OVERVIEW: What every practitioner needs to know

Rubella virus is single stranded RNA virus of the Togaviridae family (genus Rubivirus). Rubella virus infection gives rise to two distinct clinical entities based on when the virus is acquired. When acquired postnatally, the virus produces a mild illness with a characteristic rash. However, when acquired during fetal development, the virus gives rise to the congenital rubella syndrome (CRS), which can be devastating. Its association with CRS led to the development of an effective vaccine in 1970. In countries that have adopted effective rubella vaccine strategies, the rates of natural rubella infection and CRS have plummeted. Unfortunately, many areas of the world lack effective rubella vaccine programs, and some groups in countries with access to the vaccine choose to forgo childhood immunizations. This leaves a substantial portion of the world population susceptible to rubella virus infection and CRS.

Are you sure your patient has rubella? What should you expect to find?

Postnatal Infection

20-50% of infected individuals are asymptomatic.

Prodromal symptoms

Young children: Younger patients are often asymptomatic until rash onset but can have mild coryza and diarrhea.
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Adolescents and adults: Older patients frequently have prodromal symptoms for 1-5 days prior to the onset of rash. These can include eye pain (primarily with lateral and upward gaze), sore throat, headache, lymphadenopathy, fever (<38.5°C), aches, chills, anorexia, and nausea. Older patients may also exhibit upper respiratory tract infection symptoms and malaise.

Rash

The typical rash arises about 18 days (range 14-21 days) after exposure. It begins on the face and spreads centrifugally over 24 hours to the rest of the body, including the hands and feet. It is most confluent on the face and upper body, often remaining patchy on the lower extremities. On day 2, the rash fades from the face and, by day 3, has resolved completely.

The rash is composed of areas of discrete erythematous maculopapular lesions that can be pruritic (more common in older than younger patients).

The duration, pattern, and extent of rash during rubella infection can vary widely. Described patterns include fleeting macular rashes, scarlatiniform rash, morbilliform rash, and a slapped-cheek rash similar to that seen with erythema infectiosum.

Lymphadenopathy

Rubella demonstrates a distinctive pattern of lymphadenopathy manifest by enlargement of the post-auricular and sub-occipital nodes.

Generalized lymphadenopathy has also been described.

Lymphadenopathy is generally noted 1-7 days prior to the onset of rash.

Joint Involvement

Arthralgia is frequently reported in women (up to 70%) but is less common in men and children.

Frank arthritis, often of fingers, wrists, and knees, can accompany complaints of arthralgia.

Joint symptoms typically begin in the first week after the onset of the rash, and, in some cases, they can take several weeks to resolve.

CRS

All organ systems can be involved in the rubella-infected fetus, leading to an impressive array of possible findings at birth. CRS is characterized by the classic triad of cataracts, cardiac abnormalities, and deafness. Findings in infants with CRS include:

Common Features

Small for gestational age (SGA)

Prematurity

Sensorineural hearing loss

Eye findings: Cataracts, pigmented retinopathy, glaucoma, and others

Congenital heart disease: Patent ductus arteriosis (PDA) and peripheral pulmonic stenosis are most common, but other structural abnormalities may occur.

CNS: Microcephaly, meningoencephalitis

Hepatosplenomegally

Thrombocytopenic purpura

Large anterior fontanel

Cryptorchidism/inguinal hernia

Uncommon Features

Hepatitis with jaundice

Generalized lymphadenopathy

Hemolytic anemia

Pneumonitis

How did the patient develop rubella infection? What was the primary source from which the infection spread?

Postnatal Infection: In the pre-vaccine era, rubella epidemics occurred in 6-9 year cycles with highest incidence in late winter and spring. In countries with effective vaccination programs, natural rubella infection is rare and is generally associated with travel to endemic regions. Infected individuals shed virus from the nasopharynx for 7 days prior to and 14 days after onset of the rash, with peak viral loads occurring 5 days prior to and 6 days following the onset of rash. The virus is transmitted via respiratory droplets and close contact with infected individuals.
CRS: Fetal rubella infection occurs when a rubella non-immune pregnant woman is infected. During maternal viremia, the virus infects the placenta, allowing the virus to pass into the fetal circulation. The virus readily infects embryonic stem cells of a wide variety of lineages once in the fetus, leading to the array of findings in CRS.

Which individuals are of greater risk of developing symptomatic rubella infection?

