CONTINUING EDUCATION :: CYTOMEGALOVIRUS INFECTION


lovirus (cCMV), although severe adverse effects may occur.6 Healthy individuals recover from infection without problems and treatment is not required.12


Laboratory testing for CMV diagnosis Detection of CMV infection is particularly important in cCMV infection (pregnant women and newborns) as well as in im- munocompromised individuals (e.g., SOT, SCT and in HIV patients). Since immunocompetent individuals are not at risk for developing complications, testing is not required. As the symptoms are not specific, laboratory testing is required to diagnose CMV infection. The main laboratory methods for di- agnosing CMV are serology and molecular testing. Depending on the population being tested, one method is favored over the other or a combination of both is preferred. The following sections describe when serology and/or molecular testing are best used for detection of CMV.


Figure 1: Antibody kinetics in CMV infection.


Serology in adults and infants older than 12 months Initial infection leads to the production of CMV-specific im- munoglobulin M (IgM) antibodies that persist in the blood for a short period of time and later to the production of IgG antibod- ies that can persist forever (Figure 1).13,14


The main challenge


with IgM antibody detection is that some individuals can have persistent IgM levels for over a year.15


IgM can be also detected


in reactivation or reinfection. Therefore, the detection of IgM does not confirm an active primary infection. Furthermore, IgM antibodies are not highly specific and false positive results may occur.16


A primary CMV infection can be distinguished from


a past infection by measuring immunoglobulin G (IgG) sero- conversion (follow-up collection samples required) and/or IgG avidity. IgG avidity tests evaluate the binding strength of IgG antibodies to the virus. Low-binding strength (low avidity) IgG antibodies are produced in response to initial CMV infection, and over the course of 2–4 months, develop into high binding strength (high avidity) (Figure 1).17


Therefore, high avidity IgG


would indicate a past infection while low avidity IgG would indicate a primary infection. Due to the potential complications of CMV infection, particularly in pregnant women, is impor- tant to distinguish between primary infection, past infection, reactivation, and reinfection.


CMV testing in pregnancy In the United States, routine screening for CMV infection during pregnancy is not recommended by the Centers for Disease


Detection parameter


IgM IgG Information gained Active infection


Past infection: Persistant IgM is possible.


Past infection: Indicates past CMV infection but does not indicate when infection occurred.


IgG avidity


Primary infection: Low avidity IgG antibodies


Past infection: High avidity IgG antibodies


Table 1: Serological testing in CMV infection. MLO-ONLINE.COM DECEMBER 2022 9


infection after maternal primary infection. These estimates are based on data from the MFMU Network Randomized Trial to Prevent Congenital Cytomegalovirus.23


This CMV calculator


predicts cCMV infection in the context of primary maternal CMV infection and no ultrasonographic indications of congenital infection. Having this information may aid in patient counseling and decision making.24


This calculator considers the results of


an IgM antibody test, IgG avidity, and presence or absence of virus in maternal plasma. Serological assays using glycoprotein B (gB) as an antigen


for IgG antibody detection in pregnant women are included in some guidelines for screening pregnant women in Europe.25-27 In general, the IgG antibody response to CMV gB is delayed by up to 100 days (Figure 1; Table 1).28


Therefore, IgG antibodies


against gB indicate a past infection and a recent or primary infection can be excluded. These results are comparable to the finding of high avidity IgG antibodies. However, only 82% of CMV‐infected individuals produce IgG antibodies against gB.29


Control and Prevention (CDC). The main reason is that available diagnostics cannot predict whether the fetus will be infected. Additionally, there is no vaccine available or treatment to prevent fetal infection. However, other countries, particularly Europe, recommend routine serological screening for CMV of pregnant women.18,19


Although prenatal screening is not recommended in some countries, pregnant women can consult their obstetricians and request a test to determine their CMV immune status. Typically, serological testing is offered for this purpose as a stand-alone test or as part of a (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) ToRCH panel.20 A combination of serological testing (IgM, IgG avidity, and IgG seroconversion) can help to discriminate between active infection, past infection, reactivation, and reinfection (Tables 1 and 2).15,21,22


In fact, the Maternal-Fetal Medicine Units (MFMU) Network from NIH provides a CMV calculator to estimate cCMV


Consequently, a negative result can be a false-negative.


Therefore, it is highly recommended to look at a combination of IgM, IgG seroconversion, IgG avidity, and antibodies against gB.


Fetal population testing When an active infection is detected in a pregnant woman, the next step is to check fetal infection. There are two prenatal tests that can be used: non-invasive (ultrasound examination) and invasive (amniocentesis). CMV isolation from amniotic fluid


Primary infection detection Not possible


IgM can be detected during primary, recurrent, or reinfection


Possible IgG seroconversion Possible


Detected low avidity IgG antibodies


Discrimination between active primary vs. reactivation/reinfection Not possible


IgM can be detecetd during primary, recurrent, or reinfection


Possible


Past infection by detecting IgG antibodies against late stage markers (anti-gB IgG) (only 82% of the population)


Possible High vs. low IgG avidity antibodies


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