# Fever of Unknown Origin in Children and Adults

## Overview
Classic definition (Petersdorf and Beeson, 1961): temperature >38.3C (101F) on multiple occasions, lasting >3 weeks, with no diagnosis after 1 week of inpatient evaluation. Modified modern definition: no diagnosis after appropriate outpatient or inpatient evaluation including specific minimum workup. Etiologic distribution differs significantly by age: infections dominate in children; malignancy and autoimmune disease increase in adults. Despite advances in diagnostics, 5-15% of FUO cases remain undiagnosed, and these generally have favorable outcomes.

## Etiologic Categories by Age

| Category | Pediatric FUO (% of cases) | Adult FUO (% of cases) | Key Diagnoses |
|----------|---------------------------|------------------------|---------------|
| Infection | 40-60% | 20-30% | EBV/CMV, UTI, osteomyelitis, endocarditis, TB |
| Autoimmune/Inflammatory | 10-20% | 15-25% | sJIA / Adult Still disease, GCA/PMR, SLE, IBD |
| Malignancy | 5-10% | 15-25% | ALL, lymphoma, RCC, hepatocellular carcinoma |
| Miscellaneous | <5% | ~10% | Drug fever, factitious fever, VTE, thyroiditis |
| Undiagnosed | 10-20% | 10-30% | Generally favorable prognosis |

### Pediatric FUO
**Infections (~40-60%)**: most common category in children. Viral syndromes (prolonged EBV, CMV, adenovirus); UTI (especially in young children without localizing symptoms); Bone and joint infections (osteomyelitis, septic arthritis); Endocarditis (especially with congenital heart disease); Cat scratch disease (Bartonella henselae); Tuberculosis; Deep-seated abscess (intra-abdominal, hepatic, pelvic); **Autoimmune/inflammatory (~10-20%)**: Systemic juvenile idiopathic arthritis (sJIA) — quotidian fever pattern; Kawasaki disease (especially incomplete forms); Inflammatory bowel disease; SLE; **Malignancy (~5-10%)**: Leukemia (especially ALL); Lymphoma; Neuroblastoma; **Undiagnosed (~10-20%)**: generally good prognosis.

### Adult FUO
**Infections (~20-30%)**: Endocarditis (especially subacute); Tuberculosis (including extrapulmonary); Intra-abdominal abscess; HIV; Osteomyelitis; CMV, EBV; **Malignancy (~15-25%)**: Lymphoma (most common malignant cause); Leukemia; Renal cell carcinoma; Hepatocellular carcinoma; Metastatic carcinoma; **Autoimmune/inflammatory (~15-25%)**: Adult-onset Still disease (quotidian fevers, salmon-colored rash, arthritis); Giant cell arteritis/polymyalgia rheumatica (>50 years); SLE, polyarteritis nodosa, granulomatosis with polyangiitis; Sarcoidosis; Inflammatory bowel disease; **Miscellaneous (~10%)**: Drug fever; Factitious fever; Venous thromboembolism; Thyroiditis; Familial Mediterranean fever; **Undiagnosed (~10-30%)**: lower percentage in elderly (more likely to have identifiable cause).

<image>Pie charts comparing the etiologic distribution of FUO in pediatric versus adult populations showing the relative proportions of infection, malignancy, autoimmune, miscellaneous, and undiagnosed categories</image>

## Diagnostic Approach

### Initial Evaluation (Both Ages)
**Detailed history**: travel, animal exposures, occupational exposures, medications, family history of autoimmune or autoinflammatory disease, immunization status, surgical history, dental work. **Comprehensive physical exam**: repeat frequently — findings may evolve; pay attention to skin, eyes, lymph nodes, cardiac murmurs, hepatosplenomegaly, joints, temporal arteries (adults >50) **Fever pattern documentation**: quotidian (daily spikes returning to normal — sJIA, adult-onset Still disease), double quotidian (malaria, endocarditis), periodic (familial Mediterranean fever, cyclic neutropenia in children)

### First-Tier Workup
CBC with differential and peripheral smear; ESR and CRP (very high ESR >100 suggests endocarditis, abscess, malignancy, temporal arteritis) Comprehensive metabolic panel including LFTs, LDH; Urinalysis and urine culture; Blood cultures (multiple sets, before antibiotics); Chest X-ray; Peripheral smear review; HIV testing (adults and adolescents); PPD or IGRA.

### Second-Tier Workup
ANA, RF, complement levels; Ferritin (markedly elevated >10,000 in sJIA, adult Still disease, hemophagocytic lymphohistiocytosis) Procalcitonin (may help distinguish bacterial from non-bacterial); EBV, CMV serologies; Bartonella antibodies (children with cat exposure); Serum protein electrophoresis (adults); CT of chest, abdomen, pelvis with contrast; Echocardiogram (endocarditis evaluation); Ophthalmologic exam (uveitis in sJIA, sarcoidosis; Roth spots in endocarditis).

