Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection

Abstract

BACKGROUND Cytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury. METHODS We performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays. RESULTS Using unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins — the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3–binding protein (Gal-3BP) — were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe ( n = 17) and asymptomatic ( n = 26) cCMV, with 100%–93.8% positive predictive value, and 92.9%–92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSION Analysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses. FUNDING Israel Science Foundation (530/18 and IPMP 3432/19); Research Fund – Hadassah Medical Organization.

Adipokines as Diagnostic and Prognostic Markers for the Severity of COVID-19

“…For example, chemerin levels were determined in intrauterine infections with cytomegalovirus (CMV), which can cause infant brain damage [58]. Chemerin levels in amniotic fluid were highly predictive of the severity of congenital CMV, and differentiated between foetuses with severe and asymptomatic disease [59]. On the other hand, serum chemerin levels in hepatitis C virus (HCV)-infected patients positively associated with leukocyte count and negatively with markers of hepatic function, yet did not correlate with viral load and remained unaltered even after the efficient elimination of the virus, excluding HCV infection to change the circulating levels of this adipokine [60].…”

An Overview of Cytomegalovirus Infection in Pregnancy

“…Direct detection using amniocentesis and cordocentesis has a high sensitivity and specificity, but it is an invasive method. Ultrasound and magnetic resonance imaging are non-invasive, but they have a low specificity and require specialized medical personnel to properly assess abnormal findings [ 38 , 45 ].…”

Cytokine Profiling of Amniotic Fluid from Congenital Cytomegalovirus Infection

“…Multi-OMICS approaches offer new perspectives to identify relevant biomarkers. In two studies, proteomic analysis of the amniotic fluid using liquid chromatography–mass spectrometry, LC-MS, or capillary electrophoresis–mass spectrometry, CE-MS, identified a set of potential biomarkers associated with severe fetal infection [ 79 , 80 ]. Unfortunately, there was no recurrent protein between those series.…”