (Bryant et al., 1966; Phelps and
Stanislaw, 1969; Xahas rt al., 1971; Bern-
Mechanisms behind the function of fever
An elevation in body temperature might
enhance the survival of an infected organism directly by an effect of temperature
on the pathogen, indirectly by an effect of
temperature on the host's defense mechanisms, or by a combination of both direct
FEVER AND DISEASE
heim et al., 1978). Several investigators
have also reported that the bactericidal activity of leucocytes is also increased with
elevations in temperature. For example,
Sebag et al. (1977) noted that elevations in
temperature led to increased killing of
some species of bacteria, but had little effect on others. In another study, it was reported that the percentage of ingested
Staphylococcus bacteria killed increased as
temperature was raised from 26 to 36°C
(Craig and Sutter, 1966). As a result of this
study, it was suggested that fever could not
increase the intracellular killing power of
leucocytes, since most fevers in human
beings are in the range of perhaps 38 to
40°C. This is not technically correct. While
it is true that the average rectal temperature of a febrile individual might be 38 to
40°C during a fever, the average body
temperature will be considerably less,
perhaps only 36 or 37°C. This is because
the average body temperature incorporates the warmer tissues in the deep body
areas, for example the abdomen, chest
cavity, etc., along with the cooler peripheral areas, the skin, respiratory tract, limbs,
etc. Since many infections actually reside in
the cooler areas of the body, an increase in
the bactericidal activity of the white blood
cells at a temperature as low as 36°C might
still represent a beneficial effect of fever.
Another area of leucocyte function which
might be enhanced by small elevations in
temperature is lymphocyte transformation. It is well known that lymphocytes
undergo proliferation and transformation
in response to various stimulants. These
activated or "transformed" lymphocytes
are then capable of participating in various
aspects of the immune response. Studies
by Roberts and Steibigel (1977), and by
Ashman and Nahmias (1977), have shown
that in vitro temperatures approximating
moderate fevers in human beings (38.5 to
39.0°C) result in enhancement and acceleration of lymphocyte transformation in
response to various antigens. Other components of the immune response are also
thought to be enhanced by small elevations
in temperature. Among these are increased lysosome activity (l.woff, 1969;
Overgaard, 1977) and increased produc-
301
tion of interferon (Ho, 1970). Space does
not allow a detailed discussion of these
immunological processes.
Another way in which fever might be
beneficial is by a combination of direct and
indirect effects. For example, it is known
that during infections the levels of serum
iron fall in both reptiles and mammals.
This appears to be a response of the host to
some substance released by white blood
cells and currently thought to be endogenous pyrogen (Merriman et al., 1977). The
iron is stored in various sites such as the
liver and spleen and remains there until
the infection is over. Garibaldi (1972),
Weinberg (1974) and others have suggested that the growth potential of
pathogenic bacteria might be related to the
availability of iron or some other nutrient.
The reduction of some specific vital nutrient by the host organism might be a
defense mechanism, a process Kochan
(1973) termed "nutritional immunity."
Bacteria are usually able to obtain adequate amounts of iron from their growth
medium, whether this be a broth solution
or a person's plasma, by producing iron
chelating substances known as siderophores. This capacity for producing these
iron chelators by various species of bacteria has been shown by Garibaldi (1972)
to decrease with increasing temperature
in the range of normal to febrile body
temperature in mammals. Garibaldi (1972)
suggested that fever might thereby decrease growth rates of microorganisms
which are already in an iron-poor environment.
We have tested this "nutritional immunity" theory using lizards (Grieger and
Kluger, 1978). First, uninfected D. dorsalis
were subjected to afebrile and febrile temperatures. This led to no change in serum
iron levels. Following infection with A.
hydrophila, serum iron levels fell irrespective of whether the lizards were maintained at afebrile or febrile temperatures.
