Fever of unknown origin (peds)

This page is for pediatric patients. For adult patients, see: fever of unknown origin

Background

• Prolonged fever of unknown origin without identified cause generally has favorable prognosis.

Clinical Features

• Original definition
  • Fever >38.3 C on several occasions
  • Lasting for at least 3 weeks
  • No clear diagnosis after 1 week inpatient workup
• Newer definition - "Prolonged fever" with:
  • 3 outpatient visits without identifying a cause or
  • 3 inpatient days without identifying a cause or
  • 1 week of “intelligent and invasive” ambulatory investigation

Differential Diagnosis

Infections (~40-60%, most common cause in children)

• Bacterial
  • UTI/pyelonephritis (especially in infants and young children)
  • Occult abscess (intra-abdominal, hepatic, pelvic, perinephric, retropharyngeal, dental)
  • Osteomyelitis
  • Endocarditis
  • Cat scratch disease (Bartonella henselae) — one of the most common causes of pediatric FUO
  • Brucellosis (exposure to unpasteurized dairy, travel)
  • Tuberculosis (pulmonary and extrapulmonary, especially miliary)
  • Sinusitis (chronic/occult)
  • Mastoiditis
  • Lyme disease
  • Q fever
  • Rat-bite fever
  • Salmonella (enteric fever/typhoid)
  • Tularemia
  • Leptospirosis
• Viral
  • EBV (mononucleosis)
  • CMV
  • HIV (acute seroconversion or perinatal)
  • Hepatitis A, hepatitis B
  • Adenovirus
  • COVID-19
  • Parvovirus B19
• Fungal
  • Histoplasmosis
  • Coccidioidomycosis
  • Blastomycosis
  • Cryptococcosis (immunocompromised)
  • Aspergillosis (immunocompromised)
• Parasitic
  • Malaria (travel history)
  • Toxoplasmosis
  • Visceral leishmaniasis
  • Toxocara (visceral larva migrans)

Autoimmune/Inflammatory (~10-20%)

• Rheumatic
  • Systemic JIA (sJIA / Still's disease) — most common rheumatic cause of FUO in children
  • Systemic lupus erythematosus (SLE) — more common in adolescents
  • Juvenile dermatomyositis
  • Polyarteritis nodosa
  • Reactive arthritis
• Vasculitis
  • Kawasaki disease — important to consider in any child <5 years with prolonged fever; may be "incomplete Kawasaki" without classic features
  • Henoch-Schönlein purpura (IgA vasculitis)
  • Takayasu arteritis (rare in children)
• Inflammatory
  • Inflammatory bowel disease (Crohn's disease > ulcerative colitis; may present with fever and weight loss before GI symptoms)
  • Sarcoidosis (rare in young children)
• Autoinflammatory/Periodic Fever Syndromes
  • PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) — most common periodic fever syndrome in children; benign
  • Familial Mediterranean fever (FMF)
  • TNF receptor-associated periodic syndrome (TRAPS)
  • Hyper-IgD syndrome (HIDS/mevalonate kinase deficiency)
  • Cryopyrin-associated periodic syndromes (CAPS)
  • Chronic recurrent multifocal osteomyelitis (CRMO)
• Hemophagocytic
  • Macrophage activation syndrome (MAS) — especially complicating sJIA
  • Hemophagocytic lymphohistiocytosis (HLH) — primary (familial) or secondary

Malignancy (~5-10%)

• Hematologic (most common malignant cause of FUO in children)
  • Leukemia (ALL most common, AML) — most important malignancy to exclude
  • Lymphoma (Hodgkin > non-Hodgkin in older children/adolescents)
  • Langerhans cell histiocytosis
• Solid Tumors
  • Neuroblastoma (especially in children <5 years)
  • Wilms tumor
  • Ewing sarcoma / osteosarcoma (with bone involvement)
  • Hepatoblastoma

Drug Fever

• Antibiotics (beta-lactams, sulfonamides)
• Anticonvulsants (phenytoin, carbamazepine, lamotrigine)
• Atropine, anticholinergics
• DRESS syndrome
• Chemotherapy agents
• Immunizations (post-vaccination fever — usually self-limited and brief)

Central/Neurogenic Fever

• Hypothalamic dysfunction (tumor, trauma, surgery, hemorrhage)
• Autonomic dysreflexia (spinal cord injury)
• Post-neurosurgical

Factitious/Fabricated

• Fabricated or induced illness (Munchausen syndrome by proxy / medical child abuse) — consider when fever is documented only by caregiver, pattern is atypical, and no objective cause is identified
• Self-induced (older children/adolescents)

Miscellaneous

• Hemolytic anemia (sickle cell crisis, autoimmune hemolytic anemia)
• Hematoma resorption (after trauma)
• Ectodermal dysplasia (anhidrotic — impaired heat regulation, not true fever)
• Thyrotoxicosis (rare in children)
• Diabetes insipidus (dehydration-related hyperthermia)
• Infantile cortical hyperostosis (Caffey disease)
• Castleman disease (rare)
• Chronic granulomatous disease (recurrent infections)
• Cyclic neutropenia
• Idiopathic (~10-20% of pediatric FUO remains undiagnosed; most self-resolve)

Evaluation

• Clinical (preliminary) diagnosis

Management

• Treat underlying cause (once identified)
• Empiric treatment generally not recommended

Disposition

• Frequently admitted for workup

See Also

• Pediatric fever of uncertain source