Viral Congenital Infection Research Articles

Awareness of Pregnant Patients about Congenital Cytomegalovirus Infection-A Semi-Systematic Review.

Background: Cytomegalovirus (CMV) infection represents a major issue worldwide, since it constitutes the most common viral congenital infection, with a prevalence of 0.58% and 1-5% in developed and developing countries, respectively. According to recent studies, prenatal treatment significantly decreases the risk of vertical CMV transmission, and early intervention may even prevent the termination of pregnancy. This study aimed to investigate the level of awareness of CMV among pregnant patients through a semi-systematic review. Methods: We included all of the original articles investigating knowledge and awareness about CMV infection among pregnant women. Our research included the PubMed database. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, the Covidence system automatically guided us to screen the titles and/or abstracts, and then full-texts, followed by data extraction from the eligible studies. Results: We screened 764 studies altogether, with 13 studies included in this analysis. Knowledge about the existence of CMV infection risk varied between the articles, ranging from 11.4% in a study performed in Ireland to 60% reported in a study on the French population. Studies analyzing the impact of educational interventions on patients' knowledge about preventive measures reported significant improvement compared to their level of awareness before the intervention. Conclusions: Patients' awareness and knowledge about CMV seemed to be generally low or very low during the last decade before the development of effective secondary prevention methods. Educational interventions seem to be effective, and therefore their wide use could be of potential benefit. In the era of available secondary prevention of vertical transmission, it is crucial to concentrate the efforts of different stakeholders to increase the awareness of cCMV among pregnant women.

Case of Autoimmune Haemolytic Anaemia (Aiha) in an Immunocompetent 1-Month-Old Child with Congenital Cytomegalovirus (cCMV) Infection

Here we report a case of congenital CMV infection with rare presentation as haemolytic anaemia in a 50-day-old infant. Clinical manifestations of our patient were pallor, jaundice, hepatosplenomegaly, and a deranged coagulation profile. Congenital CMV being the most common viral congenital infection should be suspected in every neonate and infant presenting with haemolytic anaemia. It is also the most common non-genetic cause of SNHL and not much is yet there for its prevention except for primary prevention as the role of immunoglobulin is still under trial.

Development of a CRISPR-Cas12a rapid diagnostic for human cytomegalovirus

Despite decades of research, human cytomegalovirus (CMV) continues to contribute to significant morbidity and mortality in transplant settings and remains the leading cause of viral congenital infections. Clinical diagnosis of CMV infection and/or reactivation under these settings is completed using real time quantitative polymerase chain reaction (RT-qPCR). This assay performs well but is hampered by poor sensitivity and a lack of standardization among testing facilities. A point-of-care rapid diagnostic to determine CMV viremia could address these issues and improve patient care. In this manuscript, we introduce clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a technology to design and validate a rapid diagnostic for CMV. This system was tested using CMV spiked human saliva and urine samples. Sensitivity of the assay was ∼10 infectious units (IU)/mL. Specificity of the assay was robust and failed to detect other herpesviruses. Collectively, we have designed and validated a rapid diagnostic for CMV that overcomes limitations of the current standard diagnostic. This assay has the potential to be used as a point-of-care screening tool in transplant and neonatal settings.

Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro

Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.

Diagnosis of congenital infections in premature, low-birthweight newborns with intrauterine growth restriction caused by cytomegalovirus (CMV), herpes simplex virus (HSV), Parvo-B 19, and Zika virus: a systematic review.

To identify the prevalence of viral congenital infections in newborns classified as premature, low-birthweight, small for gestational age or intrauterine growth restriction. The definition considered for selecting papers were: P as newborns younger than 28days; V as low-birthweight, prematurity and intrauterine growth restriction; O as frequency of congenital infections with Cytomegalovirus, Parvovirus B19, Herpes Simplex, and Zika virus. The research was performed using EMBASE, LILACS, SCOPUS and MEDLINE databases, with no limitations on date and language. Eight studies were included. Manuscripts including Herpes Simplex, Zika virus or Parvovirus B19 did not fulfill the defined criteria. A wide variation in the frequency of CMV congenital infection (0-4.8%) was found, which might be attributed to regional and methodological differences between investigations. Newborn characteristics associated with CMV congenital infections may direct investigations towards these patients with a higher probability of infection. However, as data are controversial, studies concerning screening of infection are important to define recommendations of diagnosis.