We concluded that the fall in serum iron
during infections is not temperature dependent, and that the protein (endogenous pyrogen?) responsible for inducing
the fever and reducing serum iron works
independently. When we injected infected
302
MATTHEW J. KLUGER
lizards with excess iron, their mortality rate
rose significantly, suggesting that the fall in
serum iron was a host defense response.
The synergistic nature of fever and the
reduction in serum iron was demonstrated
by the results of our bacterial growth experiments. Pathogenic bacteria were
grown at afebrile (38°C) and febrile (41°C)
bath temperatures. The growth of the bacteria in a broth containing the normal
non-infected levels of iron was virtually
identical at 38 and 41°C. However, when
the iron levels in the broth were either
reduced or made less available to the bacteria by adding an iron chelator, this led to
marked reductions in the growth of the
bacteria at the febrile, but not the afebrile,
temperature. Based on these results, we
concluded that a reduction in serum iron
and the development of a fever constitute
a coordinated host defense response which
leads to a decrease in the growth potential
of pathogenic bacteria.
Further support for this theory has resulted from our investigations on fever as a
defense mechanism in rabbits. New Zea-
of the bath was raised to a febrile temperature (41°C), the growth of the bacteria
was inhibited by the low, but not the high,
iron concentrations. When the bacteria
were grown at a subphysiological level of
iron (19 pig Fe/100 ml growth medium),
there was no growth at febrile or at afebrile
temperatures. Furthermore, addition of
deferoxamine mesylate (an iron chelator)
to the growth medium slightly inhibited
the growth of the bacteria at 39 and 40°C,
severely attenuated the growth at 41°C,
and completely prevented the growth at 42
and 43°C. These data support the hypothesis that one of the mechanisms behind the
adaptive role of fever is the reduced ability
of pathogenic bacteria to grow well at elevated temperatures in an iron-poor
medium.
IMPLICATIONS
Based on the data presented above,
which suggest that fever has had a long
phylogeny, along with the specific experiland rabbits (Oryctolagus cuniculus) were in- ments which have demonstrated a survival
fected with live Pasteurella multocida (a value for fever, it is likely that any process
common rabbit pathogen), and their resul- which lowers the temperature of a febrile
tant fevers were correlated with their sur- subject (unless the fever is extremely high)
vival rates (Kluger and Vaughn, 1978). is harmful to the infected host. In addition,
The results demonstrated that there was a based on the results concerning iron and
positive correlation between the fever and infection, it appears that any process which
survival rates for fevers up to 2.25°C (a raises plasma or serum iron (e.g., eating
body temperature rise from about 39.50°C excessive amounts of iron) could be harmto 41.75°C). In a subsequent study we ful to the infected host.
found that during infection with P. mulThe converse of the above statements
tocida, plasma iron of rabbits fell from an might also be true; that is, elevating body
average of 261 pig Fe/100 ml plasma to 118 temperature above the normal febrile
pig Fe/100 ml plasma by 4 hours post- level, or reducing the iron concentration
injection, and to 66 pig Fe/100 ml plasma or accessibility (by adding iron chelators)
by 24 hours post-injection (Kluger and could have therapeutic value during infecRothenburg, 1978, 1979). To determine tion with certain species of pathogens.
whether the rise in body temperature
It is also known that other mineral con(fever) and the fall in plasma iron was a centrations change during infection. For
coordinated host defense response, P. example, serum zinc levels fall and copper
multocida were grown in vitro at various levels rise. It is not yet known, however,
temperatures and iron levels. At afebrile whether these changes along with the contemperatures (39 and 40°C) the bacteria comitant rise in body temperature congrew equally well at low (79 or 139 pig Fe/ stitute an immunological defense mecha100 ml growth medium) or high (266 pig nism. Clearly, the relationship between
Fe/100 ml growth medium) iron concen- fever and changes in trace elements is an
trations. However, when the temperature area which deser\es further study.
FEVER AND DISEASE
REFERENCES
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