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.

Analysis of Morphological Changes in the CNS and Internal Organs of Macaca mulatta Monkeys after Intracerebral Injection of a Low-Attenuated Rubella Virus Strain.

We studied the localization and severity of morphological changes in CNS and internal organs of animals intacerebrally infected with a low-attenuated rubella virus strain "Orlov-14". The data obtained can be used as morphological criteria reflecting low level of attenuation of rubella virus strains to improve the control of the safety of attenuated strains of live rubella vaccines.

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.

Immunopathology of Virus-Induced Anterior Uveitis.

Herpes simplex virus, varicella zoster virus, human cytomegalovirus, and rubella virus are the most common causes of virus-induced anterior uveitis. They can present in a variety of entities not only with typical but also overlapping clinical characteristics. These viral infections are commonly associated with ocular infiltration of T cells and B/plasma cells, and expression of cytokines and chemokines typical of a proinflammatory immune response. The infections differ in that the herpes viruses cause an acute lytic infection and inflammation, whereas rubella virus is a chronic low-grade infection with slowly progressing immunopathological responses. The outcome of an intraocular viral infection may largely be guided by the characteristics of the virus, which subsequently dictates the severity and type of the immune response, and the host immune status.

The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small?

The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.

Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus.

Viral infections during pregnancy are a significant cause of infant morbidity and mortality. Of these, rubella virus infection is a well-substantiated example that leads to miscarriages or severe fetal defects. However, structural information about the rubella virus has been lacking due to the pleomorphic nature of the virions. Here we report a helical structure of rubella virions using cryo-electron tomography. Sub-tomogram averaging of the surface spikes established the relative positions of the viral glycoproteins, which differed from the earlier icosahedral models of the virus. Tomographic analyses of in vitro assembled nucleocapsids and virions provide a template for viral assembly. Comparisons of immature and mature virions show large rearrangements in the glycoproteins that may be essential for forming the infectious virions. These results present the first known example of a helical membrane-enveloped virus, while also providing a structural basis for its assembly and maturation pathway.

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.

Epidemiological characteristics of rubella and congenital rubella syndrome in the 2012-2013 epidemics in Tokyo, Japan.

A large rubella outbreak has been observed since June 2012 in Tokyo, Japan, and a rapid increase in the number of congenital rubella syndrome (CRS) cases have also been reported in Japan since October 2012. All the clinically diagnosed and laboratory-confirmed rubella cases reported in Tokyo from January 2012 to December 2013 and all the laboratory-confirmed CRS cases from January 2012 to March 2014 were analyzed. In total, 4,116 rubella cases were reported in Tokyo. Of these, 77.2% (n=3,176) were male; the highest number of cases occurred in males aged 35-39 years and in females aged 20-24 years. Complications included arthralgia/arthritis (19.4%), thrombocytopenic purpura (0.5%), hepatic dysfunction (0.3%), and encephalitis (0.1%). The circulating rubella virus in Tokyo was genotype 2B. The most possible site of transmission was the workplace. Because of the rubella epidemic, 16 CRS cases were reported in Tokyo from March 2013 to February 2014. Domestic infection with rubella was proven for all mothers of 16 cases. This situation suggests that Japan is still working to achieve rubella elimination.

Epidemiology and laboratory diagnoses of rubella in Hokkaido district during the Nationwide Outbreak in Japan, 2011-2013.

