Control of rubella and congenital rubella syndrome (CRS) in developing countries, Part 1: Burden of disease from CRS.

Congenital rubella syndrome (CRS) can lead to deafness, heart disease, and cataracts, and a variety of other permanent manifestations. In developing countries, the burden of CRS has been assessed as follows: by surveillance of CRS; by surveillance of acquired rubella; by age-stratified serosurveys; and by serosurveys documenting the rubella susceptibility of women of childbearing age. During rubella outbreaks, rates of CRS per 1000 live births were at least 1.7 in Israel, 1.7 in Jamaica, 0.7 in Oman, 2.2 in Panama, 1.5 in Singapore, 0.9 in Sri Lanka, and 0.6 in Trinidad and Tobago. These rates are similar to those reported from industrialized countries during the pre-vaccine era. Special studies of CRS have been reported from all WHO regions. Rubella surveillance data show that epidemics occur every 4-7 years, similar to the situation in Europe during the pre-vaccination era. In developing countries, the estimated average age at infection varies from 2-3 years to 8 years. For 45 developing countries we identified serosurveys of women of childbearing age that had enrolled > or = 100 individuals. The proportion of women who remained susceptible to rubella (e.g. seronegative) was < 10% in 13 countries. 10-24% in 20 countries, and > or = 25% in 12 countries. Discussed are methods to improve the surveillance of rubella and CRS in developing countries.     

Modelling the incidence of congenital rubella syndrome in developing countries

BACKGROUND: As of 1997, less than one-third of developing countries included rubella vaccine in their national immunization programme. In countries that have achieved high coverage of measles vaccine, an ideal opportunity exists to include control of rubella and congenital rubella syndrome (CRS) in enhanced measles control activities. Data on the burden of congenital rubella syndrome are important to guide rubella vaccination policies. METHODS: We reviewed the literature to identify studies of rubella antibody prevalence in developing countries that were conducted on populations with no major selection bias, prior to wide-scale rubella vaccination in the country. We used a simple catalytic model to describe the age-specific prevalence of susceptibility to rubella virus infection in given populations. Estimates of the incidence of infection among pregnant women were calculated using expressions for the average prevalence of susceptibility to infection and the incidence of infection during gestation. To estimate the number of cases of CRS, we assumed an overall risk of 65% after infection in the first 16 weeks of pregnancy and zero risk thereafter. These estimates were derived for each country for which data were available, then for each World Health Organization region, excluding Europe. RESULTS: The estimated mean incidence of CRS per 100,000 live births was lowest in the Eastern Mediterranean region (77.4, range 0-212) and highest in the Americas (175, range 0-598). The mean of the estimates of the total number of cases of CRS in developing countries in 1996 was approximately 110,000. The range was, however, very wide, from as few as 14,000 to as many as 308,000 cases. CONCLUSIONS: Congenital rubella syndrome is an under-recognized public health problem in many developing countries. There is an urgent need for collection of appropriate data to estimate the cost-effectiveness of a potential global rubella control programme.     

Surveillance of congenital rubella syndrome (CRS) in tertiary care hospitals in Hanoi,Vietnam during a rubella epidemic

ObjectiveTo describe the epidemiology and clinical features of congenital rubella syndrome (CRS) in Hanoi, Vietnam.MethodsProspective surveillance of CRS between May 2011 and March 2012 in Hanoi, Vietnam. CRS burden was assessed by clinical examination and collection of serum samples from infants in neonatology, cardiology and pediatric departments of two tertiary care hospitals in Hanoi. All infants born during the study period with clinical manifestations of CRS and seropositivity (IgM) for rubella were included in this study.ResultsDuring the surveillance period 113 infants were identified with confirmed CRS (clinical features and positive rubella IgM). Their mean age at diagnosis was 38.4 days (range 1–152 days) and 61% were female. Clinical manifestations of CRS included low birth weight <2500 g (86.0%), congenital heart disease (63.7%), hearing impairment (63.7%) and ophthalmological abnormalities (46.9%). Other clinical features at birth included: thrombocytopenia (85.0%), neonatal purpura (74.3%), splenomegaly (63.7%), hepatomegaly (62.8%) and blueberry muffin rash (61.1%). Among the mothers of infants with confirmed CRS none had received a rubella vaccine in the past and 88.4% gave a history of rubella contact during the pregnancy under study. In most cases (84.1%) maternal infection occurred in the first trimester. During the surveillance period the estimated annual incidence of CRS was 1.13/1000 live births (95% CI 0.92–1.34).ConclusionsThese preliminary baseline data show a high burden of CRS in Hanoi, Vietnam and the urgent need for universal vaccination. Surveillance to determine and monitor the national burden of CRS is essential.     

