Fever is one of the most common signs of illness — a natural response of the immune system to infection or inflammation. But sometimes, despite extensive investigations, the cause remains elusive. This puzzling clinical scenario is termed Fever of Unknown Origin (FUO).
This detailed guide explores FUO through the lens of the mnemonic “I GOT THE FEVER”, providing a memorable and clinically relevant breakdown of causes. Whether you’re a medical student, clinician, or aspirant for NEET PG/USMLE, this article provides high-yield content with clarity.
What is Fever of Unknown Origin?
FUO was originally defined by Petersdorf and Beeson in 1961 as:
- Temperature > 38.3°C (101°F) on several occasions
- Duration > 3 weeks
- Failure to establish a diagnosis despite 1 week of in-hospital investigation
Today, the concept has evolved, but the core principle remains: persistent fever with no clear cause after appropriate investigation.
Classifications of FUO
Modern medicine recognizes subtypes of FUO for more precise categorization:
| Type of FUO | Description |
|---|---|
| Classic FUO | As per original definition (38.3°C, >3 weeks, undiagnosed) |
| Nosocomial FUO | In hospitalized patients with no infection at admission |
| Neutropenic FUO | In patients with neutrophil count <500 cells/μL |
| HIV-associated FUO | In HIV-positive patients with prolonged fever |
| Pediatric FUO | In children >3 weeks or infants >8 days with no diagnosis |
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Mnemonic: I GOT THE FEVER
To remember the causes of FUO, use the mnemonic:
“I GOT THE FEVER”
Each letter stands for a potential cause. This approach helps in thorough differential diagnosis.
I – Inflammatory Bowel Disease (IBD)
Conditions like Crohn’s disease and Ulcerative Colitis may present with:
- Recurrent fevers
- Weight loss
- Abdominal pain
- Extraintestinal manifestations (e.g., uveitis, arthritis)
These inflammatory conditions can cause systemic cytokine release leading to intermittent fevers.
G – Granulomatous Diseases
These include:
- Tuberculosis (TB)
- Sarcoidosis
- Brucellosis
- Histoplasmosis
Granulomas are a hallmark of chronic inflammation and can lead to low-grade fevers for weeks.
TB is a leading cause of FUO in developing countries.
O – Other Infections
Some infections present subtly:
- Subacute bacterial endocarditis
- Dental abscess
- Abdominal or pelvic abscess
- Cholangitis or occult urinary tract infections
Missed infections are common causes of prolonged fever, especially when symptoms are non-specific.
T – Tumours (e.g., Lymphoma)
Neoplasms, especially hematologic cancers, often cause FUO:
- Hodgkin’s lymphoma
- Non-Hodgkin lymphoma
- Renal cell carcinoma
- Hepatocellular carcinoma
B symptoms (fever, weight loss, night sweats) are classic in lymphoma.
T – Toxins / Medications
Drug fever is a diagnosis of exclusion:
- Common culprits: Antibiotics, anticonvulsants, allopurinol
- Typically appears 7–10 days after starting medication
- May have rash, eosinophilia, or liver dysfunction
Withdrawal usually resolves symptoms in 48–72 hours.
H – Hypothalamic Disease
Rare but significant:
- Neoplasms or infiltrative lesions in hypothalamus
- Multiple sclerosis involving thermoregulatory centers
- Can cause dysregulated body temperature and persistent fevers
E – Endocarditis
Subacute infective endocarditis is a classic FUO presentation:
- Insidious onset with fatigue and low-grade fever
- Murmur may be present
- Blood cultures, Echocardiography (TTE/TEE) essential for diagnosis
F – Factitious Fever
Often missed, especially in:
- Healthcare workers or patients with psychiatric illness
- Artificially induced fever using warm devices or self-injected substances
- Clues: Discrepancy between high temperature and normal pulse
Always consider after excluding organic causes.
E – Emboli
Multiple small emboli can trigger inflammatory responses:
- Pulmonary embolism
- Septic emboli from endocarditis
- Fat embolism syndrome
May present with fever, hypoxia, altered mental status.
