What is Cytomegalovirus (CMV)?

What is Cytomegalovirus (CMV)?

Cytomegalovirus (CMV) is a common herpes virus that establishes lifelong latent infection after primary exposure and causes significant disease primarily in immunocompromised patients, including transplant recipients, HIV-infected individuals, and congenitally infected newborns. 1

Basic Virology and Epidemiology

• CMV is one of eight herpesviruses that commonly infect humans, with a seroprevalence of at least 70% in adults 2
• After primary infection, the virus becomes latent in multiple organs and can reactivate during severe immune system dysregulation 3
• Transmission occurs through contact with virus-containing saliva, urine, sexual fluids, blood transfusion, organ transplantation, or from infected mother to offspring 4
• In the United States, CMV is the most common perinatally transmitted infection, occurring in 0.2%-2.2% of live-born infants 4
• CMV affects 1 in 200 live births in high-income countries and 1 in 71 in low- and middle-income countries, making it a major cause of hearing loss and brain damage 5

High-Risk Populations

The following groups face substantial risk of CMV disease and require heightened clinical vigilance:

• Solid organ transplant recipients, particularly with donor-positive/recipient-negative (D+/R-) serostatus, which represents the highest risk category 4
• Hematopoietic stem cell transplant recipients, with 15-25% incidence of CMV end-organ disease and 50-60% reactivation rates among seropositive recipients 4, 2
• HIV-infected patients, especially those with CD4+ counts <100/µL, though disease can occur at higher counts in infants 4
• Patients on aggressive immunosuppression, including anti-lymphocyte globulin, alemtuzumab, or T-cell depleting therapies 4, 2
• Congenitally infected newborns, with greatest fetal harm following primary maternal infection in early pregnancy 5

Clinical Manifestations

CMV Infection vs. Disease

• CMV active infection is diagnosed by viral culture, detection of intracytoplasmic/intranuclear inclusions, antibody-based staining, nucleic acid assays, or antigenemia studies 4
• CMV disease requires evidence of infection plus attributable symptoms, classified as either CMV syndrome or tissue-invasive disease 4

CMV Syndrome

CMV syndrome presents with one or more of the following 4, 2:

• Fever >38°C for at least 2 days
• New or increased malaise
• Leukopenia
• ≥5% atypical lymphocytes
• Thrombocytopenia
• Elevation of hepatic transaminases (ALT or AST) to 2× upper limit of normal in non-liver transplant recipients

Tissue-Invasive Disease

Gastrointestinal CMV:

• Presents with nonspecific symptoms including diarrhea, rectal bleeding, fever, abdominal pain, and weight loss 2
• Endoscopy reveals ulcerations with well-defined, punched-out appearance in up to 80% of cases 2
• Can progress to colonic perforation in severe cases 2
• Requires histopathological confirmation with "owl eye" inclusions or CMV-specific immunohistochemistry 2

CMV Retinitis:

• Most frequent severe manifestation in HIV-infected children, accounting for approximately 25% of CMV AIDS-defining illnesses 4
• Young children often asymptomatic; older children present with floaters, peripheral vision loss, or reduced central vision 4
• Diagnosis based on clinical appearance with white and yellow retinal infiltrates and associated retinal hemorrhages 4

CMV Pneumonia:

• Interstitial process with gradual onset of shortness of breath and dry, nonproductive cough 4
• Signs and symptoms of pulmonary disease in absence of other documented cause plus CMV detection in blood or bronchoalveolar lavage 4

CMV CNS Disease:

• Manifestations include subacute encephalopathy, myelitis, and polyradiculopathy 4
• CSF may show polymorphonuclear predominance (>50%), elevated protein (75%), and low glucose (30%), though 20% have normal CSF 4

Diagnostic Approach

Key principle: Serology is unhelpful for diagnosing active infection in adults due to high baseline seroprevalence. 2

Screening and Risk Stratification

• Both organ donors and recipients should be screened for CMV by serology to establish risk assessment 4
• D+/R- serostatus represents the greatest risk factor for post-transplant CMV infection 4

Active Infection Diagnosis

• Viral culture from blood buffy-coat or body fluids establishes infection and increases likelihood of disease 4
• Quantitative PCR from blood is the preferred monitoring method, with higher sensitivity than culture 4
• Antigenemia assays (pp65) can identify patients at risk for end-organ disease 4
• Tissue diagnosis requires histopathological confirmation with characteristic inclusions or immunohistochemistry for definitive tissue-invasive disease 4, 2

Monitoring in Transplant Recipients

• Specific laboratory monitoring for CMV should be included in all immunosuppression trials 4
• Duration and frequency should account for the time period when CMV viremia is most likely 4
• Use of standardized molecular quantitative assays across centers is preferable 4

Treatment Principles

Four antiviral drugs are licensed for CMV treatment: ganciclovir, valganciclovir, foscarnet, and cidofovir. 6

Standard Treatment

• Intravenous ganciclovir 5 mg/kg twice daily for 5-10 days, followed by valganciclovir 900 mg daily until completion of 2-3 week course 7
• Symptomatic congenital CMV in newborns: valganciclovir or ganciclovir reduces hearing loss in 5 out of 6 babies and improves long-term brain development outcomes 5

Resistance Management

• Foscarnet is the treatment of choice for ganciclovir-resistant CMV 7
• Strict monitoring of renal function and bivalent electrolytes required with foscarnet 7
• Concomitant normal saline administration may reduce irreversible renal damage risk 7

Prevention Strategies

• Letermovir prophylaxis (480 mg/day or 240 mg/day with cyclosporine) for 14 weeks post-transplant reduces clinically significant CMV infection (38% vs 61% placebo) in allogeneic HCT recipients 4
• Valaciclovir started after primary CMV infection in first 12 weeks of pregnancy reduces risk of fetal infection 5
• Universal prophylaxis or pre-emptive therapy strategies should be established before clinical trials begin 4

Critical Pitfalls

• Do not rely on serology alone in adults to diagnose active infection due to high background seroprevalence 2
• Ganciclovir side effects (neutropenia, thrombocytopenia) can mimic systemic CMV infection manifestations, complicating management 7
• Immunosuppression tapering is essential for recurrent infection, as corticosteroids and azathioprine are independent predictive factors for CMV reactivation 7
• Rapid emergence of resistant mutants can occur with letermovir if treatment is interrupted, underdosed, or in patients with other risk factors 4
• CD4+ count is less predictive of CMV disease risk in young infants compared to older children and adults 4