What is the recommended evaluation and management for a child with fever lasting >7 days without an identified source?

Prolonged Fever Without Focus in Children: Evaluation and Management

Initial Diagnostic Approach

For any child with fever lasting >7 days without an identified source, immediately obtain urinalysis with catheterized urine culture, complete blood count with differential, blood culture (before antibiotics), inflammatory markers (CRP and ESR), and strongly consider Kawasaki disease as a primary diagnosis. 1

Age-Specific Risk Stratification

• Neonates (0-28 days) carry the highest risk of serious bacterial infection at 13%, requiring comprehensive sepsis evaluation including lumbar puncture for CSF analysis, urinalysis, urine culture, blood culture, complete blood count, inflammatory markers, and empiric antibiotics after cultures are obtained. 2, 1

• Young infants (29-90 days) have a 9% incidence of serious bacterial infection and may be risk-stratified using validated criteria (Rochester or Philadelphia), though lumbar puncture should be strongly considered if the infant does not meet low-risk criteria. 2, 3

• Children 3-36 months have approximately 5-7% risk of serious bacterial infection in the post-vaccine era, with urinary tract infection being the most common serious bacterial infection (5-8% prevalence). 4, 5

Mandatory Initial Laboratory Evaluation

• Urinalysis and catheterized urine culture are the highest-yield tests, as UTI accounts for 8-13% of serious bacterial infections in young febrile children; bag-collected specimens are unreliable and should never be used for diagnosis. 1, 4, 3

• Complete blood count with differential to identify occult bacteremia, assess for cytopenias suggesting malignancy, and evaluate white blood cell count patterns. 1, 4

• Blood culture before any antibiotics is crucial, as occult bacteremia occurs in 1.5-2% of febrile children aged 3-36 months, with Streptococcus pneumoniae accounting for 83-92% of cases. 4, 3

• Inflammatory markers (CRP and ESR) help distinguish infectious from non-infectious causes and are essential for evaluating Kawasaki disease; ESR typically exceeds 100 mm/hr and CRP reaches ≥3 mg/dL in Kawasaki disease. 2, 1, 4

Kawasaki Disease: The Critical Diagnosis Not to Miss

Kawasaki disease must be the primary consideration in any child with unexplained fever lasting ≥5 days, as delayed diagnosis beyond 10 days dramatically increases the risk of coronary artery aneurysms from 5% to 25%. 2, 1

Clinical Criteria for Kawasaki Disease

Classic Kawasaki disease requires fever ≥5 days plus at least four of five principal features: 2, 1

1. Bilateral non-purulent conjunctival injection (bulbar, sparing the limbus)
2. Oral mucosal changes (cracked lips, "strawberry" tongue, diffuse oral erythema)
3. Polymorphous rash (maculopapular, erythrodermic, or erythema multiforme-like)
4. Extremity changes (erythema/edema of hands/feet with sharp demarcation at wrists/ankles)
5. Cervical lymphadenopathy ≥1.5 cm diameter

Incomplete Kawasaki Disease

• Incomplete Kawasaki disease is especially common in infants <1 year and carries a higher risk of coronary artery aneurysms if untreated. 2, 1

• When fever ≥5 days is accompanied by only 2-3 clinical features, obtain ESR and CRP immediately; if ESR ≥40 mm/hr and/or CRP ≥3 mg/dL, proceed with urgent echocardiography. 2, 1

• Coronary artery abnormalities on echocardiography allow diagnosis of Kawasaki disease even with only three clinical features present. 1

Urgent Echocardiography Indications

• Obtain urgent transthoracic echocardiography when ≥2 principal Kawasaki disease features are present with fever, even before day 5, to evaluate for coronary artery changes including perivascular brightness, coronary ectasia, lack of tapering, reduced left-ventricular contractility, or pericardial effusion. 1

• For infants <12 months with fever ≥5 days, obtain urgent echocardiogram even with minimal clinical features due to heightened risk of coronary involvement. 1

Treatment of Kawasaki Disease

Initiate intravenous immunoglobulin (IVIG) 2 g/kg as a single infusion plus high-dose aspirin 80-100 mg/kg/day divided into four doses within 10 days of fever onset. 2, 1

Imaging Studies

• Chest radiography is NOT indicated in well-appearing children without respiratory symptoms (cough, hypoxia, rales, tachypnea), as the diagnostic yield is <3% in this population. 1, 3, 6

• Chest radiography is appropriate when respiratory signs are present, fever >39°C, or marked leukocytosis ≥20,000/mm³, as the yield for detecting occult pneumonia increases significantly. 6

