Fever of unknown origin

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

Differential Diagnosis

Infections (~30%)

• Abscess
  • Intra-abdominal abscess (hepatic, subphrenic, pelvic, perinephric)
  • Epidural abscess
  • Dental abscess
  • Prostatitis
• Endovascular
  • Endocarditis
  • Infected vascular graft/device
  • Mycotic aneurysm
• Mycobacterial
  • Tuberculosis (pulmonary and extrapulmonary)
  • Nontuberculous mycobacteria (MAC)
• Viral
  • EBV (mononucleosis)
  • CMV
  • HIV (acute seroconversion)
  • Hepatitis B, hepatitis C
  • COVID-19
• Fungal
  • Histoplasmosis
  • Coccidioidomycosis
  • Blastomycosis
  • Cryptococcosis
  • Aspergillosis (immunocompromised)
• Parasitic
  • Malaria
  • Toxoplasmosis
  • Visceral leishmaniasis
  • Amebiasis (liver abscess)
• Bacterial
  • Osteomyelitis
  • Pyelonephritis/renal abscess
  • Cholangitis
  • Sinusitis (chronic)
  • Brucellosis
  • Q fever (Coxiella burnetii)
  • Lyme disease
  • Cat scratch disease (Bartonella)
  • Syphilis
  • Whipple's disease
  • Rat-bite fever

Malignancy (~20%)

• Hematologic (most common malignant cause of FUO)
  • Lymphoma (Hodgkin and non-Hodgkin)
  • Leukemia (especially acute leukemia)
  • Multiple myeloma
  • Myelodysplastic syndrome
  • Castleman disease
• Solid Tumors
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Colon cancer
  • Pancreatic cancer
  • Atrial myxoma
  • Pheochromocytoma

Autoimmune/Inflammatory (~20%)

• Connective Tissue Disease
  • Adult-onset Still's disease (AOSD)
  • Systemic JIA (sJIA) — pediatric equivalent
  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis
  • Polymyositis/dermatomyositis
  • Mixed connective tissue disease
• Vasculitis
  • Giant cell (temporal) arteritis / polymyalgia rheumatica (especially adults >50)
  • Polyarteritis nodosa
  • Granulomatosis with polyangiitis (Wegener's)
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
  • Takayasu arteritis
  • Kawasaki disease (pediatric)
• Granulomatous
  • Sarcoidosis
  • Crohn's disease / inflammatory bowel disease
• Autoinflammatory/Periodic Fever Syndromes
  • Familial Mediterranean fever
  • TNF receptor-associated periodic syndrome (TRAPS)
  • Hyper-IgD syndrome (HIDS)
  • PFAPA syndrome (pediatric)
  • Schnitzler syndrome
• Other
  • Macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)
  • Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis)

Drug Fever

• Antibiotics (beta-lactams, sulfonamides, nitrofurantoin)
• Anticonvulsants (phenytoin, carbamazepine)
• Allopurinol
• Heparin
• Procainamide
• DRESS syndrome
• Serotonin syndrome
• Neuroleptic malignant syndrome
• Chemotherapy/biologic agents

Endocrine/Metabolic

• Thyrotoxicosis / thyroid storm
• Adrenal insufficiency
• Pheochromocytoma
• Hypertriglyceridemia (rarely)

Thromboembolic/Vascular

• Pulmonary embolism
• Deep vein thrombosis
• Hematoma (retroperitoneal, intramuscular)
• Aortic dissection (rarely)

Factitious/Habitual

• Factitious fever (self-induced)
• Munchausen syndrome / Munchausen by proxy (pediatric)

Miscellaneous

• Post-surgical/post-procedural inflammation
• Gout/pseudogout (crystal arthropathy)
• Cirrhosis / alcoholic hepatitis
• Hemolytic anemia
• Transfusion reaction
• Tissue necrosis (rhabdomyolysis, large hematoma, pancreatitis)
• Hypothalamic dysfunction (central fever)
• Periodic fever of unknown cause (~10-15% of FUO never diagnosed)

Evaluation

Workup

Phase 1

• CBC
• ESR
• TB test
• MonoSpot
• CXR
• blood culture
• ASLO
• ANA
• HIV

Phase 2

• LP
• blood culture again
• Sinus/mastoid x-ray
• Ophtho exam for iridocyclits
• CMV, Toxo, Hep A/B, Tularemia, Brucellosis, Leptospirosis, Salmonellosis
• LFTs

Phase 3

• Abd ultrasound
• Abd CT
• Gallium/Indium scanning
• UGI series with sbft
• Bone marrow
• Technetium bone scan

See Also

• Fever
• Fever of unknown origin (peds)