Rubella (German or three-day measles) is an important childhood disease that was historically widespread but is now very infrequent. It is an acute viral infection ordinarily characterized by mild constitutional symptoms, a rash similar to that of mild rubeola or scarlet fever, and enlargement and tenderness of the postoccipital, retroauricular, and posterior cervical lymph nodes. Rubella in early pregnancy may cause the congenital rubella syndrome, a serious multisystem disease with a wide spectrum of clinical expression and sequelae.
Rubella virus, the cause of rubella, is an RNA virus of the genus Rubivirus in the family Togaviridae.
Humans are the only natural host of rubella virus, which is spread either by oral droplet or transplacentally to the fetus, causing congenital infection. It is distributed worldwide and affects both sexes equally. Before introduction of the rubella vaccine in 1969, pandemics of rubella occurred every 6–9 yr, with most cases occurring in the spring. In 1964–1965, an epidemic in the United States caused more than 12 million cases of rubella and an additional 20,000 infants with congenital rubella syndrome. The peak incidence of rubella was among children 5–14 yr of age but most cases now occur among susceptible teenagers and young adults. Outbreaks have been reported among college students and in unvaccinated populations, such as Amish communities, and among unvaccinated foreign-born adults. In closed populations, such as institutions and military barracks, almost 100% of susceptible individuals may become infected. In family settings, 50–60% of susceptible family members acquire the disease.
Indigenous rubella and congenital rubella syndrome were targeted for elimination in the United States by the year 2000. From a peak of 57,686 cases in 1969 through 1989, the numbers of annual reported cases have decreased, with a slight resurgence during 1990–1991, by 99.7% to 128–192 cases of rubella and 4–11 cases of congenital rubella syndrome annually from 1992 to 1997. In 2001, only 20 cases of rubella were reported in the United States. Despite these advances, outbreaks of rubella and congenital rubella still occur, primarily among unvaccinated foreign-born adults.
During clinical illness the virus is shed in nasopharyngeal secretions, blood, feces, and urine. Virus has been recovered from the nasopharynx 7 days before exanthem and 7–8 days after its disappearance. Patients with subclinical disease are also infectious.
The pathogenesis of rubella is not well understood. Virus can be found from both infected and uninfected areas of skin, suggesting that immune processes may be important.
The risk for congenital defects and disease is greatest with primary maternal infection during the first trimester. Congenital defects occur in about 90% of infants whose mothers acquire maternal infection before the 11th week of pregnancy, diminishing to about 10–20% by the end of the first trimester, with an overall risk for the trimester being about 70%. Maternal infection after the 16th week of pregnancy poses a low risk for congenital defects, although infection of the fetus may occur.
The incubation period is 14–21 days. The prodromal phase of mild catarrhal symptoms is shorter than that of measles and may be so mild that it goes unnoticed. Approximately two thirds of infections are subclinical.
The most characteristic sign is retroauricular, posterior cervical, and postoccipital lymphadenopathy. No other disease causes the tender enlargement of these nodes to the extent that rubella does. An enanthem appears in 20% of patients just before the onset of the skin rash. It consists of discrete rose-colored spots on the soft palate (Forchheimer spots) that may coalesce into a red blush and extend over the fauces.
Lymphadenopathy is evident at least 24?hr before the rash appears and may remain for 1 wk or more. The exanthem is more variable than that of rubeola. It begins on the face ( Fig. 226–1 ) and spreads quickly. Its evolution is so rapid that the rash may be fading on the face by the time it appears on the trunk. Discrete maculopapules are present in large numbers; there are also large areas of flushing that spread rapidly over the entire body, usually within 24?hr. The rash may be confluent, particularly on the face. During the second day the rash may assume a pinpoint appearance, especially over the trunk, resembling that of scarlet fever. Mild itching may occur. The eruption usually clears by the third day. Desquamation is minimal. Rubella without a rash has been described.
The pharyngeal mucosa and the conjunctivae are slightly inflamed. In contrast to rubeola, there is no photophobia. Fever is low grade or absent during the rash and persists for 1, 2, or occasionally 3 days. Anorexia, headache, and malaise are not common.
