Fever of Unknown Origin
Defined as fever >38.3°C on several occasions, lasting >3 weeks, with no diagnosis despite 1 week of inpatient investigation (Petersdorf & Beeson criteria). The three main categories are infection (~30%), malignancy (~20%), and autoimmune/inflammatory conditions (~20%). Approximately 10–15% remain undiagnosed despite thorough investigation.
Key Facts
Classic definition: fever >38.3°C on several occasions, duration >3 weeks, no diagnosis after 1 week of investigation Infections (~30%): TB, endocarditis, abscess, osteomyelitis, CMV, EBV, HIV Malignancy (~20%): lymphoma (most common), renal cell carcinoma, hepatocellular carcinoma, leukaemia Autoimmune/inflammatory (~20%): adult-onset Still's disease, SLE, GCA/PMR, vasculitis, sarcoidosis Adult-onset Still's disease: quotidian (daily spiking) fever, salmon-pink evanescent rash, arthralgia, ferritin markedly elevated (>10,000 μg/L) PET-CT: increasingly used to identify occult infection or malignancy — sensitivity ~85–90% for FUO Undiagnosed FUO: ~10–15% remain without diagnosis; most have benign course and fever resolves Drug fever: consider in all FUO cases — temporal correlation with drug initiation; resolves on withdrawal
Overview
Key Facts
FUO requires a systematic and thorough approach. The differential is vast but can be narrowed by careful history, examination, and staged investigations.
Epidemiology
- Infections: declining proportion due to improved diagnostics; TB remains important
- Malignancy: lymphoma is the single most common malignant cause
- Autoimmune: increasingly recognised with better diagnostics
- Drug fever: underdiagnosed cause in hospitalised patients
Aetiology
Infectious (~30%): TB, endocarditis, abscess (intra-abdominal, pelvic, dental), osteomyelitis, CMV, EBV, HIV, Q fever, brucellosis Malignant (~20%): lymphoma, leukaemia, renal cell carcinoma, HCC, atrial myxoma Autoimmune (~20%): adult-onset Still's, SLE, GCA/PMR, PAN, sarcoidosis, Crohn's Miscellaneous (~15%): drug fever, factitious fever, thyrotoxicosis, adrenal insufficiency, PE, familial Mediterranean fever
Pathophysiology
- Fever: regulated by hypothalamic set-point elevation via prostaglandin E2 (PGE2)
- Pyrogens: exogenous (microbial products) and endogenous (IL-1, IL-6, TNF-alpha)
- Multiple pathological processes can sustain chronic febrile response
Clinical Presentation
Key History
- Fever pattern: quotidian (daily spike — Still's), tertian/quartan (malaria), Pel-Ebstein (Hodgkin's lymphoma — rare)
- Travel history, animal/occupational exposure
- Medication list (drug fever)
- Family history (familial Mediterranean fever)
- Immunosuppression, HIV risk factors
Key Examination
- Lymphadenopathy (lymphoma, TB, SLE)
- Heart murmur (endocarditis)
- Hepatosplenomegaly (haematological malignancy, infection)
- Dental examination (dental abscess)
- Temporal artery tenderness (GCA)
- Skin rash (Still's, vasculitis, SLE)
Red Flags
- Weight loss >10% (malignancy, TB)
- Night sweats (lymphoma, TB, endocarditis)
- New heart murmur (endocarditis)
- Neurological symptoms (CNS lymphoma, TB meningitis)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| TB | Weight loss, night sweats, lymphadenopathy, immigration history | CXR, sputum AFB, IGRA |
| Endocarditis | New murmur, splinter haemorrhages, embolic phenomena | Blood cultures ×3, TOE |
| Lymphoma | Lymphadenopathy, B-symptoms, hepatosplenomegaly | CT TAP, lymph node biopsy |
| Adult-onset Still's | Quotidian fever, evanescent rash, arthralgia, ferritin >10,000 | Ferritin, FBC, LFTs |
