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

Causes of Pyrexia of Unknown Origin (PUO) in Children

Primary Etiologic Categories

Infections are the leading cause of PUO in children, accounting for approximately 34-38% of cases, followed by inflammatory/collagen-vascular diseases (14-16%), malignancies (17%), and miscellaneous conditions, with 15-25% remaining undiagnosed. 1, 2, 3

Infectious Causes (Most Common)

Bacterial Infections:

• Occult bacterial infections including urinary tract infections (11.4% of infectious PUO cases), bacterial meningitis (6.5%), and occult abscesses requiring advanced imaging for detection 2, 4
• Tuberculosis remains a leading infectious cause, particularly in endemic areas, presenting with extrapulmonary manifestations including lymphadenitis 4
• Septic arthritis and occult pneumonia can present without obvious localizing signs, particularly in younger children 4
• Staphylococcus aureus and Gram-negative organisms (Enterobacteriaceae) are common in developing countries, especially during hot/humid months and in malnourished children 4
• Infective endocarditis must be considered in children with cardiac disease, pathological heart murmurs, or previous endocarditis history, with viridans streptococci most common after age 1 year 4
• Lemierre syndrome (septic thrombophlebitis following severe pharyngitis) in older children and adolescents 4

Atypical/Chronic Infections:

• Opportunistic mycobacterial infections (M. avium complex, M. kansasii) especially in immunocompromised patients 4
• Epstein-Barr virus presenting with atypical manifestations 2
• Cat-scratch disease (Bartonella henselae) 2
• Malaria in returned travelers (requires up to three daily blood films) 4
• Typhoid fever in developing countries 2

Inflammatory/Rheumatologic Causes

• Kawasaki disease presenting with atypical features 2
• Collagen-vascular diseases including systemic juvenile idiopathic arthritis (5% of FDG-PET/CT identified cases) 5, 3
• Inflammatory bowel disease (5% of FDG-PET/CT identified cases) 5

Malignant Causes

• Lymphomas requiring immunohistochemistry for diagnosis in poorly differentiated cases 4
• Cancers of unknown primary site (CUP) accounting for 3-5% of all malignancies 4
• Occult abdominal tumors requiring advanced imaging for detection 2

Age-Specific Considerations

Neonates and Infants (<3 months):

• 8-13% have bacterial infections, predominantly urinary tract infections 5
• Pneumonia prevalence is low (1-3%) in this age group 5
• Exposure to perinatal bacterial pathogens and lack of vaccine-based immunity increases risk 5
• Infants <28 days are at highest risk for invasive bacterial infections 5

Young Children (3-36 months):

• Congenital or cardiac disease should be excluded in febrile, ill-appearing children 4
• Occult bacterial pneumonia occurs in significant proportion despite no obvious respiratory source 4
• 25% may show pneumonia on chest radiograph despite no respiratory signs 4

Geographic and Environmental Factors

Developing Countries:

• Malaria and typhoid fever are major considerations in both acute and prolonged PUO 2
• Protein energy malnutrition increases susceptibility to bacterial infections 4
• Misuse of antibiotics complicates diagnosis by masking underlying infections 2

Special Population Considerations

Neutropenic Patients:

• Fungal causes are usually nosocomial in immunocompromised patients with severe neutropenia 4
• Require immediate evaluation and empiric antimicrobial therapy 6

Prior Antibiotic Use:

• Significantly reduces culture positivity and masks underlying diagnosis 4
• Consider withholding antibiotics ≥48 hours in stable patients with negative cultures to improve diagnostic yield 4

Common Pitfalls

• Failure to perform repeated clinical examinations is a major error; continued observation is paramount for difficult cases 2
• Premature diagnostic closure before adequate evaluation can miss serious underlying conditions 6
• Initiating empiric antibiotics before obtaining cultures may mask the underlying cause and reduce diagnostic yield 6, 4
• Overlooking travel history can miss malaria, typhoid, or viral hemorrhagic fevers 4
• Missing cardiac disease in children with unexplained fever and heart murmurs can delay endocarditis diagnosis 4