What is the best course of action for a 12-year-old patient with lymphadenopathy, pharyngitis, mild hepatomegaly, and increasing liver function tests (LFTs) and hyperbilirubinemia while on antibiotics?

Immediate Management of Suspected Infectious Mononucleosis with Drug-Induced Hepatotoxicity

Stop the current antibiotics immediately and investigate for Epstein-Barr virus (EBV) infection, as this clinical presentation—pharyngitis, lymphadenopathy, hepatomegaly, and rising LFTs with hyperbilirubinemia—is classic for infectious mononucleosis, and the antibiotic therapy (particularly if beta-lactam) may be causing additional hepatotoxicity or represents unnecessary treatment.

Clinical Reasoning and Differential Diagnosis

The constellation of findings strongly suggests infectious mononucleosis:

• Pharyngitis with lymphadenopathy is the hallmark presentation of EBV infection 1
• Mild hepatomegaly with rising LFTs occurs in approximately 80-90% of EBV cases, though severe hepatitis is uncommon 1
• Hyperbilirubinemia (bilirubin 4 mg/dL) indicates hepatocellular injury that warrants immediate attention 1
• Fever that "settled" on antibiotics may represent the natural course of viral illness rather than true antibiotic response 1

Immediate Actions Required

1. Discontinue Current Antibiotics

• Drug-induced liver injury (DILI) must be ruled out, especially if the patient received beta-lactams, which can cause hepatotoxicity 2
• Children may experience elevated LFTs during viral infections, particularly when NSAIDs and antibiotics are administered concurrently 1
• Bilirubin ≥2× ULN with rising transaminases mandates immediate cessation of potentially hepatotoxic medications 1

2. Obtain Diagnostic Testing

• EBV serology: Monospot test or EBV-specific antibodies (VCA-IgM, VCA-IgG, EBNA) 1
• Complete hepatic panel: ALT, AST, alkaline phosphatase, GGT, direct and indirect bilirubin to differentiate hepatocellular vs cholestatic injury 1
• Complete blood count with differential: Look for atypical lymphocytes (>10% suggests EBV) 1
• Viral hepatitis serologies (HAV, HBV, HCV) if not previously done 1
• Coagulation studies (INR) to assess synthetic liver function 1

3. Close Monitoring Protocol

• Repeat LFTs within 2-3 days given the rising trend and hyperbilirubinemia 1, 3
• Monitor at least 2-3 times weekly until improvement is documented 1
• Early detection through scheduled monitoring reduces peak liver injury severity (276 vs 507 IU/L in monitored vs unmonitored patients) 3

Management Based on Etiology

If EBV Confirmed (Most Likely):

• Supportive care only: No specific antiviral therapy indicated 1
• Avoid ampicillin/amoxicillin: These cause a characteristic maculopapular rash in 80-100% of EBV patients 1
• Monitor LFTs weekly until normalization 1
• Restrict contact sports for 3-4 weeks due to splenomegaly risk 1
• Most patients recover spontaneously; hepatitis typically resolves within 2-4 weeks 1

If Bacterial Infection Confirmed:

• Only restart antibiotics if clear bacterial pathogen identified (e.g., positive throat culture for Group A Streptococcus) 1
• For Group A Strep pharyngitis: Use penicillin V (50-75 mg/kg/day in 3-4 doses) or amoxicillin (50-75 mg/kg/day in 2 doses) if no EBV 1
• Avoid hepatotoxic antibiotics given current liver dysfunction 1

Thresholds for Escalation

Criteria for Hepatology Consultation:

• ALT or AST >5× baseline 1
• Bilirubin continues rising beyond 4 mg/dL 1
• INR elevation suggesting synthetic dysfunction 1
• Clinical deterioration: Encephalopathy, coagulopathy, or worsening jaundice 1

Criteria for Hospital Admission:

• Inability to maintain oral hydration 1
• Signs of hepatic decompensation (encephalopathy, coagulopathy) 1
• Bilirubin >10 mg/dL or rapidly rising 1

Common Pitfalls to Avoid

• Do not continue antibiotics empirically without confirmed bacterial infection—this risks worsening DILI 1, 2
• Do not use the same LFT thresholds for patients with baseline abnormalities vs normal baseline 4
• Do not delay antibiotic cessation when DILI is suspected—each hour of delay increases mortality risk in severe cases 5
• Do not assume fever resolution on antibiotics proves bacterial etiology—viral illnesses follow their natural course regardless 1
• Do not restart hepatotoxic medications until LFTs return to <2× ULN and bilirubin normalizes 1

Expected Clinical Course

• If EBV: LFTs typically peak within 2-3 weeks and normalize by 4-6 weeks 1
• If DILI: LFTs should improve within 7-14 days of stopping the offending agent 2
• Failure to improve warrants liver biopsy to exclude alternative diagnoses 2