What are the most common causes of Fever of Unknown Origin (FUO) worldwide and how do they differ between developed and developing countries?

Causes of Fever of Unknown Origin Worldwide

Most Common Causes Globally

Infections remain the leading cause of FUO worldwide, accounting for 35-87% of cases, followed by autoimmune diseases (2-32%) and malignancies (7-17%), with 1-14% of cases remaining undiagnosed despite extensive workup. 1, 2, 3, 4

Geographic Variation in FUO Etiology

Developed Countries:

• Infections account for 35-40% of FUO cases, with tuberculosis being less dominant than in developing regions 2, 3
• Autoimmune diseases represent 28-32% of cases, including Still's disease, systemic lupus erythematosus, and vasculitis 2, 3
• Malignancies cause 13-17% of FUO, with hematological malignancies (lymphoma and leukemia) predominating 1, 3
• Culture-negative endocarditis presents as subacute disease with low-grade fever and non-specific symptoms that confuse initial assessment 5

Developing Countries:

• Infections dominate at 57-87% of FUO cases, with tuberculosis accounting for 44% of infectious causes in some series 1, 4
• Brucellosis represents 34% of infectious FUO in endemic regions like Egypt, reflecting occupational exposures to livestock and unpasteurized dairy 1
• Urinary tract infections cause 41% of infectious FUO in some developing country cohorts, likely reflecting healthcare access patterns 1
• Typhoid fever (enteric fever) accounts for 9% of infectious FUO in endemic areas 1
• Autoimmune diseases and malignancies are proportionally less common (2-7%) compared to developed countries 1

Travel-Related FUO Patterns

Among returning travelers and migrants, the distribution differs markedly from classic FUO:

• Malaria accounts for 22% of all febrile cases and 71% of tropical diseases, making it the single most important diagnosis to exclude 6, 7
• FUO (undiagnosed fever) represents 18% of febrile travelers, with wide variability (1-45%) between studies 6
• Dengue causes 5% of febrile illness overall, but 13-18% in travelers returning from Asia 6
• Enteric fever accounts for 2.3% of febrile travelers, predominantly from South-East Asia 6, 7

Why These Three Categories Dominate

Infections as Leading Cause

Infections cause prolonged fever through several mechanisms:

• Intracellular pathogens (tuberculosis, brucellosis, Q fever, Bartonella) evade initial immune responses and require specific serologic testing that is frequently overlooked 5, 1
• Deep-seated abscesses (hepatic, splenic, pelvic) produce persistent fever without localizing signs until advanced imaging is performed 1
• Culture-negative endocarditis occurs when blood cultures are negative despite active infection, requiring echocardiography for diagnosis 5
• Atypical presentations of common infections (urinary tract infections without dysuria, pneumonia without cough) delay recognition 1, 3

Autoimmune Diseases as Major Cause

Autoimmune conditions produce FUO through:

• Systemic inflammation without specific organ manifestations early in disease course, particularly in Still's disease and vasculitis 2, 3, 4
• Overlap with infectious presentations (fever, elevated inflammatory markers, organ involvement) that prompts extensive infectious workup before considering rheumatologic causes 3
• Requirement for specialized testing (autoantibody panels, tissue biopsy) that may not be performed during initial evaluation 2

Malignancies as Significant Cause

Neoplasms cause FUO through:

• Hematological malignancies (lymphoma 39%, leukemia 31% of malignant FUO) producing cytokine-mediated fever without obvious mass lesions 1
• Paraneoplastic fever syndromes where tumor-derived pyrogens cause fever before the primary malignancy becomes apparent 4
• Increased incidence with time, as populations age and cancer prevalence rises 4

Proportion of Undiagnosed FUO Cases

Between 1-14% of FUO cases remain undiagnosed after comprehensive evaluation, with significant variation based on:

• Healthcare setting: Tertiary specialized centers report 40% undiagnosed rates initially, though many resolve spontaneously 6
• Study design: Retrospective studies show 1-14% undiagnosed, while prospective studies in specialized centers report up to 40-45% 6, 1, 2
• Geographic location: Developed countries report higher undiagnosed rates (14%) compared to developing countries (1-2%) 1, 2

Reasons for Undiagnosed Cases

Self-limiting viral infections account for 37% of undifferentiated febrile illnesses when comprehensive viral testing is performed, but these are often not pursued if severe causes are excluded and the patient improves 6

Pragmatic clinical approach: When potentially severe causes (malaria, endocarditis, tuberculosis) are ruled out and the patient is clinically improving, further diagnostic investigations are often not requested, as most unspecific fevers resolve spontaneously 6

Incomplete testing: Retrospective studies may prevent final diagnoses if incomplete testing was performed, and some studies excluded patients whose diagnoses were unknown, artificially lowering undiagnosed rates 6

Atypical presentations of treatable infections: Additional investigations in soldiers with acute undifferentiated febrile illness found Q fever and rickettsioses requiring antibiotic treatment, suggesting some "undiagnosed" cases represent missed diagnoses 6

Critical Diagnostic Pitfalls

Never assume benign self-limited illness without excluding life-threatening causes:

• Malaria must be excluded with three daily blood films in any febrile patient with tropical travel history, even with concurrent diarrhea or respiratory symptoms 7, 5
• Culture-negative endocarditis requires echocardiography (transthoracic first, then transesophageal if high suspicion) when fever accompanies new regurgitant murmur or embolic events 5
• Atypical bacterial infections (Brucella, Q fever, Bartonella) require specific serologic testing based on exposures (unpasteurized dairy, livestock contact, Mediterranean/Middle Eastern travel) 5, 1
• Avoid empiric antibiotics before obtaining at least 3 sets of blood cultures, as this obscures diagnosis of endocarditis and other bacteremic conditions 5