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Rubella

Rubella is an enveloped RNA virus belonging to the Family Togaviridae, genus Rubivirus. Rubella virus infection is generally a mild exanthematous disease associated with lowgrade fever, lymphadenopathy, and a short-lived morbilliform rash also known as "German measles" because it was originally described by a German physician in the late 1800's. Rubella virus was first isolated in 1962 and vaccines are prepared from live attenuated virus.

The average incubation period for rubella infection is 14 days, with a range of 12–23 days. Rubella is usually associated with a generalised, erythematous, maculopapular rash that lasts ≤3 days (Figure 1), lymphadenopathy usually involving the postauricular, sub-occipital and posterior cervical lymph glands, and occasionally arthritis and arthralgia. In adults and adolescents, the rash may be preceded by a 1-5 day prodrome of low-grade fever, malaise, anorexia, mild conjunctivitis, runny nose, sore throat, and lymphadenopathy. Asymptomatic rubella virus infections are relatively common and between 20%–50% of infections occur without rash. Therefore serological testing is critically important in rubella diagnosis especially in pregnancy because foetal infection resulting in congenital rubella syndrome (CRS) has devastating consequences.

The incidence of rubella has decreased dramatically in young children with the introduction of the live attenuated rubella vaccine (either monovalent vaccine or in combination with measles and mumps in the MMR vaccine), but rubella still occurs worldwide with comparatively more cases being seen in older age groups i.e. 20-24 years. Infection is spread by respiratory droplets and infections peak usually during late winter/early spring.

Figure 1 Typical erythematous maculopapular rubella rash in an adult

Typical erythematous maculopapular rubella rash in an adult

Rubella in pregnancy

When rubella virus infection occurs during early pregnancy, consequences may include miscarriage, fetal death, or an infant born with the constellation of severe birth defects known as congenital rubella syndrome.

Maternal rubella infection in the first 8 to 10 weeks of pregnancy has the highest risk for foetal damage, which may occur in up to 90% of affected pregnancies, and multiple defects are common. The risk of damage declines to between 10- 20% by 16 weeks gestation. After 20 weeks gestation foetal damage is rare.

The characteristics of CRS include intellectual disabilities, cataracts, deafness, cardiac abnormalities, intrauterine growth retardation and inflammatory lesions of the brain, liver, lungs and bone marrow. The most common congenital defects are cataracts, heart defects, and hearing impairment. Other complications, such as neurological disorders and thrombocytopenia, may occur but are relatively rare. Any combination of these defects may occur, but deafness and retinopathy may occur alone following infection after the first 8 weeks of pregnancy. Some infected infants may appear normal at birth, and defects like auricular sensorineural deafness, may be detected later.

Rubella re-infection can occur in individuals who have both natural and vaccine induced antibodies. Occasional cases of CRS after re-infection in pregnancy have been reported but foetal damage is very rare in this situation because there are pre-existing levels of IgG antibodies. It is therefore recommended that all pregnant women with suspected rubella or exposure to rubella should be serologically tested, irrespective of a history of previous vaccination, clinical rubella or a previous positive rubella antibody result. Pregnant women should be advised to restrict contact with individuals with confirmed, probable or suspected rubella for up to 6 weeks (2 incubation periods). Pregnant women with confirmed rubella should be advised about the risk to the foetus.

Serological testing for rubella

Rubella antibody testing remains the main diagnostic tool available to either establish a previous exposure to rubella or rubella vaccination or a current infection/re-infection with rubella.

The graph below outlines the typical appearance of IgG and IgM antibodies after infection.

Graph oultines typical appearance of IgG and IgM antibodies after infection.

Acute rubella infection is indicated by presence of rubella IgM or 4-fold or greater increase in rubella IgG 10-21 days apart. Rubella IgM may not appear until a week after clinical symptoms. Sera for IgG testing should be taken 7-10 days after onset of illness and repeated 2 to 3 weeks later. The most recent date of potential exposure should be obtained, if possible, to calculate the potential incubation period.

A number of commercial assays for testing immunity i.e. IgG to rubella are available. Antibody levels determined as per standard ELISA assays are used quantitatively to indicate the result. Unlike rubella IgG measurements, there is no agreed cut off level or standard for a quantitative rubella IgM result and each assay and therefore each laboratory has it's own limits set for a negative, equivocal and positive result as per the manufacturers guidelines. The Table 1 below indicates the World Health Organisation recommended interpretation of rubella IgG and IgM results, alone and in combination.