V – Vasculitis
Autoimmune diseases cause fever due to systemic inflammation:
- Temporal arteritis
- Takayasu arteritis
- Polyarteritis nodosa
- Systemic lupus erythematosus (SLE)
Common features include rash, joint pain, renal dysfunction.
E – EtOH Induced Liver Disease (Alcoholic Hepatitis)
Alcoholic liver disease may lead to:
- Fever
- Hepatomegaly
- Elevated liver enzymes
- Leukocytosis with left shift
Distinguishing it from infective hepatitis is important.
R – Rheumatologic Disease
Connective tissue disorders like:
- SLE
- Adult-onset Still’s disease
- Rheumatoid arthritis (RA)
- Mixed connective tissue disease
Autoimmune pathologies often present with fever, rash, fatigue.
Diagnostic Workup of FUO
A stepwise approach prevents unnecessary testing.
Step 1: Clinical History
- Travel, occupation, animal exposure
- Medication history
- Family history of autoimmune or hereditary diseases
Step 2: Physical Examination
- Look for clues: lymphadenopathy, joint swelling, murmurs, rashes
Step 3: Initial Investigations
| Test | Purpose |
|---|---|
| CBC with differential | Leukocytosis, eosinophilia, anemia |
| ESR, CRP | Inflammation markers |
| LFTs, RFTs | Organ involvement |
| Chest X-ray | Lung infection, lymphoma |
| Blood cultures (3 sets) | Rule out bacteremia, endocarditis |
| Urine analysis and culture | UTI or pyelonephritis |
Step 4: Advanced Imaging
- CT scan of chest/abdomen/pelvis
- Echocardiography for endocarditis
- PET-CT for occult infections or tumors
Step 5: Targeted Tests Based on Clues
- ANA, dsDNA for SLE
- Bone marrow biopsy for hematological causes
- Liver biopsy if hepatomegaly + elevated LFTs
Management of FUO
Treatment depends on:
- Identified cause
- Severity of symptoms
- Presence of red flags
If Cause Found:
| Condition | Management |
|---|---|
| Tuberculosis | Anti-TB therapy |
| Endocarditis | IV antibiotics for 4–6 weeks |
| Lymphoma | Chemotherapy ± Radiation |
| Autoimmune disease | Steroids, immunosuppressants |
If Cause Not Found:
- Re-evaluate after 1–2 weeks
- Avoid empiric antibiotics or steroids unless acutely ill
- Reconsider factitious fever
Summary Table: “I GOT THE FEVER” Mnemonic
| Mnemonic Letter | Cause Category | Examples / Notes |
|---|---|---|
| I | Inflammatory Bowel Disease | Crohn’s, Ulcerative colitis |
| G | Granulomatous Disease | TB, Sarcoidosis, Brucella |
| O | Other Infections | Abscesses, UTIs, Cholangitis |
| T | Tumors | Lymphoma, Renal cancer |
| T | Toxins / Medications | Drug-induced fever |
| H | Hypothalamic Disease | CNS lesions, MS |
| E | Endocarditis | SBE, prosthetic valve infections |
| F | Factitious | Self-induced fever |
| E | Emboli | PE, septic emboli |
| V | Vasculitis | SLE, PAN, Takayasu |
| E | EtOH-Induced Liver Disease | Alcoholic hepatitis |
| R | Rheumatologic Disease | SLE, Still’s, MCTD |
Frequently Asked Questions (FAQs)
Q1: How long must a fever persist to be considered FUO?
A: More than 3 weeks with no clear cause after 1 week of appropriate investigation.
Q2: What is the most common cause of FUO globally?
A: Infections like tuberculosis remain most common in low-income countries, while neoplasms and autoimmune diseases are leading causes in developed nations.
Q3: Is factitious fever common?
A: It is rare but important to suspect in repeated undiagnosed fevers, especially in healthcare workers.
Q4: How is endocarditis detected in FUO?
A: With multiple blood cultures and echocardiography (especially transesophageal echo).
Q5: Can a patient with FUO have normal lab results?
A: Yes. Early-stage autoimmune or neoplastic conditions may not show abnormal labs initially.
