Human Cytomegalovirus (CMV)
Human cytomegalovirus (CMV), also called human herpesvirus 5 (HHV-5), is a double-stranded DNA virus in the subfamily Betaherpesvirinae. It spreads through body fluids (saliva, urine, blood, semen, vaginal secretions, breast milk) and across the placenta. Unlike Epstein-Barr virus, which mainly targets B cells, or herpes simplex virus, which mainly targets nerve cells, CMV can infect a wide range of cells: dermal endothelial cells, monocytes/macrophages, epithelial cells and fibroblasts.
After the acute infection, CMV establishes lifelong latency in myeloid progenitor cells in the bone marrow and in circulating CD14+ monocytes. In people with a healthy immune system, CMV infection is usually silent. In those with severe immunosuppression, however (HIV/AIDS with a CD4 count below 50 cells/µL, organ transplant recipients, or patients on high-dose immunosuppressants), the virus reactivates, causing serious organ damage and deep, necrotic skin lesions that can be life-threatening.
Pathogenesis and Destruction of Skin Microvessels
Entry Receptors and Reactivation in Endothelial Cells
- Cell entry: CMV uses its envelope glycoprotein complexes (gB, gH/gL/gO and the gH/gL/UL128/UL130/UL131A pentamer) to bind PDGFR-α, EGFR and integrin αvβ3 receptors on endothelial cells and white blood cells.
- Reactivation and microvascular necrosis: when T-cell immunity is severely impaired, latent virus in monocytes reactivates and replicates explosively within the endothelial cells of skin blood vessels.
- How necrotic skin ulcers form (cytopathic and ischemic effects):
- The virus enlarges endothelial cells, distorts their nuclei and destroys them directly (cytolysis).
- Endothelial necrosis activates clotting and blocks dermal microvessels (microvascular thrombosis), causing ischemia, necrosis of the epidermis and dermis, and deep ulcers with a weeping, necrotic base.
Hypersensitivity Reactions and Skin Rash
In people with normal immunity, a CD8+ T-cell response against CMV antigens in the skin can produce a measles-like (morbilliform) rash, which can be especially florid if the patient is given a beta-lactam antibiotic, much as happens with EBV.
Cutaneous and Systemic Clinical Forms
CMV Infection in Immunocompetent Hosts:
- CMV mononucleosis: prolonged fever, fatigue, muscle aches and mild swelling of the neck nodes. Unlike EBV, CMV rarely causes exudative pharyngitis, and the Monospot (heterophile antibody) test is negative.
- Rash after ampicillin/amoxicillin: a widespread, deep red maculopapular rash appearing 7–10 days after starting a beta-lactam antibiotic.
CMV Skin Disease in Immunocompromised Hosts
Skin involvement is highly varied and severe:
- Necrotic perianal and anogenital ulcers: the classic presentation. Red papules or blisters quickly turn into deep, punched-out, well-demarcated ulcers with a gray-black necrotic pseudomembrane, and they are very painful.
- Necrotic purpura and bullae: scattered purpuric papules or blood-filled blisters on the limbs and trunk, caused by necrotizing vasculitis in the dermis.
- Accompanying multi-organ disease: often alongside CMV retinitis (which can cause blindness), ulcerative bleeding esophagitis or colitis, and interstitial pneumonitis.
Congenital CMV Infection: transmitted from mother to fetus across the placenta during the mother's acute infection.
- "Blueberry muffin" rash: scattered dark reddish-purple macules and papules over the body, caused by blood cell production in the dermis (extramedullary dermal hematopoiesis).
- Systemic abnormalities: microcephaly, sensorineural hearing loss (the leading cause of non-genetic congenital deafness), periventricular calcifications, enlarged liver and spleen, and low platelets.
Differential Diagnosis of Skin Ulcers in Immunocompromised Patients
| CMV Ulcer (Cytomegalovirus) | HSV Ulcer (Herpes Simplex) | Recurrent Syphilitic Chancre (Syphilis) |
|---|---|---|
| Perianal, genital, thighs, skin folds | Around the mouth, lips, genitals, perianal area | Genitals, anus, oral cavity |
| Deep, punched-out ulcer with necrotic pseudomembrane, very painful | Clustered blisters that break into shallow ulcers with scalloped edges, painful | Shallow ulcer, clean base, firm raised edge, PAINLESS |
| Enlarged cells with "owl's eye" intranuclear inclusions | Multinucleated giant cells, ballooning degeneration | Plasma cell infiltrate, endarteritis |
| CMV IHC (+), CMV DNA real-time PCR (+) | Tzanck smear (+), HSV-1/2 PCR (+) | Dark-field microscopy, RPR / TP-PA (+) |
Diagnostic Workup at Haute-Derma
Clinical Assessment and Underlying Immune Status:
- Identifying chronic, progressively necrotic perianal or genital ulcers in patients with HIV (CD4 < 50 cells/µL) or organ transplants.
- Ophthalmology review (fundoscopy) to rule out coexisting CMV retinitis.
Biopsy of the Ulcer Edge:
- Sampling: the biopsy must include both the edge and the base of the ulcer, where dermal microvessels are most abundant.
- Classic microscopic findings:
- Markedly enlarged endothelial and epithelial cells (cytomegaly, 2–4 times normal size).
- "Owl's eye" intranuclear inclusions: a deep red eosinophilic inclusion inside the nucleus, separated from the nuclear membrane by a clear halo.
Immunohistochemistry (IHC) and PCR:
- IHC with monoclonal anti-CMV antibodies (anti-CMV IEA/EA): confirms CMV antigen in tissue cells even when clear owl's eye inclusions are not seen.
- Quantitative real-time CMV DNA PCR: measures the viral load in ulcer swabs and blood to track disease progression and response to treatment.
Management and Treatment at Haute-Derma
Systemic Antiviral Therapy
- Induction phase (14–21 days):
- Ganciclovir (IV): 5 mg/kg every 12 hours. First choice for severe ulceration or when internal organs are involved.
- Valganciclovir (oral): 900 mg twice daily with food. Used for mild to moderate disease in patients who can take oral medication.
- Maintenance phase (secondary prophylaxis):
- Valganciclovir (oral): 900 mg once daily, continued until antiretroviral therapy has kept the CD4 count above 100–150 cells/µL for more than 6 months.
- Managing resistance (ganciclovir resistance from UL97 / UL54 mutations): switch to foscarnet (60 mg/kg IV every 8 hours) or cidofovir (5 mg/kg IV weekly).
Local Ulcer Care and Immune Recovery
- Clean the ulcer daily with 0.2% chlorhexidine or dilute povidone-iodine.
- Apply biologic dressings or moisture-retaining hydrocolloid dressings to promote granulation. Add an antibiotic ointment if there is secondary bacterial infection.
- Optimize antiretroviral therapy to raise CD4 counts in HIV, or reduce immunosuppressant doses in transplant recipients.