Costs of congenital rubella syndrome (CRS) in Oman: evidence based on long-term follow-up of 43 children

As part of the national plan for elimination of rubella and congenital rubella syndrome (CRS), Oman established a national registry of CRS cases. As of May 2005, the registry included 43 surviving CRS cases, with a mean age of 11.9 years. Clinical examinations found that 84% had ocular defects, 84% had auditory/speech defects, 70% had neurological manifestations, and 42% had cardiac defects. Lifetime medical, special education, and rehabilitation costs were assessed. Using a discount rate of 3%, the average direct lifetime cost per surviving CRS patient was estimated at 18,644 US dollars. When including predicted lost productivity due to CRS, the average discounted direct and indirect lifetime costs per surviving CRS patient amounted to 98,734 US dollars.     

Quantitative investigations of different vaccination policies for the control of congenital rubella syndrome (CRS) in the United Kingdom.

The paper examines predictions of the impact of various one-, two- and three-stage vaccination policies on the incidence of congenital rubella syndrome (CRS) in the United Kingdom with the aid of a mathematical model of the transmission dynamics of rubella virus. Parameter estimates for the model are derived from either serological data or case notifications, and special attention is given to the significance of age-related changes in the rate of exposure to rubella infection and heterogeneous mixing between age groups. Where possible, model predictions are compared with observed epidemiological trends. The principal conclusion of the analyses is that benefit is to be gained in the UK, both in the short and long term, by the introduction of a multiple-stage vaccination policy involving high levels of vaccination coverage of young male and female children (at around two years of age) and teenage girls (between the ages of 10-15 years), plus continued surveillance and vaccination of adult women in the child-bearing age classes. Model predictions suggest that to reduce the incidence of CRS in future years, below the level generated by a continuation of the current UK policy (the vaccination of teenage girls), would require high rates of vaccination (greater than 60%) of both boys and girls at around two years of age. Numerical studies also suggest that uniform vaccination coverage levels of greater than 80-85% of young male and female children could, in the long term (40 years or more), eradicate rubella virus from the population. The robustness of these conclusions with respect to the accuracy of parameter estimates and various assumptions concerning the pattern of age-related change in exposure to infections and ''who acquires infection from whom'' is discussed.     

Quantitative investigations of different vaccination policies for the control of congenital rubella syndrome (CRS) in the United Kingdom

The paper examines predictions of the impact of various one-, two- and three-stage vaccination policies on the incidence of congenital rubella syndrome (CRS) in the United Kingdom with the aid of a mathematical model of the transmission dynamics of rubella virus. Parameter estimates for the model are derived from either serological data or case notifications, and special attention is given to the significance of age-related changes in the rate of exposure to rubella infection and heterogeneous mixing between age groups. Where possible, model predictions are compared with observed epidemiological trends. The principal conclusion of the analyses is that benefit is to be gained in the UK, both in the short and long term, by the introduction of a multiple-stage vaccination policy involving high levels of vaccination coverage of young male and female children (at around two years of age) and teenage girls (between the ages of 10-15 years), plus continued surveillance and vaccination of adult women in the child-bearing age classes. Model predictions suggest that to reduce the incidence of CRS in future years, below the level generated by a continuation of the current UK policy (the vaccination of teenage girls), would require high rates of vaccination (greater than 60%) of both boys and girls at around two years of age. Numerical studies also suggest that uniform vaccination coverage levels of greater than 80-85% of young male and female children could, in the long term (40 years or more), eradicate rubella virus from the population. The robustness of these conclusions with respect to the accuracy of parameter estimates and various assumptions concerning the pattern of age-related change in exposure to infections and 'who acquires infection from whom' is discussed.     

