RUBELLA AND CONGENITAL RUBELLA

RUBELLA AND CONGENITAL RUBELLA

Current Diagnosis

• Laboratory confirmation of rubella is necessary to exclude other diseases with similar clinical symptoms.

• Laboratory diagnosis is normally done by serologic testing and increasingly also by molecular diagnostic methods, including reverse-transcriptase polymerase chain reaction.

Current Therapy

• There is no specific therapy for the treatment of acute rubella or congenital rubella syndrome.

• Rubella in pregnant women requires a careful diagnosis and counseling based on thorough risk assessment.

• Patients with congenital rubella syndrome should be referred to specialists depending on their congenital defects.

• Protection against rubella and congenital rubella syndrome relies on vaccination.

Rubella is normally a mild, self-limiting rash-fever illness. Infection during pregnancy, however, can result in fetal death or congenital defects known as congenital rubella syndrome (CRS). Rubella virus is a single-stranded RNA virus (family Togaviridae) of which only one serotype but several genotypes are known.

Epidemiology

Humans are the only known natural host for rubella virus, and before the first licensed vaccine was introduced in 1969, the virus circulated worldwide, causing epidemics every few years.

Rubella spreads mainly via aerosols, but in contrast to measles, a close and prolonged contact is usually required for transmission.

Children with CRS can shed large quantities of virus for many months after birth. In unvaccinated populations, approximately 15% to 20% of women of childbearing age are susceptible to the disease and can become infected during pregnancy.

Effective vaccination programs have already led to the elimination of rubella and CRS in some countries (e.g., the United States and Finland). However, routine rubella vaccination has not yet been introduced in many developing countries in Africa and Asia, and endemic virus continues to circulate in many countries worldwide.

Insufficient vaccination rates in industrialized countries and the refusal to be vaccinated for religious and other reasons represent a considerable threat to control and elimination goals of the World Health Organization (WHO).

Reinfections with rubella virus are possible and have been reported more often after vaccination than after natural primary infection.

Normally, reinfections are asymptomatic and congenital malformations seem to be very rare.

Clinical Manifestations

Rubella virus normally causes only a mild disease, and it is estimated that depending on the cohort, between 20% and 50% of infections are subclinical. The incubation period lasts about 2 weeks (range, 12–23 days), at the end of which a maculopapular rash can appear, which spreads from the face to the trunk and limbs. Lymphadenopathy can develop before the rash and can persist for up to 2 weeks after rash.

Especially in adults, a prodromal phase may be observed with fever, malaise, and other uncharacteristic symptoms. Viremia occurs for about 1 week before onset of rash, and virus can be transmitted from around 1 week before, until up to nearly 2 weeks (and exceptionally longer) after onset of rash.

Complications

Rubella infection acquired after birth is rarely associated with complications other than arthralgia and arthritis in post-pubertal women. Male patients and prepubertal girls only rarely have these symptoms. Joint symptoms normally last a few days, but they sometimes persist for up to 1 month. Encephalopathy and thrombocytopenia are other rare complications associated with rubella.

Infection during pregnancy can lead to miscarriage and, especially if acquired in the first trimester, is likely to result in congenital defects. The range and severity of the damages is related to the developmental stage of the fetus at the time of infection. The most common manifestations of CRS include defects of the eyes (e.g., cataracts, glaucoma, pigmentary retinopathy), ears (e.g., deafness), heart (e.g., patent ductus arteriosus, pulmonary artery stenosis, ventricular septal defect, neonatal myocarditis) and the central nervous system (e.g., microcephaly, meningoencephalitis, mental and motor retardation, speech, behavior and psychiatric disorders). Most of the clinical features are permanent, but some are transient (e.g., intrauterine growth retardation, hepatosplenomegaly, thrombocytopenic purpura, hemolytic anemia, bone lesions). Not all manifestations are apparent at birth; some appear only later in life (e.g., type 1 diabetes mellitus, thyroid dysfunction).

