Maria Jevitz Patterson
Rubella (German measles) is no longer endemic in the United States. Because of its worldwide distribution, imported cases continue to occur, although these sporadic cases do not result in sustained transmission.1,2 Rubella is usually a minor illness in adults. Of major significance, however, is the high incidence of a constellation of congenital defects in children whose mothers are infected during early pregnancy. Typical anomalies, known collectively as the congenital rubella syndrome (CRS), include hearing impairment, cardiac defects, cataracts, and developmental delay.
PATHOPHYSIOLOGY
Rubella is a member of the Togaviridae family with an approximately 10-kb single-stranded, positive-sense polyadenylated RNA genome and a lipid envelope. Currently, standardized nomenclature for wild-type and vaccine rubella viruses describes 2 clades, 9 recognized genotypes, and 4 provisional genotypes.4 The virion is roughly spherical, 60 to 70 nm in diameter, with an icosahedral nucleocapsid composed of multiple copies of a single virus-specified structural capsid protein (C) that is covered by a lipid envelope in which 2 virus-specified structural glycoproteins (E1 and E2) are embedded. E1 appears to function in attachment, fusion, hemagglutination, and neutralization.
Humans are the only natural host. Direct person-to-person airborne spread by infected droplets appears to be the usual mode of transmission. The patient with subclinical infection is also a source of rubella virus. Patients are most contagious for a few days before and after the onset of rash, although virus may be present in pharyngeal secretions for as long as 1 week before and 2 weeks after the onset of rash (Fig. 320-1). Prolonged shedding occurs only in patients with congenital rubella syndrome, not when acquired postna-tally; infants may remain contagious for months after birth.
EPIDEMIOLOGY
Although rubella occurs in all areas of the world, epidemiologic patterns vary from country to country. Mathematic modeling predicts that elimination of transmission requires approximately 90% immunity among children.5,6 Prior to widespread use of rubella vaccines in the United States, when 85% of the population was immune, rubella occurred primarily in children during the elementary school years. A small minority did not become infected until early adulthood.
FIGURE 320-1. Rubella. The rash consists of erythematous macules and papules that appear initially on the face and spread inferiorly to the trunk and extremities, usually within the first 24 hours. (From Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; 2009.)
Following licensure of the first vaccine in 1969 until 1989, the reported incidence of rubella declined more than 99% in the United States (eFig. 320.1 ). Since 2001, annual reported rubella cases (< 25) and congenital rubella cases (< 4) declined further.7 Beginning with the 2005–2006 school year, all 50 states required and enforced the second dose of measles-mumps-rubella (MMR) vaccine for school entry.5,10
Outbreaks during the years of changing epidemiology were confined essentially to unimmunized populations, religious communities that traditionally decline vaccination, settings in which young adults congregate, and among specific racial/ethnic groups from countries where rubella vaccine is not routinely used. Many countries have yet to achieve good rubella vaccination rates. By 2006, 75% of children globally still lived in countries without national policies for rubella vaccination,11 with an estimate of more than 100,000 infants born with congenital rubella syndrome annually.12
POSTNATAL RUBELLA
CLINICAL MANIFESTATIONS
The clinical manifestations of postnatal rubella range from inapparent infection to a characteristic pattern of adenopathy, rash, and low-grade fever. The incubation period is from 14 to 21 days. Primary replication occurs in the nasopharynx, followed by viremia at approximately days 5–7 and rash at days 14–17 (Fig. 320-1). A typical clinical course begins with adenopathy involving primarily the postauricular, occipital, and posterior cervical nodes, which may be slightly painful and tender. Although symptoms usually clear promptly as the rash fades, nodes may remain palpable for several weeks. Adolescents and adults may complain of malaise, headache, a low-grade fever, sore throat, and mild coryza during a 1-day to 5-day prodromal period that frequently accompanies the onset of adenopathy.
The rubella rash is variable but usually brief. It may be no more than a transient blush, but classically it persists for 2 to 3 days in a pattern that has been called kaleidoscopic because of its changing appearance. Initially, small, irregular pink macules begin on the face and spread rapidly (usually within 24 hours) to the neck, trunk, arms, and ultimately legs. By the next day, these lesions may have coalesced, developed a maculopapular component, and become scarlatiniform.
An exanthema consisting of punctate or slightly larger red spots on the soft palate may be present during the late prodrome and early rash phase.