Postnatal Infection: Rubella non-immune individuals (unvaccinated and no prior natural infection)
CRS: Fetus of rubella non-immune mothers (first trimester > second trimester > third trimester)

Beware: there are other diseases that can mimic rubella infection:

Postnatal Infection: Measles has a similar but more pronounced fever and rash. Children with measles are more ill appearing at presentation. Other viral infections (e.g., enterovirus and adenovirus) can present with diffuse rash, fever, and lymphadenopathy. Toxoplasmosis is another cause of postauricular and suboccipital lymphadenopathy.
CRS: Due to the array of findings associated with CRS, there is considerable overlap between many of the congenital infection syndromes. Of the congenital infections, cytomegalovirus is most similar in presentation.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Postnatal Infection: Complete blood count (CBC) with differential will often show leukopenia with lymphopenia more often than neutropenia. Thrombocytopenia is occasionally seen later in the course.
CRS: CBC may show thrombocytopenia and less commonly anemia. Liver transaminases may be elevated with hepatic involvement.

Results that confirm the diagnosis

Postnatal Infection

Viral Culture: Virus can be recovered from the nasopharynx and blood during the prodromal phase and up to 4 days following the onset of rash.

Serology: The presence of rubella-specific IgM in acute serum (persists for about 2 months) or a four-fold rise in rubella-specific IgG from acute to convalescent samples suggests recent infection. IgG antibody avidity may also be used for diagnosis. The presence of low-avidity antibodies suggests rubella infection within the previous 2 months. High-avidity antibodies suggest remote infection.
CRS

Viral Culture: Virus can be recovered at birth from urine, blood, and nasopharyngeal swabs. The likelihood of virus recovery declines over the first year of life. Virus can be isolated from most affected tissues but is not commonly performed.

Serology: Rubella-specific IgM can be detected at birth and can persist throughout the first year of life. Low-avidity rubella-specific IgG can be detected at birth and can persist for more than 1 year. Detection of rubella-specific IgG beyond 6 months of age is consistent with congenital infection.

Polymerase chain reaction (PCR): PCR is used primarily in prenatal diagnosis. PCR can also detect virus in most affected tissues, but it is not routinely recommended for the diagnosis of a congenitally infected infant or in the setting of postnatal infection.

What imaging studies will be helpful in making or excluding the diagnosis of rubella infection?

Postnatal Infection: Magnetic resonance imaging (MRI) of the brain may be helpful if encephalitis is a concern.
CRS: Central nervous system (CNS) imaging with cranial ultrasound or MRI may help to define the degree of CNS involvement and aid in determining prognosis.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Postnatal Infection: Consider an Infectious Diseases consult to aid in confirming diagnosis. Neurology may be helpful in managing encephalitis. Input from a Hematology/Oncology specialist may be useful if there is significant thrombocytopenia or if the origin of lymphadenopathy and leukopenia is not clear.
CRS: Severely affected patients often require care in a neonatal intensive care unit with assistance from a variety of subspecialty services. Input from Pediatric Infectious Diseases may be helpful in confirming the diagnosis. Assistance from Pediatric Ophthalmology can be useful to determine the extent of eye involvement. Pediatric Cardiology should be consulted to assess and treat congenital heart disease, and Pediatric Neurology can help in managing immediate CNS symptoms, such as encephalitis and seizures. Consultation from Palliative Care services should be considered for infants with extensive or severe organ system involvement. Other consultations should be guided by specific findings.

If you decide the patient has rubella infection, what therapies should you initiate immediately?

Postnatal Infection: No antiviral therapy is effective for postnatal rubella infection. Infected individuals should be counseled to avoid pregnant, non-immune individuals. Supportive therapy should be based on symptoms.
CRS: Likewise, no specific antiviral therapy is effective for patients with CRS. Supportive therapy should be targeted to involved systems.

What complications could arise as a consequence of rubella infection?

Postnatal Infection

Arthritis/Arthralgia: Polyarticular arthralgias and arthritis are common findings in post-pubertal adolescents and adults. Joint involvement is generally self-limited.

Encephalitis: Neurologic involvement is a less-common complication of infection (1:500-1:6000 cases of rubella) and is thought to be post-infectious in nature. Mortality associated with neurological complications can be as high as 50%, but full recovery usually occurs in surviving patients. Rarely, individuals can develop a progressive rubella panencephalitis as a remote consequence of rubella infection.

