Non-primary Cytomegalovirus Infection Research Articles

Maternal Cytomegalovirus (CMV) Serology: The Diagnostic Limitations of CMV IgM and IgG Avidity in Detecting Congenital CMV Infection.

Congenital cytomegalovirus (cCMV) is a common congenital viral infection. Testing for cCMV usually begins with assessing maternal CMV serology, specifically IgM and IgG antibodies. A negative maternal CMV IgM suggests a low risk of recent maternal CMV infection, thereby suggesting a low risk of cCMV in the fetus. Consequently, cCMV is often ruled out when maternal CMV IgM is negative. In our perinatal autopsy and placental pathology database, we identified 5 cases of cCMV despite negative maternal CMV IgM results in the second trimester. In all 5 cases, fetal abnormalities were first detected by ultrasound in the second trimester, prompting maternal CMV testing. Since second trimester maternal CMV IgM was negative in all cases, cCMV was considered unlikely, thus precluding further prenatal CMV testing in 4 of these cases. The diagnosis of cCMV was subsequently made through placental and/or autopsy examinations. Following this diagnosis, retrospective CMV serology and IgG avidity testing was performed on stored frozen first-trimester maternal blood samples in 3 cases. Among these, the first-trimester samples in 2 cases were IgG+, IgM+, and exhibited low IgG avidity, suggesting a primary maternal CMV infection around the time of conception. In the third case, both first and second-trimester maternal blood samples were IgG+, IgM-, and showed high IgG avidity, suggesting a non-primary maternal CMV infection (i.e., reactivation or reinfection of CMV). A negative maternal CMV IgM in the second trimester cannot exclude cCMV infection. While CMV IgG avidity testing and analysis of stored frozen first-trimester maternal blood samples provide valuable insights, they have limitations. CMV PCR performed on amniotic fluid is a useful prenatal diagnostic tool. For cases of unexplained fetal abnormalities or death, autopsy and placental examination are recommended.

Pitfalls in the Serological Evaluation of Maternal Cytomegalovirus Infection as a Potential Cause of Fetal and Neonatal Involvements: A Narrative Literature Review.

Cytomegalovirus (CMV) is the most common cause of intrauterine infection and serological assays are the primary tools for assessing CMV infections during pregnancy. CMV-specific immunoglobulin M (IgM) antibodies have been used as a diagnostic marker for primary CMV infection in pregnant women, although CMV-IgM has been detected in non-primary CMV infections. IgG avidity testing may aid the distinguishing of primary from non-primary CMV infection; however, there is no standardized assay for detecting this difference. Moreover, when maternal serology shows positive CMV-IgG with negative CMV-IgM findings, vertical transmission probability following primary CMV infection is often excluded. However, symptomatic congenital CMV infections in the context of negative findings for maternal CMV-IgM have been reported recently. The absence of CMV-IgM is recognized in both primary and non-primary CMV infections. Furthermore, maternal non-primary CMV infections during pregnancy may yield a greater proportion of symptomatic congenital CMV infections than previously thought. If universal prenatal screening is performed, ultrasonography for abnormal fetal findings should be conducted regardless of CMV-IgM antibody status. If not universally screened, CMV antibody screening should be performed whenever routine fetal ultrasound reveals abnormal findings. For suspected fetal CMV infection, amniotic fluid or postnatal infant urine CMV-DNA testing is required.

Natural History of Congenital Cytomegalovirus Infection in Highly Seropositive Populations.

Maternal preconceptional cytomegalovirus (CMV) immunity does not protect the fetus from acquiring congenital CMV infection (cCMV). Nonprimary infections due to recurrence of latent infections or reinfection with new virus strains during pregnancy can result in fetal infection. Because the prevalence of cCMV increases with increasing maternal CMV seroprevalence, the vast majority of the cases of cCMV throughout the world follow nonprimary maternal infections and is more common in individuals of lower socioeconomic background. Horizontal exposures to persons shedding virus in bodily secretions (young children, sexual activity, household crowding, low income) probably increase the risk of acquisition of an exogenous nonprimary CMV infection and fetal transmission. In addition, more frequent acquisition of new antibody reactivities in transmitter mothers suggest that maternal reinfection by new viral strains could be a major source of congenital infection in such populations. However, the exact frequency of CMV nonprimary infection in seroimmune women during pregnancy and the rate of intrauterine transmission in these women are yet to be defined. Usually, the birth prevalence of cCMV is high (≥7:1000) in highly seropositive populations. There is increasing evidence that the frequency and severity of the clinical and laboratory abnormalities in infants with congenital CMV infection born to mothers with nonprimary CMV infection are similar to infants born after a primary maternal infection. This is particularly true for sensorineural hearing loss, which contributes to one third of all early-onset hearing loss in seropositive populations. This brief overview will discuss the need for more research to better clarify the natural history of cCMV in highly seropositive populations, which, in almost all populations, remains incompletely defined.