Fever is uncommonly as high as 39°C (102.2°F) to 39.5°C (103.1°F), but may be absent in children. Polyarthralgia and polyarthritis are common manifestations of rubella among women, less common in men, and uncommon in children. Joint symptoms are also associated with rubella vaccine, particularly in postpubertal females of HLA-DR2 and HLA-DR5 type.15 However, no causal relationship between vaccine and persistent joint symptoms has been validated.16
Postinfectious encephalitis, clinically indistinguishable from that following measles or varicella, is a rare complication of rubella that occurs less frequently than postmeasles encephalitis. Symptoms and signs of central nervous system involvement usually develop 2 to 4 days after onset of rash.
Many patients have slight transient decrease in platelet count during the course of uncomplicated rubella. Prognosis is generally excellent. Thrombocytopenia may sometimes be prolonged for 1 to 2 weeks.
DIAGNOSIS
Diagnosis of rubelliform rashes in acutely ill, febrile children and in young adults requires accurate historical information from parents: vaccine history, source of exposure, prodrome, and progression of rash. Other childhood exanthems, as well as the possibility of primary vaccine failure should be considered.18 Clinical diagnosis is unreliable. Laboratory testing is required. Rubella can be diagnosed by isolating the virus, detecting viral nucleic acid by polymerase chain reaction or demonstrating rising titers of rubella antibody in serum (Fig. 320-2).19
Rubella serum antibody is measured in a variety of test systems based on neutralization, hemagglutination inhibition, complement fixation, latex agglutination, radial hemolysis, immunoblot, enzyme immunoassay (EIA), and IgG avidity. Interpretation of antibody testing should always be guided by clinical, epidemiological, and immunization status data.
Hemagglutination inhibition (HI), previously the serologic standard, has been replaced by EIA that detects antibody to viral proteins E1, E2, and C, while HI detects antibody only to E1. In patients with clinical rubella, rubella-specific IgM HI and EIA antibodies are detectable within 24 to 48 hours after onset of the rash. The patterns of rubella-specific IgM HI, CF, and EIA responses during rubella are also illustrated in Figure 320-2.
The presence of antibody at exposure confirms past rubella infection (or rubella vaccination), indicates protection from another episode of the disease, and in the pregnant woman obviates rubella-induced congenital malformation. Although no antibody titer is absolutely correlated with protection,22 absence of rubella hemagglutination inhibition or enzyme immunoassay (EIA) antibodies (<10 IU) at the time of exposure indicates susceptibility to rubella. National seropositive rates (1999–2004) showed immunity sufficient to interrupt transmission (children, 96.2%; adolescents, 93.7%; adult women, 91.5%; adult men, 88%).11 However, nearly 10% of women lacked protective antibody to prevent congenital rubella syndrome.
FIGURE 320-2. Schematic illustration of the natural history of rubella. CF, complement-fixing antibodies; EIA, enzyme immunoassay; HI, hemagglutination inhibition. (Source: Adapted from Cooper LZ, Krugman S. Clinical manifestations of postnatal and congenital rubella. Arch Ophthalmol. 1967;77:434-439.)
TREATMENT AND PREVENTION
In the United States, widespread use of live attenuated rubella vaccine, first licensed in 1969, has prevented epidemics, and even endemicity, and protected vaccine recipients from disease, with the ultimate goal of preventing fetal infection and the serious consequences of congenital rubella syndrome. The vaccine used exclusively in the United States and most other countries is the subcutaneously administered RA27/3 strain. Recommendations for rubella vaccination are provided in Chapter 244.
Although vaccine immunity is generally less robust than that acquired from wild-type infection, the vaccine stimulates both persistent and long-term humoral and cell-mediated immunity. Primary vaccine failure in up to 5% of those receiving vaccine occurs following the first dose. Determination of immune status requires documentation of 2 doses of MMR or laboratory confirmation.
CONGENITAL RUBELLA
Maternal infection with rubella during the first trimester of pregnancy frequently results in fetal infection following placental infection during maternal viremia. Congenital infection produces a spectrum of illness known as the congenital rubella syndrome (CRS), a result of viral-induced vasculitis that affects many organs and tissues.