Especially in older girls and women, polyarthritis may occur with arthralgia, swelling, tenderness, and effusion but usually
Figure 226-1 Rash of rubella (German measles). (From Korting GW: Hautkrankheiten bei Kindern und Jugendlichen, 3rd ed. Stuttgart, Germany, FK Schattauer Verlag, 1982.)
without any residuum. Any joint may be involved, but the small joints of the hands are affected most frequently. The duration is usually several days to 2 wk; rarely it persists for months. Paresthesia also has been reported.
CONGENITAL RUBELLA SYNDROME.
The diagnosis of rubella may be apparent from the clinical symptoms and physical examination, but it is usually confirmed by serology or virus culture. The spleen is often slightly enlarged. The white blood cell count is normal or slightly reduced; thrombocytopenia is rare, with or without purpura. Hemagglutination-inhibition (HI) antibody has been the reference method of determining immunity to rubella, but newer methods that are easier to perform are now used more commonly. Latex agglutination, enzyme immunoassay, passive hemagglutination, and fluorescent immunoassay appear to be equal or superior to the HI test in sensitivity. Immunoglobulin (Ig) M antibodies are detectable in the first few days of illness and are considered diagnostic. Detection of IgM antibodies, which do not cross the placenta, in the newborn is especially useful for the diagnosis of congenital rubella syndrome. Seroconversion, or a fourfold increase in IgG titer, is diagnostic.
Rubella virus can be cultured from the nasopharynx and blood. It is detected by the ability of rubella-infected African green monkey kidney (AGMK) cells to resist challenge with enterovirus.
Because similar symptoms and rashes can occur with many other viral infections, rubella is a difficult disease to diagnose clinically except when the patient is seen during an epidemic. A history of having had rubella or rubella vaccine is unreliable; immunity should be determined by antibody testing. Particularly in its more severe forms, rubella may be confused with the mild types of scarlet fever and rubeola. Roseola infantum (exanthem subitum) is distinguished by a higher fever and the appearance of the rash at the end of the febrile episode rather than at the height of the signs and symptoms. Infectious mononucleosis may have a rash but is associated with generalized lymphadenopathy and characteristic atypical lymphocytosis. Enteroviral infections accompanied by a rash can be differentiated in some instances by accompanying respiratory or gastrointestinal manifestations and the absence of retroauricular lymphadenopathy. Drug rashes may be extremely difficult to differentiate from the rash of rubella, but the characteristic enlargement of the lymph nodes strongly supports a diagnosis of rubella.
There is no specific antiviral therapy; treatment is entirely supportive. Antipyretics (acetaminophen or ibuprofen) are indicated for fever.
Complications are relatively uncommon in childhood. Encephalitis similar to that seen with measles occurs in about 1 in 6,000 cases. The severity is highly variable, and there is an overall mortality rate of 20%. Symptoms in survivors usually resolve within 1–3 wk without neurologic sequelae. Thrombocytopenic purpura occurs at an overall rate of 1 in 3,000 cases.
The most important consequence of rubella in a pregnant woman is congenital rubella syndrome. Progressive rubella panencephalitis is a persistent, slowly progressive rubella infection of the central nervous system (see Chapter 226.1 ).
CONGENITAL RUBELLA SYNDROME.
Congenital rubella affects virtually all organ systems. The most common manifestation is intrauterine growth retardation. Other common findings include cataracts, bilateral or unilateral, which are frequently associated with microphthalmia; myocarditis and structural cardiac defects (e.g., patent ductus arteriosus or pulmonary artery stenosis); “blueberry muffin” skin lesions, similar to those seen in congenital cytomegalovirus infection; hearing loss from sensorineural deafness; and meningoencephalitis. Persistent infection leads to pneumonia, hepatitis, bone lucencies, thrombocytopenic purpura, and anemia. Later sequelae include motor and mental retardation.
The diagnosis is confirmed by finding rubella-specific IgM antibody in the neonatal serum, or by culturing rubella virus from the infant (nasopharynx, urine, or tissues). Virus can be shed in the urine for 1 yr or longer. Prenatal diagnosis of fetal rubella infection can be made either by isolating the virus from amniotic fluid or by identification of rubella-specific IgM in cord blood.
Infants with the complete spectrum of the congenital rubella syndrome have a grim prognosis, especially when the neurologic symptoms continue to progress throughout infancy. The prognosis is better for infants with fewer stigmata of the syndrome, presumably those who were initially infected later in gestation. Only about 30% of infants with encephalitis appear to escape residual neuromotor deficitis, including an autistic syndrome.