Hematologic Manifestations: Hemorrhagic complications, such as thrombocytopenic purpura, are also unusual, occur more frequently in children than in adults, and completely resolve in most cases.
CRS: Acute complications of CRS were previously discussed. Other long-term complications may develop over weeks to years, including:

Mental retardation and behavioral disorders

Spastic diplegia

Endocrinopathies, specifically diabetes

Seizure disorders

What should you tell the family about the patient's prognosis?

Postnatal Infection: Patients with rubella infection have an excellent prognosis. Exceptions include patients with encephalitis in which prognosis is related to the severity and extent of encephalitis.
CRS: Prognosis is directly related to the number and severity of organ systems involved. Of surviving children with CRS, 60-90% have hearing loss, 10-20% have mental retardation, and about 35% have visual deficits.

What if a pregnant woman is exposed to rubella virus?

Exposure to rubella virus during pregnancy can be very concerning because of the potential for CRS. Reassurance can be provided if the woman is already known to be immune to rubella. If this information is not available, serologic testing should be performed immediately to assess the risk for primary infection. If the results are negative, they should be repeated in 2-3 weeks after the exposure (and again at 6 weeks if the second test is negative) to determine whether she has seroconverted. A positive rubella-specific IgM or a four-fold rise in rubella-specific IgG between acute and convalescent samples suggests recent infection. In addition, virus can be isolated from nasopharyngeal samples, blood, urine, or cerebrospinal fluid.
PCR can be used to make a prenatal diagnosis of congenital infection. PCR analysis of chorionic villous samples, amniotic fluid, or fetal blood is likely more useful than measurement of rubella-specific IgM in fetal blood. Because of the wide spectrum of possible congenital abnormalities, ultrasound diagnosis alone is unlikely to be helpful.
There is no specific therapy that decreases the risk for CRS in the setting of exposure to rubella virus during pregnancy. Administration of immunoglobulin to susceptible individuals can prevent clinical manifestations of rubella infection, but infants with CRS have been born to women who were treated with immunoglobulin shortly after exposure to virus. Thus, immunoglobulin is not recommended for post-exposure prophylaxis. Some would offer immunoglobulin administration to a pregnant woman exposed to rubella virus when termination of pregnancy is not considered.

How do you contract rubella infection and how frequent is this disease?

Rubella is primarily transmitted via respiratory droplets. Virus is present in respiratory sections of infected individuals from 7 days prior to 14 days after the onset of rash. The incubation period is typically 14 days, with a range of 12 and 23 days. Virus can be transmitted from people with subclinical infections. Importantly, infants with CRS are highly contagious and can shed virus for more than 1 year after birth.
Humans are the natural reservoir for rubella virus and are the only source of infection. Rubella virus has a worldwide distribution, although vaccination efforts have significantly reduced the incidence of rubella disease in many areas. In temperate areas, infection is more common in late winter and early spring months. In the pre-vaccine era, epidemics occurred every 6-9 years, with most cases occurring in children 5-9 years of age.
During an epidemic, the incidence of infection was 50-90% in susceptible hosts of a community. The incidence of infection approached 100% in household contacts. The last epidemic in the United States was in 1964 and occurred as part of a worldwide pandemic from 1962 to 1965. During that epidemic, approximately 12.5 million cases of rubella and 20,000 cases of CRS were reported in the United States.
There was a substantial decline in cases of rubella infection and CRS in the United States following the licensing of rubella vaccine in 1969, and outbreaks began to occur in adolescents and young adults instead of young children. Since the mid-1990s, most cases of rubella in the United States occurred in Hispanic young adults, and most cases of CRS occurred in infants born to Hispanic mothers. Vaccination efforts had eliminated endemic rubella in the United States by 2004. Recent increased vaccination efforts in the Americas have also been successful. All countries in the Americas routinely vaccinated children against rubella by the end of 2009, and the last confirmed case of endemic rubella infection in the Americas occurred in Argentina in 2009.
Rubella remains endemic in many parts of the world, and a substantial number of cases of rubella infection and CRS still occur each year. Importation of rubella virus remains a risk, emphasizing the need for continued vaccination and surveillance.

What pathogens are responsible for this disease?

Hiro and Tasaka established the viral etiology of rubella in 1938. Rubella virus was successfully grown in tissue culture by groups in Boston and Washington, DC, in 1962. Rubella virus is a single-stranded, positive-sense RNA virus. It is the only member of the Rubivirus genus within the Togaviridae family. The Togaviridae family is also comprised of the Alphavirus genus, which includes viruses, such as Sindbis virus and Semliki Forest virus. Humans are the only known host for rubella virus, whereas alphaviruses are capable of replicating in both arthropods and vertebrate hosts.