The pathophysiologic basis of rubella’s teratogenicity is still not fully elucidated. At the cellular level, damage is linked to impaired replication, perturbation of cell growth, apoptosis, and postulated interaction between the viral nonstructural protein p90 and host cell regulatory proteins.12,15,29 Timing of infection is of great importance.30-32 Prospective studies after laboratory-confirmed rubella in pregnancy have documented that the rate of fetal infection is 90% after symptomatic maternal rubella during the first 12 gestational weeks; it drops to 25% to 30% during the second trimester and rises to 60% to 100% during the last weeks of gestation. During the second trimester, the fetus develops increasing immunologic competence and no longer seems susceptible to the chronic infection characteristic of intrauterine rubella during the early weeks.
In general, earlier infection produces more extensive damage. Cardiac defects, cataracts, and glaucoma occur predominantly after maternal rubella during the first 2 months of pregnancy. Hearing loss and neurologic manifestations may occur any time during the first and, less commonly, into the second trimester. Late in pregnancy, infection does not appear to be teratogenic. Risk after reinfection, though much less than after primary rubella, has been documented.33,34
CLINICAL MANIFESTATIONS
The consequences of rubella in utero are varied and unpredictable. Spontaneous abortion, stillbirth, live birth with anomalies (single or multiple), and normal infants are represented in this spectrum. Virtually every organ may be involved, transiently, progressively, or permanently.
During the newborn period, congenital rubella may be manifested by a number of acute conditions that are self-limiting in infants who survive. Neonatal thrombocytopenic purpura, characterized by a variable number of red purple macular “blueberry muffin” lesions, is the most common and striking of these manifestations (Fig. 320-3). It is usually associated with a high incidence of other transient lesions, such as radiolucencies in the metaphyseal portions of the long bones, hepatosplenomegaly, hepatitis, hemolytic anemia, and bulging anterior fontanelle with or without cerebrospinal fluid pleocytosis. This clinical picture represents the most severe evidence of congenital infection. Low birth weight, congenital heart disease, cataracts, deafness, and developmental delay with and without microcephaly frequently accompany these transient lesions.
Patent ductus arteriosus and atrial and ventricular septal defects are the most common cardiac lesions encountered. The most characteristic ocular anomaly is a pearly nuclear cataract, unilateral or bilateral, frequently associated with microphthalmia. Congenital glaucoma is clinically indistinguishable from hereditary infantile glaucoma. Retinopathy is probably the most common ocular manifestation of congenital rubella.
Permanent sensorineural deafness caused by damage to the organ of Corti may be severe or mild, bilateral or unilateral. Deafness and communication disorders may be the only overt manifestations of congenital rubella, especially if maternal infection occurs after the first 8 weeks of pregnancy.
Delayed psychomotor development during infancy is a hallmark of congenital rubella with the most common consequence of the permanent brain damage being mental retardation, ranging from mild to profound. Behavior disturbances and manifestations of minimal cerebral dysfunction are also common. Less common are severe spastic diplegia and autism.
Progressive rubella panencephalitis, a severe progressive neurologic deterioration beginning during the second decade of life, is a rare complication of congenital rubella.
Cell-mediated immune responses (CMI) are impaired selectively in children with congenital rubella. Purified lymphocyte cultures from children with congenital rubella fail to respond to rubella virus antigen, as measured by lymphocyte transformation and synthesis of interferon and leukocyte migration inhibition factor. Responses to phytohemagglutinin, a nonspecific T-cell mitogen, are also depressed, but to a lesser extent. Impairment of CMI is more severe in children infected during the first 2 months than in later stages of gestation. Most infants with congenital rubella no longer shed virus and have a normal pattern of serum immunoglobulin at age 1 year. Rare infants have persistent severe dysglobulinemia characterized by low levels of IgG with or without elevation of IgM.
FIGURE 320-3. Infant with congenital rubella. Note “blueberry muffin” appearance with multiple petechiae. (Source: Courtesy of Louis Z. Cooper.)