Symptomatic congenital cytomegalovirus disease following non-primary maternal infection: a retrospective cohort study

BackgroundScarce data exist about screening, diagnosis and prognosis of non-primary Cytomegalovirus (CMV) during pregnancy. We aimed to examine antenatal diagnosis of maternal non-primary CMV infection and to identify risk factors for congenial CMV disease.MethodsRetrospective cohort of 107 neonates with congenital symptomatic CMV infection, following either primary (n = 95) or non-primary (n = 12) maternal CMV infection. We compared the groups for the manifestations and severity of congenial CMV disease, as well as for possible factors associated with the risk of developing CMV related infant morbidity.ResultsDisease severity is not similar in affected newborns, with a higher incidence of abnormal brain sonographic findings, following primary versus non-primary maternal CMV infection (76.8% vs. 8.3%, p < .001). Symptomatic congenital CMV disease following a non-primary infection is more frequent if gestational hypertensive disorders and/or gestational diabetes mellitus have ensued during pregnancy (33.3% vs. 9.9%, p <0.038), as well as if any medications were taken throughout gestation (50% vs. 16.8%, p <0.016). CMV-IgM demonstrates a low detection rate for non-primary maternal infection during pregnancy compared to primary infection (25% vs. 75.8%, p = 0.0008).ConclusionNon-primary maternal CMV infection has an impact on the neonate. Although not readily diagnosed during pregnancy, knowledge of risk factors may aid in raising clinical suspicion.

A case of non-primary cytomegalovirus infection in a pregnant woman whose fetus developed congenital cytomegalovirus infection

A case of non-primary cytomegalovirus infection in a pregnant woman whose fetus developed congenital cytomegalovirus infection

New diagnostics and methods of assessing pregnant women at risk of cytomegalovirus

Human cytomegalovirus (CMV) infection can occur in pregnant women by primary infection or by non-primary infection, namely by either reactivation of the latent virus or reinfection with a different strain1. In all cases the mother can transmit the virus to the fetus through the placenta2,3. In the diagnosis of primary CMV infection, the gold standard is maternal seroconversion to CMV-specific antibodies. Currently, women are not routinely screened for CMV before conception or during pregnancy, thus CMV seroconversion is infrequently documented1. Lastly, serological diagnosis of non-primary CMV infection is very difficult and very often unreliable since no optimal diagnostic methods are currently available. Today, the fetal compartment can be only studied by amniocentesis and ultrasound examination for the diagnosis and prognosis of CMV infection and generally, invasive diagnostic protocol can be only suggested to pregnant women with evidence of primary CMV infection acquired early in gestation and in case of abnormal findings suggestive of congenital infection1. Therefore, a correct maternal diagnosis makes so that invasive prenatal diagnosis is only offered in selected cases. This report points out how a CMV-screening program combined with an advanced diagnostic protocol performed on pregnant women could identify those at high risk of transmitting the virus to their fetus. Furthermore, we evaluated the possible role of soluble HLA-G (sHLA-G) molecules detected in maternal and fetal samples in order to more accurately assess a greater risk of CMV-transmission and fetal/neonatal injury.

Seroprevalence and susceptibility to primary cytomegalovirus infection among childbearing women

