Ocular Involvement in Congenital Infections - TORCH. / Augenbeteiligung bei kongenitalen Infektionen ­ TORCH.

This review summarises the ophthalmological findings in congenital infections. Intrauterine infections are an important cause of childhood blindness. The most common infections are grouped under the acronym TORCH, which stands for Toxoplasma gondii, others, rubella, CMV, and herpes simplex. Overall, these infections are not very common in first-world countries during pregnancy, but are of particular importance because of the threat to vision. Diagnosis of infection or reactivation is a gynaecological challenge. However, ophthalmological examination of newborns can be appropriately targeted if the causative agent is known. The most important therapeutic agents used in the newborn are summarised.

Phylogenetic analysis of congenital rubella virus from Indonesia: a case report.

BACKGROUND: Rubella is a common inherited infection resulting in congenital cataracts and a significant cause of permanent vision loss in developing countries. In 2016, Indonesia had the highest number of congenital rubella syndrome (CRS) cases globally. Here, we report the first genotype of the rubella virus extracted from the eye lens from a child with congenital cataracts due to CRS. CASE PRESENTATION: A female neonate was delivered by an elective caesarean delivery with normal birth weight at term from a 24-year-old mother in the rural setting. The baby presented with bilateral congenital cataracts, small-moderate secundum atrial septal defect, severe supravalvular pulmonary stenosis, and profound bilateral hearing loss. She also had microcephaly and splenomegaly. The patient's serology showed persistent positive IgG for rubella virus at the age of four years and four months. Following extraction during cataract surgery, viral detection of the lenses identified the presence of rubella. Phylogenetic analysis confirmed that the virus was grouped into genotype 1E. CONCLUSIONS: Our study reports the first phylogenetic analysis of the rubella virus extracted from the eye lens of a child with CRS in Indonesia. The detection of the rubella virus from eye lenses is remarkably promising. Our findings also emphasize the importance of molecular epidemiology in tracking the origin of rubella infection toward achieving virus eradication.

Infections at the maternal-fetal interface: an overview of pathogenesis and defence.

Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym 'TORCH' (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission.

Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Relatives of rubella virus in diverse mammals.

Since 1814, when rubella was first described, the origins of the disease and its causative agent, rubella virus (Matonaviridae: Rubivirus), have remained unclear1. Here we describe ruhugu virus and rustrela virus in Africa and Europe, respectively, which are, to our knowledge, the first known relatives of rubella virus. Ruhugu virus, which is the closest relative of rubella virus, was found in apparently healthy cyclops leaf-nosed bats (Hipposideros cyclops) in Uganda. Rustrela virus, which is an outgroup to the clade that comprises rubella and ruhugu viruses, was found in acutely encephalitic placental and marsupial animals at a zoo in Germany and in wild yellow-necked field mice (Apodemus flavicollis) at and near the zoo. Ruhugu and rustrela viruses share an identical genomic architecture with rubella virus2,3. The amino acid sequences of four putative B cell epitopes in the fusion (E1) protein of the rubella, ruhugu and rustrela viruses and two putative T cell epitopes in the capsid protein of the rubella and ruhugu viruses are moderately to highly conserved4-6. Modelling of E1 homotrimers in the post-fusion state predicts that ruhugu and rubella viruses have a similar capacity for fusion with the host-cell membrane5. Together, these findings show that some members of the family Matonaviridae can cross substantial barriers between host species and that rubella virus probably has a zoonotic origin. Our findings raise concerns about future zoonotic transmission of rubella-like viruses, but will facilitate comparative studies and animal models of rubella and congenital rubella syndrome.

Congenital infections as contributors to the onset of diabetes in children: A longitudinal study in the United States, 2001-2017.

BACKGROUND: Maternal infections during pregnancy, particularly with rubella virus, were reported to increase the risk of diabetes in children. Widespread vaccination has decreased the number of infants with congenital rubella syndrome in the United States, although it remains a problem in developing countries. Because vaccine hesitancy has recently increased, we investigated the association between congenital infections with subsequent diabetes risk in children in the United States. METHODS: Using data from a nationwide private health insurer for years 2001-2017, 1 475 587 infants were followed for an average of 3.9 years (maximum 16.5 years). Information was obtained regarding congenital infections (rubella, cytomegalovirus, other congenital infections) and perinatal infections, as well as for the development of diabetes mellitus and diabetic ketoacidosis. RESULTS: There were 781 infants with congenital infections and 73 974 with perinatal infections. Diabetes developed in 3334 children. The odds of developing diabetes for infants with congenital rubella infection were 12-fold greater (P = .013) and, for infants with congenital cytomegalovirus infection, were 4-fold greater (P = .011) than infants without congenital or perinatal infection. Infants with other congenital infections had 3-fold greater odds of developing diabetes (P = .044). Results were similar for diabetes ketoacidosis. Infants with other perinatal infections had 49% greater odds of developing diabetes during the follow-up period (P < .001). CONCLUSION: Congenital and other perinatal infections are associated with elevated risks of developing diabetes mellitus during childhood. Vaccination for rubella remains an important preventive action to reduce the incidence of diabetes in children.

