Can Epstein-Barr virus (EBV) flare up again in an adolescent or young adult with a history of infectious mononucleosis?

Can EBV Flare Up Again?

Yes, Epstein-Barr virus can reactivate after initial infection, though this is uncommon in healthy adolescents and young adults—most concerning is the development of chronic active EBV infection (CAEBV), which requires aggressive evaluation and management. 1, 2

Understanding EBV Persistence and Reactivation

After primary infection (infectious mononucleosis), EBV establishes lifelong latency in memory B-cells and can switch between latent and lytic life cycles, giving it the ability to cause chronic relapsing or reactivating infections. 3, 4 Over 90% of adults worldwide carry EBV asymptomatically after their initial infection. 5, 6

In Immunocompetent Individuals

• Typical course: Most healthy adolescents and young adults who recover from infectious mononucleosis do not experience clinically significant reactivation. 7, 5
• Asymptomatic viral shedding: The virus can periodically reactivate and shed in oral secretions without causing symptoms—this is normal and not considered a "flare-up." 6
• Antibody persistence: Over 90% of normal adults maintain IgG antibodies to VCA and EBNA antigens reflecting past infection, not active disease. 7

Chronic Active EBV Infection (CAEBV)

CAEBV represents true pathological reactivation and is characterized by persistent or recurrent infectious mononucleosis-like symptoms lasting beyond the typical recovery period. 1, 2

Diagnostic Features of CAEBV:

• Persistent or intermittent fever, lymphadenopathy, and/or hepatosplenomegaly lasting weeks to months 1
• Recurrent debilitating fatigue, sore throat, lymph node pain, headache, myalgia, and arthralgia 1
• High IgG antibody titers against EBV VCA (≥1:640) and EA (≥1:160), though thresholds vary by laboratory 2
• Presence of IgA antibodies against VCA and/or EA, which is unusual in typical past infection 2
• Quantitative EBV PCR showing viral loads >10^2.5 copies/μg DNA in peripheral blood mononuclear cells 1, 2

Critical Red Flags:

• Persistent fever beyond 10 days after initial EBV diagnosis is not typical of uncomplicated primary infection and warrants immediate further investigation. 2
• The combination of persistent fever, lymphadenopathy, and hepatosplenomegaly is particularly concerning for CAEBV. 1, 2

Life-Threatening Complications

EBV-associated hemophagocytic lymphohistiocytosis (HLH) can develop during primary infection or reactivation, presenting with: 1, 2

• Persistent high-grade fever
• Cytopenias
• Extremely elevated ferritin levels (>1000 ng/mL) 2
• Requires prompt recognition and immunosuppressive therapy 2

Lymphoproliferative disorders: Patients with CAEBV can progress to T-cell or NK-cell malignant lymphomas, making early recognition critical. 1, 2

When to Suspect Reactivation vs. New Illness

Evaluate for CAEBV if:

• Symptoms persist or recur more than 6 weeks after initial mononucleosis diagnosis 1, 2
• New onset of severe symptoms in someone with known past EBV infection 1
• Development of unusual complications (skin lesions, cardiovascular manifestations, neurological symptoms) 1

Consider alternative diagnoses:

• Secondary bacterial infection during recovery from primary EBV infection 2
• Other causes of mononucleosis-like illness (CMV, HIV, Toxoplasma gondii, adenovirus) if heterophile tests are negative 7, 8

Special Populations at Higher Risk

Immunocompromised patients have significantly increased risk of EBV reactivation and complications: 7, 4, 9

• Transplant recipients on immunosuppression
• Patients with primary immunodeficiencies affecting NK and/or T cell systems 9
• Those on thiopurine therapy (risk of fatal infectious mononucleosis-associated lymphoproliferative disorders) 7

For these patients, immunomodulator therapy should be reduced or discontinued if possible, and antiviral therapy with ganciclovir or foscarnet may be considered in severe cases despite limited supporting evidence. 7

Management Approach

For suspected CAEBV or persistent symptoms:

• Obtain quantitative EBV PCR on peripheral blood mononuclear cells 1, 2
• Check EBV-specific antibody patterns (VCA IgG, VCA IgM, VCA IgA, EA, EBNA) 7, 2
• Measure ferritin levels to assess for HLH 2
• Consider cytokine analysis if HLH suspected 1, 2
• Bone marrow examination may be necessary if HLH is suspected 2

Critical pitfall: Assuming all EBV infections are self-limiting can lead to delayed diagnosis of CAEBV or HLH, both of which require aggressive management and have poor prognosis if untreated. 1, 2