Rubella was historically viewed as a variant of measles or scarlet fever. Not until the mid-1900s was a separate viral agent for rubella isolated. After an epidemic of rubella in Australia in the early 1940s, the ophthalmologist Norman Gregg noticed the occurrence of congenital cataracts among infants whose mothers had reported rubella infection during early pregnancy, and congenital rubella syndrome (CRS) was first described.
Rubella virus is a member of the Togaviridae family and the only member of the genus Rubivirus. This single-stranded RNA enveloped virus measures 50–70 nm in diameter. Its core protein is surrounded by a single-layer lipoprotein envelope with spike-like projections containing two glycoproteins, E1 and E2. There is only one antigenic type of rubella virus, and humans are its only known reservoir.
Pathogenesis and Pathology
Although the pathogenesis of postnatal (acquired) rubella has been well documented, data on pathology are limited because of the mildness of the disease. Rubella virus is spread from person to person via respiratory droplets. Primary implantation and replication in the nasopharynx are followed by spread to the lymph nodes. Subsequent viremia occurs, which in pregnant women often results in infection of the placenta. Placental virus replication may lead to infection of fetal organs. The pathology of CRS in the infected fetus is well defined, with almost all organs found to be infected; however, the pathogenesis of CRS is only poorly delineated. In tissue, infections with rubella virus have diverse effects, ranging from no obvious impact to cell destruction. The hallmark of fetal infection is chronicity, with persistence throughout fetal development in utero and for up to 1 year after birth.
Individuals with acquired rubella may shed virus from 7 days before rash onset to ∼5–7 days thereafter. Both clinical and subclinical infections are considered contagious. Infants with CRS may shed large quantities of virus from bodily secretions, particularly from the throat and in the urine, up to 1 year of age. Outbreaks of rubella, including some in nosocomial settings, have originated with index cases of CRS. Thus only individuals immune to rubella should have contact with infants who have CRS or who are congenitally infected with rubella virus but are not showing signs of CRS.
The largest recent rubella epidemic in the United States took place in 1964–1965, when an estimated 12.5 million cases occurred, resulting in ∼20,000 cases of CRS. Since the introduction of the routine rubella vaccination program in the United States in 1969, the number of rubella cases reported each year has dropped by >99%; the rate of vaccination coverage with rubella-containing vaccine has been >90% among children 19–35 months old since 1995 and >95% for kindergarten and first-grade entrants since 1980. In 1989 a goal for the elimination of rubella and CRS in the United States was set, and in 2004 a panel of experts agreed unanimously that rubella was no longer an endemic disease in this country. The criteria used to document lack of endemic transmission included low disease incidence, high nationwide rubella antibody seroprevalence, outbreaks that were few and contained (i.e., small numbers of cases), and lack of endemic virus transmission (as assessed by genetic sequencing). In the United States, interruption of endemic transmission of rubella virus has been sustained since 2001.
Although rubella and CRS are no longer endemic in the United States, they remain important public health problems globally. The number of rubella cases reported worldwide in 1999 was ∼900,000; this figure declined steadily to 165,000 in 2007. However, numbers of rubella cases are substantially underestimated because cases in many countries are identified through measles surveillance systems that are not specific for rubella. In developing countries, an estimated 110,000 cases of CRS occur during nonepidemic years.
Acquired rubella is characterized by a generalized maculopapular rash that usually lasts for up to 3 days (Fig. 193-1). Up to 50% of rubella virus infections may be subclinical or inapparent. The rash is usually mild and may be difficult to detect in persons with darker skin. In children, rash is usually the first sign of illness. However, in older children and adults, a 1- to 5-day prodrome often precedes the rash and may include low-grade fever, malaise, and upper respiratory symptoms. The incubation period is 14 days (range, 12–23 days).
Mild maculopapular rash of rubella in a child.
Lymphadenopathy, particularly occipital and postauricular, may be noted during the second week after exposure. Although acquired rubella is usually thought of as a benign disease, arthralgia and arthritis are common in infected adults, particularly women. Thrombocytopenia and encephalitis are less common complications.