Congenital rubella also poses a risk of insulin-dependent diabetes mellitus (IDDM). By age 10 years, the risk is at least 4 times greater in children with congenital rubella syndrome than among healthy children, and by adult life, the risk is 10- to 20-fold greater. In one group of adult survivors, 40% had IDDM. The high prevalence of pancreatic islet cell cytotoxic or surface antibodies in congenital rubella patients with and without IDDM may reflect the in utero infection of pancreatic cells and play a role in the pathogenesis of the IDDM in genetically susceptible individuals. Thyroiditis also has been described. A comprehensive summary of the early and delayed manifestations of congenital rubella syndrome is published elsewhere.15
DIAGNOSIS
Despite the critical clinical management and attendant important implications about termination of pregnancy, prenatal diagnosis suffers from inaccuracy and is not without risk.15 Maternal serum IgM testing is not recommended unless there is a history of rubella or contact with a person with rubella-like illness. If positive, a second confirmatory and independent assay is required (IgM capture, IgG avidity, or polymerase chain reaction).14,22,35,36 Intrauterine diagnosis can be attempted by reverse transcriptase-polymerase chain reaction in chorionic villous samples at 10 weeks gestation, or in amnionic fluid at 15 weeks gestation and 8 or more weeks after maternal infection, or by detection of fetal IgM at 22 weeks gestation in fetal blood from ultrasound-guided cordocentesis. None of these methods predicts fetal infection with complete accuracy. Abnormal test results should be confirmed prior to any intervention. Relying on good clinical and epidemiologic data and conventional serologic assays remains the standard.
The infant with congenital rubella may remain chronically infected for many months after birth. Virus has been detected in pharyngeal secretions, urine, cerebrospinal fluid, and cataract tissue. Reverse transcriptase-polym-erase chain reaction using dried blood spots, lens aspirates, and oral fluids offers additional evidence for diagnosis in early infancy.15,37
Newborn infants with congenital rubella have serum rubella antibody titers comparable to those of their mothers. Much of this antibody is transplacentally acquired IgG, but the presence of rubella-specific IgM reflects in utero antibody production by the fetus and, when present, is diagnostic of congenital rubella. In all but rare infants, by the end of 1 year, IgG is usually the dominant rubella antibody. Detectable levels of antibody persist for years in most children but by age 5 years, approximately 20% of children with this disease have undetectable levels of antibody. Immunologic tolerance has been proposed as a mechanism for this finding.
PROGNOSIS
Mortality in a group with various abnormalities due to congenital rubella was approximately 10% and greatest during the first 6 months of life. In a group of 58 infants with neonatal thrombocytopenic purpura, mortality exceeded 35% after the first year of follow-up; this was not usually a consequence of bleeding but of sepsis, congestive heart failure, and general debility.
A number of children with multisystem involvement make excellent adjustments over the years.39,40 Among a group of approximately 300 survivors of the 1963 to 1964 US rubella epidemic followed to young adulthood, approximately one third were leading relatively normal lives; one third lived with their parents and may have “noncompetitive employment”; and one third required care in facilities with support personnel present 24 hours a day.41
TREATMENT AND PREVENTION
The optimal management of the pregnant woman with positive rubella titer exposed to rubella is unclear, but practical suggestions have been provided. Documentation of rubella immune status before pregnancy is a pivotal public health strategy, avoiding later diagnostic confusion, preventing misinterpretation of laboratory data, and allowing revaccination if the titer is low. Preconception screening and postpartum immunization remain fundamental to US strategy.
Ideally, postpubertal females should know their immune status preconception and be vaccinated only after assurance that they are not pregnant and can avoid pregnancy for at least 1 month after vaccination. Pregnant women should not be immunized, but should be tested for rubella susceptibility. The immediate postpartum period is an excellent time to vaccinate susceptible women, although barriers to postpartum or postabortal vaccination remain challenging. Vaccine virus has been isolated in human breast milk, but poses no hazard to the infant. The use of gamma globulin (commercially available human immunoglobulin) in prophylaxis of rubella during pregnancy does not prevent rubella or congenital rubella in a predictable or reliable fashion.
Infants with congenital rubella syndrome are contagious as long as they are shedding virus in their pharyngeal secretions. There is no specific therapy for congenital rubella. Early detection of auditory and visual impairment and incorporation of adequate educational therapy, including parent education and counseling, is important.
The overwhelming success of US immunization strategy has resulted in low-incidence, high vaccination rates of school age children, high population immunity, and an adequate surveillance system.1Continued opportunities for vaccination remain: premarital, preconception, postpartum, as well as evaluation of the foreign-born, healthcare workers, and previously immunized children posttreatment for malignancy. The establishment of immunization registries in many states is critical to ensure national prevention of this formerly common, mild childhood disease and devastating fetal infection.