Chapter 320. Rubella

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 caused by this congenital infection, known collectively as the congenital rubella syndrome (CRS), include hearing impairment, cardiac defects, cataracts, and developmental delay.

Rubella is a member of the Togaviridae family (a single serotype and the only member of the genus Rubivirus) with an approximately 10-kb (9762 nucleotides) single-stranded, positive-sense polyadenylated RNA genome and a lipid envelope (thus the Latin name of toga or cloak). The virus was first isolated in 1962 by Weller from the urine of his son.3 Currently, standardized nomenclature for wild-type and vaccine rubella viruses describes 2 clades, 9 recognized genotypes, and 4 provisional genotypes.4 Rubella shares physicochemical properties with group A arboviruses. 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. In addition, there are two virus-specified nonstructural proteins (p90 and p150). The virus is thermolabile; inactivation is rapid at 37°C (98.6°F) and at room temperature. However, it can be stored for short periods at 20°C (4°F) and is relatively stable for months at 60°C (76°F).

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). Infection acquired postnatally does not produce a chronic carrier state. Prolonged shedding occurs only in patients with congenital rubella syndrome, not when acquired postnatally, which is characterized by chronic infection; 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. After vaccine introduction, there was a marked shift in epidemiology and a shift in age at which those who are susceptible became infected.

When rubella was endemic in the United States, its seasonal peak occurred in late winter and spring. Its greatest impact resulted from epidemics that occurred at 4-year to 7-year intervals in industrialized countries. 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). This was followed by a resurgence in 1989 to 1991, but reported incidence from 1992 to 1996 was the lowest ever recorded, with an all-time low of 128 cases reported in 1995 and a subsequent recognition of interruption of endemicity. Since 2001, annual reported rubella cases (< 25) and congenital rubella cases (< 4) declined further.7 In addition, the seasonal peak disappeared, leaving no temporal or geographic clustering or indigenous transmission.7,8,9 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 in the United States 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, which underscores the importance of documenting patient country of origin. A 1995 WHO global survey showed that only 78 of 214 countries had national policies for rubella vaccination. By 2006, 75% of children globally still lived in countries without these policies,11 with an estimate of more than 100,000 infants born with congenital rubella syndrome annually.12 Molecular techniques allowing sequence identification of wild-type and vaccine rubella assist global surveillance, tracking of transmission, investigation of postvaccine cases, confirmation of importations, and documentation of elimination.13,14 The global measles eradication effort should enhance rubella elimination.

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. In young children, the mild prodrome is usually overlooked.

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. The face is frequently clearing by the time a full-blown rash is seen on the lower legs, where coalescence is uncommon. Desquamation is rare.

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. These lesions are not pathognomonic of rubella. Scarlet fever, infectious mononucleosis, measles, and other viral exanthems may be accompanied by similar palatal lesions.

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. Symptoms typically appear with the rash or within several days after its onset, but rarely may precede onset of rash by several days. Joint involvement, frequently symmetric, may range from subjective morning stiffness to full-blown arthritis characterized by swelling, redness, tenderness, and effusion. Objective signs and symptoms usually clear within several days to 2 weeks, but rarely may persist several months. The proximal interphalangeal joints are affected most frequently, but other joints may be involved. Paresthesia, most typically numbness and tingling, often accompanies, and may outlast, joint symptoms. Joint manifestations in rubella produce no deformity. 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 decrease in platelet count during the course of uncomplicated rubella. This thrombocytopenia usually occurs within 1 week after onset of rash. Presenting complaints usually include purpura, epistaxis, bleeding from the gums, hematuria, and gastrointestinal bleeding. Abnormal capillary fragility also contributes to the problem of hemostasis. Prognosis is generally excellent, but fatalities due to uncontrolled central nervous system hemorrhage do occur rarely. Although thrombocytopenia may sometimes be prolonged, most patients become symptom free within 2 weeks. The incidence of thrombocytopenia following vaccine is significantly less than after natural infection.17

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 (measles, human herpes virus 6 and 7, adenovirus, enterovirus, parvovirus B19, and various arboviruses), 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 Virus isolation is less practical because of relative lability of rubella virus and the complexity of the assay, and isolation is being replaced by the polymerase chain reaction method.