Congenital Rubella Syndrome
The most serious consequence of rubella virus infection can develop when a woman becomes infected during pregnancy, particularly during the first trimester. The resulting complications may include miscarriage, fetal death, premature delivery, or live birth with congenital defects. Infants infected with rubella virus in utero may have a myriad of physical defects (Table 193-1), which most commonly relate to the eyes, ears, and heart. This constellation of severe birth defects is known as congenital rubella syndrome. In addition to permanent manifestations, there are a host of transient physical manifestations, including thrombocytopenia with purpura/petechiae (e.g., dermal erythropoiesis, “blueberry muffin syndrome”). Some infants may be born with congenital rubella virus infection but have no apparent signs or symptoms of CRS and are referred to as infants with congenital rubella infection only.
Table 193-1 Common Transient and Permanent Manifestations in Infants With Congenital Rubella Syndrome |Favorite Table|Download (.pdf)
Table 193-1 Common Transient and Permanent Manifestations in Infants With Congenital Rubella Syndrome
|Transient Manifestations||Permanent Manifestations|
|Interstitial pneumonitis||Congenital heart defects (patent ductus arteriosus, pulmonary arterial stenosis)|
Thrombocytopenia with purpura/petechiae (e.g., dermal erythropoiesis, or “blueberry muffin syndrome”)
|Eye defects (cataracts, cloudy cornea, microphthalmos, pigmentary retinopathy, congenital glaucoma)|
|Intrauterine growth retardation||Microcephaly|
|Meningoencephalitis||Central nervous system sequelae (mental and motor delay, autism)|
Clinical diagnosis of acquired rubella is difficult because of the mimicry of many illnesses with rashes, the varied clinical presentations, and the high rates of subclinical and mild disease. Illnesses that may be similar to rubella in presentation include scarlet fever, roseola, toxoplasmosis, fifth disease, measles, and illnesses with suboccipital and postauricular lymphadenopathy. Thus laboratory documentation of rubella virus infection is considered the only reliable way to confirm acute disease.
Laboratory assessment of rubella infection is conducted by serologic and virologic methods. For acquired rubella, serologic diagnosis is most common and depends on the demonstration of IgM antibodies in an acute-phase serum specimen or a fourfold rise in IgG antibody titer between acute- and convalescent-phase specimens. The enzyme-linked immunosorbent assay IgM capture technique is considered most accurate for serologic diagnosis, but the indirect IgM assay is also acceptable. After rubella virus infection, IgM antibody may be detectable for up to 6 weeks. In case of a negative result for IgM in specimens taken earlier than day 5 after rash onset, serologic testing should be repeated. Although uncommon, reinfection with rubella virus is possible, and IgM antibodies may be present. To detect a rise in IgG antibody titer indicative of acute disease, the acute-phase serum specimen should be collected within 7–10 days after onset of illness and the convalescent-phase specimen ∼14–21 days after the first specimen.
IgG avidity testing is used in conjunction with IgG testing. Low-avidity antibodies indicate recent infection. Mature (high-avidity) IgG antibodies most likely indicate an infection occurring at least 2 months previously. This test helps distinguish primary infection from reinfection.
Rubella virus can be isolated from the blood and nasopharynx during the prodromal period and for as long as 2 weeks after rash onset. However, as the secretion of virus in individuals with acquired rubella is maximal just before or up to 4 days after rash onset, this is the optimal time frame for collecting specimens for viral cultures. Rubella RNA detection by reverse-transcriptase polymerase chain reaction (RT-PCR) is a more recently developed technique for rubella diagnosis.
Congenital Rubella Syndrome
A clinical diagnosis of CRS is reasonable when an infant presents with a combination of cataracts, hearing impairment, and heart defects; this pattern is seen in ∼10% of infants with CRS. However, as with acquired rubella, laboratory diagnosis of congenital infection is highly recommended, particularly because most features of the clinical presentation are nonspecific and may be associated with other intrauterine infections. Early diagnosis of CRS facilitates appropriate medical intervention for specific disabilities and prompts implementation of infection control measures.
Diagnostic tests used to confirm CRS include serologic assays and virus isolation. In an infant with congenital infection, serum IgM antibodies may be present for up to 1 year after birth. In some instances, IgM may not be detectable until 1 month of age; thus infants who have symptoms consistent with CRS but who test negative shortly after birth should be retested at 1 month. A rubella serum IgG titer persisting beyond the time expected after passive transfer of maternal IgG antibody (i.e., a rubella titer that does not decline at the expected rate of a twofold dilution per month) is another serologic criterion used to confirm CRS.
In congenital infection, rubella virus is isolated most commonly from throat swabs and less commonly from urine and cerebrospinal fluid. Infants with congenital rubella may excrete virus for up to 1 year, but specimens for virus isolation are most likely to be positive if obtained within the first 6 months after birth. Rubella virus in infants with CRS can also be detected by RT-PCR.
