Rubella

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Rubella
Last Updated: June 29, 2006 Email to a Colleague

Synonyms and related keywords: rubella, German measles, 3-day measles, roseola, röteln, roetheln, third disease, congenital rubella syndrome, CRS

AUTHOR INFORMATION Section 1 of 11
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Author: Elias Ezike, MD, Fellow, Department of Pediatrics, Division of Pediatric Infectious Diseases, Children's Hospital of Michigan
Coauthor(s): Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University; Basim Asmar, MD, Director, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan; Professor, Department of Pediatrics, Wayne State University School of Medicine


Elias Ezike, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Infectious Diseases Society of America

Editor(s): Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Disclosure





INTRODUCTION Section 2 of 11
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Background: The name rubella is derived from a Latin term meaning "little red." Rubella is generally a benign communicable exanthematous disease. It is caused by rubella virus, which is a member of the Rubivirus genus of the family Togaviridae. Nearly one half of individuals infected with this virus are asymptomatic. Clinical manifestations and severity of illness vary with age. For instance, infection in younger children is characterized by mild constitutional symptoms, rash, and suboccipital adenopathy; conversely, in older children, adolescents, and adults, rubella may be complicated by arthralgia, arthritis, and thrombocytopenic purpura. Rare cases of rubella encephalitis have also been described in children.

The major complication of rubella is its teratogenic effects when pregnant women contract the disease, especially in the early weeks of gestation. The virus can be transmitted to the fetus through the placenta and is capable of causing serious congenital defects, abortions, and stillbirths. Fortunately, because of the successful immunization program initiated in the United States in 1969, rubella infection and congenital rubella syndrome rarely are seen today.

The few cases of rubella recorded in recent years involve susceptible individuals who have not been immunized with rubella vaccine and do not have a history of previous rubella infection.

An independent panel convened by the Centers for Disease Control and Prevention (CDC) in 2004 found that about 91% of the US population is immune to rubella. This explains the decreased number of outbreaks of rubella and congenital rubella syndrome reported in the recent years.


Pathophysiology:


Postnatal rubella

The usual portal of entry of rubella virus is the respiratory epithelium of the nasopharynx. The virus is transmitted via the aerosolized particles from the respiratory tract secretions of infected individuals. The virus attaches to and invades the respiratory epithelium. It then spreads hematogenously (primary viremia) to regional and distant lymphatics and replicates in the reticuloendothelial system. This is followed by a secondary viremia that occurs 6-20 days after infection. During this viremic phase, rubella virus can be recovered from different body sites including lymph nodes, urine, cerebrospinal fluid, conjunctival sac, breast milk, synovial fluid, and lungs. Viremia peaks just before the onset of rash and disappears shortly thereafter. An infected person begins to shed the virus from the nasopharynx 3-8 days after exposure for 6-14 days after onset of the rash.

Congenital rubella syndrome

Fetal infection occurs transplacentally during the maternal viremic phase, but the mechanisms by which rubella virus causes fetal damage are poorly understood. The fetal defects observed in congenital rubella syndrome are likely secondary to vasculitis resulting in tissue necrosis without inflammation. Another possible mechanism is direct viral damage of infected cells. Studies have demonstrated that cells infected with rubella in the early fetal period have reduced mitotic activity. This may be the result of chromosomal breakage or due to production of a protein that inhibits mitosis. Regardless of the mechanism, any injury affecting the fetus in the first trimester (during the phase of organogenesis) results in congenital organ defects.


Frequency:


In the US: During the 1962-1965 worldwide epidemic, an estimated 12.5 million rubella cases occurred in the US, resulting in 20,000 cases of congenital rubella syndrome. Since the licensing of the live attenuated rubella vaccine in the United States in 1969, a substantial increase has been noted in the vaccination coverage among school-aged children and the population immunity. In 2004, the estimated vaccination coverage among school-aged children was about 95%, and the population immunity was about 91%.
As a result of the progress made in vaccination against rubella, a remarkable drop has occurred in the number of cases of rubella and congenital rubella syndrome. For instance, in 1969, a total of 57,686 cases of rubella and 31 cases of congenital rubella syndrome were recorded. Subsequently, from 1993-2000, the number of cases of rubella recorded annually decreased to a range of 128-364, and cases of congenital rubella syndrome also dropped to 4-9 cases per year. Since 2001, the annual number of rubella cases ranged from a record low of 7 in 2003 to 23 in 2001, and congenital rubella syndrome cases between 0-3 per year (see Table 1, Images 1 and 2).

An independent panel convened by the CDC in 2004 to assess progress towards elimination of rubella and congenital rubella syndrome in the United States concluded unanimously that rubella is no longer endemic in the United States. In fact, the pattern of virus genotypes isolated in recent years was consistent with virus originating in other parts of the world.

Following the near record-low levels in rubella incidence in the United States, the occurrence of isolated outbreaks among susceptible adults has also become rare. In fact no outbreak of rubella was reported from 2000-2005, in contrast to the preceding year interval, 1996-1999, when 16 outbreaks were reported. The median number of cases per outbreak was 21. The most recent cases occurred in New York during 1997-1998, Kansas in 1998, Nebraska in 1999, and Arkansas in 1999. Most of these outbreaks were reported in college campuses, military installations, prisons, and workplaces, including health care environments. In most instances, the individuals involved in these outbreaks have no history of rubella immunization. In addition, most of the outbreaks have been reported among persons who emigrated from countries where rubella is not included in the routine immunization schedule.

