What are the symptoms and management of Epstein-Barr Virus (EBV) in a patient with persistent tonsillitis and fever?

Symptoms and Management of Epstein-Barr Virus Infection

Primary Symptoms of EBV Infection

The classic presentation of EBV infectious mononucleosis includes sore throat, fever, tonsillar enlargement, fatigue, lymphadenopathy, pharyngeal inflammation, and palatal petechiae, typically occurring in patients aged 15-24 years. 1

Core Clinical Features

• Sore throat and tonsillar enlargement with pharyngeal inflammation are hallmark symptoms 1
• Fever (typically mild) accompanied by cervical lymphadenopathy 1, 2
• Fatigue that can be profound and debilitating 3
• Palatal petechiae on the soft palate, which is particularly characteristic 4
• Hepatosplenomegaly with potential liver dysfunction 2, 4

Additional Manifestations

• Lymphocytosis with atypical lymphocytes on blood smear 4
• Skin eruptions may occur 4
• Headache, myalgia, and arthralgia in some patients 3

Incubation Period

• The incubation period is unusually long at approximately 6 weeks, distinguishing it from most acute viral illnesses 5

When to Suspect Complicated EBV Infection

Persistent high-grade fever beyond 10 days after initial EBV diagnosis is atypical for uncomplicated infection and warrants immediate investigation for Chronic Active EBV (CAEBV) or hemophagocytic lymphohistiocytosis (HLH). 6, 3

Red Flags Requiring Further Evaluation

• Persistent or recurrent symptoms lasting >3 months that cannot be explained by other conditions 6
• Fever persisting beyond 10 days from diagnosis 6, 3
• Recurrent debilitating fatigue with sore throat and lymph node pain 3
• Persistent lymphadenopathy and hepatosplenomegaly 3

Diagnostic Approach

Initial Testing for Acute Infection

• Heterophile antibody test is the best initial diagnostic test with 71-90% accuracy, though it has a 25% false-negative rate in the first week of illness 1
• Lymphocyte count <4,000/mm³ makes infectious mononucleosis unlikely 1
• EBV-specific IgM antibodies confirm acute infection but are more costly and take longer than heterophile testing 1

Testing for Complicated or Persistent Infection

For patients with persistent symptoms beyond 10 days or concerning features, perform quantitative EBV PCR on whole blood with a threshold of >10^2.5 copies/μg DNA in peripheral blood mononuclear cells suggesting CAEBV. 6, 3

• Markedly elevated antibody titers (VCA-IgG ≥1:640 AND EA-IgG ≥1:160) are characteristic of CAEBV 6, 3
• Presence of IgA antibodies to VCA and/or EA is unusual in typical past infection and supports CAEBV diagnosis 6, 3
• Ferritin levels >1,000 ng/mL suggest HLH and require urgent evaluation 6, 3
• Cytokine analysis showing elevated inflammatory cytokines indicates HLH or CAEBV 3
• Bone marrow examination may be necessary if HLH is suspected to look for hemophagocytosis 6, 3

Management Strategy

Uncomplicated Infectious Mononucleosis

Symptomatic relief is the mainstay of treatment; glucocorticoids and antivirals do not reduce the length or severity of illness. 1

• Provide supportive care with rest, hydration, and analgesics 1
• Never prescribe antiviral drugs (acyclovir, valacyclovir, ganciclovir) as they are completely ineffective against latent EBV 7
• Avoid athletic participation for the first 3 weeks due to risk of splenic rupture 1

Chronic Active EBV Infection (CAEBV)

Patients with CAEBV have poor prognosis and often require aggressive immunomodulatory therapy, as they can progress to T-cell or NK-cell malignant lymphomas. 6, 3

• Early recognition is critical in symptomatic patients 3
• Consider aggressive immunomodulatory therapy for confirmed CAEBV 3
• In severe refractory cases, rituximab or stem cell transplantation may be necessary 3

EBV-Associated HLH

For HLH, prompt recognition and treatment with immunosuppressive therapy, potentially including corticosteroids, is necessary. 3

• This is a life-threatening complication requiring urgent intervention 3
• Ferritin >1,000 ng/mL with persistent fever and cytopenias should trigger immediate HLH workup 6, 3

Critical Pitfalls to Avoid

• Assuming all EBV infections are self-limiting can lead to delayed diagnosis of CAEBV or HLH, both requiring aggressive management 3
• Overlooking HLH can be life-threatening and requires prompt diagnosis and treatment 3
• Prescribing antivirals for any EBV-related condition is inappropriate and ineffective 7, 1
• Failing to investigate persistent fever beyond 10 days, as this is not typical of uncomplicated primary EBV infection 6, 3

Special Populations

Children

• Primary EBV infection in children up to 10 years is usually asymptomatic or shows nonspecific courses 2
• Children are at highest risk of airway obstruction, which is the most common cause of hospitalization from infectious mononucleosis 1

Immunocompromised Patients

• Patients with immunosuppression are more likely to have fulminant EBV infection 1
• Severe multiorgan involvement can occur even in immunocompetent individuals, though this is rare 8