What is the appropriate diagnostic and treatment approach for a patient presenting with pyrexia of unknown origin?

Pyrexia of Unknown Origin: Diagnostic and Treatment Approach

Definition and Initial Assessment

For patients presenting with pyrexia of unknown origin (PUO), defined as fever ≥38.3°C persisting for at least 3 weeks without diagnosis despite 3 outpatient visits or 3 inpatient days of investigation, immediately obtain comprehensive blood cultures before any antimicrobial therapy and proceed with risk-stratified imaging based on clinical context. 1

Immediate Diagnostic Workup

Mandatory First-Line Investigations

• Obtain blood cultures before any antibiotics to maximize diagnostic yield—this is non-negotiable 1, 2, 3
• Complete blood count with differential to assess absolute neutrophil count (ANC) and classify severity: Mild (1.0-1.5 × 10⁹/L), Moderate (0.5-1.0 × 10⁹/L), Severe (<0.5 × 10⁹/L) 1, 2, 3
• Inflammatory markers (CRP, ESR) are essential for guiding advanced imaging decisions 1
• CT scans of thorax, abdomen, and pelvis represent the minimal imaging standard for all PUO patients 1

Critical Physical Examination Components

Focus specifically on:

• Head and neck examination for lymphadenopathy (tuberculosis commonly presents with lymphadenitis) 1
• Rectal examination for occult abscesses 1
• Pelvic and breast examination to exclude malignancy 1
• Cardiac auscultation for pathological murmurs suggesting endocarditis 1

Risk-Stratified Management Algorithm

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

This constitutes a medical emergency requiring same-day broad-spectrum antibacterial therapy without waiting for culture results. 1, 3

• Initiate immediate broad-spectrum antibiotics (do not delay for any diagnostic testing) 2, 3
• Monitor hemodynamically unstable patients every 2-4 hours with urgent infectious disease consultation 1, 3
• Consider prophylactic levofloxacin or ciprofloxacin 500 mg daily for severe neutropenia 1, 3

MODERATE-RISK: Stable Patients with Normal/Mild Neutropenia

• Proceed with systematic diagnostic evaluation before empiric antimicrobials 4
• Perform chest radiography for most patients, especially when pneumonia suspected 5
• For recent thoracic, abdominal, or pelvic surgery patients: obtain CT of operative area in collaboration with surgical service if initial workup unrevealing 5

Advanced Imaging Strategy

FDG-PET/CT Indications

When initial diagnostic tests fail to establish etiology, perform FDG-PET/CT if transport risk is acceptable—this has 84-86% sensitivity and 56% diagnostic yield. 1

• Must be performed within 3 days of initiating oral glucocorticoids if steroids are necessary 1
• Shows high clinical impact in 79% of cases, prompting specialist referrals or antimicrobial changes 1, 3
• Demonstrates 88% accuracy in identifying fever source in immunosuppressed patients 1, 3
• Note limitation: insufficient evidence for PUO with normal inflammatory markers 1

Abdominal Imaging Decision Algorithm

• Without abdominal symptoms/signs or liver abnormalities: Do not routinely perform abdominal ultrasound or POCUS 5
• With recent abdominal surgery OR abdominal symptoms OR abnormal liver tests: Perform formal bedside diagnostic ultrasound 5
• CT imaging may be preferred over ultrasound when comprehensive evaluation needed, though ultrasound avoids radiation 5

Major Etiologic Categories to Systematically Exclude

Infectious Causes (40% of cases) 6

• Tuberculosis remains the leading infectious cause, particularly extrapulmonary manifestations 1
• Occult abscesses requiring advanced imaging 1
• Malaria in returned travelers: requires up to three daily blood films 1, 3
• Opportunistic mycobacterial infections (M. avium complex, M. kansasii) in immunocompromised patients 1
• Viral hemorrhagic fevers with appropriate epidemiologic context—implement isolation precautions 1, 3

