Congenital Virus Infection Research Articles

Placental Cytomegalovirus Infection.

In the United States, cytomegalovirus is the most common congenital viral infection and the number 1 cause of nonhereditary sensorineural hearing loss. The vast majority of infants may be asymptomatic, especially if cytomegalovirus is contracted later in the pregnancy, and some symptoms may have a delayed onset. Therefore, it is important for the pathologist to identify the common histologic findings to help confirm the diagnosis so the child can be followed for late sequelae. Histologic examination of the placenta is important in live births and in cases of intrauterine fetal demise. Chronic lymphoplasmacytic villitis and fibrotic, avascular villi are the most common findings. When present, Cowdry A intranuclear and basophilic intracytoplasmic inclusions are characteristic. Immunohistochemistry for cytomegalovirus can highlight these inclusions as well as the associated eosinophilic debris. In addition, polymerase chain reaction or viral culture on placental or fetal samples can be performed for confirmation.

Spotlight on … infection in obstetrics and gynaecology

Spotlight on … infection in obstetrics and gynaecology

Abortion and Zika Virus Congenital Infection.

Abortion and Zika Virus Congenital Infection.

Answer - Abortion and Zika Virus Congenital Infection.

Answer - Abortion and Zika Virus Congenital Infection.

Cytomegalovirus (CMV) seroprevalence in the adult population of Germany.

BackgroundInfection with cytomegalovirus (CMV) remains asymptomatic in most immunocompetent hosts, but is the leading cause of congenital viral infection worldwide and can be life-threatening in immunocompromised individuals. We aimed to assess CMV seroprevalence in a nationally representative sample of adults in Germany and to identify sociodemographic factors associated with CMV seropositivity.MethodsBlood samples from 6552 participants (18–79 years) of the “German National Health Interview and Examination Survey 1998”, a population-based sample of the adult population in Germany, were tested for the presence of CMV antibodies using an Ig-multiplex assay. Weighted seroprevalence was calculated and weighted binomial regression was used to identify factors associated with CMV seropositivity.ResultsOverall CMV seroprevalence was 56.7% (95%CI: 54.8–58.7%), with a higher seroprevalence in women (62.3%) than in men (51.0%). Seroprevalence increased with age: from 31.8% to 63.7% in men and from 44.1% to 77.6% in women when comparing the 18–29 with the 70–79 year age-group, respectively. CMV seroprevalence in women of childbearing age (18–45 years) was 51.7%. Factors significantly associated with CMV seropositivity were age, country of birth, smoking status, education, living in northern Germany and number of household members. In addition, having attended child care was associated with seropositivity in men, and number of siblings and living in East Germany in women.ConclusionOur results indicate that half the women of childbearing age were susceptible for primary CMV infection during pregnancy. CMV screening during pregnancy and informing seronegative women about CMV risk reduction measures could prevent congenital CMV infections with its serious consequences.

Abortion in Cases of Zika Virus Congenital Infection.

The emergency in international public health caused by the Zika virus gave rise to the discussion about abortion in cases of congenital Zika virus syndrome (CZS). Therefore, we propose to carry out a bibliographic review on abortion in these cases. Five databases were searched using the following terms: abortion, miscarriage, and zika, with the interposition of the Boolean operator "AND." In the selected literature, we found references to the lack of information concerning the risks and severity of CZS, to the great psychological distress suffered by pregnant women, and to the risk of unsafe abortions as a justification for abortion in cases of CZS. However, it is necessary to have available tests that could diagnose, in the first trimester of pregnancy, that the fetus has been affected by the virus, and that it may have important limitations, in order to subsidize the qualified discussion about abortion in these cases.