Safety profile of rubella vaccine administered to pregnant women: A systematic review of pregnancy related adverse events following immunisation, including congenital rubella syndrome and congenital rubella infection in the foetus or infant.

BACKGROUND: Data on the safety of inadvertent rubella vaccination in pregnancy is important for rubella vaccination programs aimed at preventing congenital rubella syndrome. METHODS: The association between monovalent rubella or combination vaccinations in or shortly before pregnancy and potential harm to the foetus was examined by conducting a systematic review and meta-analysis using fixed effect methods and simulation. RESULTS: Four cohort studies of inadvertently vaccinated and unvaccinated women were found, 15 cohorts of pregnant women who were rubella susceptible at time of inadvertent vaccination and 9 cohort studies with no information on susceptibility and case series. No case of vaccine associated congenital rubella syndrome (CRS) was identified. Cohort studies with an unvaccinated comparison group were limited in number and size, and based on these only a theoretical additional risk of 6 or more cases of CRS per 1000 vaccinated women (0% observed, upper 95% CI 0.6%) could be excluded. Based on cohorts of vaccinated rubella susceptible pregnant women a maximum theoretical risk of 1 CRS case in 1008 vaccinated women (0% observed, upper 95% CI 0.099%) was estimated. Asymptomatic rubella vaccine virus infection of the neonate was also noted (fixed effects estimate of risk overall 1.74%, 95% CI 1.21, 2.28). CONCLUSION: There is no evidence that CRS is caused by rubella-containing vaccines but transplacental vaccine virus infection can occur. CRS is effectively prevented by vaccination, thus the risk/benefit balance is unequivocally in favour of vaccination. The data confirm previous recommendations that inadvertent vaccination during pregnancy is not an indication for termination of pregnancy.

Rubella virus, Toxoplasma gondii and Treponema pallidum congenital infections among full term delivered women in an urban area of Tanzania: a call for improved antenatal care.

BACKGROUND: A significant proportion of newborns in the developing countries are born with congenital anomalies. OBJECTIVE: This study investigated congenital infections due to Rubella virus, Toxoplasma gondii, Treponema pallidum among presumed normal neonates from full term pregnant women in Mwanza, Tanzania. METHODS: Sera from mothers were tested for Treponema pallidum and Toxoplasma gondii infection while newborns from mothers with acute infections were tested for T. pallidum and T. gondii, and all newborns were tested for Rubella IgM antibodies. RESULTS: A total of 13/300 (4.3 %) mothers had T. pallidum antibodies with 3 of them having acute infection. Two (0.7 %) of the newborns from mothers with acute infection were confirmed to have congenital syphilis. Regarding toxoplasmosis, 92/300 (30.7 %) mothers were IgG seropositive and 7 had borderline positivity, with only 1/99 (1%) being IgM seropositive who delivered IgM seronegative neonate. Only 1/300 (0.3 %) newborn had rubella IgM antibodies indicating congenital rubella infection. CONCLUSION: Based on these results, it is estimated that in Mwanza city in every 100,000 live births about 300 and 600 newborns have congenital rubella and syphilis infections, respectively. Rubella virus and T. pallidum are likely to be among common causes of congenital infections in developing countries.

Congenital B-cell Acute Lymphoblastic Leukemia with Congenital Rubella Infection.

BACKGROUND: Congenital B-cell Acute lymphoblastic leukemia (ALL) is a rare malignancy. CHARACTERISTICS: A newborn infant presented with purpuric spots and ecchymotic patches, blueberry muffin rash, depressed neonatal reflexes, respiratory distress and hepatosplenomegaly. Peripheral smear revealed atypical blast cells. Serum ELISA was positive for Rubella IgM and IgG antibodies. Flow cytometry suggested congenital B-cell ALL. OUTCOME: The baby died after 3 days due to suspected intracranial hemorrhage. MESSAGE: Congenital leukemia may be rarely associated with congenital rubella infection.

