Rubella
Rubella (i.e., German measles, third disease) typically is a subclinical or mild exanthematous infection of children and adults. Gestational rubella can have deleterious effects on the fetus. The infant may have physical and mental abnormalities, such as cataracts, congenital heart disease, deafness, microcephaly, or psychomotor retardation, or present with severe neonatal disease that may include thrombocytopenia, bleeding, hepatosplenomegaly, pneumonia, and myocarditis. Some manifestations of congenital rubella infection may not appear until years or decades later, even among patients asymptomatic at birth (8).
The rubella virus is an enveloped, single positive-stranded ribonucleic acid (RNA) virus that is spherical and has spike-like projections containing hemagglutinin. Only one antigenic type of the virus is known, but there are differences between rubella virus strains in their properties (e.g., hemagglutination, cell tropism), virulence, and teratogenicity. Man is the only natural host for rubella virus, but some animals such as primates, rabbits, and ferrets can be infected under experimental conditions. Rubella virus has three structural polypeptides; two are envelope acylated glycoproteins (E1 and E2) observed as spikes in the form of E1-E2 heterodimers on the virion surface, and one is a nonglyco-sylated RNA-associated capsid protein (C). E1 contains the domains responsible for binding to host cell receptors and for hemagglutination. The function of E2 is not well defined, but it may carry strain-specific antigens, partial hemagglutination epitopes, and a weak neutralizing domain associated with virus infectivity. The C protein may be involved in the transfer of viral RNA into host cell cytoplasm (28). Rubella virus also possesses a nonstructural polyprotein (p200); this polyprotein and its cleavage products (p150, p90) have enzymatic activities (e.g., helicase, replicase, protease) and are involved in viral RNA replication (29,30). Molecular techniques such as the polymerase chain reaction (PCR) and nucleotide sequencing allow the differentiation between rubella virus strains. This is useful in the analysis of the molecular epidemiology of the virus and in differentiating between wild-type virus and the RA 27/3 vaccine strain when rubella virus is isolated from individuals with possible vaccine-related adverse effects (31,32).
Person-to-person transmission usually occurs by airborne spread of infected respiratory secretions, and direct contact with virus-containing urine or feces is a less likely route of infection. Although rubella virus can be recovered from the genital tract of infected women, vertical transmission during pregnancy is believed to occur almost exclusively through the placenta (33,34).
On entry into the body in cases of postnatal infection, the rubella virus multiplies in nasopharyngeal epithelial cells and in local lymph nodes. This is followed by a period of viremia and shedding from the throat. It is during this maternal viremic phase that placental and fetal infection occurs. The frequency and nature of fetal involvement depends on the mother’s immune status against the virus and the timing during gestation of maternal rubella (8).
The mechanisms by which the virus ravages the fetus are not clearly understood. Necrotic placental vascular endothelial cells can serve as a source of virus-infected emboli. Damage to endothelial cells can lead to thrombosis of small blood vessels, resulting in hypoxic tissue damage (35,36). Rubella-infected cells have diminished mitotic activity as a result of chromosomal breaks. They produce a growth-inhibiting protein and show ultrastructural mitochondrial
changes that may interfere with cell metabolism. The virus damages the cytoskeletal microtubular system by altering the arrangement of actin filaments (37). Rubella virus generally establishes a chronic nonlytic infection in the fetus and can potentially infect any organ (29). As with other viruses, it can induce apoptosis of infected cells, but a role for this in its teratogenicity has not been demonstrated. Focal lysis of infected cells can be seen in some organs, but inflammation is not a salient feature of congenital rubella (35). Noninflammatory necrosis in the structures of the heart, eyes, brain, and ears have been seen in aborted rubella-infected fetuses (29). Growth-retarded infants have reduced cell numbers on histopathologic examination (38). Moreover, the virus can modify cell receptors for specific growth factors (39). Late-onset manifestations of congenital rubella may be as a result of viral persistence with ongoing cell destruction or to organ damage by means of a number of immune mechanisms such as circulating rubella-specific immune complexes, defective cytotoxic effector cell function, or the development of autoimmunity (28,40-44). The rubella virus E1 and E2 proteins, but not the C nucleoprotein, appear to be responsible for autoantibody induction (45).
