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. 2015 Jul 1;212(1):57-66.
doi: 10.1093/infdis/jiu604. Epub 2014 Oct 31.

Identification of Serologic Markers for School-Aged Children With Congenital Rubella Syndrome

Terri B Hyde  1 , Helena Keico Sato  2 , LiJuan Hao  1 , Brendan Flannery  3 , Qi Zheng  1 , Kathleen Wannemuehler  1 , Flávia Helena Ciccone  2 , Heloisa de Sousa Marques  4 , Lily Yin Weckx  5 , Marco Aurélio Sáfadi  6 , Eliane de Oliveira Moraes  7 , Marisa Mussi Pinhata  8 , Jaime Olbrich Neto  9 , Maria Cecilia Bevilacqua  10 , Alfredo Tabith Junior  11 , Tatiana Alves Monteiro  12 , Cristina Adelaide Figueiredo  13 , Jon K Andrus  14 , Susan E Reef  1 , Cristiana M Toscano  14 , Carlos Castillo-Solorzano  14 , Joseph P Icenogle  1 ; CRS Biomarker Study Group
Collaborators, Affiliations

Identification of Serologic Markers for School-Aged Children With Congenital Rubella Syndrome

Terri B Hyde et al. J Infect Dis. .

Abstract

Background: Congenital rubella syndrome (CRS) case identification is challenging in older children since laboratory markers of congenital rubella virus (RUBV) infection do not persist beyond age 12 months.

Methods: We enrolled children with CRS born between 1998 and 2003 and compared their immune responses to RUBV with those of their mothers and a group of similarly aged children without CRS. Demographic data and sera were collected. Sera were tested for anti-RUBV immunoglobulin G (IgG), IgG avidity, and IgG response to the 3 viral structural proteins (E1, E2, and C), reflected by immunoblot fluorescent signals.

Results: We enrolled 32 children with CRS, 31 mothers, and 62 children without CRS. The immunoblot signal strength to C and the ratio of the C signal to the RUBV-specific IgG concentration were higher (P < .029 for both) and the ratio of the E1 signal to the RUBV-specific IgG concentration lower (P = .001) in children with CRS, compared with their mothers. Compared with children without CRS, children with CRS had more RUBV-specific IgG (P < .001), a stronger C signal (P < .001), and a stronger E2 signal (P ≤ .001). Two classification rules for children with versus children without CRS gave 100% specificity with >65% sensitivity.

Conclusions: This study was the first to establish classification rules for identifying CRS in school-aged children, using laboratory biomarkers. These biomarkers should allow improved burden of disease estimates and monitoring of CRS control programs.

Keywords: CRS; biomarkers; congenital rubella syndrome; immune response; rubella; serology.

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Conflict of interest statement

Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1
Figure 1
Representative immunoblots made by the Typhoon 9410 imager for serum samples from a child with congenital rubella syndrome (CRS), the mother of the child, and 2 children without CRS, as well as assay controls. The amount of serum used in each portion of the blot is indicated. A scan of an immunoblot using monoclonal antibodies (MAb) to the individual proteins is included at right for comparison. The amount of the protein signal is given in E1 units, which is defined as the amount of E1 signal obtained with 2 μL of assay control serum run in parallel with study sera. Note that signal for each serum was normalized to the control serum run on the same blot. For example, the signal strength of the E1 bands for the children without CRS are seen by inspection to both be less than that of the E1 band in the control for that run. Data in the table are from the immunoblots shown, and these immunoblots are one of 3 replicates which were averaged for these sera to provide the results used for comparisons made in this study.
Figure 2
Figure 2
Box plots showing the distribution of each biomarker for children with and without congenital rubella syndrome (CRS), São Paulo, Brazil, 2008–2011. Abbreviation: IgG, immunoglobulin G.
Figure 3
Figure 3
Receiver operating characteristic curves and estimates of areas under the receiver operating characteristic curve (AUCs) for each biomarker among children with and without congenital rubella syndrome (CRS), São Paulo, Brazil, 2008–2011. Abbreviation: IgG, immunoglobulin G.
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