The rubella virus is a member of the Togaviridae family and is the sole member of the genus Rubivirus. Rubella virus virions are round and are covered with a lipid envelope. The diameter of virus particles varies from about 57 nm to 86. It has spikes, formed by glycoproteins E1 and E2, which extend up to 8 nm from the membrane of the rubella virion surface, and are formed into parallel rows.
The RV virion contains an RNA genome enclosed within an icosahedral capsid composed of multiple copies of a basic protein, C, of 33 kDa. Surrounding this nucleocapsid is a lipid bilayer in which viral glycoproteins El (58 kDa) and E2 (42 to 47 kDa) are embedded.
Rubella is overcome easily with light symptoms during the childhood. Children usually develop few or no constitutional symptoms, but adults may experience a 1–5-day prodrome of low-grade fever, headache, malaise, mild coryza, and conjunctivitis. Сervical lymphadenopathies are characteristic and precede the rash by 5–10 days. Arthralgia or arthritis may occur in up to 70% of adult women with rubella. Rare complications include thrombocytopenic purpura and encephalitis. These complications are thought to arise from RV persistence in corresponding tissues of the host.
Still, the most significant consequence of rubella infection is the transfer of rubella virus to an unborn fetus, where significant defects often result. The dissemination of the virus to the fetus probably begins with placental infection during maternal viremia. Possible mechanisms of cytopathogenicity include induction of apoptosis by the virus and inhibition of cell division.
The rubella virus establishes a chronic infection in the fetus, congenital rubella syndrome (CRS), and its elimination may take years. CRS can occur in 80–85% of cases of primary rubella virus infection during the first trimester of pregnancy.
Rubella is a highly contagious infectious disease. Rubella is transmitted through direct or droplet contact from nasopharyngeal secretions and has an average incubation period of 17 days (range: 12–23 days). Persons with rubella are most infectious when rash is erupting, but they can shed virus from 7 days before to 7 days after rash onset. Most RV infections produce lifetime immunity mediated by circulating antibodies and specific T lymphocytes. There is only one serotype of the rubella virus.
Large-scale rubella vaccination during the past decade has practically eliminated rubella and CRS in many developed and in some developing countries. Before the introduction of the vaccine, up to 4 children in every 1000 live births were born with CRS worldwide. Still, even today, more than 100,000 children in developing countries are born with CRS each year. CRS rates are highest in African and South-East Asian regions where vaccine coverage is lowest. In the EU, the disease rate is over 4 000 cases in 2014; 96% of them were registered in Poland.
Many studies have shown that viral protection is mostly induced by neutralizing antibodies. The rubella specific IgM antibodies are usually detected within 4 days after the onset of rash and for 4–8 weeks thereafter, but in some cases these antibodies can persist for over a year. IgG antibodies appear during the acute phase (7 to 30 days postonset) and persist at varying levels for life.
During viral infection, antibodies specific to three structural proteins of the rubella virus develop; the protective immune response is predominantly directed toward the glycoproteins, mainly against the glycoprotein E1.
Since the symptoms of rubella are often not specific, and many cases of rubella are asymptomatic, the diagnosis of rubella is rarely based upon clinical symptoms. The presence of rubella virus in nasal, throat, urine, blood, and cerebrospinal fluid specimens from persons with suspected rubella should be proven by virus isolation or alternatively viral nucleic acid should be detected by polymerase chain reaction. Immunological tests are by far the most popular in the diagnostics of rubella.
Serum assays are used for 3 main purposes:
1) for determining seroconversion after RV vaccination by the level of IgG;
2) for evaluation of the immunity to virus by the level of IgG, determining the need to vaccinate women at reproductive age;
3) to diagnose possible infection in pregnant women by the level of IgM and by the avidity of IgG.
Detection of rubella-specific IgM alone cannot be considered absolute proof of a recent primary infection for several reasons. IgM response after primary infection may be prolonged, lasting up to several years. Furthermore, sometimes rubella IgM is detectable in the case of mild secondary infection occuring despite a vaccination. This secondary infection is regarded as safe for the fetus. False-positive IgM results may also be artifacts due to various reasons.
This issue of doubtful IgM results is especially important when investigating suspected rubella in pregnant women because of the risk of CRS, so additional diagnostic tests should be used in such situations. Аvidity of IgG, which in most cases begins to increase 3 months following rubella infection, is another independent parameter allowing to differentiate between recent and past infection. For example, in one study low avidity specific IgG was detected in 91% of sera taken at 3–4 months after exposure to rubella virus; at 5–7 months after exposure only 21% of sera remained low avidity [Thomas et al., 1992].
The IgG avidity assay is gaining popularity as a diagnostic method for the assessment of the time of infection. According to the recommendations of the Center for Disease Control and Prevention, USA, if IgM of the first probe is positive, avidity of IgG of the second probe, collected in 5-10 days, should be also measured. If the IgM and IgG of this second probe are positive, but the IgG avidity is high, this may indicate either a false-positive IgM result or a benign secondary infection [CDC.VPD Surveillance Manual, 5th Edition, 2012].
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