Internationally: Rubella occurs worldwide. The number of reported cases is high in countries where routine rubella immunization is either not available or was recently introduced. For instance, in Mexico in 1990, a total of 65,591 cases of rubella were reported. After the introduction of rubella vaccine into the childhood immunization schedule in 1998, the number of reported cases declined 68% to 21,173. In Europe, the incidence of rubella remains high. For instance, in 2003, a total of 304,320 cases were reported; 41% of these were from the Russian Federation, and 40% were from Romania.
Although the burden of congenital rubella syndrome is not well characterized in all countries, more than 100,000 cases are estimated to occur each year in developing countries alone. In Europe, a total of 47 cases of congenital rubella syndrome were reported from 2001-2003; 32% were from the Russian Federation, and 36% were from Romania.

Mortality/Morbidity: The morbidity and mortality rates of rubella disease dropped remarkably since the licensing of live attenuated rubella vaccine in 1969. In fact, in 1969, complicated rubella infection caused 29 fatalities in the United States, whereas from 1992-2001, only 0-2 deaths per year were recorded (see Table 1 and Image 3).

In contrast to postnatal rubella, which is not a debilitating disease, congenital rubella infection may result in growth delay, learning disability, mental retardation, hearing loss, congenital heart disease, and eye, endocrinologic, and neurologic abnormalities.

TABLE 1. Reported cases of Rubella, Deaths from Rubella, and number of cases of Congenital Rubella Syndrome (CRS) in the United States from 1969-2006*†

YEAR NUMBER OF CASES NUMBER OF DEATHS CASES OF CRS
1969 57,686 29 31
1970 56,552 31 77
1971 45,086 20 68
1972 25,507 14 42
1973 27,804 16 35
1974 11,917 15 45
1975 16,652 21 30
1976 12,491 12 30
1977 20,395 17 23
1978 18,269 10 30
1979 11,795 1 62
1980 3,904 1 50
1981 2,077 5 19
1982 2,325 4 7
1983 970 3 22
1984 752 1 5
1985 630 1 0
1986 551 1 5
1987 306 0 5
1988 225 1 6
1989 396 4 3
1990 1,125 8 11
1991 1,401 1 47
1992 160 1 11
1993 192 0 5
1994 227 0 7
1995 128 1 6
1996 238 0 4
1997 181 0 5
1998 364 0 7
1999 267 0 9
2000 176 0 9
2001 23 2 3
2002 18 NA †† 1
2003 7 NA 1
2004* 7 NA 0
2005* 11 NA 1
2006* 1 NA 1

* = Data for reporting years 2004, 2005, and 2006 are provisional

†Data are from CDC: Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep 1997 Oct 31; 45(53): 1-87; CDC: Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
1996 Oct 25; 44(53): 1-87; Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
1994 Oct 21; 42(53): 1-73; Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep
2005 April 22; 52(54): 73-78; Deaths: National Center for Health Statistics Mortality Report for respective
years; and congenital rubella syndrome data from the National congenital Rubella Syndrome Registry.

†† NA indicates that data are not available


Race: No ethnic difference in incidence has been clearly demonstrated, although the characteristic rash is more difficult to diagnose in persons with dark skin.

Sex: No appreciable differences in infection rates by sex are apparent in children, but in adults, more cases are reported in women than in men. Rubella arthralgia and arthritis are more frequent in women than in men.

Age: Before licensing of the live attenuated vaccine in 1969, rubella in the United States was primarily a disease of school-aged children, with a peak incidence in children aged 5-9 years. Following widespread use of rubella vaccine in children, peak incidence has shifted to persons older than 20 years, who comprise 62% of cases of rubella reported in the United States.




CLINICAL Section 3 of 11
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History:

Postnatal rubella
Exposure: Rubella virus is transmitted from person to person via the aerosolized particles from the respiratory tract. A history of exposure may not be present. Individuals may acquire the infection from a completely asymptomatic patient or from an individual shedding the virus during the incubation period.
Incubation period: The incubation is usually 14-21 days after exposure to a person with rubella.
Prodromal phase: Prodromal symptoms are unusual in young children but are common in adolescents and adults.
The following signs and symptoms usually appear 1-5 days before the onset of rash:

Eye pain on lateral and upward eye movement (a particularly troublesome complaint)

Conjunctivitis

Sore throat

Headache

General body aches

Low-grade fever

Chills

Anorexia

Nausea

Tender lymphadenopathy (particularly posterior auricular and suboccipital lymph nodes)

Forchheimer sign (an enanthem observed in 20% of patients with rubella during the prodromal period; can be present in some patients during the initial phase of the exanthem; consists of pinpoint or larger petechiae that usually occur on the soft palate)
Congenital rubella history focuses on the following:
The number of weeks of pregnancy when maternal exposure to rubella occurred (The risk of congenital rubella syndrome is higher if maternal exposure occurs during the first trimester.)
Maternal history of immunization or medical history of rubella
Evidence of intrauterine growth retardation during pregnancy
Manifestations suggestive of congenital rubella syndrome in a child
Physical:

Postnatal rubella
Rash

The exanthem of rubella consists of a discrete rose-pink maculopapular rash ranging from 1-4 mm.

Rash in adults may be quite pruritic.

