Pathogenesis of fever

pathogenesis of fever
reference- Harrison's Principles of internal medicine
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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 d istinct receptors for microbial products called Toll-like receptors are located on the hypothalamic endothelium. D irect activation of Toll-like receptors by microbial products → PGE-2 production → fever

11. 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.

12. 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 .

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

14. 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. I n contrast to hyperpyrexia it does not involve pyrogenic molecules. I t does not respond to anti-pyretics.