Cytomegalovirus (CMV)
Summary
Cytomegalovirus (CMV), also known as Human Herpesvirus 5 (HHV-5), is a ubiquitous herpesvirus that establishes lifelong latent infection after primary exposure. Most immunocompetent individuals are infected asymptomatically or with a mild mononucleosis-like illness. However, CMV causes severe disease in immunocompromised patients: CMV Retinitis (Blindness in AIDS, CD4 less than 50), CMV Colitis, CMV Pneumonitis (Transplant recipients), and CMV Encephalitis. Congenital CMV is the leading infectious cause of congenital deafness and neurodevelopmental disability worldwide. Diagnosis is by CMV PCR (Blood/Tissue) or Histopathology (Owl's Eye inclusions). Treatment is with Ganciclovir (IV) or Valganciclovir (Oral); Foscarnet or Cidofovir are second-line. Prevention in transplant includes CMV prophylaxis or pre-emptive monitoring. [1,2]
Clinical Pearls
"Monospot-Negative Mono": Primary CMV in immunocompetent adults presents like Glandular Fever (EBV) but with Negative Monospot (Heterophile antibody test).
CMV Retinitis = CD4 less than 50: In HIV/AIDS, CMV retinitis occurs at very low CD4 counts. "Pizza Pie" or "Cottage Cheese and Ketchup" fundus appearance.
Congenital CMV = Commonest Congenital Infection: Leading infectious cause of sensorineural hearing loss. Screen neonates with symptoms.
Transplant CMV: Major cause of morbidity. D+/R- (Donor positive, Recipient negative) highest risk. Prophylaxis or Pre-emptive strategy.
Prevalence
- Highly Prevalent: 50-80% of adults seropositive by age 40 (Higher in developing countries).
- Transmission: Saliva, Urine, Sexual contact, Blood transfusion, Organ transplant, Vertical (Congenital).
At-Risk Groups
| Group | Risk |
|---|---|
| Immunocompetent | Asymptomatic or Mild mononucleosis. Self-limiting. |
| HIV/AIDS (CD4 less than 50) | CMV Retinitis, Colitis, Encephalitis. Opportunistic infection. |
| Solid Organ Transplant (SOT) | CMV Syndrome, Tissue-Invasive Disease. D+/R- highest risk. |
| Haematopoietic Stem Cell Transplant (HSCT) | CMV Pneumonitis (High mortality). |
| Congenital (In Utero) | Primary maternal infection during pregnancy → Congenital CMV. |
| Neonates (Perinatal) | Breast milk transmission. Usually asymptomatic in term infants. |
Virology
- CMV = Human Herpesvirus 5 (HHV-5).
- Latency: After primary infection, establishes lifelong latency in myeloid progenitor cells (Monocytes).
- Reactivation: When immune control is lost (Immunosuppression, HIV, Transplant).
Mechanism of Disease
- Primary Infection: Usually asymptomatic or mild mononucleosis in immunocompetent.
- Latency Establishment: Virus persists in myeloid cells.
- Reactivation (Immunosuppression): Virus replicates, causes end-organ disease.
- Tissue Tropism: Retina, GI tract, Lung, Liver, CNS.
- Histopathology: Owl's Eye Inclusions (Large cells with intranuclear inclusions). Pathognomonic.