Background: Amaternal primary cytomegalovirus (CMV) infection during pregnancy is more likely to transmit CMV frommother to fetus with more severe sequelae of congenital infection compared with a maternal non-primary CMV infection (reinfection or reactivation). The aim of this study is the evaluation of CMV seroprevalence and susceptibility to primary CMV infection among Greek and immigrant pregnant and non-pregnantwomenof reproductive age. Methods & Materials: From January 2011 to September 2013, a total of 3,121 pregnant and non-pregnant women of childbearing age, were tested for CMV-IgG and IgM antibodies. Out of 3,121 women the 1,683 were Greeks and 1,438 were immigrants from developingcountries.Of the1,683Greeksand1,438 immigrants the 755 and 815 respectivelywere pregnant. Detection of CMV-specific IgG and IgM antibodies was carried out by EIA and electrochemiluminescence immunoassay (ABBOTT, AxSYM CMV IgG and IgM Microparticle Enzyme Immunoassay and Roche CMV IgG and IgM electrochemiluminescence immunoassay on cobas e 411 analyzer) according to the manufacturer’s instructions. Results: CMV-IgG and IgM antibodies were detected in 617 (66.49%) and 7 (0.75%) non-pregnant and 537 (71.12%) and 2 (0.26%) pregnant Greek women respectively, whereas CMV IgG and IgM antibodies were detected in 581 (93.26%) and 7 (1.12%) non-pregnant and 789 (96.81%) and 1 (0.12%) pregnant immigrant women respectively. The susceptibility to primary CMV infection of non-pregnant and pregnant Greek women was found to be 33.51% (311/928) and 28.88% (218/755) respectively, whereas the susceptibility to primary CMV infection of no-pregnant and pregnant immigrant women was 6.74% (42/623) and 3.19% (26/815) respectively. Statistical analysis by x2 test showed significantly higher susceptibility to primary CMV infection in non-pregnant and pregnant Greek women than in immigrant women. Conclusion: (a) The prevalence of specific antibodies to CMV in pregnant and non-pregnant Greek women of childbearing age is high. (b) The CMV seroprevalence in pregnant and non-pregnant immigrant women is significantly higher than in Greek women. (c) The susceptibility to primary CMV infection is significantly higher in pregnant and non-pregnant Greek women than in immigrants. (d) A remarkable number of Greek women of reproductive age remain at risk of primary CMV infection during pregnancy.

Re-evaluation of the VIDAS® cytomegalovirus (CMV) IgG avidity assay: Determination of new cut-off values based on the study of kinetics of CMV–IgG maturation

BackgroundIn case of cytomegalovirus (CMV) infection, differentiation between primary and non-primary CMV infection can be of major importance for the correct management of pregnant women or immunocompromised patients. Besides CMV–IgM and IgG, CMV–IgG avidity measurement is now commonly used to distinguish primary from non-primary infection. ObjectiveTo re-evaluate the performance of the VIDAS CMV–IgG avidity assay in comparison with 2 other techniques (Architect Abbott and Liaison DiaSorin) and to study the kinetics of CMV–IgG avidity maturation. Study designA panel of 135 sequential samples collected from 31 patients with a proven primary infection (attested by very recent CMV–IgG seroconversion) was tested with VIDAS, Liaison and Architect CMV–IgG avidity assays. Moreover, 235 routinely collected samples, CMV–IgG and CMV–IgM positive, were analyzed with Liaison, VIDAS and an in-house CMV–IgG avidity assay. Results and conclusionsThe analysis of all the data allowed suggesting new VIDAS cut-off values of 0.40 for low avidity and 0.65 for high avidity, which significantly increase the test performance and enable better patient managements. Using these VIDAS new cut-off values, all of the 31 primary infections were correctly dated. Comparatively, 25 out of 31 were correctly dated with the Architect assay and 29 out of 31 with the Liaison assay. We also demonstrated that the VIDAS CMV–IgG avidity assay allows observing correctly the maturation of CMV–IgG avidity, which could be useful as an additional parameter for diagnosis of a recent CMV infection.

National Prevalence Estimates for Cytomegalovirus IgM and IgG Avidity and Association between High IgM Antibody Titer and Low IgG Avidity

Primary cytomegalovirus (CMV) infection of the mother during pregnancy presents risk of CMV infection of the fetus with resulting permanent disability. CMV IgM antibody is generated following primary CMV infection but also can appear during nonprimary CMV infection and is thus of limited diagnostic use by itself. In contrast, the presence of low CMV IgG avidity has been shown to be a unique and reliable serologic indicator of primary CMV infection. We measured CMV IgG and IgM antibody levels and IgG avidity in sera from a population sample of 6,067 U.S. women aged 12 to 49 years from NHANES (National Health and Nutrition Examination Survey). The CMV IgG prevalence was 58% overall and increased strongly with age. The CMV IgM prevalence was 3.0% overall and remained relatively flat across age groups. The prevalence of low IgG avidity was 2.0% overall, decreased sharply with age, and was seen mainly among IgM-positive sera. Fourteen to 18% of the CMV IgM-positive sera were low IgG avidity, presumably representing primary CMV infection. High CMV IgM antibody titer was a strong predictor of low IgG avidity. The ability to reliably identify primary CMV infection during pregnancy is important for management of the pregnancy, including possible treatment options for the fetus. Both IgM and IgG avidity measurements provide useful clinical information for evaluating primary CMV infection, although commercial tests for CMV IgG avidity are not yet widely available in the United States.

