Epstein-Barr Virus (EBV)
Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is an enveloped double-stranded DNA virus of the Herpesviridae family. It spreads mainly through saliva (hence "the kissing disease") and targets two main cell populations: the epithelial cells of the nasopharynx and B lymphocytes. After the acute infection, the virus establishes lifelong latent infection in memory B cells.
Although EBV is best known for infectious mononucleosis (IM), its effects on the skin and mucosa are remarkably varied, ranging from a distinctive drug-related immune rash and acute childhood eruptions to chronic epithelial proliferations and malignant lymphomas in immunocompromised patients. At Haute-Derma, our approach to EBV-related skin disease combines the clinical picture in the skin and mucosa with serology and biopsy using EBER in situ hybridization.
Pathogenesis and B-Cell/Epithelial Tropism
Entry Receptors and the Two Phases of Infection
- Attachment and entry: The EBV glycoprotein gp350/220 binds specifically to the CD21 (CR2) receptor on B cells. In epithelial cells, the virus uses gH/gL/gp42 to bind HLA class II and integrins (αvβ6, αvβ8).
- Lytic phase: The virus replicates heavily in nasopharyngeal epithelium and B cells, lysing them and releasing virus particles into saliva and blood.
- Latent phase: The viral DNA circularizes into an episome in the B-cell nucleus and expresses latent membrane proteins (LMP-1, LMP-2) and noncoding RNAs (EBER1, EBER2). These immortalize the B cell and help it evade immune destruction.
The CD8+ T-Cell Response and Atypical Lymphocytes
- To control the expansion of EBV-infected B cells, the body mounts an intense CD8+ T-cell response.
- On a peripheral blood smear, these activated CD8+ T cells are large, with irregular nuclei and basophilic cytoplasm that wraps around neighboring red cells. They are called atypical lymphocytes (Downey cells).
Skin and Mucosal Manifestations
Infectious Mononucleosis (IM):
- Classic triad: High fever, exudative pharyngitis or swollen tonsils, and enlarged posterior cervical or generalized lymph nodes.
- Ampicillin/amoxicillin-induced rash:
- Occurs in 80%–100% of IM patients who are given an aminopenicillin (ampicillin, amoxicillin).
- Mechanism: This is not a true IgE allergy. EBV overstimulates T-cell immunity, causing a temporary hypersensitivity to the drug.
- Appearance: An extensive, deep red morbilliform maculopapular rash over the whole body, appearing 7–10 days after starting the drug. It is very itchy and fades on its own once the drug is stopped, without blistering or severe peeling.
Oral Hairy Leukoplakia (OHL):
- A specific lesion caused by lytic EBV replication in the spinous cells of the tongue epithelium, typically seen in people with HIV/AIDS (CD4 < 200) or on immunosuppressive drugs.
- Appearance: Raised white plaques with vertical, thread-like folds (hairy appearance), concentrated on the lateral borders of the tongue (on one or both sides).
- Key feature: Cannot be scraped off (unlike oral Candida infection).
Gianotti-Crosti Syndrome (Infantile Papular Acrodermatitis):
- An acute immune skin reaction to EBV (and some other viruses) in children aged 6 months to 12 years.
- Appearance: Firm pink-red or purplish papules 1–10 mm across, symmetrically distributed on the face, buttocks, forearms and lower legs (acral distribution), sparing the trunk.
EBV-Associated Cutaneous Lymphoproliferative Disorders:
- Hydroa vacciniforme-like lymphoma (HVLL): A rare T/NK-cell lymphoma that begins as sun-sensitive lesions (blisters that break, form necrotic crusts and leave pox-like scars on the face and hands).
- B/T-cell proliferations in immunocompromised patients: Deeply ulcerated, necrotic plaques or nodules arising when EBV-immortalized B cells develop into benign or malignant lymphoma (DLBCL).
Differential Diagnosis of EBV-Related Mucosal Lesions and Rashes
| Oral Hairy Leukoplakia | Oral Candidiasis | Oral Lichen Planus |
|---|---|---|
| Lateral tongue (one or both sides) | Buccal mucosa, palate, dorsal tongue | Both buccal mucosae, lateral tongue |
| CANNOT BE SCRAPED OFF | SCRAPES OFF EASILY, leaving red mucosa | CANNOT BE SCRAPED OFF |
| White plaques with vertical, hair-like folds | Curd-like white pseudomembranes | Lacy white network (Wickham striae) |
| EBV replication in epithelial spinous cells | Yeast (Candida albicans) | T-cell-mediated autoimmune disease |
Our Diagnostic Process at Haute-Derma
Clinical History and Peripheral Blood Smear:
- We look for the mononucleosis triad and any recent aminopenicillin use.
- Peripheral blood smear: Identifies atypical lymphocytes (Downey cells > 10% of white cells).
Serology:
- Heterophile antibody test (Monospot / Paul-Bunnell test): Detects heterophile antibodies in the blood (sensitivity > 85% in adults, but may be negative in children under 4).
- EBV-specific antibody panel:
- VCA-IgM (viral capsid antigen IgM): Positive from the acute stage and disappears after 4–8 weeks (confirms acute infection).
- VCA-IgG: Appears early and persists for life.
- EBNA-1 IgG (EBV nuclear antigen 1): Appears only late, 3–4 months after the acute infection. Its presence helps rule out a recent primary infection.
Biopsy and Molecular Testing:
- Skin or mucosal biopsy: Indicated when oral hairy leukoplakia (OHL) or lymphoma is suspected.
- EBER in situ hybridization (EBV-encoded RNA): Detects EBV's small EBER1/2 RNAs in the nuclei of the affected cells.
Management and Treatment Protocol at Haute-Derma
Managing Infectious Mononucleosis (IM) and Amoxicillin Rash
- Supportive care: Rest, and stop aminopenicillins (amoxicillin, ampicillin) immediately. The rash clears on its own in 1–2 weeks without lasting effects.
- Fever and sore throat: Acetaminophen (paracetamol) or ibuprofen. Aspirin must not be used in children.
- CRITICAL ACTIVITY RESTRICTION: Patients with IM must avoid contact sports and strenuous exercise for at least 3–4 weeks because of the risk of acute splenic rupture and life-threatening internal bleeding.
Treating Oral Hairy Leukoplakia (OHL)
- Oral antivirals (when lesions are bothersome or a cosmetic concern):
- Valacyclovir: 1000 mg 3 times daily for 14 days.
- Acyclovir: 800 mg 5 times daily for 14 days.
- Note: OHL plaques respond and clear quickly but often return after treatment stops if the underlying immunosuppression is not improved.
- Topical treatment: Podophyllin resin 25% solution or topical retinoic acid flattens lesions quickly.
- Optimizing immune function: Patients with HIV are referred to infectious disease specialists to optimize their antiretroviral (ARV) therapy.