Two genotypes have been identified based on sequencing of the rubella virus E1 gene. Genotype I is most prevalent in the Americas, Europe, Russia, and Japan. Genotype II is limited to Asia and Europe. The two genotypes are antigenically very similar, so that only one rubella virus serotype is recognized.

How do these pathogens cause disease?

Postnatal Infection

Because it is rarely fatal and good animal models are not available, relatively little information exists regarding the pathogenesis of rubella infection. In postnatal rubella, virus first infects the nasopharyngeal respiratory epithelium and then spreads to regional lymph nodes. A 7- to 9-day period of localized replication is followed by viremic spread throughout the body. Viremia and viruria peak between 10 and 17 days following infection, whereas viral shedding in respiratory secretions can occur up to 24 days following initial exposure.
Virus-specific IgM can be detected within a few days of the onset of the rash and gradually becomes undetectable by 8 weeks following infection. Virus-specific IgG is first detectable around 2 weeks following infection and typically persists for life. Cell-mediated immune responses develop rapidly and also persist. A transient suppression of lymphocyte function can occur early in the course of infection.

Congenital Rubella

Transplacental infection of the fetus occurs during the viremia that accompanies maternal infection. It is more likely to occur in the setting of primary maternal infection, although congenital infection has been reported with maternal reinfection. The risk of fetal infection is greatest when maternal infection occurs during the first trimester, decreases during the second trimester, but then increases again late in gestation, near term. CRS is more likely to occur with maternal infection during the first trimester. For instance, congenital anomalies have been reported in 85% of infants following maternal infection in the first 8 weeks of pregnancy, 52% of infants following maternal infection in gestational weeks 9-12, 16% of infants following maternal infection in gestational weeks 13-20, and in no infants following maternal infection after 20 weeks gestation.
Following transplacental infection, virus disseminates throughout the fetus and persistently infects a wide range of cell types. Although its pathogenesis is incompletely understood, the teratogenicity associated with CRS may be due to factors such as virus-induced apoptosis, inhibition of cell division through effects on actin assembly, and disturbance of other signaling pathways that contribute to cellular proliferation and survival. Some of the tissue damage leading to CRS is also likely related to placental and embryonic angiopathy with ensuing vascular insufficiency.
Appreciable transplacental transfer of rubella-specific IgG occurs during the second half of pregnancy. Fetal immunoglobulin production also increases late in gestation, contributing to total amounts of virus-specific IgG. Over time, virus-specific IgG decreases and, in some cases, can become undetectable in congenitally infected children. Virus-specific IgM is present in congenitally infected neonates and can remain detectable for the first 12 or more months of life. Cell-mediated immune responses are less robust in congenitally infected neonates than in postnatally infected patients. Suppression of cellular immune function can be present in congenitally infected neonates.

What other additional laboratory findings may be ordered?

Although rubella infection is definitively diagnosed by isolating virus from a patient sample using tissue culture, the majority of cases are diagnosed serologically. Other routine laboratory testing is not helpful in distinguishing rubella from other types of diseases.

How can rubella infection be prevented?