Hygiene promotion might be better than serological screening to deal with Cytomegalovirus infection during pregnancy: a methodological appraisal and decision analysis

BackgroundCytomegalovirus infection is the most frequent viral congenital infection, with possible consequences such as deafness, or psychomotor retardation. In 2016, the French High Council of Public Health was mandated to update recommendations regarding prevention of cytomegalovirus infection in pregnant women. We summarize a critical appraisal of knowledge and deterministic decision analysis comparing the current no-screening situation to serological screening during pregnancy, and to hygiene promotion.MethodsScreening was defined as systematic serological testing, during the first trimester, with repeated tests as needed, to all pregnant women. Outcomes were: 1) severe sequela: intellectual deficiency with IQ ≤ 50 or hearing impairment < 70 dB or sight impairment (≤ 3/10 at best eye); 2) moderate sequela: any level of intellectual, hearing or sight deficiency; and 3) death or termination of pregnancy. We simulated the one-year course of cytomegalovirus infection in a cohort of 800,000 pregnant women. We developed a deterministic decision model, using best and min-max estimates, extracted from systematic reviews or original studies.ResultsRelevant data were scarce or imprecise. We estimated that 4352 maternal primary infections would result in 1741 foetal infections, and an unknown number of maternal reinfections would result in 1699 foetal infections. There would be 788 cytomegalovirus-related consequences, including 316 foetal deaths or terminations of pregnancy, and 424 moderate and 48 severe sequelae. Screening would result in a 1.66-fold increase of poor outcomes, mostly related to a 2.93-fold increase in deaths and terminations of pregnancy, not compensated by the decrease in severe symptomatic newborns. The promotion of hygiene would result in a 0.75-fold decrease of poor outcomes, related to both a decrease in severe sequelae among symptomatic newborns (RR = 0.75; min-max: 1.00–0.68), and in deaths and terminations of pregnancy (RR = 0.75; min-max: 0.97–0.68).ConclusionsPrevention of cytomegalovirus infection during pregnancy should promote hygiene; serological screening should not be recommended.

Low birth weight and head circumference as potential biomarkers of sensorineural hearing loss in asymptomatic congenitally CMV-infected infants.

Congenital cytomegalovirus infection (cCMV) represents the most common viral congenital infection and non-genetic cause of childhood sensorineural hearing loss (SNHL). Newborns with symptomatic cCMV disease are at high risk for long term neurologic sequalae. However, most newborns with cCMV are asymptomatic and have a significantly better prognosis. About 10 % may develop sequalae, mainly SNHL. This study aimed to evaluate risk factors associated with the development of sensorineural hearing loss, in children with asymptomatic congenital CMV infection. A total of 70 patients with asymptomatic cCMV were retrospectively evaluated. Maternal age, type and trimester of maternal infection, maternal or newborn treatment as well as gestational age and anthropometric measures of newborns were examined as predictors of SNHL. The incidence of SNHL in children with asymptomatic cCMV correlated with low birthweight as well as with both birth weight and head circumference low z-scores adjusted for gestational age. Logistic regression analysis confirmed these results. There was no association between type or trimester of maternal infection and the development of SNHL. Study results underscore the need for biomarkers to identify asymptomatic cCMV infants at risk for SNHL development, suggesting that z-scores of birth weight and head circumference adjusted for gestational age may be examined as such in larger cohorts.

Detection of congenital cytomegalovirus in newborns using nucleic acid amplification techniques and its public health implications.