Zika Care Connect: Establishing a Provider Network for the Management of Zika Virus

Background: Access to specialty care providers for the management of infants congenitally exposed to Zika virus is critical to ensure appropriate and coordinated care. Early diagnosis and prompt initiation of specialty care has the potential to mitigate the long-term impact of Zika on children and families. Additionally, coordination of care and mental health services can assist and support affected families. Purpose: To improve access to recommended healthcare services for infants with congenital Zika virus infection through the development of a network of specialty care providers. Methods: Under …

Blueberry Muffin Baby: An Unusual Presentation of Infantile Neuroblastoma

AbstractNeuroblastoma is the most common solid tumor of infancy presenting clinically in a plethora of different and sometimes unpredictable ways with a wide range of symptoms. Young children can present with bluish skin metastases that may resemble bruising secondary to child abuse. Blueberry muffin baby had been reported to be a manifestation of either dermal erythropoiesis secondary to some congenital viral infections or neoplastic infiltrations. Among the neoplastic diseases, neuroblastoma has been the most common association with these subcutaneous skin metastases. Here, we report 2 months infant with neuroblastoma who presented with abdominal distension and multiple blueberry muffin nodules.

Kongenitális és perinatális vírusfertőzések és következményeik

Kongenitális és perinatális vírusfertőzések és következményeik

Kongenitális és perinatális vírusfertőzések korszerű mikrobiológiai diagnosztikája

Kongenitális és perinatális vírusfertőzések korszerű mikrobiológiai diagnosztikája

Type I interferons instigate fetal demise after Zika virus infection.

Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/β receptor (IFNAR)-deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1-/-) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1-/- dams mated with Ifnar1+/- sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/-) or do not express IFNAR (Ifnar1-/-) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1-/- than within the Ifnar1+/- concepti. Yet, rather unexpectedly, we found that only Ifnar1+/- fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1-/- littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.

Birth Prevalence of Congenital Cytomegalovirus (CMV) infection in a cohort of pregnant women in Bangladesh

Cytomegalovirus (CMV) is a frequent cause of congenital infection in humans in all regions of the world. In contrast to most congenital viral infections, congenital CMV infection and disease have been consistently demonstrated in populations with a high seroprevalence. Three hundred pregnant women were studied prospectively in their 1st, 2nd and 3rd trimester to determine the seroprevalence and seroconversion of CMV in pregnancy. After birth, babies were also tested for anti CMV IgM to determine the rate of birth prevalence. Anti CMV IgG and IgM tests were performed by chemiluminescence methods. All 300 (100%) pregnant women were anti CMV IgG positive and 180 (60%) were subsequently anti CMV IgM positive during different trimesters of pregnancy. Birth prevalence of CMV IgM antibody was 1.3% among babies of anti CMV IgM positive mothers whereas none in CMV IgM negative mothers (OR 1.01, 95% CI .996-1.027).It may be concluded that CMV IgG seroprevalence is high among Bangladeshi pregnant women and the rate of CMV reactivation is also high during pregnancy. Despite protection by maternal immunity a certain percent of babies acquire congenital CMV infection.

22: Identifying zika virus (ZIKV)-silenced gene targets in the placenta at a transcriptome-wide scale using AGO-clip sequencing technology

We and others have recently demonstrated that the placental trophoblast serves as a reservoir for viral proliferation throughout pregnancy. How ZIKV evades normal endogenous mechanisms of viral suppression in the placenta is poorly understood. Based on established evidence that placenta-specific miRNAs (such as C19MC) serve as potent gene silencers by binding the 3’ untranslated region (3’UTR), we hypothesized that identification of disrupted silenced placental miRNA targets following ZIKV infection at a transcriptome wide scale would elucidate means of evasion and potential therapeutic targets. Argonaute protein cross-linking immunoprecipitation coupled to high-throughput sequencing (AGO-CLIP-seq) served to directly identify targets of miRNAs by mapping AGO-RNA interactions. Using the Illumina TruSeq small RNA platform, we performed AGO-CLIP-Seq from primary human placental tissue (n=9). Analytics were completed on customized mapping pipelines, and annotated against human assemblies (Gencode). In validation experiments, we compared loss of silenced gene expression in isolated trophoblasts from n=10 unrelated donors infected in vitro with 1x105 pfu ZIKV or mock controls. The approach and results of the AGO-CLIP-seq analyses are shown in Fig. 1A. Consistent with placental-specific patterning, AGO-miRNA loading demonstrates a clear predominance (∼28% of total expression) of C19MC placental-specific miRNA coverage, which are significantly enriched and account for 25% (115/447) of unique 3’ UTR targets (Fig. 1B). In 10 unrelated subjects, we observed evidence of significantly disrupted miRNA-mediated gene silencing following infection of placental trophoblasts with ZIKV (Fig. 1C). Given their role in regulating apoptosis (CASP3) and fetal growth (IGFBP3), we find several to be of likely significance. This study is a novel approach to identify targets of viral mediated suppression, including several unique miRNA targets that may play a role in allowing ZIKV to infect placental trophoblastse. We speculate that miRNA mediated RNA control is a fundamental, rapid, molecular means of regulating the transcriptome in congenital viral infections, and our findings offer potential novel therapeutic targets.

