pathogenesis of fever reference- Harrison's Principles of internal medicine & other ppt from slideshare...

1. PATHOGENESIS OF
FEVER
- ADARSH APPAIAH A K

2. BODY TEMPERATURE
Controlled by the hypothalamus
– (preoptic anterior hypothalamus)
– (posterior hypothalamus)
Monitoring of body temperature
1. peripheral warmth / cold receptors- from skin
2. blood bathing the region of hypothalamus

3. Normal Mean Temperature
The mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F)
– Low at 6 a.m.
– High at 4 to 6 pm
– Daily variation(circadian rhythym): 0.5°C (0.9°F)
The maximum normal oral temperature is 37.2°C (98.9°F) at 6 am
and 37.7°C (99.9°F) at 4pm.
# For every increase of 1°C over 37°C, there is a 13% increase in oxygen
consumption.

4. -0.4°C +0.4°C
TM oral rectal
-------I-----------I-------------I--------
• The metabolic rate of humans consistently produces more heat
than is necessary to maintain the core body temp. in the range of
36.5°c – 37.5°c

5. DEFINITION
Fever is an elevation of body temperature that exceeds the normal
daily variation and occurs in conjunction with an increase in the
hypothalamic set point.
A.M. Temperature of >37.2°C (98.9°F) or
P.M. Temperature of >37.7°C (99.9°F)
would define a fever.

6. Pathogenesis of fever
The term pyrogen (Greek pyro, “fire”) is used to describe
any substance that causes fever.
-Pyrogens (exogenous pyrogens)
-Pyrogenic cytokines(endogenous pyrogens)

7. Pyrogens
• Exogenous pyrogens are derived from outside the patient.
• Most are microbial products, microbial toxins, or whole
microorganisms.
• Egs-lipopolysaccharides(endotoxin)-produced by all gram-negative
bacteria
-Enterotoxins of staphylococcus aureus and group A & group B
streptococcal toxins(superantigen)

8. Pyrogenic cytokines
• Cytokines are small proteins that regulate immune, inflammatory, and
hematopoietic processes.
• Some cytokines also produce fever.
• A wide spectrum of bacterial and fungal products induce the
synthesis and release of such pyrogenic cytokines.
• These include IL-1, IL-6, TNF, Ciliary neurotropic factor.
• These cytokines trigger the hypothalamus to raise the set point to
febrile levels.

9. Elevation of hypothalamic setpoint by cytokines
Pyrogens and pyrogenic cytokines interact with the endothelium of the
capillaries of circumventricular vascular organs(organum vasculosum of
lamina terminalis) surrounding the hypothalamic regulatory centers.
↓
PGE-2 is released by the hypothalamic endothelial cells.
↓
This in turn triggers the PGE-2 receptor(EP-3) on glial cells.
↓
This results in release of cAMP(neurotransmitter).
↓
neuronal endings from thermoregulatory centers are activated by cAMP

10. ↓
This leads to changes in hypothalamic setpoint.
# There are distinct receptors for microbial products called Toll-like
receptors are located on the hypothalamic endothelium.
Direct activation of Toll-like receptors by microbial products →
PGE-2 production → fever

12. • Once the hypothalamic setpoint is raised, neurons in the vasomotor center
are activated and vasoconstriction commences.
• Shunting of blood away from the periphery to the internal organs
essentially decreases heat loss from the skin, and the person feels cold.
• Shivering is not required if heat conservation mechanisms raise blood
temperature sufficiently.
• Liver also contributes to increasing core temperature.

13. • The processes of heat conservation (vasoconstriction) and heat
production (shivering and increased nonshivering thermogenesis)
continue until the temperature of the blood bathing the hypothalamic
neurons matches the new thermostat setting.
• Once that point is reached, the hypothalamus maintains the temperature
at the febrile level by the same mechanisms of heat balance that
function in the afebrile state.
• When the hypothalamic set point is again reset downward (due to (1)
reduction in pyrogen concentration or (2) use of antipyretics), the processes
of heat loss through vasodilation and sweating are initiated. Loss of heat
by sweating and vasodilation continues until the blood temperature at
the hypothalamic level matches the lower setting.

14. Hyperpyrexia
A fever of >41.5°C (>106.7 °F) is called hyperpyrexia.
*seen in CNS hemorrhages (most common), trauma & severe
infections.

15. Hyperthermia
• Hyperthermia is characterized by an uncontrolled increase in body
temperature that exceeds the body’s ability to lose heat.
• The setting of the hypothalamic thermoregulatory center is
unchanged.
• In contrast to hyperpyrexia it does not involve pyrogenic molecules.
• It does not respond to anti-pyretics.