Molecular epidemiology of rubella virus in Asia: Utility for reduction in the burden of diseases due to congenital rubella syndrome

BACKGROUND: Rubella is a mild disease mainly of infants, involving a rash and a fever. However, when women who have no immunity to rubella are infected during the early stage of pregnancy, their babies are often born with congenital rubella syndrome (CRS), which is characterized by a few disorders including deafness, cataracts and heart malformations. To prevent CRS, several strains of live attenuated rubella vaccine have been developed and introduced into immunization programs in many countries. In most Asian countries except Japan, Singapore and Taiwan, rubella remains uncontrolled, and the burden of diseases from CRS is high. In order to develop a control program to reduce the number of CRS cases in Asian countries, it is necessary to conduct a survey of rubella and CRS cases, and to then determine the genotype of the circulating rubella virus in each country. METHODS: Cases of rubella and CRS, based on national reporting systems or active surveillance in the Asian countries, are summarized. Sequences of the E1 gene of the virus isolates from the Asian countries were compared by phylogenic analysis. RESULTS: Recent studies of the molecular epidemiology of rubella virus worldwide revealed that there are two genotypes, and that genotype I is circulating almost worldwide, while genotype II is an Asian prototype restricted to the Asian continent. Genotype I viruses fall into a number of groups, some of which are geographically localized. Antigenically these two genotypes are cross-reactive and immunization with either virus results in immunity to all rubella viruses. DISCUSSION: The hypotheses that rubella virus has evolved on the Asian continent is proposed. The World Health Organization (WHO) has recognized that a rubella immunization program can be combined with the measles immunization program. Inclusion of rubella in the expanded program of immunization (EPI) of measles would be ideal in Asian countries, as it would be efficient and cost effective to administer one injection containing a three-combined vaccine (MMR). It would also be desirable given that WHO require laboratory tests to confirm the presence of measles or rubella as part of it's measles control project, because rubella is often misdiagnosed as measles.     

A profile of mothers giving birth to infants with congenital rubella syndrome. An assessment of risk factors

To formulate strategies for elimination of congenital rubella syndrome, it is important to identify risk factors for delivering an infant affected by it. We analyzed cases of congenital rubella syndrome in infants born from 1970 to 1985 and reported to either one of two independent Centers for Disease Control surveillance systems. Mothers of infants with congenital rubella syndrome identified in both surveillance systems were disproportionately younger than mothers giving birth in the United States. The risk for delivering an infant with congenital rubella syndrome was approximately 2.5 times higher for blacks compared with whites for both reporting systems. A total of 18% of infants with congenital rubella syndrome born since 1979 were Hispanic (national population average, 7%). Both surveillance systems showed that, although primiparous mothers were at highest risk, 39% of women delivering infants affected by congenital rubella syndrome had had at least one previous live birth, suggesting that postpartum immunization could have prevented these congenital rubella syndrome cases. Young, black, and Hispanic primiparous women represent populations at elevated risk for delivering a congenital rubella syndrome-affected infant and should be specifically targeted for immunization.     

Measles, mumps and rubella immunization at nine months in a developing country

The antibody responses and reactogenicity of a measles, mumps and rubella vaccine in 9-month-old and 15-month-old black children in South Africa were compared. The antibody response to the measles component was marginally better in the older group, but no differences were observed in the response to the mumps and rubella components. Reactogenicity was similar in the two age groups. Therefore it is possible that a trivalent measles, mumps and rubella vaccine can safely and effectively replace routine measles immunization at 9 months of age in this population. Whether routine immunization policy should incorporate such a vaccine depends on the extent of acceptance of measles vaccination. In urban populations of developing countries with high rates of measles immunization, routine vaccination at 9 months might interrupt circulating wild type rubella and provide sufficient herd immunity to protect susceptible women of childbearing age. It also should decrease significantly the complications associated with wild type mumps infection. The replacement of measles vaccine by a trivalent vaccine may be very cost-effective.     

Rubella seroprevalence in an unvaccinated population in Izmir: recommendations for rubella vaccination in Turkey.

