If the body temperature is above 37,2
C
and is associated
with sweating, hyperventilation, and vasodilatation in the skin,
we speak of fever. At the beginning, gradual increase in body
temperature is observed together with muscle shivering,
vasocontriction in the skin, and piloerection. This situation is
called chills. Increased body temperature is achieved by lowered
loss of heat. Vasoconstriction in the skin and subcutaneous
tissue is the cause of pale color and dryness, the affected
person has a feeling of coldness. At the same time the
production of heat in the organism increases. The muscle tonus
increases, the spasms accur. Spasms may occur mainly in
children. When the vasodilatation starts in the skin, the
feeling of warmth and sweating occurs.
Fever may be provoked by many stimuli. Most often, they are bacteria and their endotoxins, viruses, yeasts, spirochets, protozoa, immune reactions, several hormones, medications, and synthetic polynucleotides. These substances are commonly called exogenic pyrogens. Cells stimulated by exogenic pyrogens form and produce cytokines called endogenic pyrogens. Endogenic pyrogens centrally affect the thermosensitive neurons in the preoptic area of the hypothalamus increase the production of heat and decrease in heat loss. The body temperature increses until it reaches the set point. This information is transferred by temperature of blood that flows around the hypothalamus. The decrease of temperature is controlled by activation of mechanisms regulating increased outcome of heat to the surrounding area. Increased outcome continues in favourable case until the new equilibrium is achieved.
The most important endogenic pyrogens are IL-1, IL-6
and cachectin also called the tumour
necrosis factor-
(TNF-
). These are glycoproteins that also
have other important effects. They are produced especially by
monocytes and macrophages but also by endothelial cells and
astrocytes. Also the interferons 
, 
and 
display the
pyrogenic activity.
After administration an endotoxin in an experiment, the
level of plasmatic TNF-
increases and fever occurs. Increased
concentrations of IL-1 and TNF-
are also found in sepsis. The
production of these cytokines is regulated by the positive feedback
mechanism. Besides this, macrophages activated by IFN-
may
increase the production of IL-1 and TNF-
primary induced by other
stimuli. On the other hand, glucocorticoids and prostaglandins
of group E may display inhibitory effect on the production of IL-1
and TNF-
. Released IL-1 and TNF-
are transported by blood. They
affect the target cells in the close proximity or in distant
sites. The target cells have specific receptors for IL-1 and
TNF-
. In the hypothalamus, IL-1 and TNF-
trigger the synthesis
of prostaglandis of group E from the arachidonic acid of cytoplasmic
membranes of target cells. Precise mechanism by which prostaglandin
PGE
reset the central thermostat, is not known.
Aspirin and the non-steroidal antiphlogistics display
antipyretic activity by inhibiting the cyclo-oxygenase, an enzyme responsible
for the synthesis of PGE
(these antipyretics don't inhibit
the production of TNF-
or IL-1). Glucocorticoids work
antipyretically by inhibiting the production of IL-1 and TNF-
,
and by inhibiting the metabolic processes of arachidonic acid.
In the process of fever, IL-1 and TNF-
play the central
role. Except introduced activity in fever,
they interfere with
many mechanisms in an organism. Some of their effects are
executed with the participation of metabolites of arachidonic
acid. IL-1 and TNF-
affect myelopoesis, release of neutrophils and
enhancement of their functions. They cause vasodilatation and
the increase the adhesivity of
cells, increase the production of PAF and
thrombomodulin by endothelial cells, proteolysis and
glycogenolysis in muscles, mobilisation of lipids from
adipocytes, proteosynthesis and glycogenolysis in the liver,
induce proliferation of fibroblasts, activate osteoclasts and
the release of collagenase from chondrocytes, induce slow wave
sleeping activity in the brain, the release of ACTH, beta
endorfins, growth hormone and vasopressin, the release of
insulin, cortisol, and catecholamines. TNF-
and partially also IL-1
in longlasting operation may cause cachexia mainly by decreasing the
appetite. It is so in chronic infections, inflammatory
processes, and in neoplastic processes.
Beside that, TNF
and IL-1 significantly increase the immune
response by activation of T-cells and stimulation of IL-2
production.
IL-1 enhances B-cells proliferation. It is interesting that
these processes have the temperature optimum at 39,5
. It follows that
the fever can be supposed as a positive factor. Fever and specific
effects of IL-1 and TNF-
form together highly integrated
processes that are involved in the response to infection and
acute inflammation processes.
Interferons, and especially IFN-
(formed by
T lymphocytes and NK cells) may enhance this reponse. Several
parts of this complex response have protective and the others
may have malignant consequences. Septicemia, or septic shock is
an overshot response of the organism. In this
complicated reaction of the organism, it is not easy to decide
whether fever should be treated by antipyretics or not. By
antipyretics the symptoms of fever may be suppressed but it is
uncertain if it is reasonable to suppress also the positive
efects of fever and everything that is connected with it. This
complex process (fever) mobilizes not only the immune system
but also those
processes that improve the nutrition of cells and have
protective importance on their activity.
In the majority of diseases, fever is caused by pyrogens. There are situations, when fever may be caused directly by changes in the center of thermoregulation without the participation of exogenic and may be also endogenic pyrogens. This occurs in brain tumours, intracranial bleeding, and thrombosis.