Malignant Causes (20% of cases) 6

• Lymphomas must be excluded via immunohistochemistry in poorly differentiated cases 1
• Cancers of unknown primary (CUP) account for 3-5% of malignancies presenting with fever 1

Inflammatory/Autoimmune Causes (15% of cases) 6

• Still's disease: spiking fever, rash, arthritis, markedly elevated CRP/ESR 1
• Systemic juvenile idiopathic arthritis (5% of pediatric PUO cases) 1
• Inflammatory bowel disease (5% of pediatric PUO cases) 1

Drug-Induced Fever

• Review all medications including BRAF inhibitors (commonly cause pyrexia 2-4 weeks after initiation), immunosuppressants, and chemotherapy agents 2

Specialized Diagnostic Procedures

When Lung Infiltrates Present on CT

• Bronchoscopy and bronchoalveolar lavage (BAL) should be available within 24 hours 1
• BAL performed at segmental bronchus supplying radiographic abnormalities 1
• Transbronchial biopsies contraindicated in febrile neutropenic and thrombocytopenic patients 1
• If tissue required: use CT-guided percutaneous biopsy, video-assisted thoracoscopy, or open-lung biopsy 1

Definitive Microbiological Results

The following definitively indicate causative pathogens:

• P. jirovecii, Gram-negative aerobes, pneumococci, Nocardia, M. tuberculosis, or Aspergillus from BAL/sputum 1
• Positive Legionella pneumophila serogroup 1 antigen in urine 1
• Positive Aspergillus galactomannan in blood or BAL 1
• Positive quantitative P. jirovecii PCR >1450 copies/ml 1

Special Population Considerations

Returned Travelers

• Three daily blood films for malaria 1, 3
• Assess viral hemorrhagic fever risk with appropriate isolation 1, 3
• Consider cephalosporins or fluoroquinolones for fever with significant diarrhea 3
• Tinidazole or metronidazole for suspected amoebic dysentery 3

Pediatric Patients

• Neonates and infants <3 months: 8-13% have bacterial infections, predominantly UTI; infants <28 days at highest risk 1
• Children with fever >38.5°C: Consider bacterial pneumonia if chest recession and respiratory rate >50/min in those under 3 years 1, 3
• 25% may show pneumonia on chest radiograph despite no obvious respiratory source 1, 3
• Consider infective endocarditis in children with cardiac disease, pathological murmur, or previous endocarditis 1

Postoperative Patients

• For recent thoracic, abdominal, or pelvic surgery: perform CT of operative area when fever occurs several days postoperatively and alternative cause not identified 5
• Decision timing should be made in collaboration with surgical services 5

Critical Pitfalls to Avoid

• Never diagnose "fever of unknown origin" in resource-limited settings—always assume and treat infection when fever cannot be explained 1
• Do not delay antimicrobial therapy in febrile neutropenic patients while waiting for culture results 2
• Do not postpone urgent antimicrobial therapy for bronchoscopy/BAL 1
• Avoid unnecessary antibiotics in patients with recovered neutrophil counts who are afebrile and asymptomatic 2
• Do not withhold antibiotics in hemodynamically unstable patients for diagnostic procedures 1

Management When Diagnosis Remains Elusive

At 48 Hours (No Identified Cause, ANC ≥0.5 × 10⁹/L)

• Low-risk patients: Consider changing to oral antibiotics 2
• High-risk patients on dual therapy: Aminoglycoside may be discontinued 2

At 4-6 Days (Persistent Fever)

• Consider initiating antifungal therapy 2
• For suspected aspergillosis (based on CT findings): use voriconazole or liposomal amphotericin B 2
• Perform high-resolution chest CT looking for nodules with haloes or ground-glass changes 2

Undiagnosed Cases

• Up to 50% of patients have no cause found despite adequate investigations 7
• Reassuringly, undiagnosed PUO cohort has good prognosis 7
• In stable patients without progressive disease, careful clinical observation for new symptoms/signs is preferred over multiple antimicrobial courses 4