Rubella and congenital rubella syndrome: global update.

Worldwide, it is estimated that there are more than 100.000 infants born with congenital rubella syndrome (CRS) each year. In 1998, standard case definitions for surveillance of CRS and rubella were developed by the World Health Organization (WHO). In 2001, 123 countries/territories reported a total of 836.356 rubella cases. In the future more countries are expected to report on rubella as a global measles/rubella laboratory network is further developed under the coordination of WHO. Operational research is being conducted to improve rubella surveillance. This includes projects on initiating CRS surveillance, comparative studies on diagnostic laboratory methods, and molecular epidemiology research to expand the global understanding of patterns of rubella virus circulation. In 1996 a WHO survey found that 78 od 214 reporting countries/territories (36%) were using rubella vaccine in their routine immunization services. By the en of 2002 a total of 124 of the 214 counties/territories (58%) were using rubella vaccine. Rubella vaccine use varies by stage of economic development: 100% for industrialized countries, 71% for countries with economies in transition, and 48% for developing countries. A safe effective rubella vaccine is available, and there are proven vaccination strategies for preventing rubella and CRS. A WHO position paper provides guidance on programmatic aspects of rubella vaccine introduction. The introduction of rubella vaccine is cost-effective and cost-beneficial but requires ongoing strengthening of routine immunization services and surveillance systems.     

Vaccination against rubella and measles: quantitative investigations of different policies.

This paper uses relatively simple and deterministic mathematical models to examine the impact that different immunization policies have on the age-specific incidence of rubella and measles. Following earlier work by Knox (1980) and others, we show that immunization programmes can, under some circumstances, increase the total number of cases among older age groups; the implications for the overall incidence of measles encephalitis and of congenital rubella syndrome are examined, paying attention both to the eventual equilibrium and to the short-term effect in the first few decades after immunization is initiated. Throughout, we use data (from the U.K., and U.S.A. and other countries) both in the estimation of the epidemiological parameters in our models, and in comparison between theoretical predictions and observed facts. The conclusions defy brief summary and are set out at the end of the paper.     

Epidemiology of rubella and congenital rubella syndrome in Japan before 1989

Epidemiological studies of rubella and congenital rubella syndrome (CRS) in Japan have been conducted since the first nationwide rubella epidemic of 1965–1969 and subsequent epidemics of 1975–1977, 1982, 1987–1988, and 1992–1993. Rubella was non-endemic in Japan before the 1975–1977 epidemic, and endemic thereafter. Japan started a selective rubella vaccination program for junior high school girls in 1977, and universal rubella vaccination of children of both sexes in 1989. No nationwide rubella epidemics have occurred since 1994.Only three children with CRS were reported in Japan before 1964; however, many children with CRS were identified in 1965 when a rubella epidemic struck Okinawa, which has many the United States military bases. After the 1965–1969 and 1975–1977 rubella epidemics on the Japanese mainland, small numbers of children with CRS were identified (hospital survey). These findings led to the hypothesis that, compared to U.S. rubella virus strains, Japanese strains of rubella virus are less teratogenic. This hypothesis strongly affected the development of rubella vaccines in Japan. However, retrospective seroepidemiological studies attributed the CRS in many children in Okinawa to the high rate of rubella infection in pregnant women. According to the survey conducted at special schools for the deaf, 83, 232, 77, and 167 children were born with CRS on the Japanese mainland respectively after the 1965–1969, 1975–1977, 1982, and 1987–1988 nationwide rubella epidemics, suggesting that the incidence of CRS in Japan is in fact comparable to that in the U.S. and Europe.Rubella epidemics in children have been effectively prevented since 1994. However, a rubella outbreak among adult males and CRS occurred between 2012 and 2014.     