ENTEROVIRALES AS A REASON OF INTRAUTERINE INFECTIONS OF FETUS AND NEONATAL DISEASES

Introduction. Intrauterine infections remain an urgent issue of modern Perinatology and belong to the group of diseases diagnosis of which is associated with some difficulties. The number of causative agents of intrauterine infections in case of ante-, intra- and perinatal infectionis practically unlimited. However, one of the first places belongs to pathogens of viral infections with enteroviruses being of the most interest, as a transplacental (vertical) way of infection the fetus and neonates was proved. The significance of enteroviruses in the pathology of the fetus and neonate is unknown, since there is no verification ofserotypes of enteroviruses in pregnant women and neonates.The objective is to determine the effect of enteroviruses on the fetus and neonate based on the verification of circulating enteroviruses serotypes, the definition of risk factors of the perinatal anamnesis, clinical course ofintrauterine enteroviral infection.Materials and methods. Clinical and laboratory examination of 834 mothers and their sick neonates with suspected intrauterine infections in the first 3 days of life was conducted. The subject of the study was a group of 224 infants with congenital viral infections. Intrauterineenteroviral infection was verified in 108 cases. General clinical and special methods of research were used. Specific diagnosis of intrauterine enteroviral infection was made using the cultural method, polymerase chain reaction and the modified reaction of complement binding withthe use of poly- and monovalent enteroviral diagnostic sera on the enzyme-immunoassay analyzer. Material for examination of children and mothers was the blood taken from the umbilical and peripheral veins and feces. Statistical processing was carried out with the computation of parametric and nonparametric criteria. The results of the research. In 224 children with congenital viral infections during verification of an etiological pathogen, prenatal enteroviral infections was diagnosed in 108 cases (48.2%), including 54 (50,0%) mature and 54 (50.0%) premature ones. In most casesenteroviruses were verified in association with other intrauterine enteroviral infection pathogens (mixed forms) in 91 (84,3%): in association with respiratory vi ruses in 33 (36,3%), with the causative agents of TORCH-group in 27 (29,7%), with bacterial pathogens in 31 (34,0%) and in the form of monoinfection in 17 (15,7%) neonates. On the basis of laboratory examinations the role of various serologicaltypes of enteroviruses in the structure of congenital viral infections in neonates was identified for the first time, with serotypes of entero 68-71 – in 67 (62,0%), echo – in 32 (29,6%) and Coxsackie B – in 15 (13,9%) predominating.The most severe course of infection was observed in premature infants. The most severe course of intrauterine enteroviral infection with the fatal outcome was observed in neonates in case of association of Coxsackie B6 with bacterial pathogens and influenza virus.Summary. On the basis of specific diagnostic methods, the role of various enteroviruses serotypes in the pathology of the fetus and neonates was identified. The most common perinatal risk factors for the development of intrauterine enteroviral infection in neonates are the presence of acute respiratory viral infections in pregnant women,abortion, premature labor, anemia, placental dysfunction, preeclampsia. The fact that enteroviruses cause visceral forms of lesions (serotypes of Coxacques B and ECHO) as well as subclinical forms of infection (serotypes of entero-68-71) in newborns was proved. Increased frequency (48,2%) of enteroviral isolation in neonate patients withintrauterine enteroviral infections, peculiarities of the severe clinical course motivate early diagnosis in case of visceral and generalized forms of intrauterine infections.

