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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
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)
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.
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.
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:
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. , ,
Concerning ultrasound findings or confirmed maternal infection should also prompt fetal testing. In these scenarios, 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.
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.
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.
| Gene | Antiviral Drug(s) |
|---|---|
| UL54 | Ganciclovir, cidofovir, foscarnet |
| UL97 | Ganciclovir, maribavir |
| UL27 | Maribavir |
| UL56 | Letermovir |
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. | |
ARUP Laboratory Tests
Quantitative Polymerase Chain Reaction
Qualitative Polymerase Chain Reaction (PCR)
Semi-Quantitative Chemiluminescent Immunoassay (CLIA)
Semi-Quantitative Chemiluminescent Immunoassay (CLIA)
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Massively Parallel Sequencing
References
-
CDC - Cytomegalovirus (CMV) and Congenital CMV Infection
Centers for Disease Control and Prevention. Clinical overview of CMV and congenital CMV. Last reviewed Aug 2020; accessed Sep 2022.
-
26000539
American College of Obstetricians and Gynecologists. Practice bulletin no. 151: cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy. [published corrections appear in Obstet Gynecol. 2016;127(2):405 and in Obstet Gynecol. 2016;127(2):405]. Obstet Gynecol. 2015;125(6):1510-1525.
-
29955859
Miller JM, Binnicker MJ, Campbell S, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2018 update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis. 2018;67(6):e1-e94.
-
29596116
Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation.Transplantation. 2018;102(6):900-931.
-
12588074
Taylor GH. Cytomegalovirus. Am Fam Physician. 2003;67(3):519-524.
-
26902990
Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Gyamfi-Bannerman C. Diagnosis and antenatal management of congenital cytomegalovirus infection. Am J Obstet Gynecol. 2016;214(6):B5-B11.
-
30817026
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients—guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13512.
-
27307504
Preiksaitis JK, Hayden RT, Tong Y, et al. Are we there yet? Impact of the first international standard for cytomegalovirus DNA on the harmonization of results reported on plasma samples. Clin Infect Dis. 2016;63(5):583-589.
-
CDC - Cytomegalovirus (CMV) and Congenital CMV Infection laboratory testing
Centers for Disease Control and Prevention. Laboratory testing for CMV and congenital CMV. Last reviewed Apr 2020; accessed Sep 2022.
-
33523119
Dollard SC, Dreon M, Hernandez-Alvarado N, et al. Sensitivity of dried blood spot testing for detection of congenital cytomegalovirus infection. JAMA Pediatr. 2021;175(3):e205441.
-
16125456
Navalpotro D, Gimeno C, Navarro D. PCR detection of viral DNA in serum as an ancillary analysis for the diagnosis of acute mononucleosis-like syndrome due to human cytomegalovirus (HCMV) in immunocompetent patients. J Clin Virol. 2006;35(2):193-196.
-
31318908
López-Aladid R, Guiu A, Mosquera MM, et al. Improvement in detecting cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance using next generation sequencing. PLoS One. 2019;14(7):e0219701.
-
23985916
Sahoo MK, Lefterova MI, Yamamoto F, et al. Detection of cytomegalovirus drug resistance mutations by next-generation sequencing. J Clin Microbiol. 2013;51(11):3700-3710.