BACKGROUND: The European Advisory Group on the Expanded Program on Immunization of WHO has recommended that by 2010 or earlier congenital rubella should be well-controlled or eliminated in all countries in Europe. Debate on the introduction of rubella vaccine into national immunization schedules continues to occur, and data on rubella and congenital rubella syndrome in Turkey are insufficient. OBJECTIVE: To determine age-specific rubella seroprevalence in the 1- to 29-year-old unvaccinated population in Izmir, Turkey. METHODS: A total of 600 unvaccinated persons 1 to 29 years old were selected for the study with cluster sampling in Izmir, Turkey. The information on sociodemographic characteristics and disease history was gathered for each participant, and in 580 of them rubella-specific IgG antibodies were assayed quantitatively by the micro-enzyme immunoassay. RESULTS: Of the 580 participants tested for rubella antibodies, 135 (23.3%) were seronegative. The proportions of susceptible individuals were 61.7, 29.5, 12.4, 10.3 and 8.4% in the age groups of 1 to 4, 5 to 9, 10 to 14, 15 to 19 and 20 to 29 years, respectively. Of the young women 15 to 19 years of age, 13.5% were susceptible to rubella infection. CONCLUSIONS: Because a substantial proportion of women in their childbearing years are susceptible to rubella, immunization efforts should be directed at infants or prepubertal children.     

An epidemic of congenital rubella in Barbados

Rubella and congenital rubella syndrome (CRS) are preventable, but epidemics of rubella and CRS are not infrequent in the Caribbean and other developing countries. As a result of a surveillance system initiated after an epidemic of rubella in the Barbadian population in 1996, cases of CRS were identified and investigated. A total of seven cases of CRS were proven to be rubella IgM-positive. The infants were found to have a mean birthweight of 2587 g and a mean gestational age of 38 weeks. The clinical course, complications and outcome of those infants were documented and the cost of acute hospital care for each patient was also recorded. Cataracts in four infants, congenital heart disease in three and central nervous system abnormalities in five were the major clinical abnormalities. In four infants, two or more clinical systems were affected. The combined total hospital stay was 105 days (mean 15, range 0-44). A national effort to immunize all those at risk and a strict surveillance programme are essential to prevent future epidemics. This would lead to a significant reduction in the number of cases of rubella and CRS and could effect substantial savings in the national health budget.     

Economic evaluation of the 7-vaccine routine childhood immunization schedule in the United States, 2001

OBJECTIVE: To evaluate the economic impact of the routine US childhood immunization schedule: diphtheria and tetanus toxoids and acellular pertussis; tetanus and diphtheria toxoids; Haemophilus influenzae type b conjugate; inactivated poliovirus; measles, mumps, and rubella; hepatitis B; and varicella vaccines. DESIGN: Decision tree-based analysis was conducted using population-based vaccination coverage, published vaccine efficacies, historical data on disease incidence before vaccination, and disease incidence reported for 1995-2001. Costs were estimated using the direct cost and societal (direct and indirect costs) perspectives. Program costs included vaccine, administration, vaccine-associated adverse events, and parent travel and time lost. All costs were inflated to 2001 US dollars, and all costs and benefits in the future were discounted at a 3% annual rate. PARTICIPANTS: A hypothetical 2001 US birth cohort of 3,803,295 infants was followed up from birth through death. MAIN OUTCOME MEASURES: Net present value (net savings) and benefit-cost ratios of routine immunization. RESULTS: Routine childhood immunization with the 7 vaccines was cost saving from the direct cost and societal perspectives, with net savings of 9.9 billion dollars and 43.3 billion dollars, respectively. Without routine vaccination, direct and societal costs of diphtheria, tetanus, pertussis, H influenzae type b, poliomyelitis, measles, mumps, rubella, congenital rubella syndrome, hepatitis B, and varicella would be 12.3 billion dollars and 46.6 billion dollars, respectively. Direct and societal costs for the vaccination program were an estimated 2.3 billion dollars and 2.8 billion dollars, respectively. Direct and societal benefit-cost ratios for routine childhood vaccination were 5.3 and 16.5, respectively. CONCLUSION: Regardless of the perspective, the current routine childhood immunization schedule results in substantial cost savings.     

Burden of congenital rubella syndrome (CRS) in India: <Emphasis Type="Italic">A systematic review</Emphasis>

Background

Rubella, though a mild, vaccine-preventable disease, can manifest with severe teratogenic effects in the fetus labeled as congenital rubella syndrome (CRS) due to primary maternal rubella infection. Despite a reduction in disease burden of several vaccine-preventable diseases through childhood immunization, CRS continues to account for preventable severe morbidity including childhood blindness, deafness, heart disease, and mental retardation.