Vaccination against rubella and measles: quantitative investigations of different policies

This paper uses relatively simple and deterministic mathematical models to examine the impact that different immunization policies have on the age-specific incidence of rubella and measles. Following earlier work by Knox (1980) and others, we show that immunization programmes can, under some circumstances, increase the total number of cases among older age groups; the implications for the overall incidence of measles encephalitis and of congenital rubella syndrome are examined, paying attention both to the eventual equilibrium and to the short-term effect in the first few decades after immunization is initiated. Throughout, we use data (from the U.K., and U.S.A. and other countries) both in the estimation of the epidemiological parameters in our models, and in comparison between theoretical predictions and observed facts. The conclusions defy brief summary and are set out at the end of the paper.     

A model-based evaluation of the national immunization programme against rubella infection and congenital rubella syndrome in The Netherlands

In order to improve the prevention of cases of congenital rubella syndrome in The Netherlands, in 1987 the selective vaccination strategy against rubella infection in girls was replaced by mass vaccination. This decision was supported by mathematical model analyses carried out by Van Druten and De Boo. In order to compare the predicted impact of the rubella vaccination programme with the current available data in more detail, a similar model was built. Although the model predicts elimination of the rubella virus, data show that virus circulation is still present at a higher level than expected by the model. Simulation studies indicate that import of infection and a lower vaccine effectiveness, related to possible asymptomatic reinfection of vaccinated people, could be sources contributing to the present virus circulation. Even though the number of infections is much higher than the number of reported cases of disease, limited serosurveillance data and case notification data show that females of childbearing age are well protected by immunization.     

Current epidemiology of rubella and congenital rubella syndrome in Australia: progress towards elimination

This study evaluates the evidence for elimination of rubella and congenital rubella syndrome (CRS) in Australia, drawing on three national serosurveys conducted between 1996 and 2007 and supported by statutory notification and vaccine coverage data. Anti-rubella IgG seropositivity was defined as ≥ 10 IU/ml by EIA. Between 1998 and 2007, rubella notifications fell >100-fold, to an average of 2 cases per million and there were five confirmed cases of CRS, two of which were locally acquired in 2003. Weighted overall seropositivity remained constant among 1-49 year-olds (89.6% in 1999; 88.1% in 2007). Between 2002 and 2009, 95% of children received at least one dose of the measles-mumps-rubella (MMR) vaccine. All three serosurveys provided estimates for R less than 0.5, well below the epidemic threshold of 1. All available data are supportive of Australia being considered for elimination status. Further reductions in incidence of CRS will require continued attention to vaccine coverage in overseas-born women, as well as the maintenance of current high coverage level of two-dose MMR vaccination.     

Accelerated rubella control and the prevention of congenital rubella syndrome]

Congenital rubella syndrome (CRS) is associated with substantial morbidity and mortality and with high costs. Today, as a result of improved vaccination and epidemiological surveillance efforts directed at eradicating measles from the Western Hemisphere, there has been a notable increase in the ability to detect, prevent, and control rubella and CRS. The importance of these measures is undeniable, and this piece examines the components that are essential in moving ahead to reduce these major public health problems in Latin America and the Caribbean. One step in that direction would be to integrate the surveillance of measles with that of rubella and CRS.     

Specific immunoglobulins in infants with the congenital rubella syndrome.

