What are the potential causes and treatment options for Pyrexia of Unknown Origin (PUO) in an adult patient with no significant past medical history?

Pyrexia of Unknown Origin (PUO): Causes and Management

Definition and Initial Diagnostic Workup

PUO is defined as fever ≥38.3°C lasting at least three weeks with no cause identified after three days of inpatient investigation or three outpatient visits. 1

Immediate Actions

• Obtain blood cultures from peripheral vein and all indwelling catheters before starting any antimicrobials 2
• Perform complete blood count with differential to assess for neutropenia (ANC <0.5 × 10^9/L indicates severe neutropenia requiring immediate broad-spectrum antibiotics) 2
• Order chest imaging (X-ray or CT) for respiratory symptoms or persistent fever 2

Major Causes of PUO

The causes fall into four broad categories, with specific entities to actively investigate 3, 1:

Infectious Causes

• Tuberculosis remains a leading cause, particularly in HIV-positive patients, and can affect any organ system 4
• Bacterial infections including occult abscesses, endocarditis, and osteomyelitis 3
• Viral infections (HIV, CMV, EBV) 3
• Fungal infections in immunocompromised patients 2

Inflammatory/Autoimmune Causes

• Inflammatory bowel disease (Crohn's disease) can present as PUO with minimal gastrointestinal symptoms in young adults 5
• Connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, vasculitis) 3
• Sarcoidosis 4

Neoplastic Causes

• Lymphomas (Hodgkin's and non-Hodgkin's) 3
• Leukemias 3
• Solid tumors with metastases 4

Miscellaneous Causes

• Drug-induced fever (BRAF inhibitors commonly cause pyrexia 2-4 weeks after initiation) 6
• Thromboembolic disease 3

Systematic Investigation Strategy

History Taking Priorities

Take a detailed medication history to identify drug-induced causes (immunosuppressants, BRAF inhibitors, chemotherapy agents) 6

Document environmental exposures at home, work, and frequently visited places: specifically ask about mold, birds, down feathers, animals, metal dusts, wood dust, livestock, and recent occupational changes 6

Laboratory Testing Sequence

First-tier tests: 2, 3

• Blood cultures (multiple sets from different sites)
• CBC with differential and absolute neutrophil count
• Comprehensive metabolic panel
• Inflammatory markers (ESR, CRP)
• Urinalysis and urine culture

Second-tier serological testing if connective tissue disease suspected: 6

• ANA, RF, anti-CCP antibodies
• Anti-dsDNA, complement levels (C3, C4)
• Creatine phosphokinase, myoglobin, aldolase
• Antisynthetase antibodies (Jo-1)
• Anti-Scl-70/topoisomerase-1 for scleroderma
• Anti-SSA/Ro and anti-SSB/La for Sjögren syndrome
• ANCA for vasculitis

Advanced Imaging

For prolonged unexplained fever beyond initial workup, FDG-PET/CT should be performed as it has high sensitivity and specificity for detecting infections, inflammatory processes, and occult malignancies 2, 4

High-resolution chest CT is indicated if fungal infection suspected, looking for nodules with haloes or ground-glass changes 2, 7

Management Algorithm Based on Clinical Scenario

Severe Neutropenia (ANC <0.5 × 10^9/L)

Initiate broad-spectrum antibacterial therapy immediately without waiting for culture results 2, 7

Do not delay antimicrobial therapy while awaiting diagnostic workup 2, 7

Persistent Fever >4-6 Days Despite Antibiotics

Consider initiating empiric antifungal therapy (voriconazole or liposomal amphotericin B for suspected aspergillosis) 2, 7

Perform bronchoalveolar lavage if infiltrates found on imaging 2

Low-Risk Patients with Recovered Neutrophil Counts

For patients with ANC ≥0.5 × 10^9/L at 48 hours who are afebrile and asymptomatic, consider switching to oral antibiotics or discontinuing aminoglycosides 2

Avoid unnecessary antibiotic continuation in recovered, afebrile patients 2

Stable Patients with No Diagnosis After Extensive Workup

In stable patients without progressive disease, careful clinical observation for new symptoms is preferred over empiric antimicrobial courses 8

Up to 50% of PUO cases remain undiagnosed despite adequate investigation, but this cohort has a good prognosis 3

Critical Pitfalls to Avoid

Signs and symptoms of infection may be minimal or absent in neutropenic patients, especially those on corticosteroids—maintain high suspicion even with low-grade fever 7

BRAF inhibitor-induced pyrexia typically occurs 2-4 weeks after starting therapy and requires drug discontinuation plus antipyretics (acetaminophen/NSAIDs), not antibiotics 6

Consider colonoscopy if abdominal CT shows bowel wall thickening, as inflammatory bowel disease can present as PUO with minimal GI symptoms 5

Thrombocytopenia may preclude invasive diagnostic procedures—assess risk-benefit and consider platelet transfusion before procedures 7