Diagnosis and Differential Diagnosis

A rubella diagnosis based on clinical symptoms alone is unreliable. Laboratory confirmation is necessary to exclude other rash-fever diseases such as infections caused by measles virus, parvovirus B19, human herpesvirus 6, dengue virus, enteroviruses, and group A Streptococcus. Rubella-specific immunoglobulin (Ig) M, which normally persists for 2 to 3 months but occasionally much longer, points to a current or recent infection. False-positive IgM results occur more often with indirect serologic assays than with antibody-capture assays and are sometimes linked to rheumatoid factor or cross- reacting non-rubella IgM antibodies. During pregnancy, false-positive IgM tests are of particular concern. A significant increase in rubella- specific IgG antibody titer between acute and convalescent phase sera also indicates a recent infection with rubella virus. IgG avidity testing can also differentiate between old and recent infections. The virus can also be detected by reverse transcription polymerase chain reaction (RT-PCR) or virus isolation in cell culture.

Fetal infections are usually diagnosed either by rubella-specific IgM in fetal blood or by rubella virus in amniotic fluid. However, the time point for testing is critical. After birth, laboratory confirmation of CRS is normally done by detecting rubella-specific IgM, which is almost always detectable during the first 3 months of life but only very rarely after the age of 18 months. Detection of rubella-specific IgG antibodies at a time when maternal antibodies have normally disappeared also suggests a congenital infection. In addition, detecting rubella virus by isolation in cell culture or by RT-PCR in respiratory secretions, oral fluid, urine, cerebrospinal fluid, or lens aspirates of infants with CRS may be possible for up to 1 year and sometimes even longer.

Treatment

No specific therapy exists, either for acute cases of rubella or for CRS cases, and emphasis must therefore be on prevention. Rubella infection during pregnancy requires a careful laboratory diagnosis, comprehensive risk assessment, and counseling. Depending on the defects, children with CRS should be referred to specialists as early as possible.

Prevention

The first rubella vaccine was licensed in 1969 in the United States and contained a live-attenuated strain obtained after serial passaging of a wild-type isolate. Since then, several other vaccine strains have been prepared, and strain RA 27/3, which was licensed in 1979, is currently the most widely used worldwide. Rubella vaccine is available in combination with measles and mumps vaccines (MMR) and as a quadrivalent vaccine containing additionally a varicella component (MMRV) (ProQuad). About 95% of all vaccinees develop an immune response; occasional failures may be due to inappropriate storage and handling of the vaccine, coexisting infections, or the presence of passively acquired antibodies. Antibodies induced by vaccination are thought to be long-lasting (>20 years) and to provide lifelong protection in most vaccinees.

Immunity against rubella infection is usually assumed if a rubella- specific IgG titer of at least 10 IU/mL is present. The immune status of women should be checked before pregnancy, and, if necessary, vaccination should be offered. Health care workers in contact with pregnant women should also be immune.

Vaccination is contraindicated in pregnancy, although inadvertent vaccination is no indication for therapeutic abortion. Although some studies reported cases of congenital infection after vaccination during pregnancy, cases of CRS due to rubella vaccine strains do not seem to occur or must be very rare. Other contraindications include severe immunosuppression and severe allergic reactions to components of the vaccine. Only very few and rare side effects are known following rubella vaccination, but lymphadenopathy, joint symptoms, and rash are sometimes observed.

References

1.     Banatvala J.E., Brown D.W. Rubella. Lancet. 2004;363(9415):1127– 1137.

2.    Best J.M. Rubella. Semin Fetal Neonatal Med. 2007;12(3):182–192.

3.     Best J.M., Castillo-Solorzano C., Spika J.S., et al. Reducing the global burden of congenital rubella syndrome: Report of the World Health Organization Steering Committee on research related to measles and rubella vaccines and vaccination, June 2004. J Infect Dis. 2005;192(11):1890–1897.

4.    Cooper L.Z., Alford Jr. C.A. Rubella. In: Remington J.S., Klein J., Wilson C.B., Baker M.D., eds. Infectious Diseases of the Fetus and Newborn Infant. 6th ed Philadelphia: Elsevier Saunders; 2006:893–926.

5.     da Silva e Sá G.R., Camacho L.A., Siqueira M.M., et al. Seroepidemiological profile of pregnant women after inadvertent rubella vaccination in the state of Rio de Janeiro, Brazil, 2001–2002. Rev Panam Salud Publica. 2006;19(6):371–378.

6.      Reef S.E., Redd S.B., Abernathy E., et al. The epidemiological profile of rubella and congenital rubella syndrome in the United States, 1998–2004: The evidence for absence of endemic transmission. Clin Infect Dis. 2006;43(Suppl. 3):S126–S132.

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