Pyrexia of Unknown Origin (PUO): A Comprehensive 2026 Guide to Fever of Unknown Origin (FUO)

Pyrexia of unknown origin (PUO), commonly referred to as **fever of unknown origin (FUO)**, continues to challenge clinicians worldwide. As of early 2026, with advancements in molecular diagnostics, imaging, and global data sharing, diagnostic yields have improved significantly—yet FUO remains a diagnostic odyssey for many patients. This prolonged fever without an initial clear cause can cause significant anxiety, but modern approaches often lead to resolution or spontaneous recovery.

This in-depth guide covers the definition, categories, common causes, diagnostic strategies, management, prognosis, and latest 2025-2026 insights into FUO/PUO. Drawing from recent peer-reviewed literature, it aims to provide evidence-based information for patients, healthcare professionals, and researchers.

*Image: A digital thermometer displaying a high fever reading, exceeding the 38.3°C threshold commonly used in FUO definitions.*

### Defining Fever of Unknown Origin

The syndrome of FUO was first systematically defined in 1961 by Petersdorf and Beeson as:

- Fever >38.3°C (101°F) on multiple occasions.

- Duration >3 weeks.

- No diagnosis after one week of inpatient investigation.

This classic definition has evolved. Recent 2025 updates, including a comprehensive BMJ review, adapt it to outpatient settings and advanced diagnostics, requiring uncertainty after appropriate investigations rather than mandatory hospitalization.

FUO encompasses over 200 potential etiologies and varies by age, geography, and immune status. In children, infections predominate; in adults, noninfectious causes are increasingly recognized.

### Categories of FUO

To guide evaluation, FUO is classified into four main categories:

1. **Classic FUO** — Community-acquired in immunocompetent patients (most common in adults).

2. **Nosocomial FUO** — Hospital-acquired, often device- or procedure-related.

3. **Neutropenic FUO** — In patients with neutropenia (e.g., post-chemotherapy); high infection risk.

4. **HIV-associated FUO** — Linked to opportunistic infections or HIV itself.

These categories, established in the 1990s and reaffirmed in recent reviews, help tailor diagnostic approaches.

### Etiology: Common Causes in 2026

Causes fall into five groups, with distributions varying by region and era. Recent series show infections declining in developed countries due to better diagnostics, while undiagnosed cases rise—with often benign outcomes.

*Image: Illustrative breakdown of FUO etiologies, showing proportions for infections, noninfectious inflammatory diseases, malignancies, miscellaneous, and undiagnosed cases.*

#### Infections (20-40%)

Still leading globally, especially in endemic areas:

- Tuberculosis (extrapulmonary).

- Endocarditis (culture-negative).

- Abscesses (intra-abdominal).

- Viral (CMV, EBV).

*Image: Illustration of infective endocarditis on a heart valve, a frequent infectious cause of prolonged fever.*

#### Noninfectious Inflammatory Diseases (NIID) (20-30%)

Rising in Western cohorts:

- Adult-onset Still's disease.

- Vasculitides (e.g., giant cell arteritis).

- Systemic lupus erythematosus.

#### Malignancies (10-30%)

- Lymphomas (most common).

- Leukemias.

- Solid tumors.

#### Miscellaneous (10-20%)

- Drug fever.

- Factitious fever.

- Thromboembolic events.

#### Undiagnosed (up to 50%)

Many resolve spontaneously with excellent prognosis.

Geographically: Infections dominate in developing regions; NIID and malignancies in developed ones.

### Diagnostic Approach: Systematic and Iterative

Diagnosis relies on history, examination, and targeted testing—avoiding indiscriminate "shotgun" approaches.

*Image: A clinician performing a thorough history and physical examination, the foundation of FUO evaluation.*

1. **History and Repeated Exams** — Travel, exposures, medications, family history.

2. **Basic Investigations** — Blood cultures, CBC, ESR/CRP, urinalysis, chest imaging.

3. **Advanced Imaging** — CT, echocardiography.

4. **Key Tool: FDG-PET/CT** — Revolutionized FUO workup with high diagnostic yield (>70-80% in recent studies), localizing infection, inflammation, or malignancy.

*Image: Example FDG-PET/CT scan demonstrating focal uptake, aiding in identifying hidden sources of fever.*

Additional tools: Molecular sequencing for obscure pathogens; biopsies as needed.

Empirical therapy (antibiotics/steroids) is generally avoided to prevent masking diagnosis.

### Management and Treatment

Treatment is etiology-directed:

- Infections → Targeted antimicrobials.

- NIID → Immunosuppression.

- Malignancy → Oncology referral.

Symptomatic relief with antipyretics. In neutropenic cases, guidelines support early empirical antifungals if fever persists.

Multidisciplinary input (infectious diseases, rheumatology) optimizes outcomes.

### Prognosis

Overall favorable, especially for undiagnosed cases, which often resolve spontaneously with low mortality (<10% in modern series). Worse in elderly or malignancy-related FUO.

### Advances in 2026

- Increased PET-CT utilization and guidelines.

- Distinction between FUO and inflammation of unknown origin (IUO).

- AI and genomic tools emerging for prediction.

### When to Seek Help

Consult a physician if fever >38.3°C lasts >3 weeks, particularly with weight loss, night sweats, or other symptoms.

### Conclusion -

FUO/PUO is challenging but often treatable or self-limiting. A methodical approach, leveraging tools like PET-CT, leads to better outcomes in 2026.

**Disclaimer**: This is educational content based on published literature. It is not medical advice. Consult a healthcare professional for personal concerns.

### Key References (Selected) -

- Petersdorf RG, Beeson PB. Medicine (Baltimore). 1961.

- Fusco FM et al. The BMJ. 2025.

- StatPearls FUO overview. 2023.

- Recent PET-CT studies (2024-2025).