Reliability of CMV-IgG kinetics in the diagnosis of CMV primary infection: sensitivity, specificity, and clinical implications

Abstract

Diagnosis of cytomegalovirus (CMV) primary infection (PI) during pregnancy relies on serology (CMV-IgG, IgM, and IgG avidity). However, as for toxoplasmosis, subsequent serology testing 3-5 weeks later is often performed to confirm the diagnosis. In this study, we aimed to show that testing CMV-IgG with different assays may lead to misinterpretation of CMV-IgG kinetics and to determine the sensitivity and specificity of CMV-IgG stability and significant increase to exclude or confirm recent CMV PI. We conducted a retrospective study on (i) a CMV-IgG external quality control program (2015-2022) and (ii) on CMV serology results obtained in our virology laboratory (2013-2023) in pregnant women with positive CMV-IgM and a subsequent serum sample collected 3-5 weeks later. Analysis of 21 CMV-IgG external quality control serum samples highlighted significant differences in CMV-IgG values, with variations up to a factor of 185 between different immunoassays for the same positive sample. In 434 pregnant women, the sensitivity of a significant CMV-IgG increase to predict recent PI was 32.9% (95% CI = 26.5-39.2), while CMV-IgG stability specificity to exclude PI <3 months was 32.9% (95% CI = 26.5-39.2). Our observations highlight the discrepancies in CMV-IgG values with different assays and the major importance of CMV-IgG avidity in the diagnosis of recent CMV PI in case of positive CMV-IgM. We also demonstrate that retesting IgG on a sample collected 3-5 weeks later is not helpful and can be confusing.IMPORTANCEThis article is the first to address cytomegalovirus (CMV)-IgG kinetics and their reliability in the serological diagnosis of CMV. In our experience, many clinical virologists and laboratory practitioners still rely on kinetics for diagnosis. However, our study clearly demonstrates that this approach is misleading and that avidity testing should always be performed. Additionally, we conducted a robust study highlighting discrepancies between CMV serology techniques, emphasizing the importance for practitioners, particularly gynecologists, to avoid monitoring serology results using different testing methods.

Keywords: CMV; IgG; IgM; avidity; pregnancy; serology.

Fig 1

IgG values obtained by the different assays used in EQA Samples (units: AU/mL for Architect, Alinity, VIDAS, Access, and Liaison; S/CO for Immulite). This figure shows the mean IgG values measured by different laboratories using various reagents and instruments in the EQA program. The y-axis represents values in AU/mL or S/CO, while the x-axis corresponds to the different EQA samples. Each point represents the mean value for a specific reagent. The upper linearity limits of each reagent are shown as horizontal dashed lines: VIDAS (150 AU/mL, purple dashed line), Access (400 AU/mL, teal dashed line), and Architect and Alinity (250 AU/mL, green dashed line). This figure visually illustrates the discrepancies in CMV-IgG values across different assays. For example, Abbott’s Architect and Beckman-Coulter’s Access systems frequently display variations exceeding a 100-fold difference, underscoring the critical impact of assay selection. These results emphasize the necessity of interpreting CMV-IgG kinetics with caution, particularly when sequential tests are conducted in different laboratories. Values from the Cobas Elecsys assay were not plotted to improve the visibility and graphical readability of the figure.

Fig 2

Study population flowchart. According to CMV-IgG avidity results, pregnant women were divided into three groups: recent primary infection excluded (>3 months), very recent primary infection (<1 month), and recent primary infection (1–2 months). In each group, we evaluated the percentage of pregnant women having either significant CMV-IgG value increase or stable CMV-IgG values.