The synonym “3-day measles” derives from the typical course of rubella exanthem that starts initially on the face and neck and spreads centrifugally to the trunk and extremities within 24 hours. It then begins to fade on the face on the second day and disappears throughout the body by the end of the third day.

Temperature: Fever usually is not higher than 38.5°C (101.5°F).

Lymph nodes: Enlarged posterior auricular and suboccipital lymph nodes are usually found on physical examination.

Mouth: The Forchheimer sign may still be present on the soft palate.
Congenital rubella syndrome (see Table 2)
The classic triad presentation of congenital rubella syndrome consists of the following:

Sensorineural hearing loss is the most common manifestation of congenital rubella syndrome. It occurs in approximately 58% of patients. Studies have demonstrated that approximately 40% of patients with congenital rubella syndrome may present with deafness as the only abnormality without other manifestations. Hearing impairment may be bilateral or unilateral and may not be apparent until the second year of life.

Ocular abnormalities including cataract, infantile glaucoma, and pigmentary retinopathy occur in approximately 43% of children with congenital rubella syndrome. Both eyes are affected in 80% of patients, and the most frequent findings are cataract and rubella retinopathy. Rubella retinopathy consists of a salt-and-pepper pigmentary change or a mottled, blotchy, irregular pigmentation, usually with the greatest density in the macula. The retinopathy is benign and nonprogressive and does not interfere with vision (in contrast to the cataract) unless choroid neovascularization develops in the macula.

Congenital heart disease including patent ductus arteriosus (PDA) and pulmonary artery stenosis is present in 50% of infants infected in the first 2 months of gestation. Cardiac defects and deafness occur in all infants infected during the first 10 weeks of pregnancy and deafness alone is noted in one third of those infected at 13-16 weeks of gestation.
Other findings in congenital rubella syndrome include the following:

Intrauterine growth retardation, prematurity, stillbirth, and abortion

Central nervous system abnormalities, including mental retardation, behavioral disorders, encephalographic abnormalities, hypotonia, meningoencephalitis, and microcephaly

Hepatosplenomegaly

Jaundice

Hepatitis

Skin manifestations, including blueberry muffin spots that represent dermal erythropoiesis and dermatoglyphic abnormalities

Bone lesions, such as radiographic lucencies

Endocrine disorders, including late manifestations in congenital rubella syndrome usually occurring in the second or third decade of life (eg, thyroid abnormalities, diabetes mellitus)

Hematologic disorders, such as anemia and thrombocytopenic purpura
Table 2. Clinicopathologic Abnormalities in Congenital Rubella

Abnormality Common/Uncommon Early/Delayed Comment
General

Intrauterine growth retardation Common Early


Prematurity Uncommon Early


Stillbirth Uncommon Early


Abortion Uncommon Early


Cardiovascular system

Patent ductus arteriosus Common Early May occur with pulmonary artery stenosis

Pulmonary artery stenosis Common Early Caused by intimal proliferation

Coarctation of the aorta Uncommon Early


Myocarditis Uncommon Early


Ventricular septal defect Uncommon Early


Atrial septal defect Uncommon Early


Eye

Cataract Common Early Unilateral or bilateral

Retinopathy Common Early Salt-and-pepper appearance; visual acuity unaffected; frequently unilateral

Cloudy cornea Uncommon Early Spontaneous resolution

Glaucoma Uncommon Early/Delayed May be bilateral

Microphthalmia Common Early Common in patients with unilateral cataract

Subretinal neovascularization Uncommon Delayed Retinopathy with macular scarring and loss of vision

Ear

Hearing loss Common Early/Delayed Usually bilateral; mostly sensorineural; may be central in origin; rare when maternal rubella occurs >4 months' gestation; sometimes progressive

Central nervous system

Meningoencephalitis Uncommon Early Transient

Microcephaly Uncommon Early May be associated with normal intelligence

Intracranial calcifications Uncommon Early

Encephalographic abnormalities Common Early Usually disappear by age 1 y

Mental retardation Common Delayed


Behavioral disorders Common Delayed Frequently related to deafness

Autism Uncommon Delayed


Chronic progressive panencephalitis Uncommon Delayed Manifest in second decade of life

Hypotonia Uncommon Early Transitory defect

Speech defects Common Delayed Uncommon in absence of hearing loss

Skin

Blueberry muffin spots Uncommon Early Represents dermal erythropoiesis

Chronic rubelliform rash Uncommon Early Usually generalized; lasts several weeks

Dermatoglyphic abnormalities Common Early


Lungs

Interstitial pneumonia Uncommon Delayed Generalized; probably immunologically mediated

Liver

Hepatosplenomegaly Common Early Transient

Jaundice Uncommon Early Usually appears in the first day of life

Hepatitis Uncommon Early May not be associated with jaundice

Blood

Thrombocytopenia Common Early Transient; no response to steroid therapy

Anemia Uncommon Early Transient

Hemolytic anemia Uncommon Early Transient

Altered blood group expression Uncommon Early


Immune system

Hypogammaglobulinemia Uncommon Delayed Transient

Lymphadenopathy Uncommon Early Transient

Thymic hypoplasia Uncommon Early Fatal

Bone

Radiographic lucencies Common Early Transient; most common in distal femur and proximal tibia

Large anterior fontanel Uncommon Early


Micrognathia Uncommon Early


Endocrine glands

Diabetes mellitus Common Delayed Usually becomes apparent in second or third decade of life

Thyroid disease Uncommon Delayed Hypothyroidism, hyperthyroidism, and thyroiditis

Growth hormone deficiency Uncommon Delayed


Genitourinary system

Cryptorchidism Uncommon Early


Polycystic kidney Uncommon Early




Causes: Rubella and congenital rubella syndrome are caused by rubella virus. Only one antigenic type of rubella virus exists, and humans are the only natural hosts. The virus is spherical with a diameter of 50-70 nm, has a central core (ie, nucleocapsid), and is covered externally by a lipid-containing envelope. The nucleocapsid is composed of polypeptide (C protein) and a single-stranded ribonucleic acid (RNA).

