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Pyrexia of Unknown Origin (PUO / FUO)

1. Definition

• Fever ≥38.3°C (≥101°F) on at least two occasions
• Illness duration of at least 3 weeks
• Diagnosis uncertain despite at least 1 week of inpatient evaluation

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state
4. Diagnosis uncertain despite a minimum standard diagnostic workup (at least 3 outpatient visits or 3 days in hospital)

Source: Harrison's Principles of Internal Medicine, 22nd Ed. (2025); Goldman-Cecil Medicine

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2. Epidemiology

• True prevalence is largely unknown and varies by geography and healthcare setting.
• A Japanese study (1990s) reported a prevalence of 2.9% among admitted patients.
• A Danish 10-year registry study recorded 6,220 FUO patients.
• The chance of remaining undiagnosed is 2-5x higher in European cohorts vs. Asian cohorts, reflecting differences in disease epidemiology and diagnostic thresholds.

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3. Broad Categories of Causes

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4. Infectious Causes (~15-40% depending on region)

Most Common Infectious Causes

Key Notes on Specific Infections

• Prior antibiotic use masking typical organisms
• Atypical organisms: Bartonella, Brucella, Coxiella burnetii, HACEK organisms (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella), Tropheryma whipplei, fungi
• Also seen in marantic (sterile thrombotic) endocarditis (paraneoplastic from adenocarcinoma) and SLE/antiphospholipid syndrome

• Extrapulmonary disease without localizing features
• Miliary TB without classical CXR pattern
• Pulmonary TB in immunocompromised (CXR may be normal)

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5. Non-Infectious Inflammatory Diseases (NIIDs) (~20-30%)

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6. Malignant Causes (~10-15%)

• Lymphoma (Hodgkin's and non-Hodgkin's) is by far the most common malignant cause - fever may precede detectable lymphadenopathy.
• Leukemia (lymphoid and myeloid types)
• Renal cell carcinoma - associated with hematuria and polycythemia; smoking history
• Hepatocellular carcinoma - occurs in cirrhosis
• Metastatic solid tumors
• Atrial myxoma - "tumor plop" on exam, intermittent fever
• Colon carcinoma - associated with Streptococcus gallolyticus (bovis) endocarditis
• In patients with known malignancy presenting with FUO, infection is still the most common cause (not the malignancy itself; the malignancy accounts for just under half of cases).

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7. Miscellaneous Causes

• Drug-induced fever (drug fever): virtually any drug can cause fever, even after long-term use. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms, now called drug-induced hypersensitivity syndrome) is an important cause. Stopping the offending drug is diagnostic and therapeutic.
• Pulmonary embolism: often overlooked; fever is common
• Thyroiditis (subacute de Quervain's)
• Factitious fever: deliberate self-induction of fever; consider when patterns are unusual
• Habitual hyperthermia / exercise-induced hyperthermia
• Thrombophlebitis

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8. History and Physical Examination

• Country of origin / residence (endemic infections)
• Travel history (malaria, leishmaniasis, histoplasmosis)
• Sick contacts, sexual behavior, IV drug use
• Zoonotic exposures (livestock, pets - cats for Bartonella)
• Dietary history (unpasteurized dairy - Brucella)
• Occupational exposures
• Recreational activities (leptospirosis from freshwater)

• Prior diverticulitis, dental procedures → abscess/endocarditis
• Blood transfusions, prosthetic heart valves, joint prostheses
• History of malignancy
• Antibiotic use (culture-negative endocarditis)
• Family history (FMF, hereditary autoinflammatory diseases)
• Medication list (drug fever)

• Fundoscopic exam (Roth spots in endocarditis)
• Heart murmur (endocarditis)
• Lymphadenopathy (lymphoma, infectious mononucleosis)
• Temporal artery tenderness/thickening (GCA)
• Hepatosplenomegaly
• Salmon-colored rash (Still's disease)
• Conjunctival suffusion (leptospirosis)
• Skin lesions (vasculitis, SLE, VEXAS)
• Joint examination (arthritis)
• Spine tenderness (vertebral osteomyelitis)