Objective

To conduct a systematic review to describe the prevalence of CRS and its contribution to major long-term handicaps in Indian population. Another objective was to estimate the susceptibility to rubella infection in Indian adolescent girls and women of reproductive age-group. We also explored strategies to decrease CRS in India by identifying the immunogenicity of rubella containing vaccines (RCV) in Indian children and women, as well as their coverage in India.

Methods

Publications reporting ‘CRS prevalence in general population as well as selected subgroups i.e., suspected intra-uterine infection, congenital ocular abnormalities, deafness, congenital heart disease, mental retardation, and congenital malformations’, ‘seroprevalence to rubella (IgG) amongst women and adolescents’, and ‘immunogenicity and coverage of RCVs’ in Indian population were retrieved through a systematic search. Primary databases employed were Medline through PubMed and IndMed, websites of the WHO, and UNICEF. No restrictions were applied in terms of study designs. The primary outcome measure was ‘congenital rubella syndrome’ (CRS) which was further categorized as ‘suspected CRS’ and ‘confirmed CRS’ as defined by World Health Organization (WHO).

Results

Comprehensive evidence about the true burden of CRS in India is not available. Almost all studies have been done in institutional/hospital set-ups and community-based studies are grossly lacking. There are no studies assessing the prevalence of CRS in general population. All studies have evaluated the CRS burden in symptomatic cohorts of children. 1–15% of all infants suspected to have intra-uterine infection were found to have laboratory evidence of CRS. About 3–10% of suspected CRS cases are ultimately proven to have confirmed CRS with the aid of laboratory tests. CRS accounts for 10–15% of pediatric cataract. 10–50% of children with congenital anomalies have laboratory evidence of CRS. 10–30% of adolescent females and 12–30% of women in the reproductive age-group are susceptible to rubella infection in India. RCVs are highly immunogenic in Indian adolescents and women. The coverage data of RCVs in India is not available. However, the coverage of MMR vaccine has been reported as 42%, 30% and 5% from Delhi, Chandigarh and Goa, respectively.

Conclusion

This systematic review identifies and explores factors associated with the prevalence of CRS in India. There is a need for urgent action in terms of revamping the national immunization policy and introduction of RCVs in the national immunization program. Active surveillance of rubella and CRS is needed to redress the burden of CRS in India.

     

Congenital rubella syndrome in a child born to Liberian refugees: clinical and public health perspectives

We describe a case of congenital rubella syndrome with typical stigmata in an infant born in New Hampshire to Liberian refugees. The infant's clinical specimens were tested for rubella. Rubella immunity status was sought for contacts. The infant's specimen cultures grew wild-type rubella virus; serum immunoglobulin M and G were positive. Eighteen of 20 contacts were rubella-immune. Family's transit history, mother's vaccination history, and infant's estimated gestational age supported congenital infection acquired overseas. Clinicians should maintain vigilance for congenital rubella syndrome in infants with relevant stigmata, particularly those whose mothers are from countries with nonexistent or recently implemented rubella vaccination programs.     

Serologic survey of rubella in the pre-vaccine era in child-care centers, schools and maternity units of Fortaleza

OBJECTIVES: To identify rubella prevalence in different ages and population groups and rubella susceptibility of pregnant and postpartum women according to age, number of children and spontaneous abortion. METHODS: Cross-sectional study of sero-survey type. Children and students were selected in day-care centers and schools distributed by health districts of Fortaleza. Pregnant and postpartum healthy women were recruited in two large maternity units and three antenatal clinics; individuals previously vaccinated and presenting chronic or acute diseases where excluded. Written consent was obtained from participants or their caretakers. Anti-rubella IgG qualitative detection was performed with an Elisa-sandwich assay. RESULTS: Mean age-specific sero-prevalence rates of 999 samples were: 2 to 5 years= 59% (136/231); 6 to 9 years= 47% (95/204); 10 to 19 years= 56% (243/432) and 20 to 39 years= 80% (106/132). The mean age of 187 pregnant and postpartum women was 23 years (10-39) with a sero-prevalence of 76% (142/187), where 62% sero-positives aged 15 to 19 and 83% aged 26 to 39 years. A higher sero-prevalence was related to womeńs age (p<0.001), history of spontaneous abortion (p= 0.03), and two or more children (p=0.01). CONCLUSIONS: The high sero-prevalence of rubella in preschool age children reflects the intense viral transmission in child-care centers. The high susceptibility in adolescents (45%), among whom pregnancy is common, emphasizes the need to introduce rubella vaccine early and keep high immunization coverages in youngsters in order to eradicate congenital rubella syndrome. Also, postpartum routine immunization against rubella in this age group is of particular benefit.     