Its outer envelope is made up of glycosylated lipoprotein, which contains 2 virus-specific polypeptides (E1, E2) and a host-cell–derived lipid. These 2 envelope proteins comprise the spiked 5- to 6-nm surface projections that are observed on the outer membrane of rubella virus and are important for the virulence of the virus.

Monoclonal antibodies directed against epitopes of E1 and E2 have neutralizing activity. Protein E1 is the viral hemagglutinin that binds both hemagglutination- and hemolysis-inhibiting antibodies.

Rubella virus is rapidly inactivated by 70% alcohol, ethylene oxide, formalin, ether, acetone, chloroform, free chlorine, deoxycholate, beta-propiolactone, ultraviolet light, extreme pH (<6.8 or >8.1), heat (>56°C), and cold (from -10 to -20°C). It is resistant to thimerosal and is stable at temperatures of -60°C or less. DIFFERENTIALS Section 4 of 11
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WORKUP Section 5 of 11
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Lab Studies:


Postnatal rubella
A clinical diagnosis of rubella may be difficult to make because many exanthematic diseases may mimic rubella infection. In addition, as many as 50% of rubella infections may be subclinical; therefore, laboratory studies are important to confirm the diagnosis of acute rubella infection.
The laboratory diagnosis of rubella can be made either though serologic testing or by viral culture. The serologic diagnosis consists of demonstrating the presence of rubella-specific immunoglobulin M (IgM) antibody in a single serum sample or observation of a significant (>4-fold) rise in rubella-specific immunoglobulin G (IgG) antibody titer between the acute and convalescent serum specimens drawn 2-3 weeks apart.
False-positive rubella IgM test results have been reported in persons with other viral infections (eg, acute Epstein-Barr virus [EBV], infectious mononucleosis, cytomegalovirus [CMV] infection, parvovirus B19 infection) and in the presence of rheumatoid factor (RF).
To demonstrate a 4-fold rise in rubella-specific IgG antibody, a serum sample should be obtained as soon as possible during the acute phase of infection and tested for rubella-specific IgG antibody. An aliquot of this serum should be frozen and stored for repeat testing later. Then, a second serum specimen is collected at 2-3 weeks and tested in the same laboratory at the same time with the first serum sample. The levels of rubella-specific IgG are compared between the first and the second sample to show a significant rise in antibody titers.
Several techniques are available for serologic testing, including the following:

Enzyme-linked immunosorbent assay (ELISA)

Immunofluorescent assay (IFA)

Latex agglutination (LA) test

Hemagglutination inhibition (HI) test

Complement fixation (CF) test

Passive hemagglutination antibody (PHA) test

Hemolysis-in-gel test
Among all the serologic tests available, ELISA is the most widely used because it is relatively inexpensive, technically easy to perform, rapid, and very sensitive.
Rubella viral cultures are time consuming, expensive, not readily available, and used mainly for tracking the epidemiology of rubella virus during an outbreak.

The most commonly used method for isolation of rubella virus from clinical specimens, taken from an infected person, is the interference technique using African green monkey kidney (AGMK) cells and an enterovirus.

The specimen (urine or nasopharyngeal swab) is inoculated onto primary AGMK monolayers. After 9-12 days, the cultures are challenged with an enterovirus. If rubella is present, it interferes with the challenge virus and no cytopathic effect (CPE) is observed on the AGMK cells. HI, CF, and immunofluorescence techniques have also been used to detect rubella-specific antigens in tissue culture.
Congenital rubella
Congenital rubella in infants and children is diagnosed by viral isolation or by serologic testing. In contrast to postnatal infection, viral isolation is the preferred technique in congenital rubella syndrome because rubella serology may be difficult to interpret in view of transplacental passage of rubella-specific maternal IgG antibody. In addition, rubella-specific IgM antibody may not be detectable at the time of evaluation. Congenital rubella syndrome has also been diagnosed using placental biopsy, rubella antigen detection by monoclonal antibody, and PCR.
Specimens used for viral isolation in congenital rubella include nasopharyngeal swab, urine, cerebrospinal fluid, and buffy coat of the blood.
In some infants with congenital rubella syndrome, rubella virus can persist and can be isolated from the nasopharyngeal and urine cultures throughout the first year of life or later.
The same serologic testing methods (ELISA, IFA, LA, HI, CF) discussed for postnatal rubella can be used to detect specific antibodies in congenital infection.
Rubella-specific IgM antibody is actively produced by the fetus or neonate and may be detected in the cord blood or neonatal serum.
Congenital rubella syndrome should be strongly suspected in infants older than 3 months if rubella-specific IgG antibody levels are observed and do not decline at the rate expected from passive transfer of maternal antibody (ie, equivalent of a 2-fold decline in HI titer per mo) in a compatible clinical situation.
Patients with concomitant immunodeficiency, such as agammaglobulinemia or dysgammaglobulinemia, may have a false-negative serology result for rubella. Therefore, viral isolation is required to confirm the diagnosis in this group of patients.
Imaging Studies:


Postnatal rubella: Imaging studies usually are not performed in postnatal rubella.
Congenital rubella syndrome
Chest radiography is indicated for infants who develop respiratory distress or other respiratory symptoms to exclude rubella-related interstitial pneumonitis or pulmonary edema that may result from congestive heart failure in children with severe or complicated congenital heart anomalies.
Radiography of the long bones may reveal radiolucencies in the metaphyses of long bones.
Echocardiography is important for patients with congenital heart defects to help diagnose the type of heart anomaly and evaluate the severity of the heart defect so that appropriate surgical plans can be made.
Computed tomography (CT) scan of the head may reveal intracranial calcifications and enlargement of the ventricles.
Magnetic resonance imaging (MRI) of the head may reveal cortical atrophy and white matter changes in patients with late-onset progressive panencephalitis.
Other Tests:


CBC count may reveal leukopenia and thrombocytopenia. It is used to monitor the course of thrombocytopenia.
Liver function tests, such as total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase levels may reveal hepatic injury due to disseminated rubella infection, especially in neonates.
Procedures:


Lumbar puncture is indicated to evaluate for possible causes in children who develop signs and symptoms of meningoencephalitis, such as full anterior fontanelle, irritability, hypotonia, seizures, lethargy, head retraction, and arching of the back.
In patients with rubella-related meningoencephalitis, cerebrospinal fluid examination usually reveals normal glucose levels, normal or slightly elevated protein levels, and mild pleocytosis (20-100 WBC/mm3) with lymphocyte predominance.
Histologic Findings:
Postnatal rubella: Histologically cutaneous lesions are nonspecific and demonstrate only a mild, superficial, perivascular, lymphocytic infiltrate.

Congential rubella: The gross neuropathologic features that present during autopsy of babies who are stillborn include microcephaly and various other malformations (ie, polymicrogyria, nonhemorrhagic subependymal germinal matrix cysts). Histologically, chronic inflammatory cells are found in the meninges and surrounding the intraparenchymal blood vessels. The vessel walls also show foci of subintimal fibrosis and mineralization.
TREATMENT Section 6 of 11
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Medical Care:

Postnatal rubella
Treatment is supportive. No specific antiviral agent for rubella is currently available.

Starch baths and antihistamines may be useful for adult patients with uncomplicated rubella and troublesome itching.

For complicated cases, treatment is as follows:

For severe arthritis affecting weight-bearing joints, encourage rest. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful, but corticosteroids are not indicated.

For patients with encephalitis, provide supportive care with adequate fluid and electrolyte maintenance.

Thrombocytopenia usually is self-limited but, if severe, consider intravenous immunoglobulin (IVIG). Corticosteroids have not demonstrated any specific benefit. Splenectomy is not indicated.
Congenital rubella syndrome
Treatment is supportive.
Provide vision screening and hearing screening for asymptomatic newborns.

Treatment of symptomatic newborns is as follows:

Provide careful evaluation of the eyes and ophthalmology referral for babies with corneal clouding, cataract, and retinopathy. Corneal clouding may indicate infantile glaucoma.

Babies with congenital rubella syndrome who develop respiratory distress may require supportive treatment in the intensive care unit.

Hepatosplenomegaly is monitored clinically. No intervention is required.

Patients with hyperbilirubinemia may require phototherapy or exchange transfusions if jaundice is severe to prevent kernicterus.

True hemorrhagic difficulties have not been a major problem; however, IVIG may be considered in infants who develop severe thrombocytopenia. Corticosteroids are not indicated.

Infants who have a rubella-related heart abnormality should be carefully observed for signs of congestive heart failure. Echocardiography may be essential for diagnosis of heart defects.
Contact isolation is required for patients with congenital rubella during hospitalizations because babies are infected at birth and usually are contagious until older than 1 year unless viral cultures have produced negative results.
Surgical Care:

Postnatal rubella: Surgical care is not indicated.
Congenital rubella syndrome
Surgical treatment may be required for congenital heart anomalies, including PDA, coarctation of aorta, ventricular septal defect (VSD), atrial septal defect (ASD), and pulmonary artery stenosis.
Surgical treatment may be required for eye defects such as glaucoma, cataract, and retinal neovascularization.
Consultations:

Infectious disease specialist: Consult an infectious disease specialist for complicated postnatal rubella and congenital rubella syndrome.
Otolaryngologist: Audiometric testing and other hearing screening tests are necessary to promptly diagnose hearing loss in children who may benefit from proper educational programs.
Cardiologist and cardiothoracic surgeon: Children with congenital heart diseases require cardiology referral and echocardiography for adequate management. Lifesaving cardiac repair may be necessary.
Ophthalmologist: An ophthalmologic evaluation and follow-up care are necessary in children with ocular abnormalities. Glaucoma, cataract, and retinal neovascularization may require surgical intervention.
Neurologist: A neurologic evaluation and follow-up care are needed for children who have CNS anomalies, including motor weakness and delay, poor balance, mental retardation, behavioral abnormalities, and learning deficits.
Rehabilitation specialist: Adequate rehabilitation programs comprising physical and occupational therapy may be beneficial for patients with motor weakness and motor delay.
Diet: Diet is as tolerated.

