How to assess and manage a patient with fever of unknown origin?

Assessment and Management of Fever of Unknown Origin

The diagnostic approach for fever of unknown origin (FUO) should begin with targeted evaluation based on risk factors, followed by a systematic workup including blood cultures, inflammatory markers, and advanced imaging such as [18F]FDG PET/CT for persistent cases. 1

Definition and Classification

• FUO is defined as fever higher than 38.3°C persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days 1
• FUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related 1
• The etiology of FUO includes infectious (30-40%), inflammatory (20-30%), malignant (10-20%), and miscellaneous causes (10-20%), with distribution varying by geographical location 1

Initial Diagnostic Workup

• Obtain detailed history focusing on travel, animal exposures, occupational risks, and medication use 2
• Perform thorough physical examination with special attention to skin, lymph nodes, heart murmurs, and abdominal findings 2
• Minimum laboratory workup should include:
  • Complete blood count with differential 2
  • Comprehensive metabolic panel including liver enzymes 2
  • Inflammatory markers (ESR, CRP) 1
  • Blood cultures (at least two sets from different sites, ideally 60 mL total) 1
  • Urinalysis and urine culture 2
• Initial imaging should include chest radiography 1
• For patients with central venous catheters, obtain simultaneous central and peripheral blood cultures 1

Advanced Diagnostic Approach

• If initial evaluation is unrevealing after 3-5 days:
  • [18F]FDG PET/CT has high diagnostic yield (56%) with sensitivity of 84-86% 1
  • PET/CT should be performed within 3 days of starting oral glucocorticoid therapy 1
  • Consider CT or MRI of chest, abdomen, and pelvis if PET/CT is not available 3
• For patients with recent thoracic, abdominal, or pelvic surgery, obtain CT imaging of the operative area 1
• For neutropenic patients with persistent fever:
  • Consider fungal infection if fever persists despite broad-spectrum antibiotics 3
  • Evaluate for invasive fungal disease with CT imaging and possibly bronchoalveolar lavage 3

Management Based on Patient Category

Neutropenic Patients

• Neutropenic fever is defined as temperature >38.3°C with ANC <1000 cells/mm³ 4
• Initiate broad-spectrum antibiotics with antipseudomonal activity within 2 hours of presentation 4
• Recommended empiric regimens include monotherapy with an antipseudomonal beta-lactam (cefepime, piperacillin-tazobactam, or a carbapenem) 4
• For high-risk patients or those with sepsis, add vancomycin to the regimen 4
• Median time to defervescence is 5 days for hematologic malignancies and 2 days for solid tumors 5
• Consider antifungal therapy only if fever persists despite antibiotics and new pulmonary infiltrates develop 3

Non-neutropenic Patients

• Treatment should target the identified cause once diagnosis is established 3
• Avoid empiric antibiotics or steroids without a specific indication, as they may mask diagnostic clues 2
• Persistent fever alone in a stable patient is rarely an indication to alter the antibiotic regimen 5

Monitoring and Follow-up

• All patients must be monitored closely for response, adverse effects, emergence of secondary infections, and development of drug-resistant organisms 5
• Daily physical examination, review of systems for new symptoms, and cultures from suspicious sites are essential 5
• For low-risk outpatients, ensure they can reach medical facility within 1 hour if clinical conditions worsen 5
• A negative [18F]FDG PET/CT can predict favorable prognosis and potentially allow a watchful waiting approach 1

Common Pitfalls to Avoid

• Avoid premature diagnosis of "fever of unknown origin" without thorough evaluation 1
• Do not add vancomycin empirically for persistent fever alone in neutropenic patients 5
• Avoid high-dose steroids without specific indication as they increase risk of hospital-acquired infection 1
• Avoid non-steroidal anti-inflammatory drugs as they may impair renal and coagulation function 1
• Remember that FUO is more often an atypical presentation of a common disease rather than an unusual disease 2