What are the typical clinical features, diagnostic workup, and recommended management for Epstein‑Barr virus infection (infectious mononucleosis) in adolescents and children?

Epstein-Barr Virus (Infectious Mononucleosis) in Children and Adolescents

Clinical Presentation

Infectious mononucleosis presents with the classic triad of fever, tonsillar pharyngitis, and lymphadenopathy, though the clinical picture varies significantly by age. 1

Age-Specific Features

Adolescents and young adults (15-24 years):

• Fever, tonsillar pharyngitis, and posterior cervical lymphadenopathy are predominant 2
• Headache, sore throat, abdominal pain, and nausea occur more frequently 3
• Profound fatigue that typically resolves within 3 months 1
• Periorbital or palpebral edema (bilateral) in one-third of patients 1
• Splenomegaly in approximately 50% and hepatomegaly in 10% 1
• Maculopapular rash in 10-45% of cases 1

Young children (0-4 years):

• Fever, runny nose, fatigue, and cervical adenitis are typical 3
• Tonsillitis and sore throat are less prominent 3
• Children aged 1-2 years represent the largest hospitalized group (27%), challenging the misconception that EBV is rare in early childhood 3
• Classic mononucleosis symptoms are often absent 3

Diagnostic Workup

Initial Laboratory Testing

The most cost-effective initial approach combines a complete blood count with differential and rapid heterophile antibody test (Monospot). 2

Complete Blood Count findings:

• Peripheral blood leukocytosis with lymphocytes comprising ≥50% of differential 1
• Atypical lymphocytes >10% of total lymphocyte count 1
• Lymphocytosis more common in children 5-15 years (84%) versus under 5 years (62%) 3

Heterophile Antibody Test (Monospot):

• Sensitivity 87%, specificity 91% 2
• Critical limitation: false-negative in children <5 years and during the first week of illness in adults 2
• Approximately 10% false-negative rate, particularly in young children 4

Confirmatory Testing

When Monospot is negative but clinical suspicion remains high, use EBV-specific serology with a three-marker approach: VCA-IgM, VCA-IgG, and EBNA-1 IgG. 4

Acute infection pattern:

• VCA-IgM positive 5
• VCA-IgG positive or negative 5
• EBNA absent 5

Past infection pattern:

• VCA-IgM negative 5
• VCA-IgG positive 5
• EBNA positive 5

Additional Laboratory Findings

Elevated liver enzymes increase diagnostic suspicion when heterophile test is negative. 2

• Alanine aminotransferase elevated in 77% of children 5-15 years versus 33% in younger children 3
• Lactate dehydrogenase elevated in 79% versus 44% respectively 3

Management

Supportive Care

Treatment is entirely supportive; antivirals and routine corticosteroids are not recommended for immunocompetent patients. 4, 1

Activity restrictions:

• Reduction of activity and bed rest as tolerated 1
• Avoid contact sports and strenuous exercise for 8 weeks or while splenomegaly persists 1
• Current guidelines recommend no athletic activity for 3 weeks from symptom onset, with shared decision-making for return timing 2

Specific indications for corticosteroids:

• Airway obstruction is the primary indication 4
• Not recommended for routine symptom management 4

Monitoring for Complications

Splenic rupture is the most feared complication, occurring in 0.1-0.5% of patients and potentially life-threatening. 1

Other complications to monitor:

• Hepatosplenomegaly 1
• Neurological manifestations 4
• Hematological abnormalities 4
• Risk factor for chronic fatigue syndrome 1

Red Flags Requiring Further Evaluation

Persistent high-grade fever beyond 10 days after EBV diagnosis warrants evaluation for chronic active EBV infection (CAEBV) or hemophagocytic lymphohistiocytosis (HLH). 6

Chronic Active EBV (CAEBV)

Diagnostic criteria:

• Persistent or recurrent infectious mononucleosis-like symptoms lasting >3 months 6, 4
• High IgG antibody titers: VCA ≥1:640 and EA ≥1:160 (laboratory-dependent) 6, 4
• Quantitative EBV PCR >10^2.5 copies/μg DNA in peripheral blood mononuclear cells 6, 4
• Presence of IgA antibodies against VCA and/or EA (unusual in typical past infection) 6, 4

Clinical significance:

• Poor prognosis requiring aggressive immunomodulatory therapy 6
• Can progress to T-cell or NK-cell malignant lymphomas 6

Hemophagocytic Lymphohistiocytosis (HLH)

Diagnostic features:

• Persistent fever, cytopenias, extremely elevated ferritin (>1000 ng/mL) 6
• Elevated inflammatory cytokines 6
• Hemophagocytosis on bone marrow examination 6
• Requires prompt immunosuppressive therapy including corticosteroids 6

Special Populations

Immunocompromised patients require prospective EBV DNA monitoring by quantitative PCR weekly for at least 4 months, with pre-emptive rituximab for rising viral loads. 4

High-risk features include:

• T-cell depletion therapy 4
• EBV donor/recipient mismatch 4
• Cord blood transplantation 4
• Steroid-refractory GVHD 4

Critical Pitfalls to Avoid

Assuming all EBV infections are self-limiting can lead to delayed diagnosis of CAEBV or HLH, both requiring aggressive management with poor prognosis if untreated. 6, 4

Relying solely on heterophile testing in children <5 years will miss many cases; use EBV-specific antibodies instead. 4, 2

Overlooking HLH can be life-threatening; persistent fever beyond 10 days demands thorough evaluation. 6

Antibody titers from different laboratories are not comparable due to subjective immunofluorescence techniques and varying reagent quality. 6, 4