What are the causes of prolonged fevers in children?

Causes of Prolonged Pediatric Fevers

Prolonged fever in children (≥14 days) most commonly results from sequential viral infections in well-appearing children, but approximately 50% of true fever of unknown origin (FUO) cases are ultimately diagnosed with infectious diseases, followed by inflammatory conditions and neoplastic diseases. 1

Definition and Initial Considerations

Prolonged fever is defined as documented daily fever for ≥14 days that remains unexplained after careful history, physical examination, and basic laboratory testing. 1 A critical first step is confirming that true fever exists, as some children referred for prolonged fever are not actually having elevated temperatures. 1

Key Distinction: Pattern Recognition

• Sequential viral illnesses: Irregular, intermittent, recurrent fevers in well-appearing children are most likely due to sequential common viral infections rather than a single prolonged illness. 1
• True FUO: Daily persistent fever for ≥14 days without diagnosis after initial evaluation. 1

Major Diagnostic Categories

1. Infectious Causes (Most Common in FUO)

Infectious etiologies account for approximately half of pediatric FUO cases ultimately receiving a diagnosis. 1

Bacterial infections:

• Urinary tract infections: The most common serious bacterial infection in febrile children, occurring in 3-7% of children with fever without source, with higher rates in girls (8.1% ages 1-2 years) and uncircumcised boys (8-12.4% in infants). 2
• Occult bacteremia: Now rare (0.004-2%) in the post-pneumococcal vaccine era, compared to 7-12% pre-vaccine. 2
• Bacterial meningitis: Risk varies by age (higher in neonates), but overall incidence has decreased with vaccination. 2
• Pneumonia: Occult pneumonia prevalence is low (1-3%) in febrile infants <3 months without respiratory symptoms. 3
• Osteomyelitis, septic arthritis, cellulitis: Should be considered based on localizing signs. 2

Viral infections:

• Herpes simplex virus can have devastating consequences in young infants. 2
• Influenza and other respiratory viruses are common causes of fever. 4
• The presence of one viral infection does not preclude coexisting bacterial infection. 2

2. Inflammatory/Rheumatologic Causes

Kawasaki Disease is a critical diagnosis not to miss:

• Presents with prolonged fever (≥5 days) as the hallmark feature. 2, 5
• Incomplete Kawasaki Disease occurs most commonly in infants, who may have prolonged fever as the sole or primary finding with subtle or fleeting additional signs. 2
• Delayed diagnosis beyond 10 days of fever onset significantly increases risk of coronary artery aneurysms. 2, 5
• Infants <6 months are at particularly high risk for coronary complications and delayed diagnosis. 2

Multisystem Inflammatory Syndrome in Children (MIS-C):

• Temporally associated with SARS-CoV-2 infection (2-6 weeks post-exposure). 2
• Children present with significantly higher temperatures and longer fever duration than routine pediatric illnesses. 2
• Requires elevated inflammatory markers (ESR/CRP) plus additional laboratory abnormalities (lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, hypoalbuminemia). 2

Autoinflammatory diseases:

• Should be considered in children with recurrent fevers who do not fit the pattern of sequential infections and lack immune deficiency hallmarks. 1
• PFAPA syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis): Most common periodic fever syndrome in childhood. 1
• Cyclic neutropenia: Consider if fever recurs with approximately 21-day periodicity. 1

3. Neoplastic Causes

Malignancies account for a portion of pediatric FUO cases. 1 Fever with hepatosplenomegaly should raise concern for:

• Leukemia or lymphoma (requires CBC with differential to assess for cytopenias, thrombocytopenia, abnormal cells). 6
• Bone marrow biopsy may be necessary to identify malignant infiltration. 6

4. Noninfectious Causes

• Metabolic/storage disorders: Lysosomal storage diseases (e.g., Niemann-Pick disease) should be considered with fever and massive hepatosplenomegaly. 6
• Drug fever and other medication-related causes. 2
• Factitious fever (requires careful history dissection). 1

Age-Specific Risk Stratification

Neonates (0-28 days)

• Highest risk group: 13% incidence of serious bacterial infection (SBI). 2
• Relatively immature immune system makes them vulnerable. 2
• Only 58% of neonates with bacteremia or bacterial meningitis appear clinically ill. 2
• Require comprehensive evaluation including lumbar puncture for CSF analysis. 3