Activity: Activity in rubella can be maintained as tolerated; however, rest is advised for patients who develop arthralgia or arthritis.


MEDICATION Section 7 of 11
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Drug therapy is currently not a component of the standard of care for rubella.


FOLLOW-UP Section 8 of 11
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Further Inpatient Care:


Infants with complicated congenital rubella syndrome who develop respiratory distress need to be admitted to a neonatal intensive care unit (NICU) for management of hypoxia and, if necessary, ventilatory support.
Some babies may develop severe feeding problems necessitating nasogastric or gastrostomy tube feeding.
Significant hyperbilirubinemia may require inpatient treatment with phototherapy or exchange transfusion.
Further Outpatient Care:


Outpatient follow-up care is not necessary for patients with postnatal rubella.
Careful follow-up care after discharge from the hospital for patients with congenital rubella syndrome is composed of the following:
Hearing evaluation
Vision screening
Developmental screening
Monitor blood sugar levels and perform thyroid function tests when clinically indicated.
Education and rehabilitation follow-up care are important for children with congenital rubella.
Deterrence/Prevention:


Prevention of outbreaks from persons infected with rubella: All persons who have contact with patients infected with rubella or children with congenital rubella syndrome (eg, caregivers, household contacts, medical personnel, laboratory workers) should be immune to rubella to prevent rubella outbreaks from persons infected with rubella virus.
Isolation of hospitalized patients: Droplet precautions and standard precautions are recommended for 7 days after the onset of rash in patients with postnatally acquired rubella infections. Contact isolation is indicated for children with proven or suspected congenital rubella infection until they are aged at least 1 year unless nasopharyngeal swab and urine cultures after age 3 months are repeatedly negative for rubella virus. Some authorities suggest that an infant should be considered infectious until 2 cultures of clinical specimens obtained 1 month apart are negative for rubella virus.

School and child care centers: Children diagnosed with postnatal rubella should be excluded from school or child care centers for 7 days after onset of the rash.

Rubella vaccine

Rubella infection may be acquired from an infected asymptomatic person or from a patient during the incubation period for which infected persons may begin to shed the virus and, therefore, are contagious before the onset of symptoms. As a result, the most effective preventive strategy for rubella infection is the administration of rubella vaccine.

In the United States, the only licensed rubella vaccine since 1979 is the 27/3 strain, which is grown in human diploid cell cultures. It is available in 3 forms: as a combined vaccine with measles, mumps, and rubella (MMR), which is most widely used; a combined vaccine with measles, mumps, rubella, and varicella (MMRV), licensed by the US Food and Drug Administration on September 6, 2005; and in monovalent rubella vaccine, which is less frequently used. All 3 forms of vaccine are administered by subcutaneous injection at a standard dose of 0.5 mL.

After administration of a single dose of rubella vaccine, protective serum antibody develops in at least 95% of recipients older than 1 year. Studies have shown that a single dose confers long-term immunity, probably lifelong immunity, against clinical and asymptomatic infection in more than 90% of immunized persons.
MMR vaccine recommendation
Routine childhood immunization: Children receive 2 doses of MMR vaccine.

The first dose of MMR is received at age 12-15 months.

The second dose of MMR is received at age 4-6 years. Children who have not received the second dose by the time they enter school should receive it as soon as possible but no later than age 11-12 years.

Persons at risk: Persons who have not received at least 1 dose of the vaccine or who have no serologic evidence of immunity to rubella are susceptible to rubella and should be immunized with MMR vaccine.

MMR vaccine is especially recommended for all adults at risk of rubella infection (eg, college students, military recruits, health care personnel).

Although birth before 1957 generally is considered presumptive evidence of rubella immunity, serologic surveys of hospital workers indicate that approximately 6% of those born before 1957 do not have detectable rubella antibody. Therefore, health care facilities should consider recommending a dose of MMR vaccine to unvaccinated personnel (whether born before or after 1957) who do not have serologic evidence of rubella immunity.

All postpubertal females without documentation of immunity should be vaccinated unless they are known to be pregnant. Birth before 1957 or clinical diagnosis of rubella is not acceptable evidence of infection for women who could become pregnant because it is only presumptive evidence, not proof, of immunity. Women receiving the vaccine should be counseled not to become pregnant within 28 days of vaccine administration.

Routine serologic testing: Such testing is not recommended before administering the vaccine.
Precautions and contraindications of MMR vaccine
Recent administration of IG: Because IG preparations may interfere with the serologic response of rubella and the other components of MMR, the vaccine should be deferred to a later date depending on the dose and the type of IG given. For instance, patients receiving high doses of IG (1600-2000 mg/kg body weight), such as those given for treatment of Kawasaki disease and idiopathic thrombocytopenic purpura (ITP), should wait as long as 11 months before receiving MMR. Conversely, patients receiving low doses (eg, 10 mg/kg used in hepatitis B prophylaxis) should wait only 3 months before receiving MMR vaccine (refer to table 3.33 on page 423 of 2003 Red Book: Report of the Committee on Infectious Diseases for all suggested intervals).

