What are the likely causes and recommended work‑up for a 12‑year‑old boy with a 20‑day persistent fever, markedly elevated C‑reactive protein, elevated erythrocyte sedimentation rate, normal procalcitonin, mild leukocytosis, mild anemia, and negative infectious, autoimmune, and tumor‑marker screens despite three courses of antibiotics?

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Diagnostic Approach to Prolonged Fever with Marked Inflammation in a 12-Year-Old

Immediate Priority: Rule Out Multisystem Inflammatory Syndrome in Children (MIS-C)

This child requires urgent evaluation for MIS-C, a potentially fatal post-SARS-CoV-2 condition that precisely matches this clinical presentation: 20-day persistent fever, CRP ~100 mg/L, ESR 60-80 mm/h, normal procalcitonin, mild leukocytosis, and negative infectious workup. 1

Why MIS-C Must Be Excluded First

  • MIS-C typically manifests 2-6 weeks after SARS-CoV-2 infection with persistent fever, markedly elevated inflammatory markers (CRP commonly >100 mg/L, ESR >40 mm/h), and normal or mildly elevated procalcitonin—exactly matching this presentation. 1

  • Normal procalcitonin is a critical diagnostic clue: procalcitonin remains normal or only mildly elevated in MIS-C despite severe inflammation, distinguishing it from bacterial sepsis where procalcitonin would be markedly elevated. 2, 3, 4

  • Cardiac complications are life-threatening: 20-55% of MIS-C patients develop left-ventricular dysfunction and approximately 20% develop coronary artery abnormalities, making urgent cardiac assessment mandatory. 1, 5

  • A negative SARS-CoV-2 PCR does not exclude MIS-C—serology is essential because MIS-C occurs weeks after infection when PCR may be negative. 1

Immediate Diagnostic Workup

Tier-1 Essential Testing (If Not Already Done)

  • SARS-CoV-2 serology (IgG, IgM, IgA) is mandatory—PCR alone is insufficient for MIS-C diagnosis. 1

  • Complete blood count with differential: Look for lymphopenia, neutrophilia, or thrombocytopenia (all seen in MIS-C). 1

  • Comprehensive metabolic panel: Assess for hyponatremia, hypoalbuminemia, or renal/hepatic dysfunction. 1, 5

  • Additional inflammatory markers: D-dimer, ferritin, LDH, fibrinogen, and IL-6 for risk stratification. 1

Tier-2 Cardiac Evaluation (Urgent—Do Not Delay)

  • Electrocardiogram: Up to 20% of MIS-C patients develop conduction abnormalities including AV block. 1, 5

  • Echocardiogram: Essential to evaluate ventricular function, coronary arteries, valvular status, and pericardial effusion. 1, 5

  • Cardiac biomarkers: Troponin and BNP/NT-proBNP are elevated in many MIS-C cases. 1, 5

Alternative Diagnoses to Consider

Kawasaki Disease

  • ESR 60-80 mm/h is consistent with Kawasaki disease, where ESR is frequently >40 mm/h and commonly ≥100 mm/h. 6

  • Diagnostic criteria: Fever ≥5 days (this child has 20 days) plus at least four of: conjunctivitis, oral mucosal changes, polymorphous rash, extremity changes, cervical lymphadenopathy. 5

  • Critical distinction from MIS-C: Kawasaki disease typically occurs in younger children (<5 years), has specific mucocutaneous features, and is not temporally associated with COVID-19. 1, 5

  • Echocardiogram is mandatory to assess for coronary artery abnormalities regardless of whether this is Kawasaki disease or MIS-C. 5

Systemic Juvenile Idiopathic Arthritis (Still's Disease)

  • Adult-onset Still's disease and systemic JIA demonstrate ESR elevation in 95-98% of cases and can present with prolonged fever and markedly elevated inflammatory markers. 6

  • Key diagnostic features: Quotidian (daily spiking) fever pattern, salmon-pink evanescent rash, arthritis, hepatosplenomegaly, lymphadenopathy. 6

  • Serum ferritin is markedly elevated (often >1000 ng/mL) and can help distinguish Still's disease from other causes. 6

  • However, RF, anti-CCP, and ANA are typically negative (as in this case), which is consistent with Still's disease. 6

Occult Malignancy

  • ESR >100 mm/h is an independent prognostic factor for mortality and can indicate underlying malignancy, though this child's ESR is 60-80 mm/h. 6

  • Tumor markers are negative, which reduces but does not eliminate malignancy concern—consider lymphoma or leukemia with peripheral blood smear and bone marrow evaluation if other diagnoses are excluded. 6

Endocarditis

  • Blood cultures should have been obtained before antibiotics to rule out infective endocarditis, especially given three courses of antibiotics. 6

  • Echocardiography is essential if endocarditis remains a consideration despite negative blood cultures. 6

Hospitalization Decision

This child requires immediate hospital admission based on the following criteria: 1, 5

  • CRP ~100 mg/L (≥10 mg/dL) mandates admission. 1, 5

  • Persistent fever for 20 days with markedly elevated inflammatory markers despite three antibiotic courses indicates severe systemic inflammation requiring urgent evaluation. 1, 5

  • Potential cardiac involvement (MIS-C or Kawasaki disease) requires continuous monitoring. 1, 5

Critical Pitfalls to Avoid

  • Do not attribute this presentation to treatment-resistant bacterial infection without first excluding MIS-C—the normal procalcitonin argues strongly against bacterial sepsis. 2, 3, 4

  • Do not delay cardiac evaluation—coronary artery abnormalities and ventricular dysfunction can develop rapidly in both MIS-C and Kawasaki disease. 1, 5

  • Do not assume negative SARS-CoV-2 PCR rules out MIS-C—obtain serology immediately. 1

  • Do not continue empiric antibiotics without a confirmed bacterial source—the normal procalcitonin (<0.5 ng/mL) has 96% negative predictive value for serious bacterial infection. 4

Recommended Immediate Actions

  1. Admit to hospital immediately for continuous monitoring and urgent cardiac evaluation. 1, 5

  2. Obtain SARS-CoV-2 serology, cardiac biomarkers, ECG, and echocardiogram urgently. 1, 5

  3. Consult pediatric rheumatology, cardiology, and infectious disease for multidisciplinary evaluation. 1

  4. If MIS-C is confirmed, first-line treatment is IVIG 2 gm/kg plus consideration of methylprednisolone 1-2 mg/kg/day. 1

  5. If MIS-C is excluded, pursue evaluation for Still's disease (ferritin, bone marrow if needed) and consider repeat imaging for occult infection or malignancy. 6

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

3
Research

Prospective study on procalcitonin and other systemic infection markers in patients with leukocytosis.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2008

5
Guideline

Evaluation of Elevated ESR with Rash in Children – Emphasis on MIS‑C

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

ESR Values and Clinical Interpretation

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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