Rubella seroprevalence among Turkish adolescent girls living in Edirne, Turkey

This study was designed to estimate the rubella seroprevalence in unvaccinated Turkish adolescent girls in urban and rural areas of Edirne, and to create preventive strategies for congenital rubella syndrome (CRS). The sample, representing 12- to 17-year-old adolescent girls, consisted of 1,600 subjects selected from school lists by systematic and random sampling, which was matched by age and urban-rural residency strata proportional to the corresponding distributions in the Edirne population. For each participant, a questionnaire was completed and rubella-specific IgG antibodies were measured. After analysis of samples, seropositivity prevalence, equivocal and seronegative samples of adolescent girls in Edirne were determined as 93.1%, 0.6% and 6.3%, respectively. Data from the present study may indicate that 6.9% of adolescent girls have considerable risk for rubella infection during pregnancy. Eliminating rubella and CRS in Turkey will require national health service efforts, including vaccination of all adolescents and all susceptible women of childbearing age.     

Rubella

Rubella is associated with an 80% risk of congenital abnormalities if acquired in the first 12 weeks of pregnancy. Reinfection in early pregnancy presents a much smaller risk. Prenatal diagnosis may be useful to assess the risk to the fetus. Congenital rubella is a progressive disease and some abnormalities will not be present at birth. Rubella and congenital rubella are usually diagnosed by detection of rubella-specific IgM; it may be difficult to confirm a diagnosis of congenital rubella in children over 3 months of age. Rubella vaccines are usually combined with measles and mumps vaccines. Their use has enabled some industrialised countries to eliminate rubella and congenital rubella. Countries should ensure that susceptible women of child-bearing age and health care workers are offered a rubella-containing vaccine. Rubella vaccine is contraindicated during pregnancy, but if a pregnant woman is inadvertently vaccinated it is not an indication for termination or prenatal diagnosis.     

Neuroimaging findings (ultrasonography,CT, MRI) in 3 infants with congenital rubella syndrome

Neuroimaging observations of three infants with congenital rubella syndrome are reported. We have observed congenital rubella syndrome lesions in the subependymal area, the basal ganglia and the deep white matter. Cranial ultrasonography defines subependymal cysts, calcification and possible vascular changes in the basal ganglia while MRI is the most sensitive to minor atrophic changes and white matter lesions. Although CT defines calcification, it is less sensitive than MRI to white matter changes and does not demonstrate subependymal cysts.     

Blueberry muffin syndrome owing to congenital rubella: case report

A case of congenital rubella is reported in a 22-day-old boy presenting with a 'blueberry muffin' rash. Late-onset blueberry muffin syndrome following congenital rubella is very rare.     

Congenital rubella syndrome despite repeated vaccination of the mother: a coincidence of vaccine failure with failure to vaccinate

Braun C, Kampa D, Fressle R, Willke E, Stahl M, Haller O. Congenital rubella syndrome despite repeated vaccination of the mother: a coincidence of vaccine failure with failure to vaccinate. Acta Pzdiatr 1994;83:674–7. Stockholm. ISSN 0803–5253
Congenital rubella syndrome occurred in a boy born to a mother who had been properly vaccinated three times before conception, but developed only low titers of rubella antibody. The non-vaccinated father most likely infected the mother on a home visit during the third to fifth weeks of gestation. He served in the army and fell ill during an outbreak of a rubella-like disease in his military unit. The mother subsequently developed a slight rash, but rubella IgM antibodies were lacking and rubella infection was not suspected. This incidence demonstrates the necessity of vaccinating all children, including boys and young men. in order to reduce the number of infections and prevent further cases of congenital rubella syndrome.     

Design of immunization programmes for developing countries

Factors to be considered in designing immunization programs in developing countries are summarized. The limiting factors will usually be costs of vaccines, administration equipment and supplies, transport and maintenance of the cold chain. Choices have to be made about the sources of vaccines, whether produced locally or imported, size of vaccine lots and type of package, and quality control of vaccines. Selection of vaccines is treated in a separate appendix, but generally 3 groups are recognized: 1) recommended for general use: smallpox, diphtheria, tetanus, pertussis, BCG, typhoid and measles; 2) recommended for special cases: polio and yellow fever; 3) not recommended for developing countries: rubella, mumps, influenza, cholera; and 4) vaccines in development stage only: arbovirus, rickettsia, trachoma, meningococci, plague and shigella. Schedules for vaccine administration are suggested, such as plans for vaccination every 2 years, plans for 4 courses of vaccinations including 1 at school entry, and special programs such as smallpox campaigns and immunization of adolescent girls and fertile women with tetanus. Finally the importance of recording of vaccinees and assessment of programs is discussed.     

