In a child with elevated erythrocyte sedimentation rate, neutrophilia, and lymphopenia, what is the differential diagnosis and initial management?

Differential Diagnosis and Initial Management of Elevated ESR, Neutrophilia, and Lymphopenia in Children

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

Any child presenting with elevated ESR, neutrophilia, and lymphopenia must be immediately evaluated for MIS-C, a potentially fatal post-SARS-CoV-2 condition that requires urgent recognition and treatment. 1

Key Clinical Features of MIS-C to Assess:

• Fever ≥38°C lasting ≥24 hours (or subjective fever of same duration) 1, 2
• Recent SARS-CoV-2 exposure or infection within the prior 4 weeks 1, 2
• Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) 1, 2
• Mucocutaneous findings (rash, conjunctivitis, oral changes) 1, 2
• Cardiovascular signs (hypotension, shock, tachycardia) 1, 2

Tier 1 Laboratory Screening (Obtain Immediately):

• Complete blood count with differential 1
• Complete metabolic panel 1
• ESR and C-reactive protein (CRP) 1
• SARS-CoV-2 PCR and serology (serology is essential because PCR may be negative weeks after infection) 1, 2

Critical threshold: If ESR and/or CRP are elevated (commonly >10 mg/dL, often >20 mg/dL in MIS-C) plus at least one of the following—lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia—proceed immediately to Tier 2 evaluation. 1

Tier 2 Evaluation (When Tier 1 Is Abnormal):

• Electrocardiogram (up to 20% develop conduction abnormalities including AV block) 1, 2
• Echocardiogram (20-55% develop left ventricular dysfunction; ~20% develop coronary artery abnormalities) 1, 2
• Cardiac biomarkers (troponin, BNP/NT-proBNP) 1, 2
• Extended inflammatory panel (D-dimer, ferritin, LDH, IL-6, fibrinogen, procalcitonin) 1, 2

Other Critical Differential Diagnoses

Kawasaki Disease

• ESR frequently >40 mm/h and often ≥100 mm/h 3, 2
• Diagnostic criteria: Fever ≥5 days plus ≥4 of the following: bilateral conjunctivitis, oral mucosal changes, polymorphous rash, extremity changes, cervical lymphadenopathy 2
• Mandatory echocardiogram to assess coronary arteries 2

Bacterial Infections (Most Common Cause Overall)

• Infection is the most common cause of extreme ESR elevation (≥100 mm/h) in children, accounting for 49.5-55% of cases 4, 5
• Specific infections to consider:
  • Osteomyelitis/septic arthritis (ESR ≥70 mm/h has 81% sensitivity) 3
  • Infective endocarditis (obtain blood cultures if fever present; consider echocardiogram) 1, 3
  • Urinary tract infection (neutrophilia and elevated ESR are common; 73% have elevated ESR) 6
  • Spinal infection (especially with back pain, fever, or risk factors) 3

Connective Tissue Diseases

• Second most common cause of extreme ESR elevation (25-26.3% of cases) 4, 5
• Systemic juvenile idiopathic arthritis/Still's disease (ESR elevated in 95-98% of cases; check serum ferritin) 3
• Systemic vasculitis (consider if recurrent symptoms or neurologic changes) 2

Malignancy

• Accounts for 12-13% of extreme ESR elevations in children 4, 5
• Associated with significantly lower hemoglobin values (mean 8.2 g/dL) and lower leukocyte counts 4, 5

Renal Disease

• Accounts for 8% of extreme ESR elevations 4
• Check for hematuria, proteinuria, renal insufficiency 1

Hospitalization vs. Outpatient Management

Admit immediately if ANY of the following:

• Abnormal vital signs (tachycardia, tachypnea, hypotension) 1, 2
• Respiratory distress of any severity 2
• Neurologic changes (altered mental status, confusion, focal deficits) 2
• Signs of shock or dehydration 2
• CRP ≥10 mg/dL 1, 2
• Evidence of cardiac involvement (abnormal ECG, elevated troponin/BNP) 1, 2
• Significantly elevated inflammatory markers 1

Outpatient management acceptable only if ALL of the following:

• Well-appearing with stable vital signs 1, 2
• No respiratory distress 2
• Normal mental status 2
• Adequate hydration 2
• Reassuring physical examination 1, 2
• Guaranteed close follow-up within 24-48 hours 1, 2

Additional Diagnostic Workup Based on Clinical Context

If Musculoskeletal Symptoms Present:

• Rheumatoid factor and anti-CCP antibodies 3, 7
• Antinuclear antibodies (ANA) 3, 7
• Creatine kinase (to rule out myositis) 3, 7

If Fever Without Clear Source:

• Blood cultures (before antibiotics if possible) 1, 3
• Chest radiography 3
• Urinalysis and urine culture 6

If Abdominal Pain:

• ESR >50 mm/h has likelihood ratio of 6.0 for serious disease in children with abdominal pain 8

Critical Pitfalls to Avoid

• Do not dismiss as viral illness without excluding MIS-C in the current epidemiologic context 1, 2
• Negative SARS-CoV-2 PCR does not exclude MIS-C—serology is essential because MIS-C occurs 2-6 weeks post-infection when PCR may be negative 1, 2
• Cardiac complications are life-threatening—up to 20% develop coronary abnormalities and 20-55% develop ventricular dysfunction 1, 2
• Rapid decompensation can occur—maintain low threshold for admission because predictors of severe progression are not fully defined 1, 2
• ESR >50 mm/h is highly informative—serious disease is approximately 7 times more likely than in children with ESR <20 mm/h 8
• Children with infectious diseases and high ESR are significantly younger and more febrile with higher leukocyte and band counts than other diagnostic categories 5

Follow-Up Strategy

• If initial workup unrevealing: Repeat ESR and CRP in 2-4 weeks 3, 7
• If inflammatory condition diagnosed: Monitor ESR every 1-3 months during active disease until remission achieved 3, 7
• CRP normalizes faster than ESR during treatment, making it more useful for monitoring acute treatment response 3, 7