Pyrexia of Unknown Origin (PUO), also known as Fever of Unknown Origin (FUO), refers to a persistent fever that remains unexplained even after thorough medical evaluation. Fever is the body’s natural response to infection or inflammation, but when it lasts for weeks without an identifiable cause, it becomes a diagnostic challenge for doctors.
Understanding the potential causes, investigations, and management of PUO is crucial for effective treatment and patient care.
What Is Pyrexia of Unknown Origin (PUO)?
The term PUO was first defined in 1961 by Petersdorf and Beeson. According to their classical definition, PUO is a fever higher than 38.3°C (101°F) on several occasions, lasting more than three weeks, and without a diagnosis after one week of hospital evaluation.
Although modern diagnostic tools have refined the criteria, the core concept remains — a prolonged fever with no clear cause after extensive testing.
Categories of PUO
PUO is classified into four main categories depending on the setting and patient type:
- Classic PUO – Occurs in otherwise healthy individuals.
- Nosocomial PUO – Develops in hospitalized patients without infection on admission.
- Neutropenic PUO – Occurs in patients with low white blood cell counts, often due to chemotherapy.
- HIV-associated PUO – Seen in patients with Human Immunodeficiency Virus infection.
Each category has distinct causes and requires tailored diagnostic approaches.
Common Causes of PUO
Although PUO can be due to hundreds of conditions, most cases fall into four main groups:
1. Infections (30–40%)
- Tuberculosis (especially extrapulmonary)
- Abscesses (liver, pelvic, or deep-seated infections)
- Endocarditis (infection of the heart valves)
- Typhoid fever, malaria, or brucellosis
2. Malignancies (15–20%)
- Lymphoma (Hodgkin and Non-Hodgkin types)
- Leukemia
- Renal cell carcinoma
- Hepatocellular carcinoma
3. Autoimmune and Connective Tissue Diseases (15–20%)
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- Vasculitis
- Adult-onset Still’s disease
4. Miscellaneous Causes
- Drug-induced fever
- Thyroiditis
- Granulomatous diseases (e.g., sarcoidosis)
- Inherited periodic fever syndromes
5. Undiagnosed Cases
Despite extensive testing, 5–15% of PUO cases remain undiagnosed, though many eventually resolve spontaneously.
Clinical Features
Patients with PUO often present with:
- Persistent fever (≥38.3°C)
- Malaise and fatigue
- Loss of appetite and weight loss
- Night sweats
- Muscle or joint pain
These nonspecific symptoms can mimic various illnesses, making diagnosis complex and time-consuming.
Diagnostic Approach to PUO
A structured, stepwise evaluation is essential for identifying the underlying cause.
1. Detailed History and Physical Examination
- Travel history, occupational exposure, animal contact, or recent surgery.
- Review of medications and family history.
- Repeated thorough physical examinations to identify new signs.
2. Basic Laboratory Tests
- Complete blood count (CBC)
- Erythrocyte sedimentation rate (ESR) / C-reactive protein (CRP)
- Liver and kidney function tests
- Urinalysis and urine culture
- Blood cultures (for bacterial infections or endocarditis)
3. Imaging Studies
- Chest X-ray for tuberculosis or pneumonia.
- Ultrasound abdomen for abscess or organ enlargement.
- CT or MRI scans for hidden infections or malignancies.
- PET-CT scans to detect inflammatory or cancerous foci.
4. Specialized Tests
- Autoimmune screening (ANA, rheumatoid factor)
- Bone marrow biopsy (for leukemia or lymphoma)
- HIV and tuberculosis testing
- Thyroid profile
- Liver biopsy, if hepatic pathology suspected.
Treatment and Management
The treatment of PUO depends on identifying the underlying cause.
While waiting for a diagnosis, empirical antibiotic therapy is generally avoided unless the patient is critically ill or neutropenic.
Management Steps Include:
- Supportive care: Adequate hydration, nutrition, and rest.
- Symptomatic treatment: Paracetamol for fever relief (avoid overuse of NSAIDs).
- Targeted therapy:
- Antibiotics or antivirals for infections.
- Immunosuppressants or corticosteroids for autoimmune diseases.
- Chemotherapy or radiation therapy for malignancies.
- Monitoring and follow-up: Regular assessment to track response and adjust therapy.
Complications
If untreated or misdiagnosed, PUO may lead to:
- Organ damage (due to chronic infection or inflammation)
- Severe weight loss and weakness
- Progression of underlying malignancy or autoimmune disease
- Sepsis or multi-organ failure in severe infections
Prognosis
The prognosis of PUO varies depending on the cause.
- Infectious causes generally have a good prognosis if treated early.
- Malignant and autoimmune causes may require long-term management.
- Up to 20% of cases resolve spontaneously without specific treatment.
Early recognition and a multidisciplinary approach significantly improve patient outcomes.
When to See a Doctor
Consult a healthcare provider if you experience:
- Fever lasting more than two weeks
- Unexplained fatigue or weight loss
- Recurrent night sweats
- No improvement after routine antibiotic use
Early evaluation helps identify the cause before complications arise.
Conclusion
Pyrexia of Unknown Origin (PUO) remains a challenging medical condition requiring careful investigation and patience. With advancements in diagnostic imaging and laboratory techniques, the causes are now identified in most cases. However, collaboration between physicians, infectious disease specialists, and pathologists is often key to reaching a diagnosis.
Proper evaluation, timely intervention, and ongoing follow-up are essential to ensure recovery and prevent serious complications.