changes that may interfere with cell metabolism. The virus damages the cytoskeletal microtubular system by altering the arrangement of actin filaments (37). Rubella virus generally establishes a chronic nonlytic infection in the fetus and can potentially infect any organ (29). As with other viruses, it can induce apoptosis of infected cells, but a role for this in its teratogenicity has not been demonstrated. Focal lysis of infected cells can be seen in some organs, but inflammation is not a salient feature of congenital rubella (35). Noninflammatory necrosis in the structures of the heart, eyes, brain, and ears have been seen in aborted rubella-infected fetuses (29). Growth-retarded infants have reduced cell numbers on histopathologic examination (38). Moreover, the virus can modify cell receptors for specific growth factors (39). Late-onset manifestations of congenital rubella may be as a result of viral persistence with ongoing cell destruction or to organ damage by means of a number of immune mechanisms such as circulating rubella-specific immune complexes, defective cytotoxic effector cell function, or the development of autoimmunity (28,40-44). The rubella virus E1 and E2 proteins, but not the C nucleoprotein, appear to be responsible for autoantibody induction (45).
Long-lasting immunity normally develops after recovery from postnatal rubella. Reinfections can occur in persons with low antibody titers, but these are usually asymptomatic. Persons with low antibody levels after rubella vaccination are more prone to reinfections than persons with similarly low titers after natural infection (34).
Circulating antibodies and cell-mediated immune responses are generated after rubella infection. Rubella-specific immunoglobin M (IgM), immunoglobin G (IgG), immunoglobin A (IgA), immunoglobin D (IgD), and immunoglobin E (IgE) antibodies are induced in response to postnatal infection (46). IgM antibodies appear early and are short lived. They usually disappear 5 to 8 weeks after onset of illness, although rubella-specific IgM antibodies rarely can persist for months or years (47). The IgM re-sponse after rubella vaccination or natural reinfection generally is weak and of brief duration (48,49,50). Moreover, rubella-specific IgM antibodies can be detected in acute infections caused by viruses such as parvovirus B19 and Epstein-Barr virus (51). Specific IgD and IgE antibodies appear early and then decline more slowly than specific IgM antibodies (46). Specific IgA antibodies generally emerge within the first 10 days of illness, and they may continue to be measurable for periods ranging from 3 weeks to several years (46,52). Rubella-specific IgG antibodies increase rapidly and persist throughout life; rubella-specific IgG1 has been shown to be the principal IgG subclass (34,53). The most vigorous antibody and lymphocyte proliferative responses in postnatal rubella are directed against glycoprotein E1 (54,55). The avidity of specific IgG to rubella antigens increases with time after primary infection; a low avidity index (less than 40%) can be seen up to 6 weeks after onset of the rubella rash, whereas a high avidity index (greater than 60%) is not seen until after 13 weeks (51). Measurement of rubella IgG avidity can be useful in women with positive rubella-specific IgM reactions, as it can help distinguish primary infections from unusually prolonged IgM persistence or from reinfection. Rubella-specific IgG also can be detected in the urine, and the results correlate well with serum IgG measurements (56). Men and women appear to differ in the nature and magnitude of their antibody responses to rubella virus structural proteins (57). Men never produce anti-E2 IgA and generate significantly lower levels of IgG antibodies directed against E2 than women. Anti-E1 IgM and IgG antibodies appear earlier in male patients, but female patients have higher levels of rubella-specific IgG antibodies after recovery from the illness. The observed gender differences in antibody responses to viral proteins may be under genetic or hormonal influences and may be related to the increased susceptibility of women to the joint complications of rubella (57).
Immune responses in congenitally infected infants differ from those observed in adults with rubella. Fetal IgM production usually begins after 16 weeks of gestation. Rubella-specific IgM antibodies are detectable until 6 to 12 months of age. Specific IgG antibody levels decrease over time; as many as 20% of affected children have no measurable antibody titers by 5 years of age (34). Circulating antirubella antibodies in infants with intrauterine infection have lower affinities to rubella antigen than antibodies from adults with natural infection (58,59). Serum antibodies to the E2 glycoprotein are quantitatively more abundant than those directed against E1 in some patients with congenital rubella, particularly among older infants. Antibody reactivities against the C protein are poor (54,60). Infants with congenital rubella have diminished cell-mediated immune responses on exposure to rubella antigens compared with children or adults with postnatal infection, and the responses are weakest for infants infected earlier during gestation. The reduction in response is mainly seen with the E1 protein (53,61).
Maternal Rubella
Epidemiology
Major epidemics of rubella formerly occurred at 6- to 9-year intervals in the United States. The last major pandemic took place between 1964 and 1965, at which time 20,000 cases of congenital rubella occurred. Rubella did not become a notifiable disease in the United States until 1966. Since licensure of the rubella vaccine in 1969, the number of postnatal rubella and congenital rubella syndrome (CRS) cases declined by 99% and 97%, respectively. The incidence of reported postnatal rubella cases declined from 0.45 per 100,000 in 1990 to less than 0.02 per 100,000 in 2002. The annual number of reported cases during that same period ranged from a high of 1,412 in 1991 to a low of 18 in 2002, with a median of 192 (19,62).