Rubella vaccine is a live attenuated virus vaccine. Three separate rubella vaccines were licensed in the United States in 1969. Since 1979, a single vaccine (the RA 27/3 strain) has been licensed in the United States. It is currently available combined with measles and mumps vaccines (MMR) or with measles, mumps, and varicella vaccines (MMRV).
The rubella vaccine is safe and immunogenic. Ninety-five percent or more of vaccinated people at least 12 months of age develop serologic evidence of immunity after a single dose, and immunity lasts for at least 15 years in more than 90% of those vaccinated. At least one dose of rubella-containing vaccine is recommended for all children 12 months of age or older. Children receiving vaccine before 12 months of age should be revaccinated when they are at least 12 months of age. A second dose of rubella-containing vaccine is recommended at 4-6 years of age to produce immunity in those who fail to respond to the first dose. The second dose of MMR may be given as soon as 28 days following the first, whereas the minimum interval between MMRV doses is 3 months.
Adults born in 1957 or later should receive at least one dose of MMR, unless they have documentation of previous vaccination or serologic evidence of immunity to measles, mumps, and rubella. MMRV should not be given to persons older than 13 years of age.
Vaccination is contraindicated in persons who experienced anaphylaxis to a vaccine component or following previous rubella vaccination. Immunodeficient and immunosuppressed patients should not be vaccinated, although MMR should be given to patients infected with HIV who are not severely immunocompromised. Otherwise immunocompetent persons treated with immunosuppressive doses of steroids (2 mg/kg/day or greater than 20 mg/day) for 14 days or more should be vaccinated at least 1 month after discontinuation of steroids. Because immunoglobulin preparations could theoretically interfere with immune responses to rubella vaccine, vaccination should be deferred for 3 months or longer following administration of blood or plasma transfusions or administration of immune globulin.
Rubella vaccine is not effective for post-exposure prophylaxis of rubella. Pregnant women should not receive rubella vaccine. In the Centers for Disease Control and Prevention’s (CDC’s) Vaccine in Pregnancy Registry, 1.5% of infants born to women who were vaccinated between 1 to 2 weeks before and 4 to 6 weeks after conception had subclinical infection, but none had congenital defects.
Vaccine-strain virus is generally not transmitted to others. A breastfeeding infant may occasionally be infected through breast milk, although serious effects have not been reported. Breastfeeding is not a contraindication to rubella vaccination. Children in a household with a pregnant woman should be vaccinated.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Castillo-Solorzan, C, Marsigli, C, Bravo-Alcantara, P. “Elimination of rubella and congenital rubella syndrome in the Americas”. J Infect Dis. vol. 204. 2011. pp. S571-8. (This report provides an overview of recent efforts to eliminate rubella from the Americas. Of note, the entire supplemental issue is devoted to rubella and CRS.)

“Achievements in public health: elimination of rubella and congenital rubella syndrome – United States, 1969-2004”. MMWR. vol. 54. 2005. pp. 279-82. (This report describes the elimination of rubella and CRS in the United States.)

Atkinson, W, Wolfe, S, Hamborsky, J. “Rubella”. Epidemiology and Prevention of Vaccine-Preventable Diseases. 2012. pp. 275-90. (This is a concise summary of rubella disease, epidemiology, and vaccine strategy.)

Cherry, JD. “Viral exanthems”. Curr Probl Pediatr. vol. 13. 1983 Apr. pp. 1-44. (This is an excellent reference describing a variety of viral exanthems.)

Hiro, Y, Tasaka, S. “Die Roteln sind eine Viruskrankheit”. Monatsschr Kinderheilkd. vol. 76. 1938. pp. 328-32. (This is the first report linking rubella to viral infection.)

Hobman, TC, Chantler, JK, Knipe, DM, Howley, PM. “Rubella virus”. Fields Virology. 2007. pp. 1069-100. (This chapter provides a thorough overview of the biology and clinical features of rubella virus infection.)

Kimberlin, DW, Richman, DD, Whitley, RJ, Hayden, FG. “Rubella virus”. Clinical Virology. 2009. pp. 1275-89. (This chapter provides a concise review of the clinical features of rubella virus infection.)

Lee, J, Bowden, DS. “Rubella virus replication and links to teratogenicity”. Clin Microbiol Rev. vol. 13. 2000. pp. 571-87. (This report provides a comprehensive review of potential mechanisms that may mediate the teratogenic effects of rubella infection.)

Parkman, PD, Buescher, EL, Artenstein, MS. “Recovery of rubella virus from army recruits”. Proc Soc Exp Biol Med. vol. 111. 1962. pp. 225-30. (This is one of two initial reports describing the isolation of rubella virus.)

Peckham, CS. “Clinical and laboratory study of children exposed in utero to maternal rubella”. Arch Dis Child. vol. 47. 1972. pp. 571-7. (This report details the risk of CRS based on the timing of maternal infection.)

Tanemura, M, Suzumori, K, Yagami, Y, Katow, S. “Diagnosis of fetal rubella infection with reverse transcription and nested polymerase chain reaction: a study of 34 cases diagnosed in fetuses”. Am J Obstet Gynecol. vol. 174. 1996. pp. 578-82. (This report is one of several examples detailing the use of PCR to detect rubella infections during pregnancy.)

Weller, TH, Neva, FA. “Propagation in tissue culture of cytopathic agents from patients with rubella-like illness”. Proc Soc Exp Biol Med. vol. 111. 1962. pp. 215-25. (This is one of two initial reports describing the isolation of rubella virus.)

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Rubella Virus