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

Causes of Pyrexia of Unknown Origin (PUO) in Children

The causes of PUO in children fall into three major categories: infections (most common), malignancies, and inflammatory/autoimmune diseases, with the specific etiologic profile varying by geographic location, immune status, and clinical context.

Major Etiologic Categories

Infectious Causes

Infections remain the leading cause of PUO in pediatric patients, with specific pathogens varying by geography and immune status. 1

Bacterial Infections

• Occult abscesses and deep-seated infections are common culprits requiring advanced imaging for detection 1
• Tuberculosis remains a leading infectious cause, particularly in endemic areas, and can present with extrapulmonary manifestations including lymphadenitis 1
• Opportunistic mycobacterial infections (M. avium complex, M. kansasii) occur especially in immunocompromised patients 1
• Endocarditis accounts for 11% of PUO cases identified by advanced imaging 2
• Septic arthritis and occult pneumonia can present as PUO without obvious localizing signs 3

Geographic and Context-Specific Infections

• In developing countries, Staphylococcus aureus predominates, especially during hot and humid months when staphylococcal skin infections are more prevalent 3
• Gram-negative organisms (Enterobacteriaceae such as Klebsiella spp and Pseudomonas aeruginosa) are more common in developing countries and may be associated with protein energy malnutrition 3
• After flooding or natural disasters, dengue hemorrhagic fever (29.4%) and leptospirosis (27.2%) become major causes 4
• In returned travelers, malaria requires up to three daily blood films for exclusion 5, 1

Less Common Infectious Causes

• Mycoplasma and Legionella can cause pleural effusion but rarely cause empyema 3
• Tuberculous empyema accounts for up to 6% of empyema cases worldwide but is rare in developed countries with modern antituberculous chemotherapy 3

Malignant Causes

Malignancies represent a critical category that must be systematically excluded in the PUO workup.

• Lymphomas (particularly non-Hodgkin's lymphoma) can present with fever as the primary manifestation and must be excluded via immunohistochemistry in poorly differentiated cases 1, 6
• Cancers of unknown primary site (CUP) account for 3-5% of all malignancies and can present with fever 1
• Occult malignancies are detectable by FDG-PET/CT, which identifies the primary site in 25% to 57% of patients with occult primary cancers 2

Inflammatory and Autoimmune Diseases

Inflammatory conditions are increasingly recognized as important causes of PUO in children.

• Systemic juvenile idiopathic arthritis accounts for 5% of PUO cases identified by advanced imaging 2
• Inflammatory bowel disease (particularly Crohn's disease) accounts for 5% of PUO cases and can present atypically with minimal gastrointestinal symptoms 2, 7
• Sarcoidosis is an important autoimmune cause to consider 8

Age-Specific Considerations

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

• Congenital or cardiac disease should be excluded in neonates and young children who are febrile and ill-appearing 3
• Occult bacterial pneumonia occurs in 25% of young children with PUO and no obvious respiratory source 5

Older Children and Adolescents

• Lemierre syndrome (septic thrombophlebitis following severe pharyngitis) is a potentially fatal condition typically seen in older children and young adults, with increasing incidence 3

Special Population Considerations

Neutropenic Children

Neutropenic children with fever represent a medical emergency with distinct infectious risks. 5

• Severe neutropenia (ANC <0.5 × 10⁹/L) with fever requires immediate same-day broad-spectrum antibacterial therapy without waiting for culture results 5, 1
• Fungal causes are usually nosocomial in origin in immunocompromised patients 3

Children with Cardiac Disease

• Infective endocarditis must be considered in patients with fever of unexplained origin and a pathological heart murmur, history of heart disease, or previous endocarditis 3
• Viridans group streptococci are the most frequently isolated organisms after the first year of life in patients with underlying congenital heart disease 3
• Staphylococcus aureus is now the most common cause of acute bacterial endocarditis in some series 3

Common Pitfalls and Caveats

Prior antibiotic use significantly reduces culture positivity and can mask the underlying diagnosis. 3

• Blood cultures should be drawn before initiating any antimicrobial therapy to maximize diagnostic yield 5, 1
• Extended periods of antibiotic therapy prior to advanced imaging may reduce inflammatory activity and lead to false negative results 2
• In patients who are not acutely ill with negative blood cultures, withholding antibiotics for ≥48 hours while obtaining additional cultures may be considered 3

The diagnosis may remain elusive despite extensive investigation. In the majority of stable patients who remain undiagnosed, careful clinical observation for new symptoms and signs is advised rather than multiple courses of antimicrobials 9. A negative FDG-PET/CT can predict favorable prognosis through spontaneous remission of fever and potentially allows a watchful waiting approach 1.