The indirect immunofluorescent technique has been used to detect and titrate the specific immunoglobulins in serum specimens from 154 infants with confirmed or suspected congenital rubella. IgM antibody was stained more efficiently in sucrose density gradient fractions than in whole serum and was detected in this way in 27 out of 40 patients with confirmed congenital rubella at ages ranging from birth to 2 years. It was present in 48 out of 50 serum specimens during the first 6 months of life and in 11 out of 38 specimens obtained at ages between 6 1/2 months and 2 years. IgM antibody was therefore estimated to persist for about 6 months in the majority of cases and up to 2 years in a few individuals. IgM antibody was also detected by this method in 11 out of 114 infants with suspected but unconfirmed congenital rubella at ages up to 5 months. The total concentrations of IgM were above the normal range in nearly all sera taken from confirmed cases during the first 3 months of life and in half the specimens obtained between the ages of 3 and 6 months. IgG antibody was detected by fluorescent staining of whole serum in all patients with congenital rubella. Geometric mean titres increased during the first 3 months of life and then declined slowly. IgA antibody was not detected, except in two patients in whom traces were present at the age of 6 months, and the total concentrations of IgA were usually within normal limits. Fluorescent staining of fractions showed that the sedimentation characteristics of rubella IgG and IgM antibodies were the same in infants as in adults. The peak IgM fractions never contained IgG antibody, and the presence of specific IgM in these fractions could usually have been safely inferred from their HAI titres. Fluorescent staining, however, was more sensitive and frequently detected IgM antibody in fractions which had no definite HAI activity. Fluorescent staining of whole serum for IgM antibody was less distinct, and often unsuccessful, even in specimens in which specific IgM was detected in the fractions. The addition of IgG- to IgM-containing fractions caused depression of IgM staining and suggested that failure to detect IgM antibody in whole serum was partly due to competitive inhibition by specific IgG.     

Progress toward control of rubella and prevention of congenital rubella syndrome --- worldwide, 2009

Rubella usually is a mild, febrile rash illness in children and adults; however, infection early in a woman's pregnancy, particularly during the first 16 weeks, can result in miscarriage, fetal death, or an infant born with birth defects (i.e., congenital rubella syndrome [CRS]). In 2000, the World Health Organization (WHO) published the first rubella vaccine position paper to guide introduction of rubella-containing vaccine (RCV) in national childhood immunization schedules. As of December 2009, a total of 130 WHO member states have introduced RCV, a 57% increase from 83 member states in 1996. In addition, goals to eliminate rubella and CRS have been established in the WHO Region of the Americas (by 2010) and the WHO European Region (by 2015), and the WHO Western Pacific Region has established targets for accelerated rubella control and CRS prevention by 2015. During 2009, a total of 121,344 rubella cases were reported from 167 member states to WHO, an 82% decrease from 670,894 cases reported in 2000 from 102 member states. This report summarizes reported rubella and CRS cases globally and progress toward global introduction and use of RCV.     

An epidemiological assessment towards elimination of rubella and congenital rubella syndrome in Singapore

ObjectiveIn line with regional and global goals for the elimination of rubella and congenital rubella syndrome (CRS), we reviewed the epidemiological situation in Singapore, based on surveillance reports on rubella and CRS, national immunization coverage and seroprevalence surveys. The aim of our review was to identify current gaps and steps taken to achieve the targets set by the World Health Organization (WHO) Western Pacific Regional Office (WPRO).MethodsEpidemiological data on clinical and laboratory-confirmed rubella cases, including CRS, notified to the Communicable Diseases Division, Ministry of Health, Singapore, from 2003 to 2013 were collated and analyzed. Vaccination coverage against rubella was obtained from the National Immunization Registry and School Health Services of the Health Promotion Board. The changing prevalence of rubella was determined from periodic serological surveys.FindingsThe incidence of indigenous rubella cases per million population decreased from 37.2 in 2008 to 7.6 in 2013 and there had been no indigenous case of CRS in 2012 and 2013. Therapeutic abortions performed due to rubella infections had become uncommon. The annual measles, mumps, and rubella (MMR) vaccination coverage in childhood population remained high ranging from 93% to 96%. The overall susceptibility to rubella in women aged 18–44 years had reduced significantly from 15.8% in 2004 to 11.0% in 2010. The prevalence of IgG antibody against rubella among Singapore children aged 1–17 years was maintained at 87.3% in 2008–2010.ConclusionAll available data indicated that Singapore has made good progress towards the elimination of rubella and CRS. It has attained the targets set by the WHO WPRO for 2015. In preparation for verification of rubella elimination, an enhanced surveillance system has been implemented to ensure that all reported cases are laboratory confirmed, and genotyping of rubella virus strains isolated is carried out to provide evidence for interruption of endemic transmission.