What are the potential causes of Pyrexia of Unknown Origin (PUO) in pediatric patients?

Causes of Pyrexia of Unknown Origin (PUO) in Children

In pediatric PUO, infectious diseases remain the most common cause (19-37.6%), followed by connective tissue/inflammatory diseases (14-15%), necrotizing lymphadenitis (8%), and malignancies (7-17%), though a substantial proportion (43-57%) may remain undiagnosed despite thorough evaluation. 1, 2, 3

Major Etiologic Categories by Frequency

Infectious Causes (Most Common: 19-37.6%)

Bacterial Infections:

• Tuberculosis is a leading infectious cause, particularly in endemic areas, presenting with extrapulmonary manifestations including lymphadenitis 1
• Occult abscesses and deep-seated infections requiring advanced imaging for detection 1
• Septic arthritis and occult pneumonia can present without obvious localizing signs, accounting for a significant proportion identified by advanced imaging 1
• Infective endocarditis must be considered in children with pathological heart murmurs, history of heart disease, or previous endocarditis; viridans group streptococci are most common after the first year of life, while Staphylococcus aureus is now the most common cause of acute bacterial endocarditis in some series 1
• Lemierre syndrome (septic thrombophlebitis following severe pharyngitis) is potentially fatal, typically seen in older children and young adults with increasing incidence 1

Geographic and Travel-Related:

• Malaria in returned travelers requires up to three daily blood films for diagnosis 1
• In developing countries, Staphylococcus aureus and Gram-negative organisms (Enterobacteriaceae) are common during hot and humid months, especially with protein energy malnutrition 1

Opportunistic Infections:

• Fungal causes are usually nosocomial in immunocompromised patients, particularly those with severe neutropenia 1
• Mycoplasma and Legionella can cause pleural effusion but rarely cause empyema 1

Connective Tissue/Inflammatory Diseases (14-15%)

• Systemic juvenile idiopathic arthritis accounts for 5% of FDG-PET/CT identified cases 1
• Inflammatory bowel disease is present in 5% of FDG-PET/CT identified cases 1
• Children with fever duration over 28 days have higher frequency of connective tissue diseases (28.3%) 2
• Arthritis as a presenting symptom is significantly related to connective tissue diseases (P<0.001) 2

Necrotizing Lymphadenitis (8%)

• This represents a distinct diagnostic category in pediatric PUO 2
• Lymph node enlargement is significantly associated with this diagnosis (P<0.001) 2

Malignancies (7-17%)

• Lymphomas must be excluded via immunohistochemistry in poorly differentiated cases 1
• Malignancies account for 7-17% of pediatric PUO cases depending on the series 2, 3

Undiagnosed Cases (43-57%)

• Almost half of pediatric PUO cases remain without diagnosis despite extensive evaluation 2, 3
• The undiagnosed portion has increased due to development of diagnostic techniques for infectious diseases, which now more readily identify and exclude common infections 2
• Children presenting with fever as the only symptom without other manifestations are significantly more likely to remain undiagnosed (P<0.001) 2

Age-Specific Considerations

Neonates and Infants (<3 months)

• 8-13% have bacterial infections, predominantly urinary tract infections 1
• Pneumonia prevalence is low (1-3%) in this age group 1
• Infants <28 days are at highest risk for invasive bacterial infections 1
• Exposure to perinatal bacterial pathogens and lack of vaccine-based immunity increases risk 1
• Congenital or cardiac disease should be excluded in neonates and young children who are febrile and ill-appearing 1

Infants and Young Children (>3 months to 36 months)

• Occult bacterial pneumonia occurs in a significant proportion with PUO and no obvious respiratory source 1
• 25% may show pneumonia on chest radiograph despite no obvious respiratory source in children with fever >38.5°C and chest recession with respiratory rate >50/min in those under 3 years 1

Critical Clinical Pitfalls

Prior antibiotic use can significantly reduce culture positivity and mask the underlying diagnosis; withholding antibiotics for ≥48 hours while obtaining additional cultures may be considered in patients who are not acutely ill with negative blood cultures 1

Avoid premature empiric antimicrobial therapy before obtaining appropriate cultures, as this may mask the underlying cause and reduce diagnostic yield 4