What is the management of pyrexia (fever) of unknown origin?

Management of Pyrexia of Unknown Origin

The management of pyrexia of unknown origin (PUO) requires a systematic diagnostic approach followed by targeted therapy based on identified causes, with consultation from infectious disease specialists when the etiology remains unclear after initial investigations. 1

Definition and Classification

• PUO is defined as fever persisting for more than 3 weeks with no identified cause despite appropriate initial investigations 1
• Different subgroups require specific investigative approaches: classical, nosocomial, neutropenic, HIV-related, and elderly 1

Initial Diagnostic Approach

• Obtain comprehensive blood cultures before initiating any antimicrobial therapy 2
• Complete blood count with differential to monitor trends and assess for neutropenia 2
• Determine severity if neutropenia is present based on absolute neutrophil count (ANC): Mild (ANC 1.0-1.5 × 10^9/L), Moderate (ANC 0.5-1.0 × 10^9/L), Severe (ANC < 0.5 × 10^9/L) 2
• Chest imaging for patients with respiratory symptoms or persistent fever 3
• Diagnostic testing should be guided by abnormalities found on initial laboratory testing rather than following a set of "routine" investigations 4

Management Algorithm Based on PUO Type

For Neutropenic PUO:

• For severe neutropenia (ANC < 0.5 × 10^9/L) with fever: Initiate broad-spectrum antibacterial therapy immediately 2
• If apyrexial and ANC ≥ 0.5 × 10^9/L at 48 hours:
  • Low-risk patients with no identified cause: consider changing to oral antibiotics 3
  • High-risk patients with no identified cause: if on dual therapy, aminoglycoside may be discontinued 3
• If fever persists at 48 hours:
  • Clinically stable: continue initial antibacterial therapy 3
  • Clinically unstable: broaden antibacterial coverage and seek infectious disease consultation 3
• For persistent fever >4-6 days: consider initiating antifungal therapy 3
• Consider FDG-PET/CT for localization of infection source, particularly in immunosuppressed patients 3

Duration of Therapy:

• If neutrophil count ≥0.5 × 10^9/L, patient is asymptomatic, afebrile for 48 hours, and blood cultures are negative: discontinue antibacterials 3
• If neutrophil count ≤0.5 × 10^9/L, no complications, and afebrile for 5-7 days: discontinue antibacterials except in high-risk cases 3
• Patients with persistent fever despite neutrophil recovery should be assessed by an infectious disease specialist and antifungal therapy considered 3

For HIV-Related PUO:

• Consider opportunistic infections including mycobacterial disease 5
• Until diagnosis is confirmed by culture, lymphadenitis should be regarded as tuberculosis and treated accordingly 3
• Restore immunocompetence with appropriate antiretroviral therapy alongside antimicrobial treatment 3

Advanced Diagnostic Strategies

• Consider FDG-PET/CT for patients with prolonged unexplained fever, which has shown high sensitivity and specificity for detecting infections and inflammatory processes 3
• For suspected invasive fungal disease, high-resolution chest CT should be performed promptly, looking for typical features such as nodules with haloes or ground-glass changes 3
• If fungal infection is suspected and infiltrates are found on imaging, bronchoalveolar lavage should be performed when possible 3

Empiric Therapy Considerations

• For suspected aspergillosis (based on CT findings): use either voriconazole or liposomal amphotericin B 3
• For suspected viral encephalitis: high-dose aciclovir after appropriate samples are taken 3
• For suspected bacterial meningitis: ceftazidime plus ampicillin (to cover Listeria monocytogenes) or meropenem 3
• In patients with clearly progressive disease despite extensive investigations, judicious use of narrow-spectrum antimicrobial therapy may be warranted 4

Pitfalls and Caveats

• Do not delay antimicrobial therapy in febrile neutropenic patients while waiting for culture results 2
• Avoid unnecessary antibiotic use in patients with recovered neutrophil counts who are afebrile and asymptomatic 2
• Up to 50% of PUO cases may remain undiagnosed despite adequate investigations, but this undiagnosed cohort generally has a good prognosis 1
• For stable patients without a clear diagnosis, careful clinical observation for new symptoms and signs is preferred over multiple courses of antimicrobials 4