Fever of Unknown Origin: Body Systems Involved
Fever of unknown origin (FUO) is not a disease of a single body system—it is a clinical syndrome that can arise from pathology in virtually any organ system, requiring a systematic multi-system evaluation to identify the underlying cause. 1, 2
Multi-System Nature of FUO
FUO represents a diagnostic challenge precisely because it can originate from diverse pathologies across multiple body systems. The condition is defined as fever exceeding 38.3°C (100.9°F) persisting for at least 3 weeks without diagnosis despite appropriate investigation. 1, 2
Primary Body Systems Commonly Involved
Infectious causes (which can affect multiple systems simultaneously):
- Respiratory system: Pneumonia, tuberculosis, and upper respiratory tract infections account for 13.5% of cases in returning travelers 3
- Gastrointestinal system: Acute diarrheal disease (13.6%), hepatitis, intra-abdominal abscesses 3
- Genitourinary system: Urinary tract infections (2.7% of cases) 3
- Hematologic/lymphatic system: Septicemia, bacteremia, and systemic infections 3
- Central nervous system: Meningitis, encephalitis (0.2% of cases) 3
Rheumatologic/inflammatory causes (systemic involvement):
- Musculoskeletal system: Adult-onset Still's disease and systemic juvenile idiopathic arthritis present with arthritis affecting knees (61-77%), wrists (69%), ankles (46-75%), and other joints 3
- Cardiovascular system: Pericarditis, myocarditis, and vasculitis 4
- Reticuloendothelial system: Hepatosplenomegaly is a common finding in systemic inflammatory conditions 4
- In 30% of FUO cases, the cause is eventually found to be a rheumatologic disease such as autoimmune disease, granulomatous disease, or vasculitis 5
Neoplastic causes (can affect any system):
- Hematologic system: Lymphomas, leukemias 3
- Solid organ malignancies: Various cancers can present with fever 3
Tropical/parasitic diseases (multi-system):
- Hematologic system: Malaria (22.2% of tropical infections in travelers) 3
- Reticuloendothelial system: Visceral leishmaniasis 3
- Central nervous system: Cryptococcosis can present as meningoencephalitis, pneumonia, cryptococcemia, or FUO 3
Key Clinical Pitfall
The critical error is attempting to localize FUO to a single body system prematurely. The diagnostic approach must be comprehensive and systematic, using history, physical examination, and laboratory clues to guide targeted investigation rather than assuming organ-specific pathology. 1, 6, 7
Approximately 17.8% of FUO cases remain undiagnosed even after extensive workup, and many represent self-limited viral illnesses affecting multiple systems simultaneously. 3 The workup should focus on identifying "potential diagnostic clues" through multi-system evaluation rather than pursuing organ-specific investigations without clear clinical direction. 5