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:
It is possible for a child with FUO to spread infection or illness to
other individuals, particularly if an infectious organism is the
underlying cause. If a child has FUO, it is best to reduce contact with
other young children or immune compromised
members until the cause of the fever has been identified.
Fever of unknown origin can occur in anyone, male or female, of any age at
any time depending upon exposure to infectious organisms such as bacteria
or viruses or to other causes of illness such as fungi, parasites, or
toxins or to underlying autoimmune or allergic conditions. Because the
underlying cause of the fever is usually recorded as the diagnosis,
accurate statistics for those presenting with FUO are not available.
Causes and symptoms
There are many possible causes of FUO; generally though, a diagnosis can
be found. The most frequent cause of FUO is still infection, though the
percentage has decreased in the early 2000s. Tuberculosis remains an
important cause, especially when it occurs outside the lungs. The decrease
in infections as a cause of FUO is due in part to improved culture
techniques that allow more precise identification of organisms and,
therefore, more appropriate treatment. In addition, advances in diagnostic
technologies have made it easier to identify non-infectious causes. For
example, tumors and autoimmune diseases were as of 2004 easier to
diagnose. An autoimmune disease is one that arises when the body's
immune system attacks its own tissue as if it were foreign. This happens
when the immune system does not recognize protein markers (antigens) on
its own cells. In some cases, reactions to medications can also cause
In about 10 percent of cases, no definite cause is found. In another 10
percent, "factitious fevers" (either self induced or no
fever at all) are identified.
General constitutional symptoms tend to occur along with fever, including
muscle aches and pains (myalgias), chills, and
. Sometimes symptoms such as a rash suggest an allergic reaction.
An infant under three months should be seen as soon by a pediatrician as
possible if a fever develops. If a toddler or older child has a fever for
more than a day or two (48 to 72 hours), with or without other symptoms,
the pediatrician should be consulted so that an early diagnosis can be
made and treatment begun. It is especially important to watch for signs of
, particularly if the child is not drinking liquids or seems too sick to
drink. A crying child with fever may have
associated with a specific condition and should be seen by the
pediatrician as soon as possible.
Few symptoms in medicine present such a diagnostic challenge as fever.
Nonetheless, if a careful, logical, and thorough evaluation is performed,
the underlying cause generally can be diagnosed. The child's
medical history is first reviewed along with travel, social, and family
history, which can reveal important clues.
The first step medically is to search for an infectious cause. Skin and
other screening tests for diseases such as tuberculosis and examination of
blood, urine, and stool are generally indicated. Antibodies to a number of
infectious agents can be measured; if antibody levels are rising, they may
point to an active infection. In some cases, a febrile agglutination test
can be performed to detect the presence in blood of certain infectious
organisms that may stimulate the immune system to produce antibodies known
as febrile agglutinins. The test helps diagnose or confirm certain febrile
diseases that are known to be associated with febrile agglutinins. These
Various x-ray studies are of value and may be performed, particularly if
organisms are identified that may indicate involvement of abdominal
organs. Imaging techniques such as ultrasound,
(CT scan), and
magnetic resonance imaging
may be performed. These enable physicians to examine areas that were once
accessible only through surgery. Furthermore, new studies using
radioactive materials (nuclear medicine) can detect areas of infection and
inflammation previously almost impossible to find, even with surgery.
The removal and microscopic examination of tiny bits of tissue (biopsy)
from any suspicious areas found on an x-ray exam can be performed by
either traditional or newer surgical techniques. Material obtained by
biopsy is then examined by a pathologist in order to look for clues as to
the cause of the fever. Evidence of infection, tumor, or other diseases
can be found in this way. Portions of the biopsy are also sent to the
laboratory for culture in an attempt to grow and identify an infectious
Fever in an individual with HIV, primary immune deficiency, recent
, or anyone else who is immunocompromised constitutes an especially
difficult problem, as these patients often suffer from many unusual
infections. HIV itself is a potential cause of fever.
Most children who undergo evaluation for FUO do not receive treatment
until a clear-cut cause is found.
or medications designed to suppress a fever such as antipyretics (
) or non-steroidal anti-inflammatory drugs (NSAIDs) will only hide the
true cause. Once physicians are satisfied that there is no infectious
cause, they may recommend medications such as acetaminophen, NSAIDs, or
corticosteroids to decrease inflammation and reduce constitutional
symptoms. Parents are advised not to give children aspirin for fever
because of a side effect called Reye syndrome, which may cause liver
failure. Fluids are replenished by having the child consume clear liquids.