A significant change in the characteristics of postnatal rubella cases has been noted between 1990 and 2000. Between 1990 and 1992, 50% to 70% of all cases were in
children 14 years of age or younger. By 2002, 72% of all cases occurred in individuals 15 to 39 years of age. Only 23% of the 18 postnatal rubella cases in 2002 were in females. Between 1995 and 2000, Hispanics comprised from 56% to 78% of all patients with this infection, most of whom were born outside the United States. Between 1996 and 1999, rubella was reported in 281 women of childbearing age, 26% of whom were pregnant at the time of rash onset (19,62). For the time period from 1990 to 1999, there were 65 outbreaks of rubella (each with five or more epidemiologically linked cases). Common settings for these outbreaks included religious communities, correctional facilities, worksites, and higher education institutions (62). Most affected individuals were either unimmunized or had unknown vaccination status (21,62-64).
children 14 years of age or younger. By 2002, 72% of all cases occurred in individuals 15 to 39 years of age. Only 23% of the 18 postnatal rubella cases in 2002 were in females. Between 1995 and 2000, Hispanics comprised from 56% to 78% of all patients with this infection, most of whom were born outside the United States. Between 1996 and 1999, rubella was reported in 281 women of childbearing age, 26% of whom were pregnant at the time of rash onset (19,62). For the time period from 1990 to 1999, there were 65 outbreaks of rubella (each with five or more epidemiologically linked cases). Common settings for these outbreaks included religious communities, correctional facilities, worksites, and higher education institutions (62). Most affected individuals were either unimmunized or had unknown vaccination status (21,62-64).
Medical students and other health professionals can also serve as vectors for rubella infection, placing susceptible pregnant women to whom they are exposed in a medical setting at significant risk (65). In a study of one hospital system in St. Louis, Missouri, 5.3% of about 6,000 new employees were found to be seronegative for rubella (66).
Approximately 10% to 20% of women of childbearing age in the United States are susceptible to rubella, and the rates are comparable for Hispanics, non-Hispanic whites, and African Americans. Hispanics aged 20 to 29 years are more likely to be seropositive for rubella if born outside the United States (67). Between 1990 and 1999, women delivering infants with CRS tended to be young (median age, 23 years), Hispanic, and foreign-born (62). Rubella susceptibility rates for women of child-bearing age in European countries generally are comparable to those found in the United States, but lower seropositivity rates are encountered among island populations such as those in Hawaii and Jamaica and in certain tropical African countries (34,68-72). Significant regional differences have been found in large countries, such as India and China (73,74).
Clinical Manifestations
Twenty percent to 50% of postnatal rubella infections are subclinical (75). Illness occurs 12 to 23 days (mean 18) after exposure. A prodrome consisting of malaise, low-grade fever that rarely lasts beyond the first day of the exanthem, headache, and conjunctivitis precedes the rash by 1 to 5 days. The exanthem consists of discrete macules or papules that initially appear on the face and behind the ears, spread downward over 1 to 2 days, and usually disappear over 3 to 5 days; rubella virus can be isolated from these skin lesions (76). Postauricular, suboccipital, and posterior cervical lymphadenopathy is common and may persist for several weeks. Complications of rubella develop more frequently in adults. Transient arthralgias may occur in as many as one-third of infected women, but arthritis is uncommon (8). Other complications are rare and include thrombocytopenic purpura, hemolytic anemia, hepatitis, Guillain-Barré syndrome, encephalitis, progressive panencephalitis, myelitis, peripheral neuritis, myocarditis, and pericarditis (8,77-80).
Pregnancy has no effect on the natural course of rubella infection. However, rubella is associated with an increased risk of miscarriages, spontaneous abortions, and stillbirths (8).
Laboratory Diagnosis
The diagnosis of rubella on clinical grounds alone is unreliable, because enteroviruses, measles virus, or parvovirus B19 may produce similar illnesses. Laboratory confirmation by virus isolation or serologic testing thus is essential in pregnant women, for whom an accurate diagnosis of gestational rubella is critical. Shirley and colleagues (81) investigated 627 patients clinically suspected of having rubella, but they could confirm this diagnosis in only 229 (37%). Human parvovirus B19 infection accounted for 7%, measles for 1%, and other infectious agents for 1%; the causes for the remaining 54% could not be determined.
