Diagnosing Pyrexia of Unknown Origin (PUO): A Systematic Approach
The diagnosis of Pyrexia of Unknown Origin requires a methodical, step-by-step approach focusing on detailed history, targeted physical examination, and strategic laboratory and imaging investigations to identify the underlying cause, which is most commonly infectious, inflammatory, or neoplastic in nature. 1
Definition and Classification
PUO is defined as:
- Fever higher than 38.3°C (100.9°F)
- Persisting for at least 3 weeks
- No diagnosis despite 3 outpatient visits or in-patient days 1
PUO can be classified into four distinct subcategories:
- Classical PUO
- Nosocomial PUO
- Neutropenic PUO
- HIV-related PUO 1
History-Taking Clues
Travel History
- Detailed geographical history: Document exact dates and places of travel 2
- Time of onset and duration of symptoms: Most tropical infections become symptomatic within 21 days of exposure 2
- Risk activities undertaken: Document specific exposures (e.g., swimming in freshwater, animal contact) 2
- Higher suspicion for endemic infections based on travel location:
- Western countries: Endocarditis, Q fever, intra-abdominal abscesses
- India/tropical regions: Tuberculosis, enteric fever, malaria, visceral leishmaniasis 1
Medication History
- Current treatments, especially immunosuppressants
- Recent antibiotics that might mask infections
- Over-the-counter medications
Social History
- Living conditions and accommodation suitability
- Smoking history 2
- Occupational exposures
- Animal contacts
- Sexual history
Physical Examination Clues
Key Signs to Identify
- Skin: Rashes, petechiae, eschar (suggests rickettsial disease)
- Lymphadenopathy: Location, consistency, tenderness
- Hepatosplenomegaly: Suggests infections (e.g., tuberculosis, brucellosis), lymphoma
- Heart murmurs: Suggests endocarditis
- Respiratory: Audible wheeze, tachypnea, use of accessory muscles 2
- Neurological: Confusion, meningeal signs
- Joint examination: Swelling, tenderness, range of motion
Special Considerations
- Travelers: Look for signs of tropical infections 1
- Immunocompromised patients: More thorough skin and mucosal examination
- Elderly: Atypical presentations common, check for subtle signs
Laboratory Investigations
Initial Workup
- Complete blood count with differential:
- Lymphopenia: Viral infections (dengue, HIV), typhoid
- Eosinophilia (>0.45×10⁹/L): Parasitic or fungal infections
- Thrombocytopenia: Malaria, dengue, acute HIV, typhoid 2
- Blood cultures: At least 2 sets (60 mL total) 1
- Acute phase reactants: C-reactive protein, erythrocyte sedimentation rate 1
- Liver function tests: Elevated alkaline phosphatase and LDH may suggest disseminated infections 2
- Urinalysis: Proteinuria and hematuria in leptospirosis 2
Targeted Testing Based on Suspicion
- Malaria films and dipstick antigen test (RDT): For all patients who visited tropical countries within 1 year; three thick films/RDTs over 72 hours to exclude malaria 2
- Serum save for serology: HIV testing for patients with pneumonia, aseptic meningitis/encephalitis, diarrhea, viral hepatitis, lymphadenopathy 2
- Stool examination: Wet preparation for amoebic trophozoites if bloody diarrhea 2
- Ferritin levels: Levels >5000 ng/mL suggest adult-onset Still's disease 1
- Glycosylated ferritin: Levels <20% highly specific for adult-onset Still's disease 1
- Procalcitonin: Useful for diagnosing bacterial infections 1
Imaging Investigations
Initial Imaging
- Chest radiograph: For all patients with PUO 1
- Abdominal ultrasound: If abdominal symptoms or liver function abnormalities present 1
Advanced Imaging
- 18F-FDG PET/CT: Consider early in the diagnostic process if initial workup is unrevealing; high diagnostic yield (56%) with sensitivity of 84-86% and specificity of 52-63% 1, 3
- Whole body MRI: Useful to rule out oncologic disease and occult abscesses 2
- CT paranasal sinuses: For neutropenic patients 2
- CT chest/abdomen/pelvis with IV contrast: For neutropenic patients or if specific organ involvement suspected 2
Diagnostic Approach by Suspected Etiology
Infectious Causes
- Tuberculosis: Extended blood cultures, tuberculin skin test, interferon-gamma release assay, biopsy of lymph nodes 1
- Endocarditis: Multiple blood cultures, echocardiography 1
- Abscesses: Targeted imaging based on symptoms 1
- Brucellosis/Q fever: Serological testing 1
Inflammatory Causes
- Adult-onset Still's disease: Ferritin, glycosylated ferritin 1
- Vasculitis: ANCA, temporal artery biopsy in elderly 1
- Connective tissue diseases: ANA, RF, anti-CCP antibodies 1
Neoplastic Causes
- Lymphomas/leukemias: Peripheral blood smear, flow cytometry, bone marrow biopsy 1
- Solid tumors: Targeted imaging based on symptoms 1
Special Scenarios
Returned Travelers
- Malaria: Three thick films/RDTs over 72 hours 2
- Dengue/viral hemorrhagic fevers: Risk assessment for VHF, serology 2
- Enteric fever: Blood cultures (sensitivity up to 80% in typhoid) 2
Neutropenic Patients
- Urgent evaluation: CT scans and bronchoscopy for pulmonary infiltrates 1
- Central venous catheters: Evaluate catheter and peripheral blood cultures for differential time to positivity 1
HIV-Related PUO
- Disseminated MAC: Look for severe anemia, elevated alkaline phosphatase, elevated LDH 2
- Immune reconstitution syndrome: Consider in patients recently started on antiretroviral therapy 2
Common Pitfalls to Avoid
- Initiating empiric antimicrobials without adequate investigation (except in neutropenic, immunocompromised, or critically ill patients) 4
- Delaying 18F-FDG PET/CT until late in the diagnostic process 1
- Starting glucocorticoid therapy without obtaining appropriate imaging 1
- Neglecting to notify infectious diseases to local health protection units 2
- Inadequate travel history documentation on laboratory request forms 2
By following this systematic approach, clinicians can efficiently work through the differential diagnosis of PUO and identify the underlying cause in most cases.