What is the diagnosis and treatment for a 19-month-old male with intermittent bilateral lower leg swelling and a red rash, who has a slightly elevated absolute neutrophil count (ANC) of 1420, normal C-reactive protein (CRP) level, mildly elevated blood urea nitrogen (BUN) level, and low globulin level?

Diagnosis: Multisystem Inflammatory Syndrome in Children (MIS-C)

This 19-month-old child with intermittent bilateral lower leg swelling, red rash, and laboratory findings showing neutrophilia (ANC 1420), normal CRP, mildly elevated BUN, and low globulin most likely has Multisystem Inflammatory Syndrome in Children (MIS-C), and requires immediate SARS-CoV-2 testing (both PCR and serology), cardiac evaluation with EKG and echocardiogram, and comprehensive inflammatory workup to guide urgent treatment decisions. 1, 2

Diagnostic Approach

Immediate Testing Required

• SARS-CoV-2 testing is mandatory using both PCR and serology, as MIS-C is temporally associated with COVID-19 exposure within the prior 4 weeks 1, 2

• Tier 1 screening labs should include complete blood count with differential (already done), complete metabolic panel, ESR, and CRP 1, 2

• Cardiac assessment is non-negotiable: obtain EKG and echocardiogram immediately, as cardiac involvement occurs in 20-55% of MIS-C cases and can include left ventricular dysfunction, coronary artery dilation, or conduction abnormalities 1, 2

• Cardiac biomarkers: measure troponin T and BNP/NT-proBNP levels to identify cardiac involvement before clinical manifestations appear 1, 2

Tier 2 Evaluation

If tier 1 screening shows elevated ESR and/or CRP with at least one other suggestive feature (lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia), proceed to tier 2 testing 1:

• D-dimer, ferritin, LDH, and procalcitonin levels 1, 2
• Albumin level (hypoalbuminemia is common in MIS-C and indicates severe systemic inflammation) 1, 2
• Blood cultures to exclude bacterial infection 3

Key Clinical Features to Assess

Fever pattern: MIS-C typically presents with temperature ≥38.0°C for ≥24 hours, with affected children having significantly higher temperatures and longer fever duration than other pediatric illnesses 1

Rash characteristics: the rash is often erythematous (salmon pink), transient, and may coincide with fever spikes, preferentially involving the trunk 1

Cardiovascular signs: assess for hypotension, shock, tachycardia, or signs of cardiac dysfunction 1

Gastrointestinal symptoms: abdominal pain, diarrhea, or vomiting are common in MIS-C 1

Extremity findings: bilateral lower leg swelling with rash may represent mucocutaneous inflammation characteristic of MIS-C 1

Important Diagnostic Considerations

Why Normal CRP Doesn't Rule Out MIS-C

While the overwhelming majority of MIS-C cases show CRP values >10 mg/dl or even >20 mg/dl 1, this child may be in early disease or represent a milder phenotype that has not been fully described in published literature 1. The presence of neutrophilia (ANC 1420), rash, and bilateral leg swelling with low globulin still warrants full MIS-C evaluation 1, 2.

Alternative Diagnoses to Consider

Adult-onset Still's disease (which can occur in children) presents with marked leukocytosis, fever, and rash, but typically shows WBC >15 × 10⁹/L with very high CRP 1, 3. The normal CRP makes this less likely.

Bacterial infection is less likely given normal CRP, but blood cultures should still be obtained if fever is present 3

Neutrophilic dermatoses (Sweet syndrome, pyoderma gangrenosum) can present with rash and neutrophilia, but typically occur in adults and show elevated inflammatory markers 4, 5

Treatment Algorithm

If MIS-C is Confirmed

First-line therapy consists of IVIG 2 g/kg plus consideration of methylprednisolone 1-2 mg/kg/day 2

Intensification therapy with methylprednisolone IV 10-30 mg/kg/day or high-dose anakinra may be necessary for refractory disease 2

Admission Criteria

Immediate hospital admission is required if any of the following are present 2:

• Abnormal vital signs
• Respiratory distress
• Neurologic changes
• Signs of dehydration or shock
• Abdominal pain or gastrointestinal symptoms

Multidisciplinary Consultation

Immediate consultation required with 2:

• Pediatric rheumatology
• Pediatric cardiology
• Pediatric infectious disease
• Pediatric hematology

Critical Monitoring

Serial cardiac monitoring: EKGs should be performed at minimum every 48 hours while hospitalized, with continuous telemetry if conduction abnormalities are present 1

Echocardiogram timing: repeat at 7-14 days and 4-6 weeks after presentation, with additional imaging at 1 year if cardiac abnormalities occurred 1

Arrhythmia surveillance: up to 20% of MIS-C cases develop arrhythmias including atrioventricular block 2

Common Pitfalls to Avoid

Do not delay evaluation based on normal CRP alone - some MIS-C patients present with milder phenotypes or early disease 1

Do not miss cardiac involvement - cardiac complications can occur even without obvious clinical signs, requiring proactive screening with EKG, echocardiogram, and biomarkers 1, 2

Do not assume bacterial infection without cultures - the neutrophilia may be part of MIS-C rather than bacterial sepsis 1, 3

Do not discharge without SARS-CoV-2 testing - both PCR and serology are needed as some children test negative by PCR but positive by serology 1