Pathogenesis of Non-Zika Congenital Viral Infections.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied.

A Tyrosine-Based Trafficking Motif of the Tegument Protein pUL71 Is Crucial for Human Cytomegalovirus Secondary Envelopment.

The human cytomegalovirus (HCMV) tegument protein pUL71 is required for efficient secondary envelopment and accumulates at the Golgi compartment-derived viral assembly complex (vAC) during infection. Analysis of various C-terminally truncated pUL71 proteins fused to enhanced green fluorescent protein (eGFP) identified amino acids 23 to 34 as important determinants for its Golgi complex localization. Sequence analysis and mutational verification revealed the presence of an N-terminal tyrosine-based trafficking motif (YXXΦ) in pUL71. This led us to hypothesize a requirement of the YXXΦ motif for the function of pUL71 in infection. Mutation of both the tyrosine residue and the entire YXXΦ motif resulted in an altered distribution of mutant pUL71 at the plasma membrane and in the cytoplasm during infection. Both YXXΦ mutant viruses exhibited similarly decreased focal growth and reduced virus yields in supernatants. Ultrastructurally, mutant-virus-infected cells exhibited impaired secondary envelopment manifested by accumulations of capsids undergoing an envelopment process. Additionally, clusters of capsid accumulations surrounding the vAC were observed, similar to the ultrastructural phenotype of a UL71-deficient mutant. The importance of endocytosis and thus the YXXΦ motif for targeting pUL71 to the Golgi complex was further demonstrated when clathrin-mediated endocytosis was inhibited either by coexpression of the C-terminal part of cellular AP180 (AP180-C) or by treatment with methyl-β-cyclodextrin. Both conditions resulted in a plasma membrane accumulation of pUL71. Altogether, these data reveal the presence of a functional N-terminal endocytosis motif that is an important determinant for intracellular localization of pUL71 and that is furthermore required for the function of pUL71 during secondary envelopment of HCMV capsids at the vAC.IMPORTANCE Human cytomegalovirus (HCMV) is the leading cause of birth defects among congenital virus infections and can lead to life-threatening infections in immunocompromised hosts. Current antiviral treatments target viral genome replication and are increasingly overcome by viral mutations. Therefore, identifying new targets for antiviral therapy is important for future development of novel treatment options. A detailed molecular understanding of the complex virus morphogenesis will identify potential viral as well as cellular targets for antiviral intervention. Secondary envelopment is an important viral process through which infectious virus particles are generated and which involves the action of several viral proteins, such as tegument protein pUL71. Targeting of pUL71 to the site of secondary envelopment appears to be crucial for its function during this process and is regulated by utilizing host trafficking mechanisms that are commonly exploited by viral glycoproteins. Thus, intracellular trafficking, if targeted, might present a novel target for antiviral therapy.

