De novo RANBP2 variant in a fetal demise case with cerebral intraparenchymal hemorrhage.

Fetal intracranial hemorrhage (ICH) may result from a wide array of causes, either associated with maternal or fetal risk factors. In the last decade, monogenic causes of susceptibility to fetal ICH have been described, in particular in association with COL4A1 and COL4A2 genes. A peculiar form of ICH is acute necrotizing encephalitis (ANE), which is characterized by a rapid-onset severe encephalopathy following an abnormal inflammatory response to an otherwise banal infection. It usually affects healthy children and it is thought to be multifactorial, with a genetic predisposition. RANBP2 gene has been extensively associated with ANE susceptibility. We hereby present a unique case of a 42-year-old secundigravida with intrauterine fetal demise at 35 weeks of gestation. Trio-based whole-exome sequencing performed on both parents and fetal DNA showed a de novo likely pathogenic variant in the RANBP2 gene on 2q13. At the fetal autopsy, subtentorial hematoma and cerebral intraparenchymal hemorrhage were present. We speculate that this might be a new phenotypic presentation of RANBP2-associated disease. However, more similar fetal cases need to be reported in order to reinforce this hypothesis

Prevalence, Outcome, and Prevention of Congenital Cytomegalovirus Infection in Neonates Born to Women With Preconception Immunity (CHILd Study)

Background. Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disabilities. We designed a prospective study to investigate the rate, outcome, and risk factors of congenital CMV (cCMV) infection in neonates born to immune women, and the potential need and effectiveness of hygiene recommendations in this population.Methods. The study was composed of 2 sequential parts: an epidemiology (part 1) and a prevention (part 2) study. Performance of part 2 depended upon a cCMV rate >0.4%. Women enrolled in part 1 did not receive hygiene recommendations. Newborns were screened by HCMV DNA testing in saliva and cCMV was confirmed by urine testing.Results. Saliva swabs were positive for HCMV DNA in 45/9661 newborns and cCMV was confirmed in 18 cases. The rate of cCMV was .19% (95% confidence interval [CI]: .11-.29%), and 3 out of 18 infants with cCMV had symptoms of CMV at birth. Age, nationality, occupation, and contact with children were similar between mothers of infected and noninfected newborns. Twin pregnancy (odds ratio [OR]: 7.2; 95% CI: 1.7-32.2; P=.037) and maternal medical conditions (OR: 3.9; 95% CI: 1.5-10.1; P= .003) appeared associated with cCMV. Given the rate of cCMV was lower than expected, the prevention part of the study was cancelled.Conclusions. Newborns from women with preconception immunity have a low rate of cCMV, which appears to be mostly due to reactivation of the latent virus. Therefore, serological screening in childbearing age would be pivotal to identify HCMV-seropositive women, whose newborns have a low risk of cCMV

Human cytomegalovirus genomes sequenced directly from clinical material: variation, multiple-strain infection, recombination and gene loss

The genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination, and gene loss. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analyzed, in the process enabling the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating variation; (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination; (iii) mutants with nonfunctional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae; and (iv) intrahost variation in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology, and pathogenesis of HCMV

Prevalence, Outcome, and Prevention of Congenital Cytomegalovirus Infection in Neonates Born to Women with Preconception Immunity (CHILd Study)

Background: Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disabilities. We designed a prospective study to investigate the rate, outcome, and risk factors of congenital CMV (cCMV) infection in neonates born to immune women, and the potential need and effectiveness of hygiene recommendations in this population. Methods: The study was composed of 2 sequential parts: an epidemiology (part 1) and a prevention (part 2) study. Performance of part 2 depended upon a cCMV rate >0.4%. Women enrolled in part 1 did not receive hygiene recommendations. Newborns were screened by HCMV DNA testing in saliva and cCMV was confirmed by urine testing. Results: Saliva swabs were positive for HCMV DNA in 45/9661 newborns and cCMV was confirmed in 18 cases. The rate of cCMV was. 19% (95% confidence interval [CI]:. 11-.29%), and 3 out of 18 infants with cCMV had symptoms of CMV at birth. Age, nationality, occupation, and contact with children were similar between mothers of infected and noninfected newborns. Twin pregnancy (odds ratio [OR]: 7.2; 95% CI: 1.7-32.2; P =. 037) and maternal medical conditions (OR: 3.9; 95% CI: 1.5-10.1; P =. 003) appeared associated with cCMV. Given the rate of cCMV was lower than expected, the prevention part of the study was cancelled. Conclusions: Newborns from women with preconception immunity have a low rate of cCMV, which appears to be mostly due to reactivation of the latent virus. Therefore, serological screening in childbearing age would be pivotal to identify HCMV-seropositive women, whose newborns have a low risk of cCMV. Clinical trials registration: www.clinicaltrials.gov (NCT03973359)

Slow cytomegalovirus-specific CD4+ and CD8+ T-cell differentiation: 10-year follow-up of primary infection in a small number of immunocompetent hosts

Differentiation of human cytomegalovirus specific T cells is a slow process requiring years. In the acute phase, EM predominate; subsequently, no contraction occurs (memory inflation) and TEMRA increase, especially among CD8+ T cells, while few LTM T cells appear. After some years, LTM stabilizes and predominate among CD4+

Diagnosis and counseling of fetal and neonatal HCMV infection.

Fetal HCMV infection is investigated by amniocentesis when a maternal primary infection is diagnosed or ultrasound (US/MRI) abnormalities are observed. In fetal blood, prognostic markers of symptomatic congenital infection may be evaluated for parental counseling. At birth, viral load measurement in body fluids may correlate with long-term sequelae, but the prognostic accuracy of symptomatic infection increases when maternal, fetal, and neonatal parameters are combined

Human cytomegalovirus (HCMV) long-term shedding and HCMV-specific immune response in pregnant women with primary HCMV infection

Human cytomegalovirus (HCMV) shedding has been extensively investigated in newborns and in young children, however, much less is known about it in immunocompetent adults. Shedding of HCMV was investigated in saliva, vaginal secretions and urine of pregnant women experiencing primary infection along with the development of the HCMV-specific immune response. Thirty-three pregnant women shed HCMV DNA in peripheral biological fluids at least until one year after onset of infection, while in blood HCMV DNA was cleared earlier. Significantly higher levels of viral load were found in vaginal secretions compared to saliva and urine. All subjects examined two years after the onset of infection showed a high avidity index, with IgM persisting in 36% of women. Viral load in blood was directly correlated with levels of HCMV-specific IgM and inversely correlated with levels of IgG specific for the pentameric complex gH/gL/pUL128L; in addition, viral load in blood was inversely correlated with percentage of HCMV-specific CD4(+) and CD8(+) expressing IL-7R (long-term memory, LTM) while viral load in biological fluids was inversely correlated with percentage of HCMV-specific CD4(+) and CD8(+) effector memory RA(+)(T-EMRA). In conclusion, viral shedding during primary infection in pregnancy persists in peripheral biological fluids for at least one year and the development of both antibodies (including those directed toward the pentameric complex) and memory T cells are associated with viral clearance