Altered immunity: Enhanced replication of vaccine viruses may occur in persons who have immune deficiency diseases and in other persons with immunosuppression. Severe immunosuppression may be caused by many disease conditions, such as congenital immunodeficiency, HIV infection, and hematologic or generalized malignancy, and by therapy with immunosuppressive agents (eg, large doses of corticosteroids). For some of these conditions, all affected persons are severely immunocompromised. For other conditions, such as HIV infection, the degree to which the immune system is compromised depends on the severity of the condition, which, in turn, depends on the disease or treatment stage. Ultimately, the patient's physician must assume the responsibility for determining whether the patient is severely immunocompromised on the basis of clinical or laboratory assessment.

Persons infected with HIV

MMR should be administered to all asymptomatic persons infected with HIV who do not have evidence of severe immunosuppression (CD4 >15%). It also should be considered for all symptomatic persons infected with HIV who do not have evidence of severe immunosuppression (see Table 3) because persons infected with HIV are at increased risk of severe complications if infected with the natural strain of rubella virus.

The benefit of immunizing nonseverely immunosuppressed patients infected with HIV with MMR vaccine outweighs any vaccine adverse effects. Studies have shown that the immunologic response to live- and killed-antigen vaccines may decrease as HIV progresses and that vaccination early in the course of HIV infection may be more likely to induce an immune response. Therefore, it is important to immunize infants infected with HIV without severe immunosuppression with MMR vaccine as soon as possible after age 1 year. Consideration should be given to administration of the second dose of MMR vaccine as soon as 28 days after the first dose rather than waiting until the child is ready to enter kindergarten or first grade.
Table 3. Age-Specific CD4+ T-lymphocyte Count and Percentage of Total Lymphocytes as a Criteria for Severe Immunosuppression in Persons with HIV

Age Range
<12 mo 1-5 y 6-12 y ³13 y
Total CD4+ T-lymphocytes <750/mcL <500/mcL <200/mcL <200/mcL
CD4+ T-lymphocytes
(as % of total lymphocytes) <15% <15% <15% <14%





Steroids

Systemically absorbed steroids can suppress the immune system in an otherwise healthy person. However, neither the dose nor the duration of therapy sufficient to cause immune suppression is well defined. Many experts agree that live virus vaccines, such as MMR and its components, may still be given when (1) steroid therapy is short term (ie, <14 d) with low-to-moderate doses, (2) low-to-moderate doses are administered daily or on alternate days, (3) long-term alternate-day treatment involves short-acting preparations, (4) steroids are used as physiologic maintenance for replacement therapy, and (5) steroids are administered topically (eg, eyes, skin), by aerosol, or by intraarticular, bursal, or tendon injection.

Most clinicians agree that persons who have received systemic steroid doses of more than or equivalent to a prednisone dose of 2 mg/kg of body weight or a total dose of 20 mg administered daily or on alternate days for an interval of more than 14 days should avoid vaccination with MMR for at least 1 month following the cessation of steroid therapy.

Persons who receive steroid doses of more than or equivalent to prednisone doses of 2 mg/kg or 20 mg total dose daily or on alternate days for an interval of less than 14 days generally can receive MMR, although some experts prefer waiting until 2 weeks after completion of therapy.

Persons who have received prolonged or extensive topical, aerosol, or other local corticosteroid therapy that causes clinical or laboratory evidence of systemic immunosuppression should also avoid vaccination with MMR for at least 1 month.
Leukemia: Persons with leukemia in remission who were not immune to measles, rubella, or mumps when leukemia was diagnosed may receive MMR or its component vaccines. For individuals who have received chemotherapy, MMR vaccine can be given 3 months after termination of chemotherapy and the patient's immune status recovery.

Pregnancy: MMR should not be given to pregnant women because of the theoretical risk of rubella infection to the fetus. Data collected by the CDC reveal the estimated risk to be 1.6%. However, no cases of congenital defects have been reported in the offspring of women who inadvertently received the vaccine in their first trimester of pregnancy. Healthcare providers should routinely conduct a rubella IgG test for all pregnant women at the earliest prenatal visit. A positive rubella IgG antibody test indicates rubella immunity. Pregnant women who are found to be susceptible should be monitored for signs of rubella during pregnancy and should be advised to avoid contact with persons with rash illness. Rubella vaccine should be administered to nonimmune persons upon completion of pregnancy, preferably prior to discharge from the hospital.

Severe illness: Generally, vaccination of persons with moderate or severe febrile illness should be deferred until they have recovered from the acute phase of their illness to avoid superimposing adverse effects of vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine.

Allergies

Rubella virus strain contained in MMR is grown in human diploid cell cultures, while the other 2 components, measles and mumps virus strains, are produced in chick embryo fibroblasts but do not contain significant amounts of egg white (ovalbumin) cross-reacting proteins. MMR also contains hydrolyzed gelatin as a stabilizer and trace amounts of neomycin. Anaphylactic reaction to MMR is rare. Recent data indicate that allergic reactions are mostly caused by other components of the vaccine, such as gelatin and neomycin.

Among persons who are allergic to eggs, the risk of serious allergic reactions, such as anaphylaxis, following administration of MMR is extremely low. For this reason, skin testing with vaccine is not predictive of allergic reactions to the vaccination and, therefore, is not required before administering MMR to persons who are allergic to eggs. Similarly, the administration of gradually increasing doses of vaccine is not required.

Nonanaphylactic reactions to MMR, such as urticaria and contact dermatitis, are not contraindications to immunization.