A child too sick to drink may be hospitalized and given intravenous
The development of FUO in certain settings, such as when it is acquired by
patients in the hospital or in immunosuppressed individuals with a low
white blood count, often needs rapid treatment to avoid serious
complications. Therefore, in these instances antibiotics may be given
after a minimal number of diagnostic studies. Once test results are known
and causative organisms identified, treatment can be adjusted
Practitioners of complementary medicine recommend herbs to treat fever. A
tea made with catnip, lobelia, and dandelion will reduce fever or catnip
tea enemas administered daily. Rest is recommended and large quantities of
clear liquids to flush out toxins and help prevent dehydration. Some
practitioners recommend letting a fever run its course or cooling the body
with cool sponge baths.
Supporting the immune system is one way to help avoid infection by
exposure to bacteria, viruses, and toxins as a potential source of fever.
Green drinks made with young barley are believed to cleanse the blood and
supply chlorophyll and nutrients for maintaining healthy tissue. Because
stress is known to produce biochemicals that reduce white blood cell
functioning, it is important to get sufficient
and reduce stress to help keep the immune system functioning well.
, and other types of stress reduction programs are available in most
The outlook for children with FUO depends on the cause of the fever. If
the basic illness is easily treatable and can be found rather quickly, the
potential for a cure is quite good. Some children may continue to have an
elevated temperature steadily or intermittently for six months or more. If
no serious disease is found, medications such as NSAIDs are used to
decrease the effects of the fever. Careful follow-up and reevaluation is
recommended in these cases.
Although FUO cannot actually be prevented because the sources are unknown,
the immune system can be strengthened to help avoid infection from
bacteria, viruses, and toxins. Several nutritional supplements are
reported to help build the immune system. These include garlic (contains
the essential trace element germanium), essential fatty acids (found in
flax seed oil, evening primrose oil, and fish oils), sea vegetables such
as kelp, acidophilus to supply natural bacteria in the digestive tract,
A and C, both powerful antioxidants that improve immune function and
increase resistance to infection. Zinc is another nutrient essential to
immune system functioning.
Immune system function requires ingesting certain essential nutrients and
avoiding others that depress immunity. A diet that improves immune system
functioning includes fresh fruits and vegetables, as many eaten raw as
possible to provide necessary enzymes; whole grain cereals, brown rice,
and whole grain pasta
for essential vitamins,
, and fiber; and non-meat sources of protein such as nuts, seeds, tofu,
legumes (beans), and eggs. Fish, fowl, and lean meats can be consumed in
small amounts. Sweets, especially if sweetened with refined sugars, should
be reduced or avoided altogether. A diet high in fats and processed foods
made with refined flours and sugars can actually suppress the immune
system. Alcohol and
should be avoided.
Acquired immune deficiency syndrome (AIDS)
—A disease associated with infection by the human
immunodeficiency virus (HIV) that attacks the immune system.
—Drugs that are designed to kill or inhibit the growth of the
bacteria that cause infections.
—A special protein made by the body's immune system as a
defense against foreign material (bacteria, viruses, etc.) that enters
the body. It is uniquely designed to attack and neutralize the specific
antigen that triggered the immune response.
—A substance (usually a protein) identified as foreign by the
body's immune system, triggering the release of antibodies as
part of the body's immune response.
Computed tomography (CT)
—An imaging technique in which cross-sectional x rays of the body
are compiled to create a three-dimensional image of the body's
internal structures; also called computed axial tomography.
—A test in which a sample of body fluid is placed on materials
specially formulated to grow microorganisms. A culture is used to learn
what type of bacterium is causing infection.
—Techniques used to prevent transplant graft rejection by the
recipient's immune system.
Magnetic resonance imaging (MRI)
—An imaging technique that uses a large circular magnet and radio
waves to generate signals from atoms in the body. These signals are used
to construct detailed images of internal body structures and organs,
including the brain.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
—A group of drugs, including aspirin, ibuprofen, and naproxen,
that are taken to reduce fever and inflammation and to relieve pain.
They work primarily by interfering with the formation of prostaglandins,
enzymes implicated in pain and inflammation.
—A poisonous substance usually produced by a microorganism or
—A medical test in which sound waves are directed against
internal structures in the body. As sound waves bounce off the internal
structure, they create an image on a video screen. Ultrasonography is
often used to diagnose fetal abnormalities, gallstones, heart defects,
and tumors. Also called ultrasound imaging.
HIV infection and AIDS
Current Pediatric Diagnosis & Treatment.
New York: McGraw Hill, 2002.
Fever of Unknown Origin.
Durham, NC: Oyster River Press, 2001.
American Medical Association.
515 N. State St., Chicago, IL 60612. Web site:
Centers for Disease Control and Prevention.
1600 Clifton Rd., NE, Atlanta, GA 30333. Web site:
Chan-Tack, Kirk M., and John Bartlett. "Fever of Unknown
, November 17, 2004. Available online at
http://www.emedicine.com/med/topic785.htm (accessed November 18,