Unexplained Fever...A Difficult Diagnosis

Medical Author: Melissa Conrad Stoppler, MD
Medical Editor: William C. Shiel, Jr., MD, FACP, FACR

Usually when a person develops a fever, he or she has pain, or cough, or other symptoms that explain why the fever is occurring. But occasionally people develop fevers without an apparent reason. When fevers persist, doctors refer to such a fever as fever of unknown origin. Abbreviated FUO, this unusual form of fever is defined by the presence of fever greater than 38.3°C (101 °F) "off and on" for more than three weeks without specific cause for the fever identified.

Research has shown that in 85 to 95% of cases, the specific cause for a fever of unknown origin can eventually be identified after extensive testing, often in a hospital setting. Doctors may need to perform a variety of diagnostic tests to help them determine the exact cause of an unexplained fever. Blood tests, a thorough physical examination, and radiological studies (most commonly a chest x-ray and/or chest and abdominal CT scans) are generally performed as a first step in the investigation of unexplained fever.

About one-third of fevers of unknown origin are caused by infections. Infections are also the most common cause of FUOs in children. Any type of infection, from a self-limiting common cold to HIVdisease, can result in fevers. In certain situations, a person may harbor a fever-producing infection that is not causing any recognizable physical signs or symptoms other than the fever. Microbiology techniques (culturing of body fluids from different sites to identify bacteria, viruses, fungi, or parasites) can sometimes identify an occult (hidden) infection. In other cases, blood tests that measure antibody levels in the blood can confirm whether an infection is present.

But infection does not account for 2 of 3 fevers of unknown origin! Cancers are estimated to cause 20-30% of FUOs. Lymphomas and leukemias are two kinds of cancer that often cause fevers, but any type of malignant tumor can be a source of fever.


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Chronic inflammatory diseases can also be a cause of FUOs. Autoimmune diseases or collagen vascular diseases, such as arthritis, lupus, diseases of the blood vessels (vasculitis, arteritis) and related conditions may cause fevers. In addition, some diseases that lead to a chronic inflammatory process in one or more regions of the body (an example is sarcoidosis) can be a source of unexplained fever.

Rare causes of unexplained fevers include (but are not limited to) taking certain medications, adrenal disease, hematomas, hyperthyroidism, pulmonary emboli , and previously undetected thrombophlebitis.

Despite extensive investigation, the cause of the fever is not identified in 5-15% of people with FUOs. Most of these people in whom no cause of fever can be identified will have a good prognosis, with the majority recovering within a period of weeks. The key to the evaluation of fevers of undetermined origin (FUOs) is consistent communication between the doctor and the patient and diligent testing as appropriate in the context of the symptoms present. This sometimes requires the consultation with subspecialists in medicine, including infectious disease specialists, rheumatologists, and oncologists.

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