THE ROLE OF MORPHOLOGICAL STUDIES OF PLACENTA IN DIAGNOSIS OF INTRAUTERINE INFECTIONSOF NEWBORNS

Introduction. Infectious disorders of the afterbirth (or placenta) are now of frequent occurrence, and have specific morphologic manifestations, which significantly affects the course of pregnancy, childbirth, intrauterine growth and development and postnatal health of the infant.The purpose of the study was to optimize the diagnosis and prognosis of the severity of intrauterine infection in neonates based on an assessment of risk factors, perinatal history and the results of morphological studies of afterbirth of those mothers, who had children with intrauterine infection.Materials and methods. Clinical and laboratory examination of 834 mothers and their diseased newborns suspected to have intrauterine infection the first 3 days of life was performed. The subject of in-depth study was a group of 224 patients with newborns with congenital infections. The control group consisted of 30 apparently healthy newborns. Confirmation of intrauterine infection was conducted based on history, physical exam data, and standard tests and using morphological studies of the born placenta.Results of the study. Among the total number of examined newborns, intrauterine infection was verified in 708 (84.9%) patients. The subject of the in-depth study was a group of 224 (31.6%) diseased newborns with congenital viral infections. Among them were term infants - 132 (58.9%) and premature babies - 92 (41.1%). Among 224 children, 77 (34.4%) mixed viral infections, 62 (27.7%) viral and bacterial infections, 53 (23.6%) mixed viral TORCH infections with monoviral infections - in 32 (14.3%). Among the risk factors, acute respiratory viral infections predominate in pregnant women (45.5%), threatening miscarriage (43.7%), anemia of pregnancy (25.0%), preterm delivery (41.1%), placental dysfunction 23.2%), preeclampsia (17.4%), asphyxia of newborns (40.6%). Analyzing the results of a histological study of 224 placentas in women who gave birth to children with congenital viral infections we revealed that in addition to specific morphologic changes caused by respiratory viruses, 54 (24%) also manifested non-specific inflammation(deciduitis, villusitis) and diverse variants of altered placental circulation. It confirms that in addition to the direct harmful effect of the virus, the secondary hypoxia and fetal supply disturbance can occur. The absence of specific signs and symptoms of viral infections in pregnant women does not exclude the need to investigate the afterbirth of children at risk to have intrauterine infection.Conclusions. The results of the histological examination of the placentas substantiate both the etiology of congenital viral infections based on specific morphological features, as well as the effect of nonspecific inflammatory changes (basal deciduitis, vylusitis) and variations of transplacental circulation disturbances on prediction the severity of congenital viral infections in newborns.

Infection of iPSC Lines with Miscarriage-Associated Coxsackievirus and Measles Virus and Teratogenic Rubella Virus as a Model for Viral Impairment of Early Human Embryogenesis.

Human induced pluripotent stem cell (iPSC) lines are a promising model for the early phase of human embryonic development. Here, their contribution to the still incompletely understood pathogenesis of congenital virus infections was evaluated. The infection of iPSC lines with miscarriage-associated coxsackievirus B3 (CVB3) and measles virus (MV) was compared to the efficient teratogen rubella virus (RV). While CVB3 and MV were found to be cytopathogenic on iPSC lines, RV replicated without impairment of iPSC colony morphology and integrity. This so far outstanding course of infection enabled maintenance of RV-infected iPSC cultures over several passages and their subsequent differentiation to ectoderm, endoderm, and mesoderm. A modification of the metabolic profile of infected iPSC lines was the only common aspect for all three viruses. This study points toward two important aspects. First, iPSC lines represent a suitable cell culture model for early embryonic virus infection. Second, metabolic activity represents an important means for evaluation of pathogen-associated alterations in iPSC lines.

Long-term Visual and Ocular Sequelae in Patients With Congenital Cytomegalovirus Infection.

