An Understanding of Pathogenesis of Fever

Fever is elevation of body temperature that is more than normal daily variation, which occur due to increase in “hypothalamic set point”. The increase in the hypothalamic set point from normal (or normothermic) to febrile is like increasing (and thereby resetting) the home thermostat to a higher level to increase the room temperature. After the hypothalamic set point is raised the neurons vasomotor center are activated and vasoconstriction occurs, first at hands and feet which shifts blood from periphery to internal organs and heat loss from skin is reduced and the patient feel cold (despite raised body temperature). At this point shivering may start (which increase heat production by muscles), but if already body temperature is raised sufficiently (by heat conserving mechanisms) there may not be any shivering. Liver also help in increasing heat production to increase core temperature.

What are pyrogens?

Pyrogen can be defined as any substance that can cause fever. Pyrogens trigger the hypothalamus to raise the set point to febrile levels and cause fever.

Exogenous/external pyrogens are microorganisms (virus, bacteria, fungi, protozoa, parasites etc.), toxins and other microbial products. All gram-negative bacteria produce pyrogen which is a polysaccharide, which is an endotoxin. Gram positive bacteria produce enterotoxins (pyrogen). Endotoxin produced by gram negative organisms is highly pyrogenic and can produce fever in human volunteers if only 2-4 nano-gram (1000 nano-gram equals 1 microgram, 1000 microgram equals 1 milligram and 1000 milligram is 1 gram) per kg body weight is injected intravenously.

Endogenous pyrogens, now known as pyrogenic cytokines are IL-1 (interleukin-1), IL-6, TNF (tumor necrosis factor), interferon alpha, ciliary neurotropic factors etc. There are various microbial (virus, bacteria, fungi, parasites etc.) products which can induce synthesis of pyrogenic cytokines in humans.

Fever can also occur in absence of any microbial infection, such as trauma, inflammation, antigen-antibody reaction, tissue necrosis etc.

Hypothalamic set point and initiation of fever:

During fever prostaglandin E2 (PG E2) is elevated in hypothalamus. When there is elevation of PGE2 in the brain the process of raising hypothalamic set point starts. PGE2 is essential for fever, but it is not a neurotransmitter for fever. The neurotransmitter for fever is cyclic AMP (adenosine 5′-monophosphate), release of which from the glial cells activates neuronal endings from the thermoregulatory center and changes hypothalamic set point either directly or indirectly.

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1 Comment

  • Myung September 23, 2012 11.50 pm

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