We report the epidemiology and laboratory diagnostic results of rubella cases from 2011 to 2013 in Hokkaido district, Japan. A total of 150 cases were officially reported as rubella; 102 (68%) involved males and 48 (32%) involved females. The highest proportion of cases were notified in 40-49-year-old age group among males and the 20-29-years-old age group among females. Forty-six cases (25 males and 21 females) had not been vaccinated, and 17 had been vaccinated, whereas 87 had the unknown vaccination status. Eighty-three cases (55.3%) showed the 3 typical principal rubella symptoms (fever, rash, and lymphadenopathy). Seven, 11, 92, and 40 cases were identified in the northern, eastern, central, and southern areas of Hokkaido district, respectively. In the central and southern areas of Hokkaido district, endemic rubella transmissions were indicated by both the epidemiological survey and molecular analyses. However, these outbreaks terminated spontaneously and did not expand to other areas of Hokkaido district. Fortunately, no congenital rubella syndrome (CRS) cases were reported during this observation period. However, to control virus transmission, prevent CRS, and maintain the routine vaccination program, the immediate introduction of an immunization strategy is required for susceptible individuals, particularly young adults.

[Epidemiologic control for rubella in pregnant women].

AIM: Evaluate effectiveness of measures specified by epidemiologic control for rubella in pregnant women. MATERIALS AND METHODS: 585 pregnant women with suspected measles were laboratory examined in 10 Regional Centers of Control for Measles and Rubella by EIA. RESULTS: 24 rubella infected pregnant women aged 16-36 years were detected among the examined pregnant women, most of those (91.7%) were either not immunized against rubella or had unknown immunization anamnesis: 16 women terminated pregnancy, in 8 women pregnancy ended with delivery at term. Of the 8 newborns only a single child had innate rubella infection (the child was clinically healthy). CONCLUSION: Epidemiologic investigation of each rubella case in pregnant women with obligatory laboratory examination of women and source of infection revealed a significant number of women at childbearing age susceptible to rubella virus that retains the possibility of birth of children with innate rubella syndrome.

Detection and genotyping of rubella virus from exanthematous patients suspected of having measles using reverse transcription-PCR.

Between July 2012 and March 2013, a total of 133 clinical specimens from 47 patients suspected of having measles were collected for virological surveillance in Aichi Prefecture, Japan. Facing the rubella epidemic, the reverse transcription (RT)-PCR protocol for measles virus (MeV) was modified to simultaneously detect rubella virus (RUBV) in these clinical specimens. As a result, 30 specimens from 15 patients were positive for RUBV and 8 specimens from 3 patients were positive for MeV. The RUBV genotype analysis for the samples from 13 patients revealed 12 samples as 2B and 1 sample as 1E. The results provided additional evidence for the difficulty in the diagnosis of exanthematous diseases based on clinical manifestations alone and the necessity of virological diagnosis to maintain the accuracy of case-based surveillance. Furthermore, the results indicated that the modified RT-PCR protocol could be useful as a routine procedure to simultaneously detect MeV and RUBV in clinical specimens of patients suspected of having exanthematous disease caused by these viruses.

Clinical epidemiological and molecular aspects of rubella outbreak with high number of neurological cases, Tunisia 2011-2012.

BACKGROUND: A large and unusually prolonged rubella outbreak occurred in Tunisia from April 2011 to July 2012 and was characterized by a high number of neurological cases. OBJECTIVES: To describe the outbreak and to perform virus genotyping of isolated virus strains. STUDY DESIGN: From January 2011 to December 2012, 5000 sera for serological diagnosis of acute rubella and 31 cerebrospinal fluid from patients with neurological symptoms were tested for the presence of rubella immunoglobulins G and M. Real-time PCR was performed on 49 throat swabs, 21 cerebrospinal fluid and 27 serum samples. Positive samples were assessed for virus genotyping by sequencing and the obtained sequences were compared to those previously isolated in the country. RESULTS: Acute rubella was confirmed in 280 patients including 15 neonates, 217 children and adults with mild rash and 48 patients with severe rubella (mainly encephalitis, n = 39). Most of acquired rubella cases (60.7%) were aged over 12 years with a male predominance observed in the age group 12-25 years (79%). Females belonged essentially to the unvaccinated age groups under 12 and over 25 years. Among the 23 samples tested positive by real-time PCR, six could be genotyped and clustered with either the 1E genotype, previously detected in Tunisia, or the 2B genotype which has never been isolated in Tunisia before. CONCLUSIONS: Gender and age distributions of the patients reflect the impact of the selective rubella vaccination program adopted in Tunisia since 2005. Genotype 1E continues to circulate and genotype 2B was probably recently introduced in Tunisia.

