What are the causes and diagnostic approaches for pyrexia of unknown origin?

Pyrexia of Unknown Origin: Causes and Diagnostic Approach

Definition and Classification

Pyrexia of unknown origin (PUO) is defined as fever ≥38.3°C (101°F) persisting for at least 3 weeks with no diagnosis despite 3 outpatient visits or 3 inpatient days of investigation 1. The condition is divided into four subcategories: classical, nosocomial, neutropenic, and HIV-related, each requiring distinct investigative strategies 2, 3.

Major Etiologic Categories

The causes of PUO fall into four broad groups, with their relative frequencies varying by geographic location and patient population 1, 2:

1. Infectious Causes

• Tuberculosis remains a leading infectious cause, particularly in endemic areas and can present with extrapulmonary manifestations including lymphadenitis 1
• Opportunistic mycobacterial infections (M. avium complex, M. kansasii) especially in immunocompromised patients 1
• Occult abscesses and deep-seated infections requiring advanced imaging for detection 4
• Malaria in returned travelers (requires up to three daily blood films) 4
• Viral hemorrhagic fevers in appropriate epidemiologic contexts 4

2. Inflammatory/Autoimmune Disorders

• Connective tissue diseases have shown increasing prevalence in recent series 5
• Vasculitides and other systemic inflammatory conditions 2
• Inflammatory bowel disease with systemic manifestations 3

3. Malignant Causes

• Lymphomas (must be excluded via immunohistochemistry in poorly differentiated cases) 1
• Cancers of unknown primary site (CUP) account for 3-5% of all malignancies and can present with fever 1
• Solid organ malignancies with occult metastases 5
• The percentage of neoplastic causes has increased in recent decades 5

4. Miscellaneous Causes

• Drug fever 2, 3
• Factitious fever 3
• Undiagnosed cases comprise up to 50% despite adequate investigation, but have favorable prognosis 2

Systematic Diagnostic Approach

Initial Mandatory Work-Up

Obtain comprehensive blood cultures before initiating any antimicrobial therapy to maximize diagnostic yield 4. The baseline evaluation must include:

• Complete blood count with differential to assess for neutropenia and cytopenia 4, 6
• Inflammatory markers (CRP, ESR) - note that FDG-PET/CT has insufficient evidence for PUO with normal inflammatory markers 1
• Thorough physical examination specifically including head/neck, rectal, pelvic, and breast examination 1
• CT scans of thorax, abdomen, and pelvis as minimal imaging standard 1
• Chest imaging (X-ray or CT) for any respiratory symptoms or persistent fever 4

Targeted Laboratory Testing

Do not perform "routine" investigations indiscriminately; instead, individualize testing based on clinical findings 7:

• Male patients: Serum AFP, β-HCG, and PSA to exclude germ cell tumors and prostate cancer 1
• Female patients with axillary adenopathy: Estrogen/progesterone receptors and mammography 1
• Urinalysis and fecal occult blood testing 1
• Liver function tests - liver biopsy remains useful in PUO investigation when other tests are unrevealing 1

Advanced Imaging Strategy

FDG-PET/CT should be performed within 3 days of initiating oral glucocorticoid therapy if steroids are necessary 1. This modality demonstrates:

• Sensitivity of 84-86% and specificity of 52-63% for identifying PUO/IUO causes 1
• Diagnostic yield of 56% with diagnostic accuracy of 76% 1
• High clinical impact in 79% of cases, prompting specialist referrals or antimicrobial changes 4
• 88% accuracy in identifying fever source in immunosuppressed patients 4
• Consider myocardial suppression preparation when cardiac etiology is suspected 1

Invasive Diagnostic Procedures

When non-invasive testing is unrevealing:

• Bone marrow examination is particularly valuable in patients with cytopenia, splenomegaly, immunodeficiency, or older age 6
• Endoscopies should be sign-, symptom-, or laboratory abnormality-guided rather than routine 1
• Laparotomy maintains diagnostic utility with improved yield in recent series, though percentage of patients requiring it remains stable 5
• Liver biopsy for suspected infections (tuberculosis), storage disorders, or when other investigations are negative 1

Risk-Stratified Management

High-Risk Patients (Severe Neutropenia)

Severe neutropenia (ANC <0.5 × 10⁹/L) with fever constitutes a medical emergency requiring immediate same-day broad-spectrum antibacterial therapy without waiting for culture results 4:

• Hemodynamically unstable patients require monitoring every 2-4 hours with urgent infectious disease consultation 4
• Antibacterial prophylaxis with levofloxacin or ciprofloxacin 500 mg daily for severe neutropenia 4

Stable Patients Without Diagnosis

In patients remaining stable without progressive disease after extensive investigation, careful clinical observation for new symptoms and signs is preferred over multiple courses of antimicrobials 7:

• Negative FDG-PET/CT predicts favorable prognosis through spontaneous resolution 1
• Undiagnosed PUO has reassuringly good prognosis in most cases 2

Special Population Considerations

• Returned travelers: Assess for malaria (three daily blood films), viral hemorrhagic fever risk with appropriate isolation 4
• Elderly patients: May represent a distinct fifth subgroup requiring tailored approach 2
• Children with fever >38.5°C: Consider bacterial pneumonia if chest recession and respiratory rate >50/min in those under 3 years; 25% may show pneumonia on chest radiograph despite no obvious respiratory source 4

Critical Pitfalls to Avoid

• Do not delay blood cultures by starting empiric antibiotics first in non-emergent cases 4
• Avoid routine endoscopy without specific clinical indicators 1
• Do not perform FDG-PET/CT after prolonged steroid therapy (ideally within 3 days of initiation) 1
• Recognize that up to 50% remain undiagnosed despite adequate investigation, but this carries favorable prognosis 2
• Judicious narrow-spectrum antimicrobial therapy may be warranted only in patients with clearly progressive disease despite extensive negative work-up 7