Adverse pregnancy outcomes among pregnant women with acute Rubella infections in Mwanza city, Tanzania.

OBJECTIVE: This study investigated the adverse pregnancy outcomes among pregnant women with acute Rubella infections in the city of Mwanza, Tanzania. METHODS: A longitudinal study was conducted between 2014 and 2016 among pregnant women attending antenatal clinics. Women were screened for Rubella IgG and IgM antibodies using enzyme immunoassay (EIA). IgM seropositive pregnant women were followed up until the end of the pregnancy to determine Congenital Rubella Syndrome, congenital infections and other pregnancy outcomes. RESULTS: The median age of 685 enrolled pregnant women was 23 (IQR: 19-27) years. A total of 629(91.8%) were Rubella IgG seropositive while 61 (8.9%) were IgM seropositive. The IgM seropositivity was found to decrease significantly from first trimester to third trimester, p<0.001. Forty six (83.6%) of 55 Rubella IgM seropositive women had adverse pregnancy outcomes and 6 (10.9%) delivered neonates with CRS, making the overall incidence of CRS to be 6/685 (0.87%). First trimester IgM seropositive women had significantly higher adverse pregnancy outcomes than those in second/third trimesters (70.4% vs. 35.7, p=0.01). CONCLUSION: There is one case of CRS in every 100 pregnancies necessitating additional strategies to reach a goal of elimination of CRS in developing countries.

Maternal Prenatal Screening and Serologies.

BACKGROUND: Maternal prenatal screening is essential in preventing pregnancy complications as well as preventing and/or predicting neonatal and infant medical issues after delivery that are due to certain communicable diseases. PURPOSE: This article is aimed at gathering and presenting the most recent information regarding the most common prenatal screening laboratory studies and the implications with the various diseases. METHODS/SEARCH STRATEGY: An extensive medical database search was performed and the most relevant medical texts regarding the subject of prenatal screening were obtained. FINDINGS/RESULTS: Maternal screenings should be performed at the first provider visit once pregnancy has been confirmed. Additional screenings vary based on the specific disease and on maternal risk factors. Methods of screenings involve measuring antigen or antibody titers, a combination of antigen/antibody titers, or by specialized genetic tests. IMPLICATIONS FOR PRACTICE: Providers responsible for pregnant women should be able to identify which diseases they need to screen for and how to interpret the findings. Neonatal providers should be able to interpret the findings and they should also be able to manage neonates appropriately. IMPLICATIONS FOR RESEARCH: Future research should be aimed at developing better, cost-effective tests for both existing diseases and new diseases that either impact large or small populations of pregnant women and their fetuses.

Newborn Glaucoma: Do not Forget Infections.

Intrauterine infections can affect various structures of the developing fetal eye. Rubella infection results in congenital cataracts, keratopathy, retinopathy and less commonly, glaucoma. Ophthalmic manifestations of intrauterine cytomegalovirus (CMV) infection have been reported to be chorioretinitis, optic nerve colobomas, and corneal opacities, but have not been implicated in congenital cataract or congenital glaucoma. Concurrent infection with both rubella and CMV virus has not been reported. We report concurrent rubella and CMV infection in a baby born with corneal opacification, severe congenital glaucoma, and congenital cataract. It is important to recognize these babies early and investigate for intrauterine infections rather than assume they are all primary congenital glaucoma. Involvement of the cornea, glaucoma, and cataract make management of these babies a major challenge requiring a multidisciplinary team approach.

Underreporting of congenital rubella in Italy, 2010-2014.

In accordance with the goals of the World Health Organization Regional Committee for Europe, the Italian national Measles and Rubella Elimination Plan 2010-2015 aimed to reduce the incidence of congenital rubella cases to <1 case/100,000 live births by 2015. In Italy, a passive national surveillance system for congenital rubella and rubella in pregnancy is active since 2005. We estimated the degree of underreporting of congenital rubella, performing a capture-recapture analysis of cases detected through two independent sources: the national surveillance system and the national hospital discharge database, in the years 2010-2014. We found that 6 out of 11 cases tracked in the retrospective case-finding from hospital registries had not been notified to the surveillance system, and we estimated a degree of underreporting of 53% for the period 2010-2014. This approach showed to be simple to perform, repeatable, and effective. CONCLUSION: In order to reduce underreporting, some actions aimed at strengthening surveillance procedures are needed. The adoption on a routine basis of the review of hospital discharge registries for case-finding, monthly zero-reporting, and actions to train and sensitize all the specialists involved in the care of pregnant women and the newborns to notification procedures are recommended. What is Known • In Italy, the incidence of congenital rubella was below the WHO target of 1/100,000 live births in 2005-2015, except for two peaks in 2008 and 2012 (5 and 4/100,000, respectively). • Further efforts are required to improve congenital rubella surveillance so that it is more sensitive and specific. The WHO proposes retrospective case-finding from hospital records as an alternative approach to detect infants with congenital rubella. What is New • Underreporting of congenital rubella in Italy was 53% in 2010-2014. • Hospital discharge registries resulted to be an appropriate source to detect congenital rubella cases.

