Residency · Residency · Medicine Pediatrics

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

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.

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