How should suspected cytomegalovirus infection be diagnosed and managed in immunocompromised adults, transplant recipients, pregnant women, and newborns?

CMV Diagnosis and Management in High-Risk Populations

Diagnose suspected CMV infection using quantitative PCR (viral load) from blood as the first-line test in all immunocompromised adults, transplant recipients, pregnant women, and newborns, and distinguish between CMV infection (viremia alone) versus CMV disease (viremia plus attributable clinical symptoms). 1, 2

Diagnostic Approach by Population

Transplant Recipients

Use quantitative molecular assays (PCR) for CMV monitoring, not serology, as the preferred diagnostic method. 1, 3

• CMV active infection is defined as viral replication detected by quantitative PCR, antigenemia assay, viral culture, or histopathologic evidence, regardless of symptoms 4, 1
• CMV disease requires both evidence of CMV infection PLUS attributable clinical symptoms, subdivided into CMV syndrome or tissue-invasive disease 4, 1

Implement monthly quantitative PCR monitoring for the first year post-transplant for all at-risk patients (except CMV donor-negative/recipient-negative combinations). 1, 3, 2

• The highest risk group is CMV donor-positive/recipient-negative (D+/R-) 4
• Use the same testing method consistently throughout monitoring—either a standardized commercially available assay or a core laboratory—to ensure accurate comparisons 3

Diagnostic Criteria for CMV Disease in Transplant Recipients

Probable CMV syndrome requires one or more of the following clinical/laboratory findings PLUS evidence of CMV in blood by PCR, antigenemia, or viral culture: 4, 1

• 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)

Definite CMV syndrome requires all the above clinical/laboratory findings with no other identifiable cause of symptoms 4, 1

Probable tissue-invasive CMV disease (e.g., pneumonia, gastrointestinal disease) requires organ-specific symptoms/signs without other documented cause PLUS CMV detected in blood and/or affected site (BAL fluid for pneumonia, endoscopic biopsy for GI disease) by PCR, antigenemia, or viral culture 4, 1

Definite tissue-invasive CMV disease requires detection of CMV in affected tissue by culture, immunohistochemistry, or in situ hybridization 4, 1

HIV-Infected Adults and Other Immunocompromised Patients

Order quantitative CMV DNA PCR from blood as the first-line test—serology (including IgM) has severely limited diagnostic value due to high false-positive rates and inability to distinguish active from latent infection. 2

• Quantitative PCR has sensitivity of 82-100% and specificity of 86-100% for active CMV infection 2
• PCR can detect CMV during neutropenia when antigenemia testing fails due to low leukocyte counts 3, 2
• Over 90% of adults have positive CMV IgG from past exposure, making serology useless for diagnosing active infection 2

CMV retinitis is the most common manifestation in HIV-infected patients with CD4+ counts <50 cells/µL 4

• Occurs as unilateral disease in two-thirds of patients at presentation 4
• Requires ophthalmologic examination for diagnosis—characteristic appearance is full-thickness necrotizing retinitis 4
• Regular ophthalmologic follow-up is needed even after immune recovery, as relapse can occur at CD4+ counts as high as 1,250 cells/µL 4

For organ-specific CMV disease:

• CMV encephalitis: Diagnose using CSF PCR (sensitivity 82-100%, specificity 86-100%) 2
• CMV pneumonitis: Diagnose using BAL fluid PCR plus serum PCR (negative BAL effectively rules out CMV pneumonia with >99% negative predictive value) 2
• CMV colitis: Serology has only 50.8% pooled sensitivity—tissue diagnosis or PCR is essential 2

Pregnant Women

Following primary CMV infection in the first 12 weeks of pregnancy, start valaciclovir (valacyclovir) to reduce the risk of fetal infection. 5

• Test for CMV only in women who develop symptoms of influenza, glandular fever, or hepatitis during pregnancy, or when routine ultrasound detects fetal anomalies suggesting possible CMV infection 5
• The risk of fetal harm is greatest following primary CMV infection in early pregnancy and appears very low following infection after 12 weeks of pregnancy 5

When maternal CMV infection is confirmed:

• If fetal infection is confirmed by amniocentesis, offer regular ultrasound scans every 2-3 weeks until birth with detailed assessment of the fetal brain 5
• Offer MRI scan of the fetal brain at 28-32 weeks of gestation (sometimes repeated 3-4 weeks later) to assess for brain damage 5
• If maternal infection occurs but fetal infection is not confirmed, still offer repeated ultrasound scans every 2-3 weeks until birth 5

Newborns

Test all babies born to women with confirmed or suspected CMV infection using a urine or saliva sample within the first 21 days of life. 5

• Around 1 in 8 babies born with CMV infection will have clinically detectable signs at birth (jaundice, rash, enlarged liver/spleen, small brain, small for gestational age) 5
• The remaining 7 out of 8 infected babies will not have features detectable by clinical examination alone 5

All infants with CMV infection at birth should be followed up at minimum until 2 years of age or later to monitor hearing and brain development. 5

In newborns with symptomatic CMV infection at birth, treat with valganciclovir or ganciclovir—this reduces hearing loss in 5 out of 6 babies and improves long-term brain development outcomes in some. 5

Critical Pitfalls to Avoid

Do not rely on serology alone in immunocompromised patients—viral load testing or tissue diagnosis is essential. 2

Remember that CMV detection does not equal CMV disease—clinical correlation is essential, particularly when using highly sensitive molecular methods. 1, 3

Exclude acute rejection as the cause of clinical symptoms before diagnosing CMV disease, especially if the affected organ is the allograft. 1

Document superinfection or coinfection with other pathogens, as these may occur concurrently with CMV. 1

Ensure consistent use of the same quantitative assay throughout monitoring, as different assays have different thresholds and cannot be directly compared. 3

Consider obtaining samples for antiviral resistance testing (UL97 and UL54 mutations) for patients who develop CMV disease, especially if antiviral prophylaxis was used. 3

Prevention Strategies

In transplant recipients, use either pre-emptive therapy (treat when viremia detected) or universal prophylaxis—establish a consistent strategy across all centers before beginning immunosuppression. 4

For pregnant women, especially those in regular contact with young children, provide education about hygiene-based measures to reduce CMV transmission risk, particularly handwashing. 5