What is cytomegalovirus (CMV)?

What is Cytomegalovirus (CMV)?

Cytomegalovirus (CMV) is a widely prevalent herpes virus that establishes lifelong chronic infection in humans and causes significant disease primarily in immunocompromised patients, including transplant recipients, those on immunosuppressive therapy, HIV-infected individuals, and congenitally infected newborns. 1, 2

Viral Characteristics and Epidemiology

• CMV is the largest of the eight herpesviruses that commonly infect humans and is a double-stranded DNA virus 2, 3
• It is the most common congenital viral infection, affecting 1 in 200 live births in high-income countries and 1 in 71 in low- and middle-income countries 4
• Among adults, 50-80% of women of childbearing age are CMV-seropositive, with higher prevalence (approximately 90%) in HIV-infected populations 1
• Over 90% of the normal adult population has IgG antibodies to CMV, indicating past exposure 5

Transmission Routes

CMV spreads through multiple routes: 1, 4

• Vertical transmission: From infected mother to fetus during pregnancy (30-40% transmission rate with primary maternal infection, 0.15-1.0% with recurrent infection)
• Perinatal transmission: Through exposure to infected cervical secretions during delivery or through breast milk (up to 53% of breastfed infants whose mothers shed virus become infected)
• Horizontal transmission: Through contact with virus-containing saliva, urine, or sexual fluids
• Iatrogenic transmission: Through transfusion of infected blood or transplantation of infected organs

Clinical Manifestations by Population

In Immunocompetent Hosts

• Most infections are asymptomatic or cause mild, self-limited illness 2, 6
• CMV IgG antibodies persist for life after initial infection, indicating immunity 5

In Immunocompromised Patients

CMV causes serious disease with both direct and indirect effects: 1

• CMV syndrome: Fever >38°C for ≥2 days, malaise, leukopenia, thrombocytopenia, atypical lymphocytosis, elevated liver enzymes
• Tissue-invasive disease: Pneumonitis, gastrointestinal disease (colitis, hepatitis), retinitis, encephalitis, nephritis
• Risk is highest in transplant recipients, particularly donor-positive/recipient-negative (D+/R-) serostatus 1

In Patients with Chronic Lymphocytic Leukemia (CLL)

• Despite T-cell exhaustion in CLL, CMV reactivation is uncommon in untreated patients because CMV-specific CD8+ T cells maintain intact functionality 1
• With BTK inhibitors like ibrutinib, 30% develop transient CMV reactivation (typically self-limited blips), but clinically significant disease and end-organ involvement remain rare 1
• CMV seropositivity does not influence overall survival in CLL patients 1

In Inflammatory Bowel Disease (IBD)

• CMV is present in 10-30% of patients with steroid-refractory IBD and associates with poor outcomes including recurrent flares, toxic megacolon, and need for surgery 1
• Purine analogues are an independent risk factor for CMV reactivation 1
• Diagnosis requires gastrointestinal tissue immunohistochemistry or PCR, not serum testing, as serum antigen and PCR do not correlate with colonic infection 1

In Congenital Infection

• CMV is the most common cause of viral infection in newborns and a major cause of sensorineural hearing loss and brain damage 4, 3
• Risk of fetal harm is greatest with primary maternal infection in early pregnancy (especially first 12 weeks) 4
• Only 1 in 8 infected newborns have clinically detectable signs at birth (jaundice, rash, hepatosplenomegaly, microcephaly, small for gestational age), but all require follow-up for at least 2 years to monitor hearing and neurodevelopment 4

Diagnostic Approach

The diagnostic strategy differs fundamentally between immunocompetent and immunocompromised patients: 5, 7

For Immunocompetent Patients

• CMV IgM and IgG antibodies are first-line tests 5
• Positive IgG alone indicates past exposure and immunity, not active infection 5
• Positive IgM suggests recent/acute infection, but false-positives occur with EBV infection and other immune activation 5

For Immunocompromised Patients

• CMV DNA quantitative PCR (viral load) from blood is the preferred test, not serology 5, 7
• Serology is unreliable because IgM may be absent despite active infection 5
• For suspected end-organ disease, obtain CMV DNA PCR or immunohistochemistry from the affected tissue (CSF for CNS disease, respiratory specimens for pneumonitis, colon biopsy for colitis) 5, 7

Gold Standards by Clinical Context

• CMV colitis/end-organ disease: Immunohistochemistry on tissue biopsy (78-93% sensitivity, 92-100% specificity) 5, 7
• Transplant monitoring: pp65 antigenemia or plasma PCR 5
• Congenital CMV: Real-time PCR on urine or saliva within first 21 days of life (100% sensitivity) 5, 4

Critical Diagnostic Pitfalls to Avoid

• Never rely on serology alone in immunocompromised patients—viral load testing or tissue diagnosis is essential 5, 7
• Never assume positive tissue PCR alone confirms CMV disease—correlation with histology/immunohistochemistry and blood PCR is necessary to distinguish true disease from colonization 5
• Never use CMV detection in peripheral blood to diagnose CMV enteritis—it may be negative even with active colonic disease 7
• Never assume negative IgM rules out CMV in pregnancy—fetal infection can occur with maternal reactivation or reinfection 5

Clinical Significance in Transplantation

• CMV infection remains a significant cause of morbidity and mortality in transplant recipients with both direct effects (end-organ disease) and indirect effects (increased risk of rejection, other infections) 1
• Risk factors include intensity of immunosuppression and D+/R- serostatus 1
• Weekly screening from day 10 to day 100 post-transplant using pp65 antigenemia or PCR enables preemptive treatment when viremia is detected 5
• Preemptive therapy guided by viral load monitoring reduces CMV disease incidence while minimizing antiviral toxicity 5