Antenatal diagnostic problem of congenital rubella

We present a preterm neonate who developed congenital rubella syndrome in a mother who had rubella at 5 months of gestation. An amniocentesis was done in the mother at that time but amniotic fluid rubella PCR was negative. Thus, inspite of prenatal screening, one cannot definitely conclude absence of perinatal transmission of rubella.     

Clinical Studies of Patients with Rubella Syndrome Occurring in a High Incidence in the Ryukyu Islands in 1965: On the Diagnostic Significance of Clinical Manifestations

The 620 cases with a history of maternal rubella and/or with one or more of cataract, CHD and deafness born in the Ryukyu Islands in 1965 were subjected to clinical studies and 360 cases were diagnosed as rubella syndrome. Rubella retinopathy makes a reliable diagnostic basis for rubella syndrome. As for the typical combination of clinical manifestations, the cases with cataract have CHD, deafness and retinopathy; the cases with CHD not accompanied by cataract have deafness and retinopathy; and the cases with deafness not accompanied by cataract and CHD either have or have not retinopathy. The cases with cataract alone or with CHD can extremely rarely be denned as having rubella syndrome. There existed the close relationship between the combination of clinical manifestations and the time of maternal rubella infection. The main clinical manifestations of rubella syndrome are cataract, congenital heart disease (CHD), and deafness appearing singly or two or more together¹⁾²⁾. Etiology of the congenital cataract, CHD, or deafness is mostly not explained; and only a small portion of the incidence is due to intrauterine rubella infection. For the future of the patients in the above conditions and for their parents, clarification as to whether they are or are not due to rubella is very important. Current general practice for the diagnosis of rubella syndrome is laboratory diagnosis that measures rubella hemagglutination inhibition (HI) antibodies³⁾⁴⁾. As the infants grows in age, the above mentioned technique may not assure an absolute judgment⁵⁾⁶⁾. This makes it necessary to arrive at diagnosis from the clinical findings. A prompt, direct diagnosis from the clinical findings alone will be very convenient. In the Ryukyu Islands where there was a high incidence of rubella syndrome in infants in the second half of 1965, we analyzed clinical findings of the affected children with cataract, CHD or deafness on the basis of serological diagnosis. The diagnostic significance of the clinical findings was so studied. Hence our report in this paper.     

Immunization rates among disabled children in Ecuador: unanticipated findings

Researchers hypothesize that impoverished parents in developing countries may forego provision of healthcare for disabled children, instead allocating scarce resources to nondisabled children or other household needs. We compared the immunization rates of 32 children with complex special heathcare needs with those of 95 nondisabled siblings in coastal Ecuador. Almost 100% (31 of 32) of the disabled children studied were immunized at a rate comparable with their nondisabled siblings. We propose that this finding is attributable to an effective national immunization program and to positive local sociocultural attitudes toward disability. These findings underscore the need for more research on disability across cultures.     

HYPERTHYROIDISM, DIABETES MELLITUS AND THE CONGENITAL RUBELLA SYNDROME

Abstract. Floret, D., Rosenberg, D., Hage, G. N. and Monnet, P. (Clinique Médicate Infantile B, Hopital E. Herriot, Lyon, France). Hyperthyroidism, diabetes mellitus and congenital rubella syndrome. Acta Paediatr Scand, 69: 259, 1980.—A male patient born to a mother who developed rubella during the tenth week of gestation presented a typical congenital rubella syndrome with mental retardation, neuro-sensory deafness, hypoplasia of the dental enamel and chorioretinitis. Hyperthyroidism occurred at the age of 3 10/12 years and was treated successfully with propylthiouracil for 4 years. The course was complicated by premature craniosynostosis and a craniectomy was performed at the age of 7 years. Overt diabetes mellitus developed at 17 years and was well controlled by insulin therapy. Histocompatibility (HLA) antigens were A2, B8, B40. Diabetes mellitus and thyroid disorders have previously been reported after congenital rubella, and recently after congenital cytomegalovirus infection. Our patient had both endocrinopathies. It is possible that HLA B8 antigens might be responsible for increased susceptibility to rubella infection.