Definition:
Fever > 38.3 °C on several occasions
Duration of fever for > 3 weeks
Uncertain diagnosis after 1 week of inpatient investigation

Etiologies – 5 main categories:
1. Infection
2. Malignancy
3. Connective tissue disease
4. Other
5. No diagnosis

Common INFECTIOUS causes:
– Unrecognized abscess (abdominal, pelvic, etc.)
– Endocarditis (less common than in past)
– EBV infection
– CMV infection
– Tuberculosis
– Osteomyelitis

Common MALIGNANCIES causes:
– Lymphoma (most common cause)
– Leukemia
– Hepatocellular carcinoma
– Tumors metastatic to the liver
– RCC
* fever is due to pyrogenic cytokines or necrotic tumors leading to infection

Common CONNECTIVE TISSUE causes:
– Adult Still’s disease (fever, Salmon-colored rash, arthritis)
– Rheumatoid arthritis
– SLE
– Temporal arteritis (>50 years old, headache, symptoms of PMR, elevated ESR)
– PMR

Common OTHER causes:
– Factitious fever (fraudulent, self injury, etc.)
– Drug fever (antibiotics, antihistamines, NSAIDs, etc.)
– Familial fever syndromes (familial Mediterranean fever)
– Hemophagocytic syndrome
– IBD
– PE
– Thyroiditis
– AND MANY, MANY MORE

Evaluation:
– Verify fevers and establish pattern
– Localize symptoms
– Identify potential exposures: workplace, pets, travel, sexual history
– History of connective tissue disease
– History of malignancy/immunosuppression
– Medications
– Familial syndromes

Management:
WITHHOLD THERAPY UNTIL THE CAUSE IS FOUND
Exceptions:
1. Neutropenic fever
2. Steroids in suspected temporal arteritis
3. Culture negative endocarditis
4. Unstable hospitalized patient

Nice article reviewing FUO:
Fever of Unknown Origin Evidence Based Review