What are the diagnosis and treatment options for Epstein-Barr Virus (EBV) infection?

Diagnosis and Treatment of Epstein-Barr Virus Infection

Diagnostic Approach

The diagnosis of EBV infection depends critically on the clinical context: primary infection (infectious mononucleosis) is diagnosed serologically, while chronic active EBV disease requires persistent symptoms plus elevated viral loads, and EBV-associated post-transplant lymphoproliferative disorder requires tissue diagnosis with EBER detection. 1

Primary EBV Infection (Infectious Mononucleosis)

• Serological testing is the gold standard for diagnosing primary EBV infection 2, 3
• Heterophile antibody tests (monospot) detect approximately 85% of infectious mononucleosis cases, though the Paul-Bunnell and monospot tests have suboptimal sensitivity 1, 2
• Definitive diagnosis requires VCA-IgM and VCA-IgG positivity with negative EBNA1 IgG (EBNA1 IgG appears weeks to months later) 1, 2
• PCR-based viral load testing plays a minor role in diagnosing primary infection in immunocompetent hosts 3

Chronic Active EBV Disease (CAEBV)

• Diagnosis requires persistent or recurrent symptoms (fever, lymphadenopathy, hepatosplenomegaly) for more than 3 months 1, 4
• Markedly elevated antibody titers are required: VCA-IgG ≥1:640 and EA-IgG ≥1:160 1, 4
• EBV DNA levels >10^2.5 copies/mg DNA in peripheral blood mononuclear cells support the diagnosis 1, 4
• Target cell identification is essential: double-staining for EBNA or EBER detection with markers for B, T, NK cells, or monocytes/macrophages using immunofluorescence, immunohistochemistry, or magnetic beads 1
• Histopathological examination with immunohistological staining and chromosomal analysis should be performed 1

EBV-Associated Post-Transplant Lymphoproliferative Disorder (PTLD)

Proven EBV-PTLD requires biopsy with histological examination and EBV detection by in situ hybridization for EBER transcripts or viral antigen detection 1

Non-invasive diagnostic methods:

• Quantitative EBV DNA-emia in whole blood, plasma, or serum 1
• PET-CT imaging (preferred over CT for extranodal disease) 1

Monitoring in high-risk transplant patients:

• Prospective screening by quantitative PCR should begin no later than 4 weeks post-transplant 1
• Weekly testing is recommended in high-risk EBV PCR-negative patients 1
• Continue monitoring for at least 4 months post-transplant, longer if poor T-cell reconstitution (patients on treatment for severe GvHD, haplo-HSCT, T-cell depletion, ATG/alemtuzumab conditioning) 1
• Whole blood, plasma, and serum are all appropriate specimens 1

Treatment Strategies

Primary EBV Infection (Infectious Mononucleosis)

Antiviral therapy with acyclovir does not ameliorate the course of infectious mononucleosis in otherwise healthy individuals and is not recommended 1, 5

• Supportive care remains the mainstay of treatment 5
• Corticosteroids may be indicated specifically for airway obstruction 1
• A pilot study combining intravenous acyclovir with prednisolone for 10 days showed clinical benefit in fulminant mononucleosis, but this is not standard practice 5

Chronic Active EBV Disease (CAEBV)

Hematopoietic stem cell transplantation is the only curative treatment for severe CAEBV and should be pursued when available 1, 4

• Antiviral agents, immunomodulative therapies (interferon gamma, IL-2, corticosteroids, cyclosporin A, immunoglobulins), and chemotherapeutic drugs have been tried without obvious effect on morbidity and outcome 1
• Autologous EBV-specific cytotoxic T lymphocytes (EBV-CTLs) showed success in 4 of 5 patients without relapse during observation, though availability is limited to selected centers 1
• Allogeneic peripheral blood or bone marrow stem cell transplantation has shown successful results in patients with severe disease 1

EBV-Associated PTLD and Preemptive Therapy

Rituximab 375 mg/m² is the primary method for preemptive therapy in patients with significant EBV DNA-emia without clinical symptoms 1, 4

Preemptive therapy indications:

• Significant EBV DNA-emia without clinical symptoms/disease in high-risk patients for EBV-PTLD 1
• Goal is to achieve negative EBV PCR or EBV DNA-emia below initial threshold without relapse 1
• Rituximab dosing: 375 mg/m² once weekly for 1-4 doses until viral load negativity 1, 4

Critical caveats:

• No universal threshold exists for initiating preemptive therapy; centers use thresholds ranging from 1,000 to 40,000 EBV copies/mL in whole blood, plasma, or serum 1
• The rate of increase in EBV copy number is clinically significant and should guide intervention 1
• Rituximab use should be restricted to highest-risk patients and followed by close monitoring for hypogammaglobulinemia with consideration of immunoglobulin replacement 1

Treatment of established PTLD:

• Reduction of immunosuppression combined with rituximab when possible 4
• Discontinuation of immunosuppressive therapy may result in spontaneous regression in some cases 1, 4
• Antiviral agents have no proven role in established PTLD because latently infected B cells do not express EBV thymidine kinase 1
• Chemotherapy or irradiation is recommended for EBV-associated B-cell lymphomas in immunosuppressed patients 5

Special Populations

Inflammatory Bowel Disease patients:

• EBV IgG screening should be considered before initiating immunomodulator therapy 1
• Anti-TNF monotherapy could be used in preference to thiopurines in EBV seronegative patients 1
• Patients on thiopurines have increased risk of EBV-associated lymphoproliferative disorders 1, 4
• Primary EBV infection during immunosuppressive therapy poses particular risk; temporary discontinuation of immunomodulators during acute infection should be considered 1, 4

Transplant patients:

• For EBV-seronegative recipients, an EBV-seronegative donor is preferred 1
• For EBV-seropositive recipients, an EBV-seropositive donor might be beneficial due to presence of EBV-positive CTLs 1
• HLA-identical family transplant recipients not receiving T-cell depletion and without GvHD have low risk and do not require routine EBV screening 1

Key Clinical Pitfalls

• Do not use antiviral drugs (acyclovir, ganciclovir, foscarnet, cidofovir) for latent EBV infection or PTLD—they are ineffective because latently infected B cells do not express viral thymidine kinase 1
• Do not rely on heterophile antibody tests alone—they miss approximately 15% of infectious mononucleosis cases 1, 2
• Do not diagnose CAEBV based on elevated antibodies and chronic fatigue alone—this requires persistent fever, lymphadenopathy, hepatosplenomegaly for >3 months plus markedly elevated titers 1, 4
• Do not routinely monitor EBV in autologous HSCT or conventional chemotherapy patients—this is not recommended 1
• Proven PTLD cannot be diagnosed without tissue biopsy—EBV DNA-emia alone is insufficient 1