Rubella virus is shed from the nasopharynx for 1 week before and 1 week after onset of the rash. However, the cultures become negative in 50% of patients by the fourth day of the rash. The virus is present in blood and urine during the week preceding the exanthem. Shortly after the rash appears, rubella virus is no longer detectable in the serum but can be found in circulating mononuclear cells for about a week. Rubella virus isolation is impractical for diagnostic purposes because it is expensive, labor intensive, and frequently unavailable to the clinician. The cell line recommended for isolation of rubella virus from clinical specimens is primary African green monkey kidney, but Vero or RK-13 can be used also. Isolation of the virus can take longer than 10 days, especially if present in low titers (82).
Serologic techniques are the most useful methods for diagnosing rubella infection. Available tests include hemagglutination inhibition, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, radioimmunoassay, hemolysis in gel, complement fixation, passive hemagglutination, and latex agglutination tests (50,82). Serum specimens obtained as soon as feasible after the appearance of the exanthem and again 2 weeks later can prove the diagnosis if seroconversion or a fourfold or greater rise in rubella-specific antibody titers can be documented. Paired sera are best tested in unison because of the variability in results of assays done on separate days or by different personnel. If measured by ELISA, hemagglutination inhibition, or radioimmunoassay, rubella-specific IgG antibodies can be found as early as 1 to 2 days before the emergence of the rash; if assayed by the less readily available passive hemagglutination method, these antibodies are not detected until 15 to 50 days after onset of the exanthem and peak approximately 6 to 7 months later. The detection of rubella-specific IgM antibodies within 28 days of the appearance of the rash usually is diagnostic, the caveats being that IgM responses sometimes can persist for a year or more after a primary infection and that they also can be detected in some patients with rubella reinfection (83). Only 50% of postnatal rubella patients have detectable IgM
on the day of symptom onset, but more than 90% become IgM positive by the fifth day after the rash appears (82). Newer tests that can be used for the diagnosis of acute postnatal rubella include avidity ELISA in which acutely infected persons have low IgG avidity compared with persons previously immune to rubella who exhibit greater IgG avidity (51). IgG produced in response to rubella vaccination shows low avidity to rubella antigens during the first 2 months after immunization, but this increases significantly over the ensuing months and remains at high levels thereafter (84). Immunoblot techniques have been developed for the sensitive detection of rubella-specific IgG, IgM, and IgA antibodies (85).
on the day of symptom onset, but more than 90% become IgM positive by the fifth day after the rash appears (82). Newer tests that can be used for the diagnosis of acute postnatal rubella include avidity ELISA in which acutely infected persons have low IgG avidity compared with persons previously immune to rubella who exhibit greater IgG avidity (51). IgG produced in response to rubella vaccination shows low avidity to rubella antigens during the first 2 months after immunization, but this increases significantly over the ensuing months and remains at high levels thereafter (84). Immunoblot techniques have been developed for the sensitive detection of rubella-specific IgG, IgM, and IgA antibodies (85).
Rubella reinfections are confirmed by a fourfold or greater rise in the titer of preexisting rubella-specific IgG antibodies. The specific IgM response is absent or weak, but it is sometimes high enough to be within the range deemed sufficient for the diagnosis of primary rubella (50).
False-positive IgM reactions can occur in sera containing rheumatoid factor, although the IgM capture assay appears to be unaffected by its presence (50). Cross-reactions between rubella and human parvovirus B19, Epstein-Barr virus, or CMV infections in specific IgM tests necessitate caution in interpreting low or equivocal levels of rubella-specific IgM antibodies (75).
Treatment
There is no specific therapy for postnatal rubella. Patients with rubella shed the virus from the nasopharynx for 1 week after appearance of the rash; therefore, these patients should avoid contact with susceptible persons until the exanthem has vanished.
Prevention
The principal goal of rubella immunization programs is the elimination of CRS. The vaccine used in the United States is the RA 27/3 attenuated live rubella virus vaccine. It is available in a monovalent form (i.e., rubella only) and in combination with measles and mumps (i.e., measles-mumps- rubella). The vaccine induces antirubella antibodies in more than 95% of recipients 12 months of age or older, and its protective efficacy is greater than 90% for at least 15 years (89). Immunizing children whose pregnant mothers are susceptible to rubella does not pose a threat to the mother or her fetus. The vaccine is recommended for all susceptible persons 12 months of age or older and usually is given at 15 months of age; a second booster dose is given to children at the time of school entry.
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