What is the best approach to managing a patient with fever of unknown origin, considering their medical history and potential for serious complications?

Approach to Fever of Unknown Origin

Definition and Initial Risk Stratification

Fever of unknown origin (FUO) is defined as temperature >38.3°C (100.9°F) persisting for at least 3 weeks without diagnosis despite appropriate investigation, and your immediate priority is determining if the patient is neutropenic or critically ill, as these patients require same-day broad-spectrum antibiotics before completing the full diagnostic workup. 1, 2

Critical First Decision Point

• Neutropenic patients (ANC <0.5 × 10⁹/L) require immediate broad-spectrum antibacterial therapy with antipseudomonal coverage (such as piperacillin-tazobactam) on the same day, without waiting for culture results 2, 3
• Non-neutropenic, hemodynamically stable patients should NOT receive empiric antibiotics, as up to 75% of FUO cases resolve spontaneously and antibiotics mask the underlying diagnosis 1, 2, 4

Mandatory Initial Workup

Laboratory Testing (Before Any Antibiotics)

Obtain at least two sets of blood cultures from different anatomical sites (ideally 60 mL total blood volume) before initiating any antimicrobial therapy to maximize diagnostic yield 5, 1, 2

Additional mandatory labs include:

• Complete blood count with differential to assess for neutropenia and cytopenia 1, 3
• C-reactive protein and erythrocyte sedimentation rate 1, 2, 6
• Comprehensive metabolic panel including liver enzymes to identify hepatobiliary sources 2, 6
• Lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies 6

Initial Imaging

Chest radiography is the only first-line imaging study recommended for all FUO patients, particularly if pulmonary symptoms are present or there is concern for tuberculosis or malignancy 5, 1, 6

Targeted History and Physical Examination

Essential Historical Elements

Focus your history on these specific high-yield areas:

• Recent travel history and geographic exposures (malaria requires three daily blood films in returned travelers) 1, 3
• Animal exposures and occupational risks 1
• Complete medication history, including recent antibiotic use that may mask infections 1, 3
• Immunosuppression history including HIV status 1

Physical Examination Priorities

Perform cardiac auscultation for new murmurs (infective endocarditis), examine skin and oral cavity, palpate all lymph node chains, and conduct rectal, pelvic, and breast examinations 1, 3

Advanced Imaging Strategy

When Initial Workup is Non-Diagnostic

If the initial evaluation is unrevealing and inflammatory markers are elevated, 18F-FDG PET/CT is the highest-yield advanced imaging modality with 56% diagnostic yield, 84-86% sensitivity, and 79% clinical impact prompting management changes 1, 2, 3

Critical timing consideration:

• Perform PET/CT within 3 days of starting oral glucocorticoid therapy if steroids are necessary 1, 2, 3
• A negative PET/CT predicts favorable prognosis through spontaneous remission and allows watchful waiting 2

Post-Surgical Patients

For patients with recent thoracic, abdominal, or pelvic surgery who develop fever several days postoperatively without an identified alternative cause, perform CT of the operative area in collaboration with the surgical service 5, 1, 2

Abdominal Evaluation

• Do NOT routinely perform abdominal ultrasound or point-of-care ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities 5, 2
• DO perform formal diagnostic ultrasound of the abdomen for patients with abdominal symptoms, abnormal liver tests, or recent abdominal surgery 5, 2

Special Population Considerations

HIV-Positive Patients

Test CD4+ T-cell counts and HIV viral load to assess immune function, and consider opportunistic infections including Mycobacterium tuberculosis, cytomegalovirus, and Pneumocystis jirovecii 1

Pediatric Patients (<3 Months)

Infants ≤90 days are at high risk for invasive bacterial infections due to perinatal bacterial pathogen exposure and lack of vaccine-based immunity, with infants <28 days at highest risk 5, 3

• 8-13% have bacterial infections, predominantly urinary tract infections 3
• Rectal temperature is the most accurate method in neonates and young children 5

Immunocompromised Patients

FDG-PET/CT demonstrates 88% accuracy in identifying fever source in immunosuppressed patients 3

Common Etiologic Categories

The differential diagnosis includes four major categories, with most cases representing uncommon presentations of common diseases rather than rare diseases 1, 6, 7:

Infectious Causes

• Tuberculosis (leading cause, particularly in endemic areas with extrapulmonary manifestations) 3
• Occult abscesses requiring advanced imaging 3
• Infective endocarditis (requires cardiac auscultation) 1

Malignant Causes

• Lymphomas (require immunohistochemistry in poorly differentiated cases) 3
• Cancers of unknown primary (3-5% of all malignancies) 3

Inflammatory/Autoimmune Causes

• Systemic juvenile idiopathic arthritis (5% of pediatric FUO cases) 3
• Inflammatory bowel disease (5% of pediatric FUO cases) 3

Critical Management Pitfalls to Avoid

Avoid high-dose steroids without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium 1, 2

Avoid NSAIDs as they impair renal and coagulation function and increase stress ulcer risk 1

Do not systematically remove central venous catheters in clinically stable patients unless there is microbiological evidence of catheter-related infection 2

Do not perform non-directed antibiotic changes or switch from one empirical monotherapy to another without clinical or microbiological data justifying spectrum extension 2

Invasive Diagnostic Procedures

If noninvasive tests are unrevealing, tissue biopsy has the highest diagnostic yield among invasive procedures 4

Consider biopsy of:

• Liver, lymph nodes, temporal artery, skin, skin-muscle, or bone marrow depending on clinical indications 4
• Sites identified as abnormal on PET/CT imaging 1

Monitoring and Re-evaluation

For neutropenic patients on antibiotics, perform daily surveillance including physical examination, review of systems for new symptoms, and cultures of suspect sites 2

Re-evaluate after 2-4 days of empirical antibiotic treatment, during which most modifications of the initial regimen will be made 2