[TORCH syndrome: Rational approach of pre and post natal diagnosis and treatment. Recommendations of the Advisory Committee on Neonatal Infections Sociedad Chilena de Infectología, 2016]. / Síndrome de TORCH: enfoque racional del diagnóstico y tratamiento pre y post natal. Recomendaciones del Comité Consultivo de Infecciones Neonatales Sociedad Chilena de Infectología, 2016.

There is a lot of bacterial, viral or parasite infections who are able to be transmitted vertically from the mother to the fetus or newborn which implicates an enormous risk for it. The TORCH acronym is used universally to refer to a fetus or newborn which presents clinical features compatible with a vertically acquired infection and allows a rational diagnostic and therapeutic approach. The traditional "TORCH test" is nowadays considered not appropriate and it has been replaced for specific test for specific pathogens under well defined circumstances. The present document reviews the general characteristics, epidemiology, pathogenesis, diagnostic and therapeutic options for the most frequently involved pathogens in the fetus or newborn with TORCH suspicion.

Síndrome de TORCH: enfoque racional del diagnóstico y tratamiento pre y post natal. Recomendaciones del Comité Consultivo de Infecciones Neonatales Sociedad Chilena de Infectología, 2016 / TORCH syndrome: Rational approach of pre and post natal diagnosis and treatment. Recommendations of the Advisory Committee on Neonatal Infections Sociedad Chilena de Infectología, 2016

There is a lot of bacterial, viral or parasite infections who are able to be transmitted vertically from the mother to the fetus or newborn which implicates an enormous risk for it. The TORCH acronym is used universally to refer to a fetus or newborn which presents clinical features compatible with a vertically acquired infection and allows a rational diagnostic and therapeutic approach. The traditional "TORCH test" is nowadays considered not appropriate and it has been replaced for specific test for specific pathogens under well defined circumstances. The present document reviews the general characteristics, epidemiology, pathogenesis, diagnostic and therapeutic options for the most frequently involved pathogens in the fetus or newborn with TORCH suspicion.

Existen numerosas infecciones bacterianas, virales y parasitarias que pueden transmitirse desde la madre al feto o recién nacido (RN) y que significan un riesgo para él. El acrónimo TORCH se utiliza en forma universal para caracterizar a aquel feto o RN que presenta un cuadro clínico compatible con una infección congénita y que permite un enfrentamiento racional, tanto diagnóstico como terapéutico. El concepto tradicional de realizar un "test de TORCH" sin consideraciones específicas a cada paciente, hoy en día se considera no adecuado y ha sido reemplazado por exámenes específicos para patógenos específicos bajo circunstancias bien definidas. El presente documento revisa las características generales, epidemiológicas, patogénicas, diagnósticas y terapéuticas de los patógenos más frecuentemente involucrados en el estudio de pacientes con sospecha de TORCH.

Pathogenesis of Congenital Rubella Virus Infection in Human Fetuses: Viral Infection in the Ciliary Body Could Play an Important Role in Cataractogenesis.

BACKGROUND: Development of congenital rubella syndrome associated with rubella virus infection during pregnancy is clinically important, but the pathogenicity of the virus remains unclear. METHODS: Pathological examination was conducted on 3 aborted fetuses with congenital rubella infection. FINDINGS: At autopsy, all 3 aborted fetuses showed congenital cataract confirmed by gross observation. Rubella virus infection occurred via systemic organs including circulating hematopoietic stem cells confirmed by immunohistochemical and molecular investigations, and major histopathogical changes were found in the liver. It is noteworthy that the virus infected the ciliary body of the eye, suggesting a possible cause of cataracts. INTERPRETATION: Our study based on the pathological examination demonstrated that the rubella virus infection occurred via systemic organs of human fetuses. This fact was confirmed by immunohistochemistry and direct detection of viral RNA in multiple organs. To the best of our knowledge, this study is the first report demonstrating that the rubella virus infection occurred via systemic organs of the human body. Importantly, virus infection of the ciliary body could play an important role in cataractogenesis.