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Cytomegalovirus - CMV. ARUP Consult®. Retrieved June 04, 2023, https://arupconsult.com/content/cytomegalovirus

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Cytomegalovirus - CMV

Cytomegalovirus (CMV) is a common infection among both children and adults. In the United States, nearly one in three children is infected by 5 years of age, and more than 50% of adults become infected by 40 years of age.  CMV can be transmitted congenitally, by blood transfusion, from an organ transplantation, or through direct contact with bodily fluids, including urine, saliva, blood, genital secretions, and breast milk. The virus may lie dormant or reactivate after the primary infection.  Although infected immunocompetent children and adults generally do not have symptoms, CMV can lead to serious complications in neonates, pregnant individuals, immunocompromised individuals, and transplant recipients. 

When CMV infection is suspected in fetuses, newborns, or transplant recipients, nucleic acid amplification testing (NAAT, such as polymerase chain reaction [PCR]) is commonly used to detect and quantify the patient’s viral load.    Serologic testing is useful to assess immunocompetent individuals, pregnant individuals with possible active infection, and prospective transplant donors and recipients during pretransplantation analysis.   

Quick Answers for Clinicians

When is it useful to test for cytomegalovirus infection?

Testing for cytomegalovirus (CMV) infection is appropriate in:

  • Immunocompromised patients who present with febrile illness, hepatitis, or colitis
  • Pregnant individuals with possible active CMV infection, which may affect the fetus
  • Neonates with congenital syndromes suggestive of CMV
  • Prospective transplant donors and prospective or recent transplant recipients
  • Immunocompetent patients who present with mononucleosis-like illness and have tested negative for Epstein-Barr virus (EBV) 
Is routine cytomegalovirus screening recommended for pregnant individuals?

Screening for primary cytomegalovirus (CMV) infection is not currently recommended for pregnant individuals in the United States.   

Which tests are available to detect cytomegalovirus infection?

Cytomegalovirus (CMV) can be detected by nucleic acid amplification testing (NAAT), serology, viral culture, and histology. Depending on the patient population, NAAT and serology are generally preferred for diagnosis. 

How comparable are cytomegalovirus test results across laboratories?

The harmonization of molecular testing (eg, nucleic acid amplification testing [NAAT]) for cytomegalovirus (CMV) has improved since the World Health Organization (WHO) put forward an international standard for CMV test calibration. However, some variability still exists in test results due to aspects of testing such as platform, specimen type, and nucleic acid extraction method. Identical specimens may vary by greater than 10-fold when different platforms are used. Therefore, guidelines recommend using the same quantitative assay and sample type each time a patient is tested for CMV during surveillance and monitoring.    Refer to ARUP Laboratory Tests for more information.

Which tests are appropriate for monitoring cytomegalovirus infection posttransplantation?

Quantitative nucleic acid amplification testing (NAAT) is preferred to monitor viral loads and antiviral treatment response in transplant recipients. It is also useful for posttransplant surveillance to inform preemptive treatment for CMV infection.  Refer to Transplantation for more information.

How do I interpret serologic test results?

In patients 12 months or older, a positive cytomegalovirus (CMV) immunoglobulin G (IgG) result suggests a past infection, whereas paired IgG results demonstrating seroconversion indicate a recent infection. 

CMV IgM testing cannot be used alone to diagnose primary CMV infection. However, it may be used alongside IgG avidity testing to confirm a current infection. Refer to Test Interpretation for additional information. 

Indications for Testing

CMV is a common virus, and most people with this infection have no symptoms. However, the following populations warrant consideration for laboratory testing:

  • Immunocompromised patients who present with febrile illness, hepatitis, or colitis 
  • Pregnant individuals with possible active CMV infection, which may affect the fetus
  • Neonates with congenital syndromes (eg, hepatosplenomegaly, microcephaly, sensorineural deafness) suggestive of CMV 
  • Prospective transplant donors and prospective or recent transplant recipients 
  • Immunocompetent patients who present with mononucleosis-like illness and have tested negative for Epstein-Barr virus (EBV) 

Laboratory Testing

Immunocompromised Individuals

Quantitative NAAT (eg, qPCR) for viral DNA in plasma or whole blood is the primary test for detecting CMV infection in immunocompromised patients because this test:

  • Quantifies viral load
  • Provides rapid and early detection
  • Offers higher sensitivity than culture 

Molecular methods are also useful to assess for possible antiviral drug resistance in immunocompromised individuals.  Serologic testing is not recommended for diagnosis in this population.

Pregnancy

Testing for CMV infection in pregnant individuals generally occurs after concerning ultrasound findings.  When primary CMV infection is suspected during pregnancy, serologic assays are the main tests used for evaluation. Diagnosis should be based on either immunoglobulin G (IgG) seroconversion (at least a fourfold increase in titers) or positive CMV IgM with low IgG avidity test results. CMV IgG avidity testing aids in distinguishing between a recent and past infection after initial serologic testing.  