Cytomegalovirus (CMV) is the most common congenital viral infection in the United States. Visual and ocular sequelae in adolescents and adults who are congenitally infected with CMV have not been well studied. Better understanding of the long-term visual and ocular sequelae can help with early detection, intervention and appropriate educational accommodations. This study evaluated 237 patients (77 symptomatic, 109 asymptomatic and 51 control) who underwent a series of age-appropriate ophthalmologic, audiologic and neurodevelopmental examinations from 1982 to 2013. The frequency and etiology of visual impairment and other nonophthalmologic findings were recorded for each patient. Ophthalmologic findings were tabulated, and risk factors for abnormalities were analyzed. Fourteen of the 77 (18.2%) symptomatic and none of the asymptomatic and control subjects had severe visual impairments (P ≤ 0.006). Moderate visual impairment did not differ between symptomatic and asymptomatic subjects. Three asymptomatic subjects had retinal scars. The most common visual or ocular sequelae in the symptomatic group were strabismus (23.4%), chorioretinal scars (19.5%), cortical visual impairment (14.3%), nystagmus (14.3%) and optic nerve atrophy (11.7%). Three symptomatic patients had delayed visual deterioration because of later occurring retinal disorders: peripheral retinal scar, rhegmatogenous retinal detachment and Coats' disease. Symptomatic CMV patients experienced more ophthalmologic sequelae and significantly worse visual outcomes than asymptomatic CMV and control patients. Later occurring retinal disorders were found in symptomatic patients, and there is no clear evidence that CMV can reactivate in the retinas of children who were congenitally infected. Major risk factors for severe visual impairment included symptomatic status, optic nerve atrophy, chorioretinitis, cortical visual impairment and sensorineural hearing loss.

FEATURES OF CENTRAL NERVOUS SYSTEM DEFEAT IN NEWBORNS WITH INTRAUTERINE VIRAL INFECTIONS

Introduction. Intrauterine infections with central nervous system lesions remain an urgent problem of modern perinatology, neonatology and pediatrics and belong to a group of diseases whose diagnosis is associated with certain difficulties. The number of pathogens of intrauterine infections with an ante, intra- and perinatal infection is practically unlimited. However, one of the first places belongs to the causative agents of viral infections, the prevalence of which is not specified in connection with the difficulties of diagnosis. The purpose of the study was to determine the features of central nervous system damage in newborns with intrauterine infections based on the results of the verification of etiologic pathogens, the evaluation of risk factors for perinatal history and the specific features of the clinical course of intrauterine infections. Materials and methods. Clinico-laboratory examination of 834 mothers and their sick newborns with suspicion of intrauterine infections in the first 3 days of life was performed. The subject of the study was a group of 224 patients with newborns with congenital viral infections. The control group consisted of 30 conditionally healthy newborns. The methods were general clinical and special studies (luminescence microscopy, culture method, polymerase chain reaction, serodiagnostics). Materials for examination in children and mothers were blood from the umbilical and peripheral veins, feces. Statistical processing was carried out with the calculation of parametric and nonparametric criteria. Results of the research. Among the total number of examined newborns with suspected congenital infection, congenital viral infections were verified in 224 (31.6%). Among them, term infants - 132 (58.9%), premature babies - 92 (41.1%). Among 224 children, 77 (34.4%) mixed virus infections, 62 (27.7%) viral and bacterial infections, 53 (23.6%) mixed-virus-TORCH infections and monoviral infections - in 32 (14.3%). It was proved that all children had different clinical variants of neurological disorders. Among the factors of perinatal risk are acute respiratory infections in pregnant women, the threat of abortion, anemia of pregnant women, early delivery, placental dysfunction, preeclampsia, birth asphyxia. When the etiologic pathogen was verified, the influenza A virus was defined in 15.6%, parainfluenza in 20.5%, adenovirus in 40.6%, the PC virus in 27.2% and enterovirus in 48.2%, cytomegalovirus - in 56.6%, the herpes simplex virus - in 22.6%. It is proved that along with severe lesions of the central nervous system in the form of cerebral edema, intracranial hemorrhages, meningoencephalitis, hypoxic-ischemic lesions with oppression syndrome, hypertensive hydrocephalic syndrome or indistinct neurologic symptoms at birth and in the first day of life in the form of moderate muscular dystonia and tremors. Characteristic signs on the neurosonogram in monovirus infections were predominantly hypoxic-ischemic structural changes, with mixed forms of viral infections, signs of intraventricular hemorrhages of I or II degree, subependimal cysts and signs of ventriculitis predominated. Conclusions. High frequency (31.6%) of virus isolation in patients with newborns at risk for intrauterine infection and their mothers, features of the clinical course of intrauterine viral infections with central nervous system damage motivate early clinical and laboratory diagnosis.