PATHOPHYSIOLOGY OF FEVER

NGUYỄN XUÂN TRÍ. MD, MSc

DEPARTMENT OF MEDICAL IMMUNOLOGY AND GENETICS
FACULTY OF MEDICINE, VIET NAM NATIONAL UNIVERSTY, HCM CITY

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TEMPERATURE REGULATION

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Homeothermic animals VS Poikilothermic animals
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• Temperature regulation is achieved through precise balancing of heat production,
heat conservation, and heat loss.
• The normal range is 36.2° to 37.7° C.
• The temperature at the core of the body (as measured by rectal temperature) is
generally 0.5° C higher than the surface temperature (as measured by oral
emperature) and has minimal fluctuations.
• Circadian rhythm: Daily fluctuation
• The daily fluctuating temperature peaks around 6 pm and is at its lowest during
sleep.

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 Control of Temperature
(Thermoregulation)

• The preoptic anterior area of the

hypothalamus.
• Peripheral thermoreceptors in the
skin and abdominal organs
(unmyelinated C fibers and thinly
myelinated Aδ fibers) and central
thermoreceptors in the spinal cord and
trigeminal ganglia provide the
hypothalamus with information about
skin and core temperatures.

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 Control of Temperature
(Thermoregulation)

Heat production: the chemical reactions of metabolism and skeletal muscle tone and contraction.
• Hypothalamic thyrotropin-stimulating hormone-releasing hormone (TSH-RH)
• Thyroid-stimulating hormone (TSH)
• Thyroxine then acts on the adrenal medulla, causing the release of epinephrine into the
bloodstream.
• Epinephrine causes vasoconstriction, stimulates glycolysis, and increases metabolic rate,
thus increasing body heat.
• Norepinephrine and thyroxine activate brown fat thermogenesis, where energy is released as
heat instead of as adenosine triphosphate (ATP).
The hypothalamus also triggers heat conservation by stimulating the sympathetic nervous
system, which stimulates the adrenal cortex and results in increased skeletal muscle tone,
initiating the shivering response, and producing vasoconstriction.

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 Pediatrics and Temperature Regulation and
Aging and Temperature Regulation
• Term infants produce body heat
primarily through the metabolism of
brown fat, but it may not be adequately
developed for cold stress.
• Small body size, greater ratio of body
surface area to body weight with heat
loss through conduction and
convection, and decreased ability to
shiver.
• Fewer sweat glands, lower sweating
rate.
• Older adults have lower body temperatures
than younger people.
• Poor responses to environmental
temperature extremes.
• Cold stress in older adults also decreases
coronary perfusion.
• Decreased shivering response.
• Slowed metabolic rate, sedentary lifestyle
• Decreased vasoconstrictor and vasodilator
responses
• Diminished or absent sweating
• Decreased amount of brown fat
• Desynchronization of circadian rhythm,
• Undernutrition, and decreased perception of
heat and cold.
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 Pathogenesis of Fever

• Fever (febrile response or pyrexia) is a temporary resetting of the hypothalamic

thermostat to a higher level in response to pyrogenic cytokines (previously known as
endogenous pyrogens) and exogenous pyrogens.
• The most frequently encountered exogenous pyrogens are the lipopolysaccharide
complexes in the cell wall of gram-positive bacteria and viruses released with rupture of the
cell wall when the microbe dies.
• Pyrogenic cytokines, including tumor TNF-α, IL-1, IL-6, and interferon-γ, are produced by
phagocytic cells as they destroy microorganisms within the host.
• The final common step for fever generation by pyrogens is the production of prostaglandin
E2 (PGE2) in both the periphery and the brain.
• PGE2 acts on warm sensitive neurons in the preoptic area of the hypothalamus. An
integrated behavioral, endocrine, and autonomic nervous system response is then initiated.

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 Pathogenesis of Fever
• The “acute phase response” is a reaction that occurs when pyrogenic and other cytokines are released in
response to infection and inflammation. In addition to fever, other symptoms occur including anorexia, fatigue,
malaise, somnolence, and loss of concentration.
• At the cellular level, inflammatory pyrogenic cytokines promote muscle catabolism and hyperglycemia
(gluconeogenesis, glycogenolysis, and insulin resistance) by stimulating release of adrenocorticotropic
hormone and glucocorticoids to support glucoseconsuming cells.
• The hepatic acute phase response involves increasing or decreasing protein synthesis. C-reactive protein,
mannose-binding protein, complement factors, ferritin, ceruloplasmin, serum amyloid A, fibrinogen, and
haptoglobin are increased. Albumin, transferrin (binds iron), retinol-binding proteins, and transthyretin
(transports thyroid hormone) are reduced.
• The erythrocyte sedimentation rate (ESR) increases as the increase in fibrinogen and other plasma
proteins decrease rouleaux formation, allowing the red blood cells to fall faster. Acute phase proteins and the
ESR can serve as biomarkers for the inflammatory response.
• The general functions of increased acute phase proteins are to opsonize and trap microorganisms and
their products, activate complement, neutralize enzymes, and modulate the host's immune response.

