Pitfalls in the Serological Diagnosis of Primary Human Cytomegalovirus Infection in Pregnancy Due to Different Kinetics of IgM Clearance and IgG Avidity Index Maturation.

Antonella Sarasini,Milena Furione,Daniele Lilleri,Alessia Arossa,Fausto Baldanti,Chiara Fornara,Maurizio Zavattoni,Arsenio Spinillo

doi:10.3390/diagnostics11030396

Abstract

Primary infection occurs when seronegative women are infected by human cytomegalovirus (HCMV). Diagnosis of primary infection is based on the following: antibody seroconversion, presence of IgM and low IgG avidity index (AI), and presence of DNAemia. The kinetics of HCMV-specific IgM antibody and maturation of AI might be very rapid or long-lasting during primary infection, which makes serological diagnosis insidious. The aims of this study were as follows: (i) to report atypical kinetics of HCMV-specific IgM antibody and AI early after onset of primary HCMV infection in a population of pregnant women, and (ii) to assess the frequency of such results. Altogether, 1309 sequential serum samples collected from 465 pregnant women with primary HCMV infection were included in the study. As a general rule, using the LIAISON®CMVIgMII and LIAISON®CMVIgGAvidityII assays, virus-specific IgM antibody levels decreased, while IgG AI increased over time during the first three months after infection onset. However, early clearance of IgM antibody and/or early IgG AI maturation occurred in 46/426 (10.7%) women. In more details, 20/426 (4.7%) and 26/418 (6.2%) women had undetectable IgM antibody or high IgG AI, respectively, when tested within 1–3 months after well-defined infection onset. Twenty sera from as many women with high IgG AI by the LIAISON assay were further tested for IgG AI by VIDAS®CMVIgGAvidityII and Mikrogen recomLineCMVIgG Avidity assays. Comparable results were obtained with VIDAS, whereas 14/20 sera gave low AI with the Mikrogen assay. In conclusion, about 11% of pregnant women undergoing a primary HCMV infection showed misleading serological results. Additional and appropriate testing might help in reducing the risk of missing HCMV primary infection in pregnancy. Furthermore, preconceptional testing should be strongly recommended.

Highlights

Of the 551 women, 48 were not pregnant, 38 had a pre-conceptional infection, and 465 had a primary infection occurring during pregnancy
The results of 1309 sequential samples from the 465 women with primary infection during pregnancy were considered for this study to evaluate the kinetics of the following: (i) specific human cytomegalovirus (HCMV) chemiluminescent immunoassay immunoassay (CLIA) and ELISA IgM antibody, (ii) IgG avidity index (AI) maturation, and (iii)
HCMV DNA-positive ten months after onset of infection. These findings suggest that, in the presence of HCMV DNAemia, a primary infection should be consistently taken into consideration

Summary

Introduction

Human cytomegalovirus (HCMV) infection is the most common causes of congenital infection, impairing child development worldwide [1], with an overall estimated prevalence of 0.7% [2]. The rate of vertical transmission is about 30–40% in pregnant women with primary infection [2,3], and is believed to be much lower (around 1%) in pregnant women with preconception immunity [2,4]. The most severe sequelae in congenitally infected newborns are the consequence of a primary infection occurring during the first trimester of pregnancy [5,6,7]. Diagnosis or exclusion of primary infection, as well as definition of the gestational age at which primary maternal infection occurred, represent critical points for a correct clinical management of pregnant women

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