Rubella Diagnosis in Pregnant Women
In the United States, screening for rubella IgG antibodies is recommended as part of routine prenatal care. Pregnant women with a positive IgG antibody serologic test are considered immune. Susceptible pregnant women should be vaccinated postpartum.
A susceptible pregnant woman exposed to rubella virus should be tested for IgM antibodies and a fourfold rise in IgG antibody titer between acute- and convalescent-phase serum specimens to determine whether she was infected during pregnancy. Pregnant women with evidence of acute infection must be clinically monitored, and gestational age at the time of maternal infection must be determined to assess the possibility of risk to the fetus. Of women infected with rubella virus during the first 11 weeks of gestation, up to 90% deliver an infant with CRS; for maternal infection during the first 20 weeks of pregnancy, the CRS rate is 20%.
No specific therapy is available for rubella virus infection. Symptom-based treatment for various manifestations, such as fever and arthralgia, is appropriate. Immunoglobulin does not prevent rubella virus infection after exposure and therefore is not recommended as routine postexposure prophylaxis. Although immunoglobulin may modify or suppress symptoms, it can create an unwarranted sense of security: infants with congenital rubella have been born to women who received immunoglobulin shortly after exposure. Administration of immunoglobulin should be considered only if a pregnant woman who has been exposed to rubella will not consider termination of pregnancy under any circumstances. In such cases, IM administration of 20 mL of immunoglobulin within 72 h of rubella exposure may reduce—but does not eliminate—the risk of rubella.
After the isolation of rubella virus in the early 1960s and the occurrence of a devastating pandemic, a vaccine for rubella was developed and licensed in 1969. Currently, the majority of rubella-containing vaccines (RCVs) used worldwide are combined measles and rubella (MR) or measles, mumps, and rubella (MMR) formulations. A tetravalent measles, mumps, rubella, and varicella (MMRV) vaccine is available but is not widely used.
The public health burden of rubella infection is measured primarily through the resulting CRS cases. The 1964–1965 rubella epidemic in the United States encompassed >30,000 infections during pregnancy. CRS occurred in ∼20,000 infants born alive, including >11,000 infants who were deaf, >3500 infants who were blind, and almost 2000 infants who were mentally retarded. The cost of the epidemic exceeded $1.5 billion. In 1982, it was estimated that the cost per child with CRS exceeded $200,000.
In most countries, there is little documented evidence to illuminate the epidemiology of CRS. Clusters of CRS cases have been reported in developing countries, and modeling studies have shown that, before the introduction of an immunization program, the incidence of CRS is 0.1–0.2 per 1000 live births during endemic periods and 1–4 per 1000 live births during epidemic periods. Where rubella virus is circulating and women of childbearing age are susceptible, CRS cases will continue to occur.
The most effective method of preventing acquired rubella and CRS is through vaccination with an RCV. One dose induces seroconversion in ≥95% of persons >1 year of age. Immunity is considered long-term and is probably lifelong. The most commonly used vaccine globally is derived from the RA27/3 virus strain. The current recommendation for routine rubella vaccination in the United States is a first dose of MMR vaccine at 12–15 months of age and a second dose at 4–6 years. Target groups for rubella vaccine in all countries include children >1 year of age, adolescents and adults without documented evidence of immunity, individuals in congregate settings (e.g., college students, military personnel, child care and health care workers), and susceptible women before and after pregnancy.
Because of the theoretical risk of transmission of live attenuated rubella vaccine virus to the developing fetus, women known to be pregnant should not receive an RCV. In addition, pregnancy should be avoided for 28 days after receipt of an RCV. In follow-up studies of 680 unknowingly pregnant women who received rubella vaccine, no infant was born with CRS. Receipt of an RCV during pregnancy is not ordinarily a reason to consider termination of the pregnancy.
As of 2008, 127 (66%) of the 193 WHO member countries recommended inclusion of an RCV in the routine childhood vaccination schedule (Fig. 193-2). Vaccination coverage varies widely among the member countries, with the European and American Regions reporting coverage of >90%. Goals for control or elimination of rubella and CRS have been established in the American Region, the European Region, and the Western Pacific Region. The other three regions (Eastern Mediterranean, South East Asian, and African) have not yet set such goals.
Countries using rubella vaccine in National Immunization Schedule, 2008. (From the World Health Organization.)