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.

Assessment of Economic Burden of Concurrent Measles and Rubella Outbreaks, Romania, 2011-2012.

We estimated the economic impact of concurrent measles and rubella outbreaks in Romania during 2011-2012. We collected costs from surveys of 428 case-patients and caretakers, government records, and health staff interviews. We then estimated financial and opportunity costs. During the study period, 12,427 measles cases and 24,627 rubella cases were recorded; 27 infants had congenital rubella syndrome (CRS). The cost of the outbreaks was US $9.9 million. Cost per case was US $439 for measles, US $132 for rubella, and US $44,051 for CRS. Up to 36% of households needed to borrow money to pay for illness treatment. Approximately 17% of patients continued to work while ill to pay their treatment expenses. Our key study findings were that households incurred a high economic burden compared with their incomes, the health sector bore most costs, and CRS costs were substantial and relevant to include in rubella outbreak cost studies.

Trends and spatial distribution of MMR vaccine coverage in Brazil during 2007-2017.

We analyzed the time trends and spatial distribution of MMR vaccine coverage in Brazil during 2007-2017. In early 2018, a measles outbreak started in the North region of Brazil, reaching 11 of the 27 federal units by January 24, 2019. In this period, 10,302 cases were confirmed. Although the reintroduction of measles in Brazil is likely due to migration from Venezuela, the spread of the virus was made possible by the low levels of MMR coverage, as a result of significant decreases during the study period. Areas with high concentration of municipalities with low coverage are more susceptible to the spread of the virus, especially in the North and Northeast regions. Increasing vaccination coverage is essential to block the ongoing outbreak in Brazil. Vaccination strategies might target priority areas, especially those with a marked decrease in coverage. Moreover, it is essential to extend actions to travelers, migrants and refugees.

Epidemiological profile and progress toward rubella elimination in China. 10 years after nationwide introduction of rubella vaccine.

BACKGROUND: Rubella-containing vaccine (RCV) became available in China in 1993 and was introduced nationwide into the Expanded Immunization Program (EPI) in 2008. We evaluated implementation and impact of RCV from 2 years prior to nationwide introduction through the 10 years after nationwide introduction. METHODS: We analyzed RCV lot-release (doses distributed) data, 1- and 2-dose RCV coverage, and rubella data from China's nationwide disease surveillance system to describe the current status and changes in rubella epidemiology between 2005 and 2017. RESULTS: While the vaccine was included into the routine immunization program in 2008, its full implementation required 4 years due to sporadic vaccine supply constraints. RCV1 and RCV2 coverage increased from 51.5% and 39.0% in 2008 to >95% during 2012 through 2016. From 2005 to 2017, the annual incidences (per million) of rubella ranged from 91.09 in 2008 down to 1.16 in 2017; reductions occurred in all age groups. The proportion of cases among individuals ≥20 years old increased from 0.97% in 2005 to 31.2% in 2017. In the better-developed eastern China, most cases were among adults; in central and western China, most cases were among children or adolescents. CONCLUSIONS: The marked decrease rubella was a result of inclusion of RCVs into EPI targeting children less than 2 years of age and achieving high level of 2-dose coverage. Rubella was reduced in absolute terms, and its epidemiology was changed to older cases with substantial inter-province variation. Ensuring full vaccination of school children and identifying strategies to reach adults with measles and rubella combined vaccines will be important to hasten elimination of rubella and prevent CRS outbreaks.

Seventy-five years of estimating the force of infection from current status data.

The force of infection, describing the rate at which a susceptible person acquires an infection, is a key parameter in models estimating the infectious disease burden, and the effectiveness and cost-effectiveness of infectious disease prevention. Since Muench formulated the first catalytic model to estimate the force of infection from current status data in 1934, exactly 75 years ago, several authors addressed the estimation of this parameter by more advanced statistical methods, while applying these to seroprevalence and reported incidence/case notification data. In this paper we present an historical overview, discussing the relevance of Muench's work, and we explain the wide array of newer methods with illustrations on pre-vaccination serological survey data of two airborne infections: rubella and parvovirus B19. We also provide guidance on deciding which method(s) to apply to estimate the force of infection, given a particular set of data.

The history of rubella and rubella vaccination leading to elimination.

Congenital rubella syndrome (CRS) was discovered in the 1940s, rubella virus was isolated in the early 1960s, and rubella vaccines became available by the end of the same decade. Systematic vaccination against rubella, usually in combination with measles, has eliminated both the congenital and acquired infection from some developed countries, most recently the United States, as is confirmed by the articles in this supplement. The present article summarizes the clinical syndrome of CRS, the process by which the vaccine was developed, and the history leading up to elimination, as well as the possible extension of elimination on a wider scale.

Jewels in the crown: The Medical Journal of Australia's 10 most-cited articles.

