Fever of unknown origin (FUO) refers to the presence of a documented elevation in body temperature for a specified time, for which a cause has not been found after basic medical evaluation. FUO is categorized as classic, hospital acquired FUO; FUO associated with low white blood cell counts (immunosuppression); and HIV-associated (AIDS-related) FUO.
Fever, an elevation of normal body temperature, is a natural response of the body that helps fight off foreign substances, such as microorganisms (bacteria and viruses), parasites, fungi, and toxins. Body temperature is set by the thermoregulatory center, located in an area in the brain called the hypothalamus. Body temperature is not constant all day, but actually is lowest at 6 a.m. and highest around 4 to 6 p.m. Temperature also varies in different regions of the body; for example, rectal and urine temperatures are about one degree Fahrenheit higher than oral temperature, and rectal temperature is higher than urine. Certain normal conditions can also effect body temperature, such as food ingestion, age, pregnancy, and certain hormonal changes.
Substances that cause fever are known as pyrogens, which can be either exogenous (originate outside the body, such as bacterial toxins) or endogenous (formed by the body's own cells in response to an outside stimulus, such as a bacterial toxin). Researchers have discovered that there are several endogenous pyrogens, each made up of small groups of amino acids, the building blocks of proteins. When these natural pyrogens, called cytokines, are injected into humans, fever and chills develop within an hour. Interferon, tumor necrosis factor, and various interleukins are the major fever-producing cytokines.
In the complex process that produces fever, cytokines cause the thermoregulatory center in the hypothalamus to reset the normal temperature level. The body's initial response is to conserve heat by vasoconstriction, a process in which blood vessels narrow and prevent heat loss from the skin and elsewhere. This process alone raises temperature by two to three degrees. Certain behavioral activities also occur, such as adding more clothes and seeking a warmer environment. If the hypothalamus requires more heat, shivering occurs.
In children, the definition of FUO is applied when fever has been present for 14 days with no apparent cause, even though physical examinations have been made and laboratory tests performed. Doctors pay special attention to the ears, nose, throat, sinuses, and chest as sites of infection, since most childhood infections are respiratory in nature. The majority of children with FUO are eventually found to have one of several infectious diseases or an autoimmune disease. In many cases the disease is common, and in some cases an allergic response is causing the fever. Fever increases the body's metabolic rate and oxygen consumption, which can have a devastating effect on individuals with poor circulation. In addition, fever can lead to seizures in the very young. Some possible infectious causes shown in studies of children with FUO are as follows: