What is Cytomegalovirus (CMV)?

What is Cytomegalovirus (CMV)?

Cytomegalovirus (CMV) is a double-stranded DNA herpesvirus that commonly infects humans and typically remains latent after primary infection, but can reactivate to cause severe, life-threatening disease in immunocompromised patients, particularly transplant recipients, patients with advanced HIV/AIDS, and congenitally infected newborns. 1

Epidemiology and Transmission

• CMV is highly prevalent globally, with 50-80% of women of childbearing age in the United States being seropositive, and approximately 90% of HIV-infected pregnant women having CMV coinfection 1
• Transmission occurs through contact with virus-containing saliva, urine, or sexual fluids; through blood transfusion or organ transplantation; or from mother to fetus during pregnancy 1
• Congenital CMV infection affects 1 in 200 live births in high-income countries and 1 in 71 in low- and middle-income countries, making it the most common cause of viral infection in newborns 2
• The most common source of infection to pregnant women is saliva and urine from young children 2

Clinical Manifestations by Population

Immunocompromised Adults

CMV disease occurs almost exclusively in severely immunocompromised patients with CD4+ counts <50 cells/µL or those receiving intensive immunosuppressive therapy. 1

• Retinitis is the most common manifestation, presenting as unilateral disease in two-thirds of patients initially, with characteristic fluffy yellow-white retinal infiltrates and intraretinal hemorrhage 1
• Colitis is the most common manifestation of CMV end-organ disease outside of retinitis 1
• Other manifestations include pneumonitis, hepatitis, esophagitis, encephalitis, and polyradiculopathy 1

Transplant Recipients

• CMV infections most frequently occur in allogeneic hematopoietic cell transplant (HCT) recipients, particularly during the early post-engraftment phase 1
• Among CMV-seropositive patients undergoing allogeneic HCT, the incidence of CMV reactivation ranges from 50-60%, with CMV disease developing in 10-30% even with prophylaxis or pre-emptive therapy 1
• The highest risk occurs in donor-positive/recipient-negative (D+/R-) transplant scenarios 1

Congenitally Infected Infants

• Approximately 1 in 8 babies born with CMV infection will have clinically detectable signs at birth, including jaundice, rash, enlarged liver or spleen, microcephaly, or being small for gestational age 2
• CMV is a major cause of hearing loss and brain damage in newborns 2
• The risk of fetal harm is greatest following primary maternal CMV infection in early pregnancy, and appears very low after 12 weeks gestation 2

Immunocompetent Adults

• CMV infection in healthy adults is usually asymptomatic or causes a mild mononucleosis-like syndrome 3
• However, severe CMV disease in immunocompetent adults appears more common than previously recognized, possibly due to immune dysfunction from comorbidities like kidney disease or diabetes 3

Diagnosis

CMV disease is defined by evidence of CMV infection with attributable symptoms, and can be subclassified into CMV viral syndrome or tissue-invasive disease. 1

Diagnostic Methods

• Histopathology with immunohistochemistry (IHC) is the gold standard for tissue-invasive disease, showing cytomegalic cells with large eosinophilic "owl's eye" inclusions (specificity 92-100%, sensitivity with IHC 78-93%) 1
• Quantitative PCR from blood or tissue can detect CMV DNA and is more sensitive than culture, useful for identifying high-risk patients and monitoring treatment response 1
• pp65 antigenemia assay detects viral antigen directly in blood leukocytes 1
• Viral culture from blood buffy coat, urine, or body fluids establishes infection but takes longer than molecular methods 1

Key Diagnostic Considerations

• A positive CMV antibody in infants <12 months indicates maternal infection, not necessarily infant infection 1
• CMV DNA detection in CSF by PCR is highly sensitive for CMV CNS disease 1
• Blood cultures will be negative in >50% of severe sepsis cases even when infection is present, so clinical judgment is essential 1

Treatment Approaches

Prophylaxis in High-Risk Populations

Letermovir 480 mg/day orally or IV (or 240 mg/day with concurrent cyclosporine) for 14 weeks post-transplant is the preferred prophylaxis for CMV-seropositive allogeneic HCT recipients, reducing clinically significant CMV infection from 61% to 38%. 1

• Valganciclovir and ganciclovir are alternatives for prophylaxis but have greater hematologic toxicity 1
• Rapid emergence of resistant mutants can occur with letermovir if treatment is interrupted, underdosed, or in patients with other risk factors 1

Treatment of Active Disease

Valganciclovir and ganciclovir are first-line agents for pre-emptive therapy and treatment of CMV disease. 1

• Standard regimen: Intravenous ganciclovir 5 mg/kg twice daily for 3-10 days, followed by oral valganciclovir 900 mg twice daily for 2-3 weeks total duration 1, 4
• Foscarnet is used for ganciclovir-resistant CMV or in patients who cannot tolerate ganciclovir, but requires strict monitoring of renal function and electrolytes with concurrent normal saline administration 1, 4
• Cidofovir is another alternative but has significant nephrotoxicity 5

Special Populations

• Pregnant women with primary CMV infection in first 12 weeks: Valaciclovir reduces risk of fetal transmission 2
• Symptomatic newborns: Valganciclovir or ganciclovir treatment reduces hearing loss in 5 out of 6 babies and improves long-term neurodevelopmental outcomes 2
• CMV colitis in inflammatory bowel disease: Consider tapering steroids as they are a significant risk factor for CMV reactivation; immunosuppressive therapy may often be continued while treating CMV infection 4

Management of Recurrent or Resistant CMV

Foscarnet is the treatment of choice for ganciclovir-resistant CMV infection. 4

• Recurrent CMV infections are commonly associated with immunosuppressive therapy, particularly corticosteroids and azathioprine 4
• High levels of foscarnet are excreted in urine and may cause genital ulceration; careful hygiene is essential 4
• In severe disseminated CMV infection, discontinuation of immunosuppressive therapy is recommended 4

Common Pitfalls and Caveats

• Do not confuse CMV infection with CMV disease: Detection of CMV DNA or positive cultures indicates infection but not necessarily disease requiring treatment 1
• Ganciclovir side effects (neutropenia, thrombocytopenia) can mimic systemic CMV infection manifestations, complicating management 4
• CMV disease can mimic numerous other diagnoses, leading to delayed diagnosis and adverse outcomes, especially in immunocompetent adults where suspicion may be lower 3
• All infants with CMV infection at birth require follow-up for at least 2 years to monitor hearing and neurodevelopment, even if asymptomatic at birth 2
• Regular ophthalmologic follow-up is essential for patients with CMV retinitis, as relapse can occur even with CD4+ counts as high as 1,250 cells/µL 1