Fever of unknown origin

Fever of unknown origin (FUO): Diagnostic challenge

Fever of unknown origin (FUO) is not a disease in itself, but a clinical situation that physicians encounter when they cannot quickly find the cause of a prolonged high fever. It is one of the most complex diagnostic challenges in medicine, requiring a systematic, step‑by‑step approach and the exclusion of a huge number of possible diseases.

What is FUO by definition?

The classic medical definition of FUO (proposed by Petersdorf and Beeson in 1961) includes three criteria:

1. Body temperature of 38.3 °C or higher, recorded on several occasions.
2. Fever lasting 3 weeks or longer.
3. Inability to establish a diagnosis after one week of intensive inpatient investigation.

Today these criteria are somewhat more flexible, but the essence remains: FUO is a prolonged fever whose cause remains unclear after standard evaluation.

"Big three" causes of FUO

Despite the term "unknown", in most cases the cause of FUO is eventually identified. All possible causes are conventionally divided into three large groups:

• Infectious diseases (~30‑40% of cases): These can be atypical presentations of common illnesses or rare infections. Most often they are hidden abscesses (e.g., in the abdominal cavity), tuberculosis, endocarditis (infection of heart valves), complicated urinary‑tract infections.
• Systemic (autoimmune) diseases (~20‑30%): Diseases in which the immune system attacks the body's own tissues. This may include adult Still's disease, systemic lupus erythematosus, vasculitis. Often accompanied by joint pain and rash.
• Oncologic diseases (~10‑20%): Most frequently FUO is caused by hematologic malignancies—lymphomas and leukemias. The fever in this case is the so‑called "paraneoplastic syndrome".

The diagnostic work‑up for FUO is painstaking work that includes numerous laboratory tests and imaging methods. Sometimes it may represent a manifestation of recurrent fever.