What is the recommended step‑by‑step diagnostic work‑up and initial management for a patient with pyrexia of unknown origin (fever ≥38.3 °C for more than three weeks) after basic history, physical examination and routine laboratory tests have been unrevealing?

Diagnostic Work-Up and Management of Pyrexia of Unknown Origin

After basic evaluation proves unrevealing, proceed immediately with CT imaging of chest, abdomen, and pelvis, followed by FDG-PET/CT if CT is non-diagnostic, as this imaging sequence has 56% diagnostic yield and 84-86% sensitivity for identifying the underlying cause. 1

Systematic Diagnostic Algorithm

Phase 1: Mandatory Initial Work-Up (Days 0-3)

Blood Cultures and Laboratory Testing:

• Obtain at least 3 sets of blood cultures from different anatomical sites before initiating any antimicrobial therapy to maximize diagnostic yield 1, 2
• Complete blood count with differential to assess for neutropenia, cytopenia, and leukemia 1
• Inflammatory markers (CRP and ESR) - note that FDG-PET/CT has insufficient evidence if these markers are normal 1
• Comprehensive metabolic panel including liver function tests to identify hepatobiliary sources 3
• Urinalysis and urine culture 2

Physical Examination - Specific Focus Areas:

• Head and neck examination for lymphadenopathy (tuberculosis, lymphoma) 1
• Rectal examination for occult abscesses 1
• Pelvic examination in women 1
• Breast examination 1
• Temporal artery palpation for tenderness (giant cell arteritis in elderly) 1
• Skin examination for rashes (Still's disease, vasculitis) 1

Initial Imaging:

• Chest radiography as baseline 2, 3

Phase 2: Advanced Imaging (Days 3-7 if diagnosis remains elusive)

CT Imaging Protocol:

• CT of thorax, abdomen, and pelvis with IV contrast as the minimal imaging standard 1
• This identifies pulmonary sources in 72% of cases and abdominal/pelvic sources with 81.82% positive predictive value 3
• Results in management changes in 45% of patients 3

FDG-PET/CT - The Preferred Advanced Modality:

• Perform if CT imaging is non-diagnostic 1, 2
• Sensitivity: 84-86%, specificity: 52-63%, diagnostic yield: 56% 1
• High clinical impact in 79% of cases, prompting specialist referrals or antimicrobial changes 1
• Critical timing: Must be performed within 3 days of initiating oral glucocorticoid therapy if steroids become necessary 1, 3
• A negative FDG-PET/CT predicts favorable prognosis and may allow watchful waiting 3

Phase 3: Targeted Investigations Based on Imaging Findings

If Lung Infiltrates Identified:

• High-resolution chest CT looking for nodules with haloes or ground-glass change (aspergillosis) 4
• Bronchoscopy with bronchoalveolar lavage (BAL) should be available within 24 hours 1
• BAL at segmental bronchus supplying radiographic abnormality 1
• Avoid transbronchial biopsies in thrombocytopenic patients 1
• If tissue needed: CT-guided percutaneous biopsy, video-assisted thoracoscopy, or open-lung biopsy 1

If Abdominal Findings:

• Formal diagnostic ultrasound for patients with abdominal symptoms or abnormal liver tests 3
• Avoid routine abdominal ultrasound without localizing signs 3

If Postoperative Patient:

• CT of operative area in collaboration with surgical services 1, 3

Phase 4: Invasive Diagnostic Procedures (>7 days without diagnosis)

Tissue Biopsy - Highest Diagnostic Yield:

• Biopsy any suspicious lesions identified on PET/CT 2
• Temporal artery biopsy if giant cell arteritis suspected (age >50, elevated ESR, headache) 1
• Bone marrow biopsy for suspected hematologic malignancy or disseminated infection 1
• Lymph node biopsy with immunohistochemistry for lymphoma 1
• Liver biopsy if hepatic abnormalities present 5

Major Etiologic Categories to Consider

Infectious Causes (Most Common)

Tuberculosis:

• Leading infectious cause, particularly in endemic areas 1
• Can present with extrapulmonary manifestations including lymphadenitis 1
• Consider opportunistic mycobacterial infections (M. avium complex, M. kansasii) in immunocompromised patients 1

Occult Abscesses:

• Deep-seated infections requiring advanced imaging for detection 1
• Particularly intra-abdominal and pelvic locations 3

Travel-Related:

• Malaria in returned travelers requires up to three daily blood films 1, 2
• Viral hemorrhagic fevers in appropriate epidemiologic contexts with isolation precautions 1, 2

Malignant Causes

Lymphomas:

• Must be excluded via immunohistochemistry in poorly differentiated cases 1
• Account for significant proportion of PUO cases 1

Cancers of Unknown Primary:

• Account for 3-5% of all malignancies and can present with fever 1

Inflammatory/Autoimmune Causes

Still's Disease:

• Manifests with spiking fever, rash, arthritis, and markedly elevated CRP/ESR 1

Giant Cell Arteritis:

• Consider in patients >50 years with elevated ESR 1

Management Approach

When to Withhold Empiric Antibiotics

In non-neutropenic, clinically stable patients:

• Avoid empiric antibiotic therapy as up to 75% of cases resolve spontaneously without definitive diagnosis 3, 5
• Empiric antimicrobials have not been shown effective and should be avoided except in specific high-risk populations 5
• Continue diagnostic evaluation rather than therapeutic trials 6

High-Risk Populations Requiring Immediate Empiric Therapy

Severe Neutropenia (ANC <0.5 × 10⁹/L):

• Constitutes a medical emergency requiring immediate same-day broad-spectrum antibacterial therapy without waiting for culture results 1
• Initiate monotherapy with antipseudomonal β-lactam (piperacillin-tazobactam) as first-line 3
• Monitor every 2-4 hours if hemodynamically unstable 1
• Urgent infectious disease consultation 1

Reassessment at 48 Hours:

• If afebrile and ANC ≥0.5 × 10⁹/L: Consider oral antibiotics in low-risk patients 4
• If still febrile but clinically stable: Continue initial antibacterial therapy 4
• If clinically unstable: Broaden coverage or rotate antibacterials with infectious disease consultation 4

Antifungal Therapy Indications:

• When pyrexia lasts >4-6 days with rising CRP, initiate antifungal therapy 4
• Suspected invasive aspergillosis: Voriconazole or liposomal amphotericin B 4
• Can combine with echinocandin in unresponsive disease 4

Critical Pitfalls to Avoid

Diagnostic Errors:

• Never diagnose "fever of unknown origin" prematurely - it is a diagnosis of exclusion requiring thorough 3-week evaluation 3
• Do not perform sinus CT routinely without localizing symptoms as abnormalities are common but non-discriminatory 3
• Do not systematically remove central venous catheters in stable patients without microbiological evidence of catheter-related infection 3

Therapeutic Errors:

• Do not use high-dose steroids without specific indication as they increase risk of hospital-acquired infection, hyperglycemia, and delirium 3
• Avoid non-steroidal anti-inflammatory drugs as they impair renal and coagulation function 3
• Do not make non-directed antibiotic changes or add aminoglycosides without clinical/microbiological justification 3
• If FDG-PET/CT is planned, do not start glucocorticoids until imaging is complete, or perform scan within 3 days of steroid initiation 1, 3

Special Population Considerations:

• In children with fever >38.5°C and chest recession with respiratory rate >50/min (under 3 years): 25% may have pneumonia on chest radiograph despite no obvious respiratory source 1
• In elderly patients, maintain high suspicion for giant cell arteritis and polymyalgia rheumatica 1

Prognosis

Favorable Outcomes:

• Patients with undiagnosed PUO after adequate investigation have good prognosis 7
• Up to 50% may have no cause found despite adequate investigations, but reassuringly this cohort has favorable outcomes 7
• Negative FDG-PET/CT predicts spontaneous remission and allows watchful waiting approach 3