• Lumbar puncture is NOT routinely indicated for well-appearing infants >3 months without toxic appearance, altered mental status, or focal neurologic deficits, as bacterial meningitis incidence is significantly lower than in the neonatal period. 1, 3

Prolonged Fever (>3 Weeks): Fever of Unknown Origin

When fever persists >3 weeks despite initial evaluation, the diagnostic approach must expand: 2, 7, 8

Etiologic Distribution

• Infectious causes account for 34-42% of prolonged FUO cases, with bacterial meningitis (6.5%) and urinary tract infection (11.4%) being most common among infections. 7, 8

• Autoimmune/inflammatory conditions represent 27% of cases, including juvenile idiopathic arthritis and systemic lupus erythematosus. 8

• Oncologic causes account for 18% of cases, with leukemia and lymphoma requiring immediate evaluation if lymph nodes are >2 cm, hard, or matted, or if hepatosplenomegaly is present with cytopenias. 1, 8

• Unknown/undiagnosed cases represent 14-50% of prolonged FUO, with many being self-limited illnesses that never receive a specific diagnosis. 1, 8

Advanced Diagnostic Evaluation for Prolonged FUO

• FDG-PET/CT whole body is the highest-yield advanced diagnostic tool for fever of unknown origin, with 84-86% sensitivity and 56% diagnostic yield. 4

• Obtain comprehensive metabolic panel including liver function tests, lactate dehydrogenase (often markedly elevated in lymphoma and leukemia), and albumin (hypoalbuminemia is common in Kawasaki disease). 1

• Consider bone marrow examination if cytopenias, thrombocytopenia, or abnormal cells are present, as it has a diagnostic yield of 23.7% in prolonged fever cases, increasing significantly with thrombocytopenia or anemia. 1

• Perform excisional or incisional lymph node biopsy with fresh tissue sent in saline if lymph nodes are >2 cm, hard, or matted, with morphology and flow cytometry as minimum methodologies. 1

Critical Pitfalls to Avoid

• Do NOT assume normal urinalysis excludes UTI—when clinical risk factors are present (age <12 months, white race, temperature ≥39°C, fever ≥2 days), obtain catheterized urine culture even with negative dipstick results. 1, 4

• Do NOT dismiss Kawasaki disease because "no other symptoms" are evident—incomplete Kawasaki disease is common in infants and can lead to serious coronary complications. 1

• Do NOT administer antibiotics before obtaining blood and urine cultures, as this may obscure diagnosis. 3

• Do NOT rely on physical examination alone in neonates <28 days—the threshold for full sepsis workup is appropriately low in this age group. 3

• Do NOT assume the presence of viral infection excludes bacterial co-infection—76% of children with fever without source have detectable viruses, but 40% of children with definite bacterial infection also have concurrent viral infections. 9

Management Algorithm for Fever >7 Days

Days 1-7: Initial Presentation

• Obtain urinalysis with catheterized urine culture, complete blood count with differential, blood culture (before antibiotics), CRP, and ESR. 1, 4
• Perform meticulous physical examination for all five principal Kawasaki disease features daily. 1
• If ≥2 Kawasaki disease features are identified, order urgent echocardiogram immediately. 1

Days 5-10: Kawasaki Disease Window

• If fever persists to day 5 and ≥4 principal features are present, confirm Kawasaki disease diagnosis and initiate IVIG 2 g/kg plus high-dose aspirin 80-100 mg/kg/day. 2, 1
• If only 2-3 features present with ESR ≥40 mm/hr or CRP ≥3 mg/dL, obtain urgent echocardiogram. 1

Days 7-21: Extended Evaluation

• Re-assess for evolving Kawasaki disease features, as serial examinations often reveal new signs. 1
• Consider chest radiography if respiratory symptoms develop. 6
• Evaluate for occult malignancy if lymphadenopathy, hepatosplenomegaly, or cytopenias are present. 1

Beyond 21 Days: Fever of Unknown Origin

• Obtain comprehensive metabolic panel, lactate dehydrogenase, and consider FDG-PET/CT whole body imaging. 1, 4
• Pursue bone marrow examination if cytopenias or abnormal cells are present. 1
• Consider lymph node biopsy if nodes are >2 cm, hard, or matted. 1

Special Consideration: Multisystem Inflammatory Syndrome in Children (MIS-C)

Consider MIS-C when there is a history of COVID-19 exposure 2-6 weeks prior and fever is higher and more prolonged than typical Kawasaki disease. 1