Serologic Screening of Pregnant Korean Women for Primary Human Cytomegalovirus Infection Using IgG Avidity Test

Primary human cytomegalovirus (CMV) infection during pregnancy is a major cause of congenital malformation. We detected primary CMV infection in pregnant Korean women by using an algorithm that comprises CMV IgG, IgM, and IgG avidity tests. During a 2-month period, 744 pregnant women who were at 10-19 weeks of gestation were consecutively enrolled in this study. Human anti-CMV IgG and IgM levels in their sera were determined by chemiluminescence immunoassays. Serum samples from the women who were positive for CMV IgG and IgM were assayed by the ARCHITECT CMV IgG avidity test in order to distinguish primary from non-primary CMV infection. Gross examination of the neonates of the women who were positive for CMV IgM was conducted. The seroprevalence of CMV IgG and IgM was estimated to be 98.1% and 1.7%, respectively. The samples from all the women who were positive for CMV IgM or with grey zone results contained high avidity CMV IgG. Seven women with positive CMV IgG and IgM results who completed follow-up up to delivery showed no gross evidence of in utero CMV transmission. Maternal primary CMV infection was not detected in any of the pregnant women included in this study cohort. CMV IgG avidity test enabled the identification of women who were at a low risk of transmitting CMV infection and provided informative for subsequent pregnancy outcomes. Compared to previous studies, the seroprevalence of CMV IgG antibody across pregnant Korean women remained unchanged.

Validation of an in-house assay for cytomegalovirus immunoglobulin G (CMV IgG) avidity and relationship of avidity to CMV IgM levels.

Measurement of cytomegalovirus (CMV)-specific immunoglobulin G (IgG) avidity has proven to be a powerful tool for distinguishing primary from nonprimary CMV infection. An in-house enzyme-linked immunosorbent assay (ELISA) for measuring CMV IgG avidity was validated using 84 sera from pregnant women who had recently seroconverted following primary CMV infection and 74 sera from individuals with past CMV infection (IgG-positive and IgM-negative profile). Of the 84 sera from pregnant women, 73 sera were collected within 120 days of the last IgG-negative sample, and 72 of these 73 sera (99%) exhibited an avidity index (AI) of <50%. In contrast, 71 of 74 (96%) sera from individuals with past CMV infection exhibited CMV AI values of > 60%. Thus, low avidity in the in-house ELISA was defined as an AI of < or = 50%, whereas high avidity was defined as an AI of > or = 60%. In additional studies, the relationship between CMV IgG avidity and CMV IgM levels was examined using 64 CMV IgG-positive sera (time since seroconversion unknown) exhibiting equivocal or positive results in a CMV IgM capture ELISA (Diamedix). Of these 64 sera, 29 exhibited IgM index values of > or = 3.0, and 27 of these 29 (93%) exhibited low IgG avidity. A similar trend was observed when a subset of these 64 sera (n = 48) was tested in another CMV IgM capture ELISA (Trinity); of 18 sera with IgM index values of > or = 3.0, 17 (94%) exhibited low IgG avidity. These findings demonstrate the validity of an in-house ELISA for CMV IgG avidity and further show that strong reactivity of CMV IgG-positive sera in either of two CMV IgM capture assays is a reliable indicator of low CMV IgG avidity, and thus, recent CMV infection.

Avidity of IgG antibodies distinguishes primary from non-primary cytomegalovirus infection in pregnant women

Background: Human cytomegalovirus (HCMV) is the most common cause of viral intrauterine infection. Fetal damage is mostly linked to maternal primary infection. It is therefore important to differentiate primary from non-primary infection in pregnant females. IgM tests often used for this purpose are not reliable enough. Objective: To evaluate an HCMV–IgG urea-elution assay for its ability to distinguish primary from non-primary infection. In this assay, soaking the antigen–antibody complex with an urea containing solution frees antibodies with low avidity but has no influence on those with high avidity. An avidity index (AI) was calculated: AI=(OD with urea/OD without urea)×100. Study design: HCMV–IgG avidity was measured on a single serum of 79 patients with past infection (pregnant women, graft recipients and blood donors) and of 63 patients (78 sera) with documented seroconversion (pregnant women and graft recipients). Sixty-one pregnant women positive or equivocal for HCMV–IgM but without a documented seroconversion were included in this study. Results: Most (72/79) of the patients with past infection had an AI>65% and all but one had an AI>50%. In pregnant women, in the case of a primary infection within the past 3 months, AI are usually (51/53)<50% and never>65%. Among the IgM positive pregnant women who lack a seroconversion history, 38 had AI>65% suggestive of an infection that had occured at least 3 months earlier, 11 had an AI in a grey area between 50 and 65% and 12 had an AI<50%, suggestive of a recent primary infection. Conclusions: In pregnant women, measurement of the IgG avidity may help to date a HCMV infection, an AI >65% highly suggests a past infection while an AI <50% corresponds to a recent primary infection.