Immunocompetent Host
| Presentation | Notes |
|---|---|
| Asymptomatic | Most common. |
| CMV Mononucleosis | Fever, Fatigue, Lymphadenopathy, Hepatosplenomegaly. Monospot Negative (Unlike EBV). Atypical Lymphocytes on blood film. Self-limiting. |
Immunocompromised Host (HIV, Transplant)
| Syndrome | Clinical Features | Notes |
|---|---|---|
| CMV Retinitis | Floaters, Visual field defects, Blindness. "Pizza Pie" / "Cottage Cheese & Ketchup" fundus (Haemorrhages + Exudates). | CD4 less than 50 in HIV. Ophthalmology emergency. |
| CMV Colitis | Diarrhoea (May be bloody), Abdominal pain, Fever. Colonic ulceration. | Biopsy shows Owl's Eye inclusions. |
| CMV Oesophagitis | Odynophagia, Dysphagia. Large shallow ulcers. | Differentiate from Candida (White plaques) and HSV (Small ulcers). |
| CMV Pneumonitis | Cough, Dyspnoea, Hypoxia. Interstitial infiltrates. | High mortality in HSCT. |
| CMV Encephalitis | Confusion, Altered consciousness, Seizures. | Rare. PCR on CSF. |
| CMV Syndrome (Post-Transplant) | Fever, Malaise, Leucopenia, Thrombocytopenia. No specific organ involvement. | Common after SOT. |
Congenital CMV
| Feature | Notes |
|---|---|
| Asymptomatic (~90%) | May still develop late sequelae (Hearing loss). |
| Symptomatic (~10%) | IUGR, Microcephaly, Periventricular Calcifications (Imaging), Hepatosplenomegaly, Jaundice, Thrombocytopenia (Petechiae/Purpura – "Blueberry Muffin" rash), Chorioretinitis. |
| Late Sequelae | Sensorineural Hearing Loss (Leading cause of non-genetic congenital deafness – ~20% of asymptomatic, ~50% of symptomatic). Developmental delay. |
Diagnosis
| Test | Use | Notes |
|---|---|---|
| CMV DNA PCR (Blood/Plasma) | Detect viraemia. Quantitative. Monitor treatment. | Gold standard for transplant monitoring. |
| CMV IgG / IgM Serology | Determine serostatus (Prior exposure). Primary infection (IgM positive + IgG seroconversion). | Limited use in immunocompromised (Antibody production impaired). |
| CMV PCR (CSF) | CMV Encephalitis. | |
| Tissue Biopsy + Histopathology | CMV Colitis, Pneumonitis. | Owl's Eye Inclusions (Large intranuclear + Cytoplasmic inclusions in enlarged cells). Immunohistochemistry. |
| Fundoscopy | CMV Retinitis. | Ophthalmology referral. Characteristic appearance. |
Congenital CMV
| Test | Use |
|---|---|
| Urine CMV PCR (Within first 3 weeks of life) | Gold standard for diagnosis of Congenital CMV. Saliva CMV PCR also used. |
| Cranial Imaging (USS/MRI) | Periventricular calcifications, Microcephaly. |
| Hearing Assessment (ABR) | Screen for SNHL. |
Transplant Monitoring
- CMV PCR Viral Load: Monitored regularly post-transplant (Weekly).
- Pre-Emptive Strategy: Initiate treatment if viraemia rises above threshold.
Management Algorithm
CMV INFECTION IDENTIFIED
(PCR Positive / Tissue-Invasive Disease / Retinitis)
↓
ASSESS IMMUNE STATUS & SYNDROME
┌────────────────┴────────────────┐
IMMUNOCOMPETENT IMMUNOCOMPROMISED
↓ (HIV, Transplant)
USUALLY SELF-LIMITING ↓
Supportive Care Only TREAT CMV DISEASE
Treatment of CMV Disease
| Agent | Route | Dose | Notes |
|---|---|---|---|
| Ganciclovir | IV | 5mg/kg BD x 14-21 days (Induction), then 5mg/kg OD (Maintenance) | First-line for serious CMV disease. |
| Valganciclovir | Oral | 900mg BD x 21 days (Induction), then 900mg OD (Maintenance) | Oral prodrug of Ganciclovir. Used for less severe disease or as step-down. |
| Foscarnet | IV | 60mg/kg TDS or 90mg/kg BD | Second-line. Ganciclovir-resistant CMV. Renal dose adjustment essential. |
| Cidofovir | IV | 5mg/kg weekly x 2 weeks, then 5mg/kg every 2 weeks | Third-line. Nephrotoxic. Must give with Probenecid + IV fluids. |
Key Side Effects
| Agent | Major Side Effects |
|---|---|
| Ganciclovir / Valganciclovir | Bone Marrow Suppression (Neutropenia, Thrombocytopenia, Anaemia). Monitor FBC. |
| Foscarnet | Nephrotoxicity, Electrolyte abnormalities (Hypocalcaemia, Hypomagnesaemia). |
| Cidofovir | Nephrotoxicity (Dose-limiting). |
Duration of Treatment
- CMV Retinitis (AIDS): Induction x 14-21 days, then Maintenance until Immune Reconstitution (CD4 >100 for 3-6 months on ART).
- CMV Colitis/Pneumonitis: 14-21 days (May be longer if severe).
CMV in HIV/AIDS
- Immune Reconstitution: Start/Optimise ART. Primary goal is to raise CD4.
- CMV Retinitis: Urgent Ophthalmology. Treat with Ganciclovir/Valganciclovir.
CMV Prevention in Transplant
| Strategy | Description |
|---|---|
| Prophylaxis | Give Valganciclovir to all at-risk patients (D+/R-, etc.) for 3-6 months post-transplant. |
| Pre-Emptive Therapy | Monitor CMV PCR weekly. Treat if viraemia rises above threshold. |
Congenital CMV Treatment
- Symptomatic Congenital CMV: Valganciclovir 6 months (Improves hearing outcomes). Start within first month of life.
| Complication | Notes |
|---|---|
| Blindness (Retinitis) | Permanent if untreated. |
| Colonic Perforation (Colitis) | Severe ulcerative disease. |
| Respiratory Failure (Pneumonitis) | High mortality in HSCT. |
| Sensorineural Hearing Loss (Congenital) | Progressive. Leading infectious cause of congenital deafness. |
| Neurodevelopmental Delay (Congenital) | Microcephaly, Cerebral Palsy. |
- Immunocompetent: Excellent. Self-limiting.
- Immunocompromised: Dependent on immune reconstitution / Transplant function. CMV Retinitis can be controlled with treatment and ART.
- Congenital CMV: Symptomatic infants have ~50% risk of significant sequelae. Asymptomatic infants have ~10-15% risk of late-onset hearing loss.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| BHIVA Guidelines: CMV in HIV | BHIVA | ART + Ganciclovir/Valganciclovir for Retinitis. Maintenance until immune reconstitution. |
| Transplant Society Guidance | International | Prophylaxis or Pre-emptive monitoring. D+/R- highest risk. |
| AAP / CDC Congenital CMV | AAP/CDC | Valganciclovir for symptomatic congenital CMV. Universal screening debated. |
What is CMV?
CMV (Cytomegalovirus) is a very common virus that most people catch at some point in their lives. In healthy people, it usually causes no symptoms or a mild flu-like illness. Once you've had it, the virus stays in your body for life but doesn't usually cause problems.
When is CMV a problem?
It becomes serious in people with weak immune systems (e.g., HIV/AIDS, organ transplant recipients), where it can cause eye problems (CMV Retinitis, which can cause blindness), gut problems (diarrhoea, bleeding), and lung problems.
It is also important in pregnancy – if a mother is infected for the first time during pregnancy, the baby can be affected (Congenital CMV), which can cause hearing loss and developmental problems.
How is it treated?
Antiviral medications (Ganciclovir or Valganciclovir) are used to treat CMV in people with weakened immune systems. These can have side effects on blood counts, so regular monitoring is needed.
Primary Sources
- Griffiths P, et al. The pathogenesis of human cytomegalovirus. J Pathol. 2015;235(2):288-297. PMID: 25205268.
- BHIVA Guidelines on Opportunistic Infections in HIV: CMV. 2021.
Common Exam Questions
- CMV Retinitis CD4 Count: "At what CD4 count does CMV Retinitis typically occur?"
- Answer: CD4 less than 50 cells/μL.
- Histopathology Finding: "What is the pathognomonic histopathological finding in CMV infection?"
- Answer: Owl's Eye Inclusions – Large cells with intranuclear and cytoplasmic inclusions.
- Monospot-Negative Mono: "A patient presents with a mononucleosis-like illness but Monospot is negative. What is the likely cause?"
- Answer: CMV (Primary Cytomegalovirus infection).
- Congenital CMV Sequelae: "What is the leading infectious cause of congenital sensorineural hearing loss?"
- Answer: Congenital CMV.
Viva Points
- Ganciclovir Side Effect: Bone marrow suppression (Neutropenia).
- Transplant CMV Risk: D+/R- (Donor CMV positive, Recipient negative) is highest risk.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.