What causes prolonged fever in a child with every illness?

Prolonged Fever with Every Illness in Children

A child who develops prolonged fever with every illness most likely has an underlying condition that amplifies or prolongs the normal febrile response, and the most critical diagnoses to exclude are immunodeficiency disorders, incomplete Kawasaki disease (especially in infants), and occult malignancy.

Key Diagnostic Considerations

Pattern Recognition is Critical

The recurrent nature of prolonged fevers with each illness suggests:

• Primary immunodeficiency disorders are a leading consideration when children have recurrent, prolonged fevers with routine infections, as these conditions impair the ability to clear pathogens efficiently 1
• Incomplete Kawasaki disease must be considered, particularly in infants under 1 year who may present with prolonged fever as the sole or primary finding with subtle additional signs that come and go 2
• Occult malignancy (leukemia or lymphoma) can manifest as recurrent prolonged fevers, especially if accompanied by cytopenias, lymphadenopathy >2 cm, or hepatosplenomegaly 3

Age-Specific Risk Stratification

The child's age dramatically changes the differential diagnosis:

• Neonates (0-28 days) with any fever ≥38°C require immediate hospitalization and full sepsis evaluation, as they have a 13% incidence of serious bacterial infection 3, 4
• Young infants (29-90 days) have a 9% incidence of serious bacterial infection and warrant comprehensive evaluation for prolonged fever 3, 4
• Infants under 1 year are at paradoxically higher risk for incomplete Kawasaki disease with coronary artery aneurysms if untreated, and may present with prolonged fever as the primary manifestation 2

Essential Diagnostic Workup

Initial Laboratory Evaluation

Every child with recurrent prolonged fevers requires:

• Complete blood count with manual differential to assess for cytopenias, thrombocytopenia, or abnormal cells suggesting leukemia 3, 4
• Inflammatory markers (CRP, ESR) are particularly helpful because levels typically elevated to CRP ≥3.0 mg/dL and ESR ≥40 mm/hr suggest significant pathology beyond simple viral illness 2
• Comprehensive metabolic panel including liver function tests to assess for hepatitis, hypoalbuminemia, or other organ involvement 3, 4
• Urinalysis and urine culture (catheterized specimen, NOT bag specimen) as UTI accounts for 8-13% of serious bacterial infections in young febrile infants 3, 4
• Blood cultures (multiple sets before any antibiotics) to identify occult bacteremia or endocarditis 3, 5

Critical Red Flags Requiring Urgent Evaluation

Immediate echocardiography is warranted if:

• Fever persists ≥5 days with any features of Kawasaki disease (conjunctival injection, oral changes, rash, extremity changes, cervical lymphadenopathy ≥1.5 cm) 2
• The child is under 6 months with fever ≥7 days and elevated inflammatory markers (CRP ≥3.0 mg/dL or ESR ≥40 mm/hr), even without classic Kawasaki criteria 2
• Coronary artery aneurysm risk increases significantly if Kawasaki disease treatment is delayed beyond 10 days of fever onset 2, 3

Immediate peripheral blood film and possible bone marrow examination if:

• Lymphadenopathy with nodes >2 cm, hard, or matted 3
• Hepatosplenomegaly with cytopenias 3
• Unexplained persistent cytopenias or thrombocytopenia 3

Immunodeficiency Screening

When prolonged fevers recur with every illness:

• Immunoglobulin levels (IgG, IgA, IgM, IgE) to screen for antibody deficiencies 1
• Lymphocyte subset analysis if cellular immunodeficiency suspected 1
• Consider referral to pediatric immunology for comprehensive evaluation of primary immunodeficiency 1

Common Diagnostic Pitfalls to Avoid

Do Not Assume Viral Illness

• The presence of one viral infection does not preclude coexisting bacterial infection or underlying serious pathology 3, 4
• Height and duration of fever alone are not predictive of major illness, but the pattern of recurrent prolonged fevers is abnormal and warrants investigation 6, 7

Do Not Delay Kawasaki Disease Evaluation

• Incomplete Kawasaki disease is easily missed, especially in infants who may have prolonged fever with fleeting or subtle additional signs 2
• Misdiagnosis commonly occurs when fever and pyuria are attributed to UTI, or when rash and conjunctivitis are attributed to antibiotic reaction 2
• Without treatment, 15-25% develop coronary artery abnormalities; with prompt therapy this decreases to ~5% 2

Do Not Give Antibiotics Before Cultures

• Administering antibiotics before obtaining blood and urine cultures may obscure the diagnosis of serious bacterial infection 3, 4
• Empiric antibiotics should only be given in unstable or deteriorating patients after cultures are obtained 5

Special Consideration: MIS-C

In the post-COVID era:

• Multisystem Inflammatory Syndrome in Children (MIS-C) occurs 2-6 weeks after SARS-CoV-2 exposure and presents with significantly higher temperatures and longer fever duration than routine pediatric illnesses 2, 3
• Children should have SARS-CoV-2 PCR or serology testing as part of the evaluation 2, 3
• MIS-C requires elevated inflammatory markers (CRP typically >10 mg/dL) plus evidence of multisystem involvement 2

Prognosis and Long-Term Outlook

• Approximately 50% of children with true fever of unknown origin will have self-limited illness and never receive a specific diagnosis, while the other 50% will ultimately be diagnosed with infectious, inflammatory, or neoplastic conditions 3
• However, a child with recurrent prolonged fevers with every illness has a higher likelihood of an identifiable underlying condition requiring treatment 1
• Delayed diagnosis of Kawasaki disease beyond 10 days significantly increases coronary artery aneurysm risk 2, 3