The prognosis of rubella in childhood is excellent. Infection usually confers permanent immunity, although reinfection may occur.
The incidence of reinfection on exposure to wild virus is 3–10% among those with a history of previous rubella and 14–18% among those immunized with the RA 27/3 vaccine. Reinfection may lead only to an IgG booster response, to both an IgM and IgG response, or to clinical rubella. Maternal reinfection during pregnancy has resulted in congenital rubella syndrome. The significance of rubella reinfection is controversial.
Rubella vaccine is derived from the RA 27/3 strain of rubella virus, which is attenuated by serial passage tissue culture in WI-38 and MRC-5 human diploid cells. The vaccine induces antibody in more than 99% of seronegative recipients and has protective efficacy in more than 90%. Vaccine virus may be shed from the nasopharynx in low titers for as long as 18–25 days after vaccination, although there is no evidence of communicability.
The initial rubella immunization, usually as measles-mumps-rubella (MMR), is recommended at 12–15 mo of age. A second immunization, also as MMR, is recommended routinely at 4–6 yr of age but may be administered at any time during childhood provided at least 4 wk have elapsed since the first dose. Children who have not previously received the second dose should be immunized by 11–12 yr of age. It is especially important for girls to have immunity to rubella before they reach childbearing age.
Pregnant women should not be given live rubella virus vaccine and should avoid becoming pregnant for 3 mo after they have been vaccinated. Routine serologic testing of postpubertal women before rubella immunization is not necessary. Inadvertent immunization is not ordinarily a reason to interrupt the pregnancy. No cases of congenital rubella syndrome have been reported in more than 200 women immunized during pregnancy with RA 27/qa3 vaccine who have been studied. Other contraindications include allergy to a vaccine component (anaphylaxis to neomycin), moderate or severe acute illness with or without fever, immunodeficiency (primary immunodeficiency, cancer and cancer therapy, long-term high-dose corticosteroids, severely immunocompromised, including those with HIV infection), and recent immunoglobulin administration (see Chapter 282 ).
Symptoms that may follow rubella immunization include fever (5–15%), rash (5%), lymphadenopathy, and arthralgias and arthritis. Joint involvement, usually seen in the small peripheral joints 10–21 days after vaccination, is uncommon in children but occurs frequently in postpubertal females with both arthralgias (25%) and transient arthritis (10%) being reported. It may last for weeks. Transient peripheral paresthesia and pain in the arms and legs are reported rarely.
All health care workers should be immune to rubella as well as to measles and varicella. Persons born before 1957 can be
considered immune to rubella, except women of childbearing age who could become pregnant. Adolescent girls and premenopausal women should either be vaccinated or have documented laboratory evidence of immunity. Maternal antibody is protective for the infant for the first 6 mo of life.
Nonpregnant susceptible contacts of persons with rubella should be vaccinated. This does not prevent infection but ensures protection for future rubella exposures.
All pregnant women, regardless of immunization history, should make every effort to avoid exposure to rubella. If a pregnant woman whose immune status is unknown is exposed to rubella, an antibody test should be performed immediately. Immune women should be reassured. Susceptible pregnant women exposed to rubella should not receive vaccine because of the potential risk of transmission of vaccine virus to the fetus. Susceptible women should undergo repeat serologic testing 3–4 wk after exposure, and, if they are still seronegative, again 6 wk after exposure. Seroconversion on either specimen indicates infection, and the mother should be counseled about the risk of transmission to the fetus and the resulting anomalies. Routine immune globulin administration for postexposure prophylaxis in pregnancy is not recommended but should be considered if termination of the pregnancy is not an option. For the susceptible pregnant woman exposed to measles for whom termination of pregnancy is a viable option and for whom timing permits documentation of seroconversion within the period of time when abortion is possible, immune globulin is not recommended because it may provide an unjustified sense of security and precludes a positive serologic diagnosis as the basis for termination of pregnancy. However, for the susceptible pregnant woman exposed to rubella for whom abortion is not an option, immunoglobulin should be administered in a dose of 0.55?mL/kg, which reduces the attack rate but does not eliminate the risk of fetal infection. Fetal infection may occur even in the absence of clinical signs in the mother. The use of intravenous immunoglobulin (IVIG) may be an alternative but has not been studied.