### Third-Tier/Advanced Workup
**PET-CT**: increasingly used early in FUO workup; high diagnostic yield (40-70%); identifies occult infections, vasculitis, malignancy; can guide biopsy site. **Bone marrow biopsy**: if cytopenias, elevated ferritin (HLH), suspected malignancy. **Temporal artery biopsy**: adults >50 with elevated ESR, headache, visual symptoms. **Liver biopsy**: if hepatomegaly, abnormal LFTs, granulomatous disease suspected. **Lymph node biopsy**: if significant lymphadenopathy. **Lumbar puncture**: if CNS symptoms. **Labeled WBC scan or gallium scan**: now largely replaced by PET-CT.

<image>Stepwise diagnostic algorithm for FUO showing first-tier through third-tier investigations with decision points for escalation and the role of PET-CT in guiding tissue biopsy</image>

## Key Diagnoses Not to Miss

### Systemic JIA / Adult-Onset Still Disease
Same disease spectrum across ages. Quotidian (spiking once or twice daily) fevers to >39C with return to baseline. Evanescent salmon-pink macular rash (appears with fever, disappears between spikes) Arthritis (may be delayed in onset) Serositis, hepatosplenomegaly, lymphadenopathy. Markedly elevated ferritin (often >1,000; very high levels suggest macrophage activation syndrome) Diagnosis of exclusion: Yamaguchi criteria (adults); ILAR criteria (children) Treatment: NSAIDs, corticosteroids, IL-1 blockade (anakinra), IL-6 blockade (tocilizumab)

### Infective Endocarditis
Must be considered in any FUO, especially with predisposing cardiac condition, dental work, or IV drug use. Modified Duke criteria: major (positive blood cultures with typical organisms, echocardiographic evidence) and minor (predisposition, fever, vascular phenomena, immunologic phenomena) Blood cultures: at least 3 sets from different sites before antibiotics. TEE superior to TTE for detecting vegetations (especially prosthetic valves) In children: more common with congenital heart disease; viridans streptococci predominate.

### Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS)
Life-threatening hyperinflammatory syndrome. Primary/familial HLH in young children; secondary HLH triggered by infection (EBV), malignancy, or autoimmune disease (MAS complicating sJIA) Classic features: persistent fever, cytopenias, hepatosplenomegaly, hyperferritinemia (often >10,000), hypertriglyceridemia, hypofibrinogenemia, elevated soluble IL-2 receptor. HLH-2004 diagnostic criteria: meet 5 of 8 criteria or molecular diagnosis. Treatment: HLH-94/2004 protocol (dexamethasone, etoposide, cyclosporine); targeted therapy; HSCT for familial forms.

### Drug Fever
Commonly overlooked; typically low-grade fever with relative bradycardia. Common culprits: antibiotics (beta-lactams, sulfonamides), anticonvulsants (phenytoin), allopurinol, heparin. Diagnosis: temporal relationship with drug initiation, exclusion of other causes, resolution with drug discontinuation. May have eosinophilia, but absence does not exclude.

## Special Considerations

### Factitious Fever
More common in adolescents and young adults, often in healthcare settings. Clues: very high temperatures without corresponding tachycardia, no diaphoresis, discrepancy between oral/rectal and simultaneous urine temperature. Observe temperature measurement; check urine temperature simultaneously. Approach with sensitivity; may indicate underlying psychiatric illness.

### Periodic Fever Syndromes
**PFAPA** (periodic fever, aphthous stomatitis, pharyngitis, adenitis): most common periodic fever in children; clockwork-like episodes every 3-6 weeks; dramatically responsive to single-dose prednisone; resolves by age 10. **Familial Mediterranean fever**: autosomal recessive (MEFV gene); Mediterranean descent; episodic fever with serositis; colchicine prophylaxis prevents attacks and amyloidosis. **TRAPS, HIDS, CAPS**: rarer autoinflammatory syndromes; genetic testing available. Consider in any child or young adult with recurrent stereotypical febrile episodes.

<image>Comparison of periodic fever syndromes showing typical age of onset, episode duration, interval between episodes, key clinical features, genetic mutations, and first-line treatment for PFAPA, FMF, TRAPS, and CAPS</image>

## Clinical Pearls
FUO in children is most often an atypical presentation of a common disease, not a rare disease. Always repeat the physical exam — new findings may emerge as the illness evolves (heart murmur, rash, arthritis, splenomegaly) Quotidian fever with evanescent rash in a child: think sJIA until proven otherwise. Very high ferritin (>10,000) should trigger consideration of HLH/MAS, adult-onset Still disease, or disseminated infection. PET-CT has become a game-changer in FUO evaluation — consider after initial workup is unrevealing rather than waiting weeks. In adults >50 with FUO and elevated ESR, always consider giant cell arteritis (may present without headache) Stop non-essential medications early in FUO evaluation — drug fever is a diagnosis of exclusion but commonly implicated. An undiagnosed FUO that resolves spontaneously almost never turns out to be malignancy — reassurance is appropriate.

## References
- Chow A, Robinson JL. Fever of Unknown Origin in Children: A Systematic Review. World J Pediatr. 2011;7(1):5-10.
- Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A Prospective Multicenter Study on Fever of Unknown Origin. Medicine. 2007;86(1):26-38.
- Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of Unknown Origin. Clin Med. 2015;15(3):280-284.
- Wright WF, Auwaerter PG. Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma. Open Forum Infect Dis. 2020;7(5):ofaa132.