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9. Diagnostic Workup

Tier 1 - Basic "Core" Workup

Tier 2 - Directed Tests Based on Clues

Tier 3 - Advanced Imaging

• Can detect a cause in 30-60% of cases when core tests are unrevealing
• Identifies metabolically active foci amenable to biopsy
• Can be directly diagnostic (e.g., large-vessel vasculitis showing aortic/large vessel FDG uptake)

• Lymph node biopsy
• Liver biopsy (granulomatous hepatitis, TB, lymphoma)
• Bone marrow biopsy (lymphoma, leukemia, VEXAS, disseminated infection)
• Temporal artery biopsy (GCA)

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10. Treatment Principles

Empirical Antibiotic / Antituberculous Therapy

• Reserve for hemodynamic instability or neutropenia
• Anti-TB therapy may be started if: positive TST/IGRA + clinical picture fitting extrapulmonary TB + from endemic region - but only after mycobacterial cultures and PCR have been collected
• If fever does not respond after 6 weeks of empirical anti-TB therapy, reconsider the diagnosis

NSAIDs and Colchicine

• NSAIDs: supportive; dramatic response in Still's disease
• Colchicine: highly effective at preventing FMF attacks; also useful in recurrent pericarditis and Behcet's disease; less effective once an FMF attack is underway

Glucocorticoids

• Impressive effect in GCA and polymyalgia rheumatica
• Avoid early empirical use - can mask fever while allowing spread of infection or lymphoma; delay diagnosis of conditions requiring specific therapy (e.g., lymphoma)
• Only use when infection and lymphoma have been sufficiently excluded and inflammatory disease is probable and debilitating

Interleukin-1 (IL-1) Inhibition

• Anakinra (IL-1 receptor antagonist): blocks both IL-1α and IL-1β
• Highly effective in autoinflammatory syndromes: FMF, cryopyrin-associated periodic syndrome (CAPS), TRAPS (TNF receptor-associated periodic syndrome), mevalonate kinase deficiency (hyper-IgD syndrome), Schnitzler's syndrome, Still's disease
• A therapeutic trial with anakinra can itself serve as a diagnostic test in suspected autoinflammatory/IL-1-driven disease

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11. Prognosis

• In patients with unexplained FUO after extensive evaluation, the large majority become symptom-free spontaneously.
• FUO-related mortality risk is highest during the early phase of the diagnostic process.
• In one cohort of 168 patients without a final diagnosis, all 4 who died did so during the index admission (2 diagnoses - intravascular lymphoma and bilateral pneumonia - were made only at autopsy).
• Prognosis after thorough evaluation is generally favorable when no diagnosis is found, as this makes serious treatable disease less likely.

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12. Special Categories of FUO (Not Classic FUO)

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13. Summary Algorithm

Fever ≥38.3°C × 2, >3 weeks, no immunocompromise, standard workup negative
                         ↓
         Comprehensive History + Full Physical Exam
                         ↓
    Tier 1: Core blood tests, cultures, CXR, HIV, TB, CMV/EBV
                         ↓
    Diagnostic clues found? → Directed tests (Tier 2)
                         ↓
    Still undiagnosed? → FDG-PET/CT
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    PET shows active focus? → Tissue biopsy
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    Still undiagnosed? → Watchful waiting (most resolve spontaneously)
    OR therapeutic trial (anakinra/colchicine if autoinflammatory likely)

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Key Sources

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapter 22 (Mulders-Manders & Rovers)
• Frameworks for Internal Medicine (Wiley, 2nd Ed.) - Chapter on FUO
• Goldman-Cecil Medicine, International Edition - Chapter 259
• Marra et al. (2024) - Metagenomic NGS in FUO, Diagnostic Microbiology and Infectious Disease (PMID 39059148)
• Sandherr et al. (2025) - AGIHO guideline: FUO in neutropenic patients, Lancet Regional Health Europe (PMID 39973942)