Table 1 Interpretation of Rubella Serology Results

Rubella Result Levels IU/mL Interpretation Comments
IgG ≤ 4.99 NEGATIVE Rubella susceptible. There are no significant levels . of detectable rubella IgG antibody. Rubella vaccination is recommended in non pregnant women and on delivery in women currently pregnant.
IgG 5-9.99 EQUIVOCAL Rubella susceptible Rubella IgG levels are l o w and n ot considered protective.
IgG ≥ 10 POSITIVE Rubella immune The World Health Organisation (W.H.O) cut-off for POSITIVE IgG antibody levels is 10 IU/mL, rubella IgG levels ≥ 10 IU/mL are considered POSITIVE. IgG levels between 10-20 IU/mL are considered low.
A booster dose of rubella vaccine is recommended, particularly in women anticipating pregnancy or at delivery in women who are already pregnant and planning more pregnancies.
IgM   NEGATIVE No detectable rubella IgM.
IgM   EQUIVOCAL Low levels of IgM antibodies in the indeterminate range for the test and the laboratory. Further testing is indicated.
IgM   POSITIVE Detectable levels of IgM antibodies that may indicate primary infection, re - infection or response post-vaccination. Further testing may be required.
IgG ≤4.99 PLUS IgM NEGATIVE     Rubella susceptible. Rubella IgG antibodies ≤ 4.99 IU/mL are considered NEGATIVE, there are no significant levels of detectable rubella IgG antibody. Rubella vaccination is recommended in non pregnant women.
IgG ≥ 10 or IgG 5-9.99 PLUS IgM NEGATIVE    

Rubella immune. The World Health Organisation (W.H.O) cut-off for POSITIVE IgG antibody levels is 10 IU/mL, rubella IgG levels ≥ 10 IU/mL are considered POSITIVE.

IgG levels between 10-20 IU/mL are considered low. A booster dose of rubella vaccine is recommended, in women anticipating pregnancy or at delivery in women who are already pregnant.

IgG ≤ 4.99 or -59.9 IgM EQUIVOCAL or POSITIVE And IgG ≥ 10 IU/mL and IgM POSITIVE or Any 4 fold increase in IgG levels 10-21 days apart     Rubella Infection. Rubella specific IgM may be detected following primary rubella infection, vaccination or re-infection of immune individuals. IgM levels with re-infection are low and transient and generally not associated with Congenital Rubella Syndrome (CRS). Rubella specific IgM antibody in cord blood or infant serum may indicate CRS. A rubella avidity test is recommended to distinguish between recent or past infection. Further confirmatory testing such as PCR may also be necessary.
IgG 5-9.99 or >10 and IgM EQUIVOCAL or POSITIVE     Rubella re-infection. Rubella re-infection can occur in individuals who have both natural or vaccine induced IgG antibody. The presence of rubella IgG and IgM antibodies suggests that this is either a secondary infection or late primary infection. Rubella avidity testing is recommended to differentiate between primary infection and re-infection. Please discuss with the Virology pathologists Prof Eftyhia Vardas or Dr Allison Glass.

Seronegative women of child-bearing age that are vaccinated should be tested for seroconversion at least 8 weeks after their last vaccination. A small percentage of women (approximately 1%) will not respond to rubella vaccine by forming IgG or IgM antibodies. All women should be screened for rubella antibodies shortly before every pregnancy or if pregnancy is contemplated, irrespective of a previous positive rubella antibody result because rare reporting errors may result in patients who are seronegative being reported as seropositive.

Serological testing of pregnant women exposed to rubella should always be performed. If the woman has an IgG antibody level below the protective level, or a low level of IgG antibodies and remains asymptomatic, a second blood specimen should be collected 28 days after the exposure (or onset of symptoms) and tested in parallel with the first to demonstrate a rise in IgG titres. If the woman develops symptoms, the specimen should be collected and tested as soon as possible. A third blood specimen may be required in some circumstances.

Rubella avidity test

The serological diagnosis of rubella infection is based on the presence of specific IgG and IgM antibodies. Assays of the avidity of IgG (i.e. the strength of IgG binding to a multivalent antigen of the virus), have been used to distinguish recent from old infections in individuals with IgG levels. At the onset of the immune response (acute phase), the IgG generated by the antigenic stimulus has low avidity (below 39%) because the antibody binds with less strength to the antigen, within 2-4 months after infection, the strength of the antibody-antigen bonds increases and this is reflected in an avidity reading of greater than 60%.

Differentiating between an asymptomatic primary rubella infection and re-infection is extremely important, because under both conditions antibody titres are increased and IgM may be present. The IgG level is important for indicating susceptibility to reinfection. Re-infection is common in women with IgG levels below 10-15 IU/mL. Re-infections, for the most part asymptomatic, pose a low risk to the foetus, but they may develop with the presence of IgM, particularly in the re-infection of vaccinated women. Avidity testing and rubella PCR testing are adjunctive tests used in the clinical diagnosis of rubella. Avidity testing is done with commercial ELISA tests and the avidity index is calculated from the cutoff ratio's obtained on the test. Rubella PCR testing is recommended either antepartum on maternal urine, on amniotic fluid after amniocentesis or postpartum on cord or infant blood in the first few weeks of life.

The current recommended rubella testing algorithm that Lancet has adopted is outlined in Figure 2 including the quantitative cut off's for IgG antibodies used for reporting and clinical decision making.

Figure 2 Rubella Testing Algorithm

Rubella Testing Algorithm

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