Fever of unknown origin

Background

• Typically defined as a persistent fever that remains undiagnosed despite an extensive initial workup
• Causes have changed over the decades as diagnostic tools have improved

Definitions

Type	Definition
Classic	Temperatures >38.3ºC without diagnosis despite 3 weeks of outpatient investigations over 3 visits, or 1 week of intensive outpatient investigation, or 3 days of inpatient investigation
Nosocomial	Temperatures >38.3ºC without diagnosis in a hospitalized acute-care patient, where infection was not community-acquired, despite 3 days of investigations including preliminary results of blood cultures at 48 hours
Neutropenic	Temperatures >38.3ºC without diagnosis in patients with neutrophils <500/μL or expected to fall to that level in 1-2 days, despite initial investigations including preliminary results of blood cultures at 48 hours
HIV-associated	Temperatures >38.3ºC without diagnosis over 4 weeks (outpatient) or 3 days (inpatient) in patients with HIV, despite initial investigations including preliminary results of blood cultures at 48 hours

Differential Diagnosis

• Infectious (16 to 52%)
  • More common: tuberculosis (especially extrapulmonary disease), culture-negative endocarditis, Epstein-Barr virus, cytomegalovirus
  • More common, in recent travelers: malaria and dengue
  • Less common: bartonellosis, brucellosis, occult abscess, salmonellosis, urinary tract infection, acute HIV, hepatitis A, hepatitis B, hepatitis E, HHV-6, HHV-7, osteomyelitis, septic arthritis
  • Less common, in recent travelers: rickettsioses, leptospirosis, schistosomiasis, gnathostomiasis, cysticercosis, enteric fever
• Neoplastic (7 to 35%)
  • More common: lymphoma, leukemia, solid organ tumour (especially renal cell carcinoma and melanoma)
  • Less common: myelodysplastic syndrome, colonic adenocarcinoma, multiple myeloma, gastric carcinoma, mesothelioma, Castleman disease
• Inflammatory (11 to 34%)
  • More common: adult-onset Still disease, systemic lupus erythematosus, polymyalgia rheumatica, temporal arteritis, inflammatory bowel disease
  • Less common: rheumatoid arthritis, polyarteritis nodosa, sarcoidosis, granulomatosis with polyangiitis, Kawasaki syndrome
• Other (2 to 20%)
  • More common: drug fever, chronic pulmonary embolism, hyperthyroidism, hematoma
  • Less common: subacute thyroiditis, hypoadrenalism, necrotizing lymphadenitis, periodic fever syndromes, hemophagocytic lymphohistiocytosis, factitious fever
• Undiagnosed (7 to 32%)

Investigations

• ESR or CRP, LDH, CK, ANA, RF, SPEP
• Blood cultures x3
• HIV serology
• Heterophile antibody test (in children or young adults)
• TST or IGRA
• CT of the abdomen and chest

Further Reading

• Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma. Open Forum Infect Dis. 2020. doi: 10.1093/ofid/ofaa132

Fever syndromes