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 Pathogenesis of Fever

• During fever, arginine vasopressin (AVP), α-melanocyte stimulating hormone (α-MSH), and
corticotropin-releasing factor are released from the brain, and systemic antiinflammatory
cytokines (i.e., IL-1 receptor agonist and IL-10) can act as endogenous cryogens or
antipyretics to help diminish and control the febrile response.
• This antipyretic effect constitutes a negative-feedback loop.
• The antipyretic effect may help explain fluctuations in the febrile response.
• When the fever breaks, the set point is returned to normal. The hypothalamus responds by
signaling a decrease in heat production and an increase in heat reduction mechanisms. The
result is decreased muscle tone, peripheral vasodilation, flushed skin, and sweating. The
individual feels very warm, replaces warm clothing with cooler clothes, throws off the covers,
and stretches out. Once the body has returned to a normal temperature, the individual feels
more comfortable and the hypothalamus adjusts thermoregulatory mechanisms to maintain
the new temperature.

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 Benefits of Fever

• A raised body temperature kills many microorganisms and has adverse effects on the
growth and replication of others.
• Higher body temperatures decrease serum levels of iron, zinc, and copper, all of which
are needed for bacterial replication.
• The body switches from burning glucose to a metabolism based on lipolysis and
proteolysis, thereby depriving bacteria of a food source.
• Increased temperature also causes lysosomal breakdown and autodestruction of cells,
thus preventing viral replication in infected cells.
• Acute-phase proteins produced by the liver during inflammation bind cations
necessary for bacterial reproduction. Heat increases lymphocytic transformation and
motility of polymorphonuclear neutrophils, thus facilitating the immune response.
Phagocytosis is enhanced, and production of antiviral interferon may be augmented

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 Febrile seizures

• Febrile seizures may occur with temperatures greater than 38°C

although most children do not develop febrile seizures until temperatures are much
higher.
• Febrile seizures are more predominant in boys before age 5 years, and genetic factors
contribute to susceptibility
• Febrile seizures are generally brief and self-limiting, lasting less than 5 minutes in 40%
of children and less than 20 minutes in 75% of children
• Prolonged febrile seizures are associated with the development of temporal lobe
epilepsy in children and are probably associated with functional changes in neurons
and neural networks.

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 Disorders of Temperature Regulation

• Hyperthermia is elevation of the body temperature without an increase in

the hypothalamic set point. Hyperthermia can produce nerve damage,
coagulation of cell proteins, and death.
• At 41°C (105.8°F), nerve damage produces convulsions in the adult. Death
results at 43°C (109.4°F). Hyperthermia may be therapeutic, accidental, or
associated with stroke or head trauma. Prevention of hyperthermia in stroke
and head trauma assists in limiting brain injury.

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 Accidental hyperthermia

• 1. Heat cramps—severe, spasmodic cramps in the abdomen and extremities that follow
prolonged sweating and associated sodium loss. They usually occur in those not
accustomed to heat or those performing strenuous work in very warm climates.
• 2. Heat exhaustion—results from prolonged high core or environmental temperatures,
which cause profound vasodilation and profuse sweating, leading to dehydration,
decreased plasma volumes, hypotension, decreased cardiac output, and tachycardia.
• 3. Heat stroke—a potentially lethal result of an overstressed thermoregulatory center.
Heat stroke can be caused by exertion, by overexposure to environmental heat, or from
impaired physiologic mechanisms for heat loss. With very high core temperatures (>40°C;
104°F), the regulatory center ceases to function and the body's heat loss mechanisms fail
• 4. Malignant hyperthermia—a potentially lethal hypermetabolic complication of a rare
inherited muscle disorder that may be triggered by inhaled anesthetics and depolarizing
muscle relaxants. producing sustained, uncoordinated muscle contractions; muscle cell
hypermetabolism

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 Therapeutic Hypothermia

• Therapeutic hypothermia is used to slow metabolism and preserve ischemic

tissue after brain trauma or during brain surgery, after cardiac arrest, and in
neonatal hypoxic encephalopathy
• Hypothermia protects the brain by reduction in metabolic rate, ATP
consumption, oxidative stress, and the critical threshold for oxygen delivery;
modulation of excitotoxic neurotransmitters and calcium antagonism;
preservation of protein synthesis and the blood-brain barrier; decreased
edema formation; and modulation of the inflammatory response.

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 Trauma and Temperature Regulation

Central Nervous System Trauma.

CNS trauma that causes CNS damage, inflammation, increased intracranial pressures, or
intracranial bleeding typically produces a temperature greater than 39°C (102.2°F). This
temperature, often referred to as neurogenic or central fever, appears with or without relative
bradycardia and is not caused by infection. The temperature is sustained, does not induce
sweating, and is highly resistant to antipyretic therapy.

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