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Pathogenesis of the rubella exanthem: distribution of rubella virus in the skin during rubella with and without rash.

In a previous assessment of the role of rubella virus in the pathogenesis of the rubella exanthem, virus was consistently isolated from cell cultures of skin biopsy specimens of the rash, and it was concluded that presence of virus in the skin was essential to evolution of the rash. For determination of whether virus is present in the skin only in association with rash, punch biopsies were performed concurrently on areas of skin with and without rash. Among paired skin specimens of 16 patients, virus was isolated from sites of rash in 12 and from the uninvolved skin in 10. In another patient, shown by serologic response and recovery of virus from the pharynx to have rubella without a rash, virus was also isolated from the skin. It is concluded that rubella virus is widely disseminated in the skin of patients with rubella irrespective of the presence or distribution of the rash, and that the presence of virus in the skin, although a constant feature of the disease, is only one of the factors involved in the pathogenesis of the exanthem.

Biopsy

Rubella, measles and mumps antibodies following vaccination of children. A potential rubella problem.

One hundred sixty-eight children immunized by one suburban Minneapolis clinic during routine pediatric visits had serum antibodies measured to determine the efficacy of rubella (HPV77 DE5 strain), measles (Edmonston B and Moraten strains), and mumps (Jeryl Lynn strain) vaccines. Serologic failure rates at the mean postvaccination times tested were as follows: rubella, 36% (4.7 years); measles, 18% (6.5 years); and mumps, 9% (4.5 years). Antibody titers shortly after vaccination were not done, so seronegative subjects may never have responded or their titers may have declined with time; our rubella data suggest the former. Children vaccinated with rubella and measles at less than 14 months of age had higher failure rates than those vaccinated at a later age. This supports postponement of rubella and measles vaccinations until at least 15 months of age. In addition to current measles reimmunization policies, consideration also should be given to reimmunizing girls who were given rubella vaccine at less than 14 months of age. Twenty-four percent (19/79) of children vaccinated with HPV77 DE5 strain rubella at 14 months or older had rubella hemagglutination-inhibiting titers less than 8. This is disturbing and, if confirmed by others, would prompt the use of a different strain of rubella vaccine for routine immunization.

Adolescent

[Rubella in pregnancy: experimental studies on the value of gamma-globulin after rubella wild virus infection (author's transl)].

Rubella infection was produced with a wild rubella virus in 24 volunteers by intranasal application. Some of the subjects were given gamma-globulin intramuscular 24 hours later. In the control group clinically manifest rubella with massive viral excretion in the throat occurred in all in whom infection had taken place. In the majority of subjects rubella virus could be demonstrated in blood shortly before the skin rash appeared. High antibody titres occurred already 20 days after the infection. In subjects who were given gamma-globulin there were no clinical signs of rubella, viral excretion in the throat was diminished and shortened and viraemia was never demonstrated, antibody response was delayed and lower. But there was no significant decrease in the infection rate after gamma-globluin administration. It is concluded that early administration of a sufficient amount of rubella antibodies achieves inhibition of rubella virus multiplication and thus decreases significantly the risk of damage to the fetus.

Adult

Immunosuppression and isolation of rubella virus from human lymphocytes after vaccination with two rubella vaccines.

Two groups of young rubella-susceptible women were vaccinated with two rubella vaccines. Heparinized blood samples were taken from all individuals the day of vaccination and 5, 7, 15, 21, 30, 35, and 42 days later. Purified lymphocytes from these samples were cocultivated with AGMK cells for rubella virus isolation. Parallel samples of lymphocytes were stimulated with phytohemagglutinin, and the rate of [14C]thymidine incorporation was determined. Rubella virus was isolated from lymphocytes collected on days 7, 15, and 21 after RA27/3 vaccination in contrast to days 7 to 35 after HPV77 vaccination. The lymphocyte response to phytohemagglutinin was markedly suppressed from day 5 to 15. Normal lymphocyte responses were restored within 1 month after vaccination with RA27/3, but even later (1 week) after HPV77 vaccine. Lymphocytes from rubella-susceptible persons infected invitro with rubella virus vaccines and stimulated with phytohemagglutin displayed a decrease in their responsiveness to the mitogen similar to that observed with lymphocytes from vaccinees. The transient immunosuppression observed in vaccinees is probably due to virus-induced functional damage of the lymphocytes since no direct cytocidal effect of rubella vaccine has been demonstrated on human lymphocytes.

Adult

Diagnosis of postnatal rubella by the enzyme-linked immunosorbent assay for rubella IgM and IgG antibodies.

