Pyrexia of unknown origin (PUO/FUO)

Main categories of causes

1. Infections
   • Tuberculosis, including extrapulmonary or miliary disease
   • Occult abscess, especially intra-abdominal, hepatic, splenic, renal, dental
   • Infective endocarditis, including culture-negative endocarditis
   • Viral infections such as HIV, CMV, EBV
   • Region and exposure-dependent zoonoses: brucellosis, Q fever, leptospirosis, etc.
2. Noninfectious inflammatory diseases
   • Adult-onset Still disease
   • Giant-cell arteritis and polymyalgia rheumatica
   • SLE, vasculitis, rheumatoid disease
   • Sarcoidosis
   • Autoinflammatory disorders
3. Malignancy
   • Lymphoma, leukemia
   • Renal cell carcinoma, hepatocellular carcinoma, and other solid tumors
   • Intravascular lymphoma is an uncommon but important occult cause
4. Miscellaneous
   • Drug fever
   • Thyroiditis
   • Thromboembolism
   • Factitious fever

Evaluation

• Fever pattern, weight loss, night sweats
• Recent drugs, including antibiotics and anticonvulsants
• Travel, animal and tick exposure, occupational exposures
• TB contact, sexual history, injection drug use
• Dental symptoms, surgery, implanted devices, immunosuppression
• Family history of periodic fever syndromes

• Skin and nail lesions, lymph nodes, temporal arteries
• Heart murmur and peripheral stigmata of endocarditis
• Hepatosplenomegaly, joint inflammation, spinal tenderness
• Fundus and neurologic examination
• Repeated examinations are often more revealing than a single exam.

• CBC with differential, platelets, ESR/CRP
• Renal function, liver profile, LDH, ferritin, CK
• Urinalysis and urine culture
• Three sets of blood cultures, preferably before antimicrobials
• Chest radiograph
• HIV test; TB testing by IGRA or tuberculin skin test
• ANA, rheumatoid factor, serum protein electrophoresis
• Abdominal ultrasound or CT, guided by findings. Harrison’s, p. 192-193

• Echocardiography if endocarditis is plausible
• CT chest/abdomen/pelvis, MRI, or biopsy of accessible lymph node, liver, marrow, skin, or temporal artery according to clues
• 18F-FDG PET-CT can be useful when inflammatory markers are elevated and initial work-up is unrevealing. A 2024 systematic review of 36 studies found PET-CT contributed to the final diagnosis in about 75% of investigated FUO/IUO cases, although specificity was modest (PET-CT meta-analysis).

Management principles

• Treat the identified cause, not the fever alone.
• Avoid routine empirical antibiotics, antitubercular therapy, or corticosteroids in stable patients because they can suppress diagnostic clues and produce false-negative cultures.
• Empirical antibacterial treatment is appropriate if the patient is hemodynamically unstable, septic, or neutropenic.
• If TB is strongly suspected, obtain appropriate mycobacterial cultures and PCR samples first where feasible, then consider treatment. Harrison’s, p. 193

Red flags needing urgent assessment