According to data from the Institute for Scientific Information (ISI), the most-cited MJA article is Cade's ground-breaking report on the effect of lithium in mania (1949; 888 citations), followed by Marshall et al's reports on the role of Helicobacter pylori in gastroduodenal disease (1985; 766 and 523 citations, respectively). Others in the "top 10" span decades and disciplines; all have a common grounding in Australian data of global relevance.

Teratogen update: congenital rubella.

It is apparent that there are many unanswered questions about the pathogenesis of CRS. For instance, the chance of embryonic infection decreases in the second semester only to increase again in the third trimester. This is presumably due to unspecified changes in the placenta. When the embryo is infected early in the first trimester it does not appear to have any conventional immunological response to prevent spread of the virus. Yet it has been suggested that only 1 in 10(3) to 10(5) of its cells become infected. If this is true, what controls the spread of the virus in the early embryo? Why does the virus not affect major morphogenetic processes? There is considerable evidence that the virus spreads through the vascular system of the infected fetus and the observed cardiovascular, CNS, and hearing defects may be primarily due to focal cytopathic damage to the walls of blood vessels and lining of the heart; subsequent organ infection and/or ischemia may lead to further damage. Damage to blood vessels is probably extensive throughout the fetus and may be the cause of the generalized growth retardation. The effects in the eye appear to be due to a direct cytopathic effect, particularly on the lens. The short susceptible period for cataract formation is consistent with the protective effect of the lens capsule. Deafness, cardiovascular and neurological damage, and retinopathy all occur when infection takes place in the first 16 weeks of gestation and are rare after this time, despite the absence of any obvious morphological or functional changes in the susceptible structures. This termination of susceptibility in the second trimester is consistent with development of the fetal immune response and increased transfer of maternal IgG. The effect on blood vessels in particular may be limited by antibody production, although existing endothelial infection and damage may be progressive. The fetus seems unable to rid itself of established intracellular virus. The causes of the well-established late manifestations remain unknown. If these serious late-appearing effects are due to prenatal damage, then it is possible that other human teratogens may also cause unexpected late symptoms. This should also be a concern in the area of animal reproductive toxicology testing.

Vacunación antirrubéolica: la vacuna y las estrategias / Vaccination antimeasles: the vaccine and the strategies

Las primeras vacunas utilizadas para uso generalizado fueron las elaboradas con las cepas HPV77 y la Cendehill en 1969. A partir de entonces diversas vacunas han estado disponibles en el mercado, pero la de uso más generalizado es la preparada con la cepa RA27/3 cultivada en células diploides humanas que es más inmunogénica y estimula tanto la producción de anticuerpos humorales como secretorios, todo ello sin que se presente un incremento de los efectos colaterales indeseables. La vacuna antirrubéolica existe en tres presentaciones: sola o asociada con otras, la viral doble (rubéola-sarampión) y la viral triple (rubéola-sarampión-parotiditis). En las tres formas la dosis es de 0.5 mL, se prepara en forma liofilizada y debe guardarse en refrigeración (entre 2§C y 8§C) antes de su reconstrucción. Una vez reconstruida debe aplicarse antes de ocho horas. En relación con la vacunación antirrubéolica, existen varias posibles estrategias. Las más importantes son: 1.No incluir a la vacuna contra la rubéola en los programas nacionales de vacunación. 2.Vacunar a todos los suceptibles mayores de un año de edad con énfasis en niños, adolescentes y mujeres adultas. 3.Vacunar a todas las niñas de 11 a 14 años de edad. Y 4.vacunar a grupos específicos: mujeres adultas rubéola-seronegativas, mujeres en el post-parto y personal médico y paramédico principalmente

The "fourth disease" of childhood: reevaluation of a nonexistent disease.

Observed and described between 1884 and 1900, "fourth disease" (Dukes disease) followed measles, scarlet fever, and rubella as the fourth clinically characterized childhood exanthem. Like rubella ("third disease") and erythema infectiosum ("fifth disease"), accepted by the medical community at about the same time, the existence of fourth disease was initially controversial. Over the following decades descriptions of hundreds of cases, outbreaks, and laboratory studies were published in the indexed medical literature. Unlike rubella and fifth disease, however, fourth disease was not subsequently proven to exist by either epidemiologic criteria or isolation of an etiologic agent. By the 1930s, it was infrequently recognized and by the 1960s had been dropped from textbooks. In this study, the authors use epidemiologic methods to reevaluate published data on English schoolchildren from 1892 to 1900 upon which the original fourth disease claim of Dukes was based. The authors conclude that fourth disease never existed. Reinterpretation of the original data suggests that cases can be completely explained as misdiagnosed rubella and scarlet fever. Misidentification of fourth disease is attributed to failures in the critical abilities of the medical and scientific communities at the time. The implications of erroneously identifying a nonexistent disease suggest that modern scientific approaches to disease identification are sound.