A semi-automated enzyme-linked immunosorbent assay (ELISA) was established for the detection of rubella IgM antibodies in non-fractionated sera. A cut-off level between rubella IgM positive and negative sera was determined by a study of sera without rheumatoid factor from 200 blood donors. Testing of 12 donor sera containing rheumatoid factor showed that 5 sera gave a positive result in the rubella IgM assay. Rubella IgM antibodies were quantified by ELISA in a study of 214 serial serum specimens drawn from 16 patients with rubella during a period of up to 10 years after the infection. Peak values of the IgM antibodies were reached approximately 8 days after onset of the rash, and the persistence of the IgM antibodies ranged from 17-90 days, with the exception of one patient with a prolonged IgM response. The rubella IgG antibodies increased slowly after the rash and reached maximum levels about 50-120 days, after which a monor decrease was observed. The results of the present study indicate that ELISA is suitable as a routine procedure for the serodiagnosis of recent rubella.

Acute Disease

Rubella in Jerusalem. 1. Seroepidemiologic findings in children born after the 1972 rubella epidemic.

Nine hundred and sixty-nine babies born after a severe rubella epidemic were tested at the age of eight months for the presence of hemagglutination inhibition antibodies to the disease. There were 208 (21.9%) seropositive babies with titers of greater than or equal to 1:16. Seven cases of congenital rubella were diagnosed at birth, 14 were confirmed by eight months and two babies, who were considered normal at the age of eight months, developed late signs of the disease. Less than 3% of the mothers of the seropositive babies had had clinically recognized rubella in pregnancy. If positive hemagglutination inhibition antibody to rubella accurately reflects congenitally acquired rubella infection, between 8.1 and 21.9% of the 969 babies had serologic evidence of the disease. For cases of congenital rubella diagnosed by the age of three years, the limits are between 8.9 and 23.7 per 1,000 live births for the risk of the disease at the height of the epidemic. Rubella vaccine was not available in Israel until after the 1972 epidemic, the effects of which justify the continued search for and immunization of seronegative women of childbearing age, in addition to routine immunization of young girls.

Adult

Absence of cell-mediated immunity to rubella virus 5 years after rubella vaccination.

The long-term effectiveness of rubella vaccination in childhood is particularly important because the ultimate goal of immunization is the prevention of infection during pregnancy. Of 25 healthy children tested 4 to 5 years after rubella vaccination, 19 showed no evidence of cell-mediated immunity (CM) to rubella virus despite the presence of hemagglutination-inhibition or complement-fixation antibodies or both. Twenty-two of 25 seropositive, naturally infected young adults showed evidence of CMI. These results indicate that fetuses of women who have been vaccinated against rubella may not be protected against damage by wild rubella infection during the pregnancy, when CMI is physiologically depressed.

Adult

Parity of women contracting rubella in pregnancy. Implications with respect to rubella vaccination.

Data from the National Congenital Rubella Surveillance Programme showed that 44% of children with congenital rubella reported to the programme were born to primiparae. This high proportion is thought to be due to the fact that there was a two-fold increase in the rate of abortion for rubella in pregnancy for women with two or more children. This higher incidence of congenital rubella in firstborns emphasises the need for rubella vaccination prior to a woman's first pregnancy.

Abortion, Therapeutic

Single-radial-hemolysis test for the assay of rubella antibody in antenatal, vaccinated, and rubella virus-infected patients.

The single-radial-hemolysis test (SRHT) is a simple, convenient, and sensitive method that provides accurate measurement of IgG antibody to rubella virus. Lipoprotein inhibitors of rubella hemagglutination do not interfere with the SRHT; thus the assay of low levels of antibody is more reliable by SRHT than by the rubella hemagglutination-inhibition test (RHIT). The technique for the SRHT in a form suitable for large numbers of tests is detailed and compared with that of the RHIT, and the reproducibility of the SRHT in routine operation is assessed. Results obtained by testing various populations in Western Australia are used to show the application of the SRHT in the diagnosis of rubella and in the monitoring of rubella vaccination programs.

Adolescent

Rubella in Jerusalem. 2. Clinical and serologic findings in children with congenital rubella.

Forty-eight children born with clinical and serologic manifestations of congenital rubella were followed for a three-year period. Expanded rubella syndrome, multiple anomalies and single defects were found, mostly in the child's first year of life. Some new organic problems were found at a later age in children who had initially been healthy but who had been followed up because of their high antibody levels to rubella. Of the 48 children, 15 (31%) were born to mothers who had had clinically and serologically diagnosed rubella during pregnancy. In 33 children (69%) the mother had had asymptomatic rubella. These findings emphasize the need to identify and immunize seronegative women before pregnancy.

Abnormalities, Multiple

Rubella antibody titer. The significance of low-titered rubella antibodies.

The hemagglutination inhibition (HAI) test is not mathematically precise and reproducible. Thus, it is critical to know whether or not the threshold titer (1 : 10) of detectable rubella antibody is indicative of true immunity. Three patients with a 1 : 10 HAI titer presented with subsequent rubella during gestation. Ninety postpartum patients with a HAI titer of 1 : 10 were vaccinated and the rubella antibody titers were reassessed. Seventeen percent of these patients responded to the vaccine challenge with an eightfold or greater rise in titer. Thus, we recommend that the patient with a low HAI titer (1 : 10) should be considered to have marginal immunity to rubella and should be vaccinated.