[A case of rubella encephalitis presenting as clinically mild encephalitis/encephalopathy with a reversible splenial lesion].

A 26-year-old male was admitted because of a fever, headache and disturbance of consciousness with lymph node swelling of the neck two days after developing a rash. A neurological examination revealed restlessness with irritability in response to sensory stimuli, such as an injection. Diffusion-weighted brain magnetic resonance imaging (MRI) revealed a hyperintense ovoid lesion in the splenium of the corpus callosum, which showed a low coefficient in the ADC map: the lesion disappeared after 22 days. An enzyme immunoassay (EIA) of the serum and cerebrospinal IgM were positive for rubella virus. The patient was therefore diagnosed with rubella encephalitis. He recovered gradually and was discharged on day 19 after the onset of symptoms without any sequelae. To our knowledge, this is the first case of rubella encephalitis presenting as clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). Although the exact mechanism underlying the development of rubella encephalitis is not well established, this case indicated that our patient had an immune-mediated secondary encephalitis. According to the survey of the pandemic of rubella from 2012 to April 2013 in Japan, the incidence of rubella encephalitis is thought to be relatively higher than was previously noted. This emphasizes the importance of vaccination for preventing encephalitis.

Epidemiología de las hospitalizaciones causadas por rubéola en la población general en España (1997-2006) / Epidemiology of hospitalisations caused by rubella in the general population in Spain (1997-2006)

Fundamento. La rubéola es benigna en niños, pero enembarazadas puede producir el síndrome de rubéolacongénita (SRC) con graves consecuencias para el feto.A pesar de que en España la cobertura vacunal actuales mayor del 95%, siguen produciéndose casos aisladosy brotes. El objetivo de este estudio es estimar la incidenciade hospitalizaciones por rubéola en España,(1997-2006).Material y método. Utilizando el conjunto mínimo básicode datos (Sistema Nacional de Vigilancia Epidemiológica)se ha calculado: tasa de hospitalización, estanciamedia y coste.Resultados. Hubo 267 hospitalizaciones, entre ellas 144por rubéola en el embarazo, 1 por SRC y 8 casos porencefalomielitis. La tasa de hospitalización global fuede 0,065 por 105 habitantes (IC95%=0,0649-0,0654). Lamediana del tiempo de hospitalización fue de 3 días. Elcoste medio de una hospitalización fue de 2.082 € y si secomplica con encefalomielitis asciende a 8.191 €.Conclusión. En España, sigue habiendo hospitalizacionespor rubéola, debidas fundamentalmente a problemasen la gestación y a complicaciones en el grupo depoblación susceptible existente(AU)

Background. Rubella is benign in children, but in pregnantwomen it can produce Congenital Rubella Syndrome(CRS) with severe consequences for the foetus. Inspite of vaccination coverage in Spain being above 95%,isolated cases and outbreaks continue to occur. Theaim of this study is to estimate the incidence of hospitalisationsdue to rubella in Spain (1997-2006).Methods. Utilising the basic minimum dataset (NationalSystem of Epidemiological Surveillance) we calculated:rate of hospitalisation, average stay and cost.Results. There were 267 hospitalisations, amongst them144 due to rubella during pregnancy, 1 due to CRS and8 due to encephalomyelitis. The overall rate of hospitalisationwas 0.065 per 105 inhabitants (IC95%=0.0649-0.0654). The average stay was 3 days. The average costof a hospitalisation was 2,082 €, and if complicated byencephalomyelitis it rose to 8.191 €.Conclusion. There continue to be hospitalisations dueto rubella, basically due to problems in gestation andto complications in the existing susceptible populationgroup(AU)