| GCA/PMR | Age >50, headache, jaw claudication, proximal myalgia | ESR/CRP, temporal artery biopsy |
| Drug fever | Temporal relationship with drug, eosinophilia | Drug history, withdrawal trial |
Diagnosis / Investigation
First-Line
- FBC with differential: leucocytosis, lymphopenia, eosinophilia, cytopenias
- CRP/ESR: degree of inflammation
- LFTs, U&Es, LDH: organ involvement
- Blood cultures: minimum 3 sets from different sites
- Urinalysis and urine culture
- CXR: TB, lymphoma, sarcoidosis
- HIV test: always include
Second-Line
- CT thorax/abdomen/pelvis: abscess, lymphadenopathy, solid organ malignancy
- Autoimmune screen: ANA, ANCA, RF, complement, ferritin
- Serology: CMV, EBV, hepatitis, Q fever, Brucella, Bartonella
- IGRA or Mantoux: TB
- TTE/TOE: endocarditis
- Peripheral blood film: haematological malignancy, haemophagocytosis
Third-Line
- PET-CT: sensitivity ~85–90% for identifying source in FUO — increasingly first choice
- Bone marrow biopsy: lymphoma, granulomatous disease, haemophagocytic lymphohistiocytosis
- Temporal artery biopsy: if GCA suspected (age >50, raised ESR)
- Liver biopsy: granulomatous hepatitis
- Lymph node biopsy: if lymphadenopathy
Management
General Approach
- Avoid empirical antibiotics unless clinically deteriorating — they obscure diagnosis
- Systematic investigation: staged approach (first, second, third-line)
- Review medication list: stop non-essential drugs to exclude drug fever
- Repeat examination: daily — new signs may emerge
Specific Treatment
- Treat underlying cause once identified
- TB: standard quadruple therapy (RIPE)
- Endocarditis: prolonged IV antibiotics
- Lymphoma: oncology referral for chemotherapy
- Adult-onset Still's: NSAIDs, corticosteroids (prednisolone 0.5–1mg/kg), IL-1 inhibitors (anakinra) if refractory
- GCA: prednisolone 40–60mg OD (start immediately if visual symptoms)
- Drug fever: withdraw causative drug — fever typically resolves within 48–72 hours
Naproxen Test
- Naproxen 250mg BD for 3 days
- Historically suggested: fever resolution suggests neoplastic cause (Naprosyn test) — limited evidence but still referenced
Referral Criteria
- Infectious diseases: complex cases, unexplained FUO
- Haematology: suspected lymphoma/leukaemia
- Rheumatology: suspected autoimmune cause
- Nuclear medicine: PET-CT for unexplained FUO
Prognosis
- ~85–90% of FUO cases eventually diagnosed with thorough investigation
- 10–15% remain undiagnosed — majority have benign course with spontaneous resolution
- Prognosis depends entirely on underlying cause
- Undiagnosed FUO: 5-year mortality ~3% (generally favourable)
- Infection-related FUO: good prognosis with appropriate treatment
- Malignancy-related FUO: variable depending on type and stage
Other Relevant Information
Categories of FUO
| Category | Definition | Common Causes |
|---|---|---|
| Classic | Fever >3 weeks, no diagnosis after 1 week inpatient | TB, lymphoma, Still's, endocarditis |
| Nosocomial | Hospitalised ≥24h, fever develops after admission | Line infection, C. difficile, drug fever, PE |
| Neutropenic | Neutrophils <0.5 ×10⁹/L, fever >3 days | Opportunistic fungi, resistant bacteria |
| HIV-associated | HIV+, fever >4 weeks (outpatient) or >3 days (inpatient) | TB, MAC, CMV, lymphoma, PCP |
FUO Investigation Yield
| Investigation | Diagnostic Yield |
|---|---|
| Blood cultures | 5–10% |
| CT TAP | 15–20% |
| PET-CT | 50–70% |
| Bone marrow biopsy | 5–15% |
| Temporal artery biopsy | Variable (if indicated) |