Infection immediately before or during the first trimester of pregnancy increases the risk of cytomegalic inclusion disease in the fetus.  When fetal infection is suspected due to maternal or ultrasound findings, CMV can be detected in the amniotic fluid by either culture or NAAT. NAAT performed using amniotic fluid is most sensitive at >21 weeks gestation. The detection of CMV in amniotic fluid does not predict the severity of congenital CMV infection. 

Neonates

In newborns, NAAT using saliva is initially performed to identify CMV infection. Following a positive result, diagnosis should be confirmed by NAAT using a urine sample (CMV can be shed through breast milk from seropositive individuals, which can lead to a false-positive saliva test result in a recently breastfed infant).  Dried blood spots (DBSs) may provide a means of retrospective diagnosis for congenital CMV infection; however, this method is not suitable for screening and is less sensitive than urine NAAT.  Refer to the CDC website for more information on testing for congenital CMV infection in newborns. 

Transplantation

In prospective transplant donors and recipients, the Third International Consensus Guidelines on Management of Cytomegalovirus in Solid-Organ Transplantation  recommends CMV IgG testing before transplantation to assess CMV risk and guide posttransplant patient management. In patients 12 months or younger, NAAT using an oral or urine specimen may be helpful to identify infection before transplantation.

Following transplantation, quantitative NAAT performed on plasma or whole blood is recommended to screen for CMV infection in at-risk individuals, guide preemptive treatment, diagnose a current infection, and monitor response to antiviral therapies. Serology should not be used for CMV diagnosis posttransplantation. When monitoring patients, consistent use of the same specimen type and assay is recommended.    Monitoring should occur according to site-specific transplantation protocols.

Immunocompetent Individuals

Most healthy individuals who acquire CMV after birth experience few symptoms and no long-term health consequences.  However, testing for CMV may be indicated in immunocompetent individuals who present with mononucleosis-like symptoms once EBV has been excluded. 

When an active CMV infection is suspected in immunocompetent individuals 12 months or older, diagnosis can be made through paired CMV IgG testing or a combination of CMV IgM and IgG avidity testing.  Qualitative NAAT may be less sensitive than serologic testing.  Refer to the CDC website for additional information regarding serologic assessment. 

Antiviral Resistance

Testing for CMV resistance to antivirals may be warranted in certain situations  and is performed with genotypic methods. Next generation sequencing (NGS) is a more sensitive method to detect resistant subpopulations than traditional Sanger sequencing.  However, with all sequencing assays, specimens with low viral loads (typically <1,000 copies/mL) may fail to amplify, thus producing inconclusive results. 

When antiviral resistance is suspected, consensus guidelines recommend testing for causative variants in the UL97 and UL54 genes, at a minimum.   Other genes (eg, UL27 and UL56) may also be implicated in drug resistance.

Genes Associated With Resistance to Common Antiviral Drugs
Gene Antiviral Drug(s)

UL54

Ganciclovir, cidofovir, foscarnet

UL97

Ganciclovir, maribavir

UL27

Maribavir

UL56

Letermovir

Test Interpretation

CMV Serologic Test Interpretation

CMV IgG

A positive result suggests past infection in persons ≥12 mos of age

Paired CMV IgG

Requires two samples taken 1-3 mos apart

Seroconversion or a fourfold or greater increase in titers offers clear evidence of recent primary infection

CMV IgM

In isolation, IgM testing is not helpful to diagnose primary CMV infection

CMV IgG Aviditya

Aids in distinguishing between recent and past CMV infection

Low avidity suggests primary CMV infection occurred within the last 2-4 mos; during the first trimester of pregnancy, patients with a low avidity result should seek consultation with an obstetrician experienced with congenital CMV infections

The clinical relevance of intermediate avidity is undetermined

High avidity suggests remote infection (>2-4 mos)

aBecause not all avidity assays have been validated, they should be interpreted with caution.

Sources: ACOG, 2015 ; CDC, 2020 

ARUP Laboratory Tests

Quantitative NAAT

Results calibrated to the WHO international standard and reported in IU/mL

Qualitative NAAT
Serology
Antiviral Resistance NGS

Assesses UL97, UL54, and UL27 genes

Assesses UL56 gene

Assesses UL97, UL54, UL27, and UL56 genes

References

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Medical Experts

Contributor

Bradley

Benjamin T. Bradley, MD, PhD
Assistant Professor (Clinical), University of Utah
Medical Director, Virology and Molecular Infectious Diseases, ARUP Laboratories
Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)
Marc Roger Couturier, PhD, D(ABMM)
Professor of Pathology (Clinical), University of Utah
Medical Director, Emerging Public Health Crises, Parasitology/Fecal Testing, and Infectious Disease Antigen Testing, ARUP Laboratories