Pyrexia and Inflammation

Pyrexia

Pyrexia (fever) means the elevation of body temperature above the normal range. It may be caused by abnormalities in the brain itself or by toxic substances that affect the temperature regulating centers. Such causes include bacterial or viral infections, abnormalities as a brain tumor and/or a syndrome which causes a vicious cycle of heat production without heat loss, which may terminate in a heat stroke.

Normally, the temperature of the body is regulated almost entirely by nervous feedback mechanisms, and almost all of these operate through a temperature regulating center located in the hypothalamus at the base of the brain. Nerve receptors in the skin and spinal cord provide feedback that drives the body to either conserve heat (pilo-erection, or hairs standing on end), produce increased quantities of heat (shivering), or increase heat loss (sweating or panting). Changes in the heat regulating process are constantly undergoing modifications that go unnoticed. In other words, heat regulation is not a static process but an ever-moving one that is important to normal body function.

Substances that may cause the "set point" of the hypothalamic thermostat to rise are called pyrogens. Many proteins, breakdown products of proteins, and certain other substances, such as lipopolysaccharide toxins (LPS or endotoxin) secreted by bacteria, can act as pyrogens. It is pyrogens secreted by toxic bacteria or pyrogens released from degenerating tissues of the body that cause fever during disease conditions. Pyrogens are extremely potent since as little as a few nanograms (nano = one billionth) injected into animals can cause a fever.

There is some debate on how pyrogens affect temperature regulation in the hypothalmus. Some feel that there is a direct effect while others feel it is an indirect effect through byproducts of macrophages and lymphocytes destroyed by ingesting toxic products. These dying white blood cells (WBC) release an "endogenous pyrogen" which then affects the hypothalmus. Regardless of the method, it is the change in the hypothalamic thermostat that induces a fever.

When the setting of the thermostat is suddenly changed from the normal level to a higher-than-normal value as a result of tissue destruction, pyrogenic substances, or dehydration, the body temperature usually takes several hours to reach the new temperature setting. During this time there is a feeling of being cold, chills and shivering, and the skin may feel cold to the touch because of vasoconstriction to reduce heat loss. This process will continue until the new temperature is reached.

When the new temperature is reached, the animal no longer feels chills or any particular effects of being hot or cold. If the substance causing fever is removed, the body will react by setting a new lower temperature on the thermostat. In attempting to reduce body temperature, there will be sweating and "flushing" of the skin due to vasodilation or increasing blood flow to the skin resulting in heat loss. This is commonly referred to as "the fever has broken".

The dangers of fever are that excessively high temperatures destroy body cells, particularly nerve cells. Destruction of nerve cells is particularly dangerous because they do not regenerate. Once a nerve cell has died it is not replaced. Other body cells are damaged as well. The pathologic findings of death due to hyperpyrexia are localized hemorrhages and degeneration of cells throughout the body.

Inflammation

Literally volumes have been written about inflammation, the inflammatory process, and its control. It is beyond the scope of this document to cover all of that information. Inflammation is a complex process involving the circulatory system and blood-born cells. It is a natural body response to an injury, be it of physical, chemical or infectious origin, and it is a necessary prelude to healing. Despite the inherent protective nature of inflammation, its effect on body tissue and organs may be excessive and cause damage. Therefore, there are conditions or situations where control of excessive inflammation provides a significant benefit to the health and well being of the individual.

The cardinal signs of inflammation are heat, swelling, redness, and pain or loss of function. Heat and redness are the result of increased blood supply due to reflex dilation of the smaller arteries. Swelling is a result of increased blood flow and blood fluids leaking from the small blood vessels (capillaries, venules) into surrounding tissues. This leakage is due to increased permeability of the cells lining the capillaries and venules. Pain or loss of function is associated with various substances released by damaged tissues that act on local nerve endings.

As blood fluids (plasma) escape into tissue spaces, numerous chemical mediators are released. These further increase the permeability of the blood vessels, leading to more swelling, heat, redness, and pain. Blood cells migrate into the tissues and release various substances. One of these is histamine from white blood cells and mast cells. This phase of inflammation is often referred to as "histamine dependent", and it is the reason antihistamines work in the early phases of inflammation. This phase may only last 30 minutes.

A second wave soon follows and is characterized by the release of a host of mediators including kinins, complement, and prostaglandins. These substances are formed or released from damaged blood and tissue cells, which causes further damage and increases the inflammatory response. Particularly in the presence of infections, additional cells migrate to the area, releasing more mediators and furthering the process. The inflammatory process continues as long as the noxious agents persist. When the noxious agents are eliminated, local mediators are rapidly turned off by dilution, removed via the lymphatics, and rapidly metabolized by enzyme systems.