Rubella virus may be cultured from the pharynx and serum as early as 1 week before the onset of rash. Virus is promptly cleared from the serum after the rash appears, but persists in pharyngeal secretions, usually for several days after the rash and, uncommonly, for as long as 2 weeks (Fig. 320-2). Urine and stool are unreliable sources of rubella virus.

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. Antibody assays on oral fluid rather than serum are being explored to facilitate diagnosis in resource-poor settings.15,20,21 This wide array of reliable tests is important to provide rapid, sensitive, economical, and reliable diagnosis. False-positive IgM imposes a dilemma in acute rubella diagnosis, particularly in the more recently introduced commercial enzyme immunoassays. The positive predictive value of these assays is lessened in the setting of low incidence. 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, and peak titers are reached within 6 to 12 days. In subclinical rubella (primary rubella without rash), rubella-specific IgM antibodies usually reach detectable levels 14 to 21 days after exposure, a time that corresponds to the onset of rash in clinical disease. The complement fixation (CF) antibody response after rubella infection is slower than the HI response. Therefore, it is sometimes possible to demonstrate a diagnostic rise in CF antibody with paired sera that would not show such a rise in HI antibody. 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. The National Health and Nutrition Examination Survey (NHANES III 1988–1994) documented substantial immunity (EIA > 10 IU): 92%, 6–11 year olds; 83%, 12–19 year olds; 85%, 20–29 year olds; 89%, 30–39 year olds; 93%, > 40 years olds).23 Subsequent 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.

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. An aerosolized measles/rubella vaccine is under study.14 Preterm infants receive vaccine at the same chronological age as term infants.24 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. Continued strong disease surveillance; rapid response to outbreaks; and efforts to identify and vaccinate children, nonimmune adolescents, and women of child-bearing age, using effective strategies to avoid missed opportunities, is critical to continued US efforts to eliminate 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, with or without stenosis of the pulmonary artery or its branches, 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. The lesion may be absent at birth or so small that it may not be detected without careful ophthalmoscopic examination. Congenital glaucoma, which might be present at birth or which might develop during infancy, is clinically indistinguishable from hereditary infantile glaucoma. The cornea is enlarged and hazy, the anterior chamber is deep, and ocular tension is increased. Retinopathy, characterized by discrete, patchy black pigmentation, quite variable in size and location, is probably the most common ocular manifestation of congenital rubella. There is no evidence that this anomaly of the pigment epithelium of the retina interferes with vision. However, recognition of this lesion is a valuable aid in the diagnosis of congenital rubella.

Permanent sensorineural deafness caused by damage to the organ of Corti may be severe or mild, bilateral or unilateral. Defects in the middle-ear structures have been reported. 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. Intellectual deterioration, myoclonus, ataxia, and seizures have progressed to death over the course of several years. High rubella antibody titers in serum and CSF, elevated spinal fluid protein and gamma globulin levels, histopathologic changes of progressive panencephalitis, and isolation of rubella virus from the brain biopsy specimen add to the obvious parallel between this condition and the subacute sclerosing panencephalitis that is a rare and late sequela of measles.

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.

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 (which does not always prove vertical transmission), or in amnionic fluid at 15 weeks gestation and 8 or more weeks after maternal infection (sensitivity 87–100%), 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, CSF, cataract tissue, and virtually every organ. These infants remain a source of infection for susceptible contacts for a year or more. Reverse transcriptase-polymerase 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. A minority, despite congenital infection, have declining titers of antibody beginning during the second year of life. 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. Loss of antibody cannot be correlated with severity of clinical disease. Rubella antibody that persists in infancy beyond age 6 months without evidence of postnatal infection essentially confirms the diagnosis of congenital rubella.

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. Sadly, lack of implementation of this critical public health strategy in the United States is highlighted by documentation that in late 1998 only 6 states required rubella susceptibility premarital screening and no state required subsequent vaccination. 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. In general, infants who carry rubella for long periods are more severely damaged and delayed in growth and development. 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.1 Complacency about US elimination of rubella transmission would be unwise. Continued 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.