Adult

Transfer of measles, mumps, and rubella antibodies from mother to infant. Its effect on measles, mumps, and rubella immunization.

Sera from 42 mother-infant pairs were examined to determine the effect of passively acquired enhanced neutralizing (ENt) antibody on immunization. The ENt antibodies to measles, mumps, and rubella were greater in term newborns than in their mothers, with mean ratio of 1.8:1, 1.3:1, and 1.2:1, respectively. In 21% to 25% of the children, these antibodies persisted until 12 months of age. When immunized with trivalent measles-mumps-rubella vaccine, children who had persisting ENt measles and rubella titers had significantly lower mean antibody responses than children without detectable antibodies to the two viruses. Persisting ENt mumps antibodies did not affect the postimmunization titers. Seroconversion rates to any of the three viruses were not different in children with or without preexisting ENt antibody.

Antibodies, Viral

In vitro effects of rubella virus, strain RA 27/3, on human lymphocytes. I. Viral inhibition of mitogen stimulation in relation to Rubella Haemagglutination inhibition antibodies.

The inhibiting effect of rubella virus on lymphocyte stimulation in vitro was studied, using purified virus of the attenuated strain RA 27/3. Addition of the virus to human lymphocytes from twenty healthy blood donors before stimulation with leuco-agglutinin (LA), a component of phytohaemagglutinin, caused a considerable inhibition of the LA response in some experiments, whereas in other experiments the inhibition was slight or non-existent. If further analysed, the results showed a correlation between the degree of inhibition and the immunity of the lymphocyte donor against rubella, as measured by haemagglutination inhibition (HI). Thus the LA-response was significantly more depressed in a group of lymphocyte donors with HI-titres ranging from 20 to 160 than in another group with HI-titre less than 5. Possible explanations of the virus-induced inhibition of the LA response and possible connection between this phenomenon and the immune response against rubella are discussed.

Adult

Rubella epidemic in an institution: protective value of live rubella vaccine and serological behavior of vaccinated, revaccinated and naturally immune groups.

A rubella epidemic occurred in an institutional population composed of 189 susceptible, 37 naturally immune, 35 previously vaccinated and 38 serologically uncharacterized children and nursing staff. The epidemic lasted 3.5 months and showed more than 5 waves. Detailed clinical and serological examinations of these subjects were made. A rash appeared in 156 (52%) of 299 persons, including 145 (87%) of 166 unvaccinated and serologically uncharacterized subjects, but not in the 72 immune persons. In the middle of the 3rd wave urgent vaccination of 61 children aged 0 to 2 years of the susceptible group reduced the rate of appearance of a rash to 11 of the children (18%), as compared with 126 (98%) of 128 subjects in the unvaccinated non-immune group. The epidemic only reached a 4th wave in the vaccinated group, but it extended to a 5th wave or more in unvaccinated subjects. None of the 35 subjects in a previously vaccinated group developed rubella, although the rate of subclinical reinfection in this previously vaccinated group was higher (35%) than that in the naturally immune group (17%). Three cases of subclinical reinfection were detected even among 6 previously revaccinated subjects.

Adolescent

Rubella vaccination in Australia: 2. Experience with the RA27/3 rubella vaccine and results of a double-blind trial in schoolgirls.

RA27/3 rubella vaccine (Almevax) was used for the first time in Australia. The seroconversion rate was similar to that seen with Cendehill vaccine (Cedevax), but there were fewer subjects with low antibody titres after Almevax vaccine. Although Almevax vaccine was associated with a significantly higher incidence of sore throat, rash and joint involvement in seronegative adults, the incidence of side effects in a double-blind trial in schoolgirls was similar for the two vaccines, and the morbidity was low in both groups. Almevax vaccination successfully boosted low antibody titres in 11 of 14 women who had previously responded poorly to Cendevax vaccination. It would be difficult to differentiate the better vaccine for the schoolgirl programme. In some clinical situations, however, one vaccine has advantages over the other.

Adolescent

Vaccination of schoolgirls against rubella. Assessment of serological status and a comparative trial of Wistar RA 27/3 and Cendehill strain live attenuated rubella vaccines in 13-year-old schoolgirls in Dudley.

A total of 1525 schoolgirls aged 13 years from 21 schools in the County Borough of Dudley, were bled for titration of rubella haemagglutinating inhibiting antibody and then were immediately vaccinated with either Wistar RA 27/3 or Cendehill strain live attenuated. Both vaccines were administered subcutaneously by syringe and needle but the Wistar RA 27/3 vaccine was also given by multiple injection apparatus. Significnatly higher conversion rates and geometric mean haemagglutinating inhibiting antibody titres were obtained in girls initially seronegative given the Wister RA 27/3 than in those given the Cendehill vaccine, regardless of the method of vaccination. The RA 27/3 strain was associated with a small but significantly greater incidence of local pain immediately on injection. With this exception, differences in the occurrence of reactions were not found between vaccines, between those initially susceptible and immune or with the level of antibody response.

Adolescent