Human cytomegalovirus (HCMV), a herpesvirus, is an important human pathogen that causes asymptomatic infections in healthy or immunocompetent individuals but can lead to severe and potentially life-threatening complications in immune-immature individuals such as neonates or immune-compromised patients such as organ-transplant recipients and HIV-positive individuals. Congenital HCMV infection represents a significant public health issue and poses substantial healthcare and economic burden to society. This virus causes the most common viral congenital infection worldwide, and is the leading non-genetic cause of sensorineural hearing loss in children in developed countries. Congenital HCMV infection is believed to fulfill the criteria of the American College of Medical Genetics to be considered as a condition targeted for a newborn screening program. This is because congenital HCMV infection can be identified during a time (within 2 days after birth) at which it would not ordinarily be detected clinically, and there are demonstrated benefits of early detection, timely intervention, and efficacious treatment of the condition. Recent progresses in developing polymerase chain reaction-based approaches to detect HCMV in samples obtained from newborns have generated much excitement in the field. In this review, we highlight the recent progress in diagnostic techniques that could potentially be used for the detection of HCMV infection in neonates and its direct implications in public health settings for diagnosing congenital HCMV infection.

Seroprevalence of Cytomegalovirus Among Paediatric Patients with Hearing Loss Attending National Ear Care Centre Kaduna Northwest Nigeria

Cytomegalovirus cause viral congenital infection at any stage of pregnancy leading to congenital defects, which can either be primary or recurrent and hearing loss is one of the common congenital CMV infection occurring in 10-15% of infected children. This study, therefore examined the seroprevalence of cytomegalovirus among paediatric patients with hearing loss attending National Ear Care Centre Kaduna northwest Nigeria. A total of 77 samples was collected from patients aged between 0-13 years, diagnosed of hearing impairment and screened for Cytomegalovirus IgG and IgM specific antibodies using ELISA method at National Ear Care Centre Kaduna State North West Nigeria. Among the 77 (100%) patients screened, 35 (45.5%) were male, while 42 (54.5%) were female with mean age (2.04). The study reveavled that, of the total numbers screened, 62 (80.5%) were IgG specific antibodies positive, while 15 (19.5%) were IgG specific antibodies negative, and none of the patient were positive for IgM specific antibodies. the result of patients based on their gender status show male patients 21 (60%) were positive while 14 (40%) were negative for CMV IgG specific antibodies. The female is 33 (78.5%) positive and 9 (21.4%) negative for CMV IgG specific antibodies. The findings hearing impairment is associated with cytomegalosvirus showing statistically significant in IgG specific antibodies (P<0.05), while in IgM it is not statistically significant. Therefore CMV infection is prevalent among patients with Hearing impairment and affect the social economic and political status of the patients.

Diagnosis, gB genotype distribution and viral load of symptomatic congenitally infected CMV patients in Cuba.

Cytomegalovirus (CMV) is the leading cause of viral congenital infection. Some viral factors have been proposed to be CMV pathogenicity markers. The objective of this study was to investigate the frequency of congenital CMV infection in symptomatic patients and the possible association with the CMV glycoprotein B (gB) genotype and viral load. A total of 361 newborns (NB) and 158 pregnant women (PW) with clinically suspected CMV infection were enrolled. Studied samples included urine, saliva, serum, vaginal swabs and amniotic fluid. CMV infection was diagnosed by multiplex nested PCR. CMV gB genotyping was performed on infected samples, followed by viral load determination. Overall, 18.7% of the tested patients were positive for CMV infection, 19.7% of NB were congenitally infected and 16.5% of PW showed active CMV infection. gB-2 was the most prevalent genotype detected (39/97 patients). gB CMV mixed infections were detected in 12 patients. gB-2 was associated with mono-infections (P<0.01). Mixed infections showed higher levels of viral load compared with gB mono-infection (P=0.03). Hepatomegaly, splenomegaly, jaundice, sepsis-like syndrome and malformations were the most prevalent clinical findings. gB-4 was more frequently associated with sepsis-like syndrome than other gB genotypes (P=0.04, odds ratio=4.3, confidence interval: 0.9 to 21.6). The difference in medians of CMV load was statistically significant among patients presenting different clinical signs (P=0.04). This study showed that CMV is a frequent cause of congenital infection in symptomatic Cuban patients. Despite gB2 being the most frequently detected, gB-4 was the only genotype associated with clinical features (sepsis-like syndrome in NB). No other associations among specific genotypes and clinical characteristics were found. Further studies are needed to clarify the role that viral load and genotype play in the outcome of congenital infection.