Young Infants (29-90 days)

• 9% incidence of SBI in this age group. 2
• May be risk-stratified using validated criteria (Rochester or Philadelphia criteria). 7
• Lumbar puncture recommended for febrile infants in this age range. 3

Older Infants and Children (>3 months to 2 years)

• Lower risk with widespread vaccination against S. pneumoniae and H. influenzae type b. 2
• Occult bacteremia now rare (0.004-2%). 2
• UTI remains most common SBI (3-7% overall). 2

Diagnostic Approach Algorithm

Initial Evaluation (All Ages with Prolonged Fever)

Mandatory testing:

• Urinalysis and urine culture (catheterized specimen, NOT bag specimen). 3
• Complete blood count with differential. 3, 6
• Blood culture (before antibiotics). 3
• Inflammatory markers (CRP, ESR, procalcitonin). 3
• Comprehensive metabolic panel including liver function tests. 3, 6

Age-specific additions:

• Neonates (0-28 days): Lumbar puncture for CSF analysis and culture. 3
• Infants 29-90 days: Lumbar puncture recommended. 3
• All ages with respiratory symptoms: Chest radiograph. 3

Kawasaki Disease Screening (Fever ≥5 days)

If fever ≥5 days with 2-3 principal clinical features OR infants with prolonged fever:

• Obtain CBC, ESR, CRP, comprehensive metabolic panel, urinalysis. 2, 5
• Urgent echocardiography is mandatory. 2, 5
• If diagnostic criteria met: Immediate treatment with IVIG 2 g/kg plus high-dose aspirin. 5

MIS-C Evaluation (In Context of COVID-19 Pandemic)

Tier 1 screening (if epidemiologic link to SARS-CoV-2):

• CBC with differential, comprehensive metabolic panel, ESR, CRP. 2
• SARS-CoV-2 PCR or serology. 2
• Proceed to Tier 2 if elevated ESR/CRP plus ≥1 of: lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, hypoalbuminemia. 2

Extended Evaluation (Fever >3 weeks)

For true FUO (≥14 days):

• Meticulous fever diary with serial clinical and laboratory evaluations. 1
• Liver function tests and consideration of serologic testing for specific infections. 3
• Imaging studies as clinically indicated. 3
• Abdominal ultrasound with Doppler if hepatosplenomegaly present. 6
• Vigilance for appearance of new signs and symptoms over time. 1

Critical Pitfalls to Avoid

Diagnostic errors:

• Assuming normal WBC rules out bacterial infection, especially in neonates. 3
• Using bag urine specimens for UTI diagnosis (unreliable). 3
• Administering antibiotics before obtaining cultures, which obscures diagnosis. 3
• Missing incomplete Kawasaki Disease in infants with prolonged fever and minimal other findings. 2
• Anchoring on MIS-C diagnosis during COVID-19 pandemic without investigating other causes. 2
• Overlooking UTI in children with other apparent infection sources (e.g., otitis media, URI) - UTI prevalence remains 4% even with concurrent infections. 2

Clinical misinterpretations:

• Attributing fever and pyuria solely to UTI when it may be Kawasaki Disease. 2
• Misdiagnosing cervical lymphadenitis as bacterial adenitis when it represents Kawasaki Disease. 2
• Confusing rash, red eyes, and red lips for antibiotic reaction rather than Kawasaki Disease. 2
• Assuming well-appearing child cannot have serious bacterial infection (only 58% of bacteremic infants appear ill). 2

Prognosis and Outcomes

For true FUO:

• Approximately 50% of children will have self-limited illness and never receive a specific diagnosis. 1
• The other 50% will ultimately be diagnosed with infectious (most common), inflammatory, or neoplastic conditions. 1
• The pace of work-up should be determined by severity of illness. 1

For specific conditions:

• Kawasaki Disease: Risk of coronary artery aneurysms increases significantly if treatment delayed beyond 10 days of fever onset. 2, 5
• UTI with pyelonephritis: 27-64% risk of renal scarring, with potential for hypertension (10-20%) and end-stage renal disease (10%) later in life. 2
• MIS-C: Can decompensate rapidly, requiring hospital admission for monitoring. 2