2130. Neonatal Immune Phenotypes and Neurodevelopmental Outcomes in Infants with Congenital Cytomegalovirus Infection (cCMV)
Authors: Medoro Alexandra K , Dhital Ravi , Flint Kaitlyn , Graber Brianna , Pifer Traci , Honegger Jonathan , Sanchez Pablo J , Shimamura Masako 
Published: December 2022

Abstract

Background
Infants with congenital cytomegalovirus infection (cCMV) are at risk for neurodevelopmental impairment (NDI). Antiviral therapy has been shown to improve neurodevelopmental outcomes but is not recommended for all infected infants. There are currently no predictive markers for NDI in infants with cCMV. Our objective was to compare neonatal T cell differentiation and memory phenotypes in CMV-infected infants with and without subsequent NDI.

Methods
Blood samples were collected from infants with cCMV and age-matched healthy controls. Peripheral blood mononuclear cells were analyzed by flow cytometry for CD4 and CD8 T cells expressing CD28, CD57, PD, CD45RA/RO, and CCR7. Demographic and clinical data were collected. NDI was defined as Bayley III/IV testing below the average range in at least one domain in infants for whom this developmental testing was available or based on diagnosis by infectious disease physician or primary care provider. Outcomes for infants with follow-up at least 6 months of age were included. Infants with isolated speech delay associated with hearing loss were not considered to have NDI.

Results
Samples were analyzed from 18 infants (Table 1) at time of diagnosis (≤ 60 days of age) and 5 uninfected age-matched controls. The frequencies of CD8+ T cells expressing CD28low (differentiation), CD57+ (terminal differentiation/senescence), PD1hi (inhibitory or exhausted phenotype) and CD45RO± (memory) phenotypes were higher for the cCMV group without NDI compared to that with NDI (Figure 1). The cCMV group without NDI had lower proportions of naïve (CCR7+/CD45RA+) effector memory, TEM (CCR7-/CD45RA-), and effector memory RA, TEMRA (CCR7-/CD45RA+) CD8+ T cells than those with NDI (Figure 2). There was no difference in memory distribution or surface marker expression of CD4+ T cells. Table 1
Demographic and clinical characteristics of the infants with congenital cytomegalovirus infection (cCMV) with and without neurodevelopmental impairment (NI) and age-matched controls. Continuous variables are compared using the Mann Whitney U test and categorical variables with the Fischer’s Exact test. There were no significant differences between infants with and without NI. Figure 1.CD8+ T cell phenotypes in cCMV groups with and without Neurodevelopmental Impairment (NDI)
Frequencies of CD8+ T cells lacking expression of CD28 (A), or expressing CD57 (B), PD-1 (C), or CD45RO (D) are shown at age ≤ 60 days. Infants with congenital CMV (cCMV) and normal neurodevelopmental outcome are shown in blue, infants with neurodevelopmental impairment are shown in red, and uninfected age-matched controls are shown in black. Data are shown as medians [interquartile range]. Groups were compared using the Mann Whitney U Test. Infants with no NDI had significantly higher frequencies of CD28- (p = 0.002), CD57+ (p = 0.001), PD-1+ (p = 0.01) and CD45RO+ (p = 0.01) CD8 T cells. * p ≤ 0.05; ** p ≤ 0.01. Figure 2.T cell memory subset distributions among cCMV groups and uninfected controls
Proportions of CD4+ (A) and CD8+ (B) naïve (CCR7+/CD45RA+), central memory, TCM (CCR7+/CD45RA-), effector memory, TEM (CCR7-, CD45RA-), and effector memory RA, TEMRA (CCR7-/CD45RA+) T cells. Infants with congenital CMV (cCMV) and normal neurodevelopmental outcome are shown in blue, infants with neurodevelopmental impairment (NI) are shown in red while uninfected age-matched controls are shown in black and gray. Comparisons between T cell groups were made using the Mann Whitney U test. Infants with cCMV without NI had significantly fewer naïve (p = 0.0001), greater TEM (p = 0.0001), and TEMRA (p = 0.005) CD8+ T cells than those with NI. The distributions of CD4+ T cells were not significantly different.

Conclusion
In this small cohort of infants infected with CMV, these data suggest that a more differentiated memory CD8+ T cell phenotype in the neonatal period may correlate with normal neurodevelopmental outcomes.

Disclosures
Alexandra K. Medoro, MD, Merck: Grant/Research Support.