Effect of cytomegalovirus infection on temporal lobe development in utero: Quantitative MRI studies

Several environmental factors, including viral infections during fetal development, are known to increase the risk of schizophrenia. Cytomegalovirus (CMV) is the main cause of viral congenital infection. Since changes in temporal lobe structures are a consistent finding in imaging studies of adult schizophrenics, we investigated possible derangement in temporal lobe development in CMV infected fetuses. Abdominal MRI (1.5 T) was performed using a single-shot fast spin echo T2-weighted sequence. MRI volumetry was employed to measure brain and temporal lobe size in 27 CMV infected fetuses and 52 gestational age matched controls in utero. The ratio of temporal lobe to whole brain was computed for each fetus and group comparisons were performed using Student's t-test or ANOVA. Temporal lobe volumes, normalized to whole brain and co-varied with gestational age; were significantly smaller in fetuses infected with CMV compared to uninfected fetuses. (Infected group mean ± SEM: 0.086 ± 0.006, controls: 0.113 ± 0.003, p < 0.0001). Infection during the 1st and 2nd trimester had a more pronounced effect than infection during the 3rd trimester. Infected fetuses with no MRI findings had significantly lower temporal lobe/whole brain ratios than controls (0.092 ± 0.008, p < 0.01, N = 11) and the lowest ratios were observed in fetuses with overt findings such as cysts or gray matter heterotopy (0.067 ± 0.015). These results demonstrate the ability of quantitative fetal brain MRI to detect previously unreported, specific deficits in brain development in CMV infected fetuses, which, in conjunction with other genetic and environmental factors, may contribute to the risk of developing schizophrenia later in life.

Ganciclovir Population Pharmacokinetics in Neonates Following Intravenous Administration of Ganciclovir and Oral Administration of a Liquid Valganciclovir Formulation

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Diagnosis of congenital cytomegalovirus infection by detection of viral DNA in dried blood spots

Background: The reference method of cytomegalovirus (CMV) isolation from urine or saliva is not a feasible routine technique for all newborns, and laboratory diagnosis of this infection would be useful both for epidemiological purposes and to enable prompt institution of adequate measures to identify and correct late sequelae. Extraction and amplification of viral DNA from dried blood spots (DBS) collected from babies in the first days of life during routine screening for genetic and metabolic disorders has been proposed for the early diagnosis of viral congenital infections. Objectives: To test the method for CMV DNA extraction from DBS and to evaluate the results obtained in newborns with and without a diagnosis of congenital infection based on viral isolation from urine and or saliva at birth. Study design: DBS from Guthrie cards collected in babies who underwent virological tests for CMV infection were tested for CMV DNA by observers blinded to the virological results. DNA was extracted from DBS both in water and in cell culture medium according to Shibata et al. with minor modifications. The products of nested polymerase chain reactions (PCR) amplifying two regions in the IE1 and gp58 genes were detected by agarose gel electrophoresis. Strict control measures were adopted to avoid carryovers and contaminations. Results: DBS from the eight symptomatic and 11 asymptomatic congenitally infected babies were positive when extraction was performed in medium, whereas extraction in water failed to identify two of the asymptomatic cases. The results obtained with the two extraction methods agreed in the remaining cases; the 71 CMV negative control babies were negative and two out of 21 cases of supposed postnatal infection were diagnosed as congenital on the basis of a positive DBS. All positive cases were identified by gp58 PCR but only slightly over half of them by IE1 PCR. Extraction in medium was more efficient than in water. Conclusions: The method of CMV DNA extraction in medium followed by amplification of the gp58 region showed 100% sensitivity and specificity compared with isolation in cell culture. Therefore, we propose this procedure to diagnose congenital CMV infection at birth and also later.