Children who developed a significant hypersensitivity reaction following the first dose of MMR vaccine should have serologic testing to determine immunity to the component of the vaccines. If shown to be immune, they should not receive a second dose of the vaccine. If the second dose is necessary, these children should have adequate evaluation for possible serious reaction to the vaccine, and skin testing should be considered before administration of the vaccine.

MMR immunization is contraindicated in children who have had immediate anaphylactic reaction following previous administration of the vaccine. However, these patients require serologic testing to determine whether they are immune to the components of the vaccine.

In case of history of anaphylactic reaction to topically or systematically administered neomycin, consultation with an allergist or immunologist is warranted. In addition, MMR should be administered only in settings where such reactions could be properly managed.
Adverse reactions to MMR

Fever of 39.4°C (103°F) or higher may develop in 5-15% of vaccine recipients from 5-12 days after immunization.

Rash develops in 5% of patients 7-10 days after vaccination.

Mild lymphadenopathy is common.

Joint pain is observed in 0.5% of young children.

Arthralgia is experienced in 25% of females who are past puberty.

Transient arthritis occurs in 10% of females who are past puberty.

Joint complaints occur approximately 7-21 days following MMR vaccination.

Rare cases of transient peripheral neuritic symptoms, such as paresthesia and pain in the arms and legs, have been reported.

Transient and benign thrombocytopenia within 2 months of immunization has been reported in 1 per 25,000-40,000 immunized children.

CNS manifestations have also been reported, but no causal relationship with rubella vaccine has been demonstrated.
Complications:


Joint involvement: Arthralgia and arthritis are the most common complications of rubella in adolescents and adults. Females are affected 4-5 times more frequently than males. The joints are involved in up to one third of adult women; the fingers, wrists, knees, and ankles are the most frequently involved. Massive effusions often accompany rubella arthritis, and symptoms may persist for 10-14 days. Arthralgia usually begins with the onset of the rash and clears without sequelae within 2-30 days.
Thrombocytopenia: This is a rare complication, occurring in 1 per 3000 cases. Children are affected more frequently than adults, and girls are affected more often than boys. It is self-limited and lasts from a few days to several months.
Neurologic manifestations: Encephalitis is a rare complication and occurs with greater frequency in children. It occurs in 1 per 5000 cases and usually is observed 2-4 days after the onset of rash. In some patients, encephalitis may accompany the rash or be delayed as much as 1 week after onset of the exanthem. Cerebrospinal fluid examination usually shows mild pleocytosis (20-100 WBC/mm3) with predominance of lymphocytes. Glucose level is usually normal, while protein levels may be normal or slightly elevated. Rubella encephalitis usually resolves with little or no significant neurologic sequelae.
Mild hepatitis has been a rarely reported complication of acquired rubella.
Prognosis:


The prognosis of postnatal rubella is good with full recovery, while congenital rubella syndrome may have a poor outcome with severe multiple-organ damage.
Patient Education:


All pregnant women should avoid any contact with persons infected with rubella.
All susceptible individuals should be immunized.
No special precaution is necessary in the household setting of a child with congenital rubella syndrome, although parents should be counseled regarding potential serious risk to pregnant women exposed to the child.
For excellent patient education resources, visit eMedicine's Children's Health Center and Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Measles; Skin Rashes in Children; and Immunization Schedule, Children.
MISCELLANEOUS Section 9 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography




Medical/Legal Pitfalls:


Failure to diagnose rubella in an infected person may result in a potential outbreak among susceptible persons.
Failure to diagnose rubella in women early in pregnancy and offer the option of therapeutic abortion may result in development of congenital rubella syndrome in their infants.
Failure to provide adequate vaccination to susceptible persons increases their risk of acquiring the infection.
Special Concerns:


Care of women who are pregnant and exposed to rubella virus
If a pregnant woman is exposed to rubella virus in the first trimester of gestation, serologic investigation should be performed promptly.

A blood sample should be obtained as soon as possible and tested for rubella antibody. An aliquot of frozen serum should be stored for possible repeated testing later to determine any rise in titers. If the woman has rubella-specific IgG antibody in a properly performed test at the time of exposure, she is immune. It is highly unlikely that her pregnancy will be complicated with congenital rubella syndrome. However, some authorities would retest her in 2-3 weeks because maternal reinfection complicated with congenital rubella syndrome has been very rarely reported in the literature.

If antibody is not detectable in the initial sample, a second serum specimen should be collected 2-3 weeks later and tested concurrently with the first serum sample in the same laboratory. If the second test result is again negative, another serology is warranted 6 weeks after exposure and is tested concurrently with the first specimen. A negative test result in both specimens indicates that infection has not occurred. A positive test result in the second and not the first (seroconversion) indicates recent infection.

The options for a woman exposed to rubella in early pregnancy include pregnancy termination for confirmed infection or administration of IG if termination is not acceptable under any circumstances.
Postexposure prophylaxis during pregnancy
IG administered to a pregnant woman following exposure to rubella is controversial and may not prevent infection of the fetus. The IG may modify the clinical manifestations in the mother without diminishing the viral replication and, therefore, leave the fetus unprotected.

Because infants with congenital rubella syndrome have been born to women who received passive immunoprophylaxis shortly after exposure, rubella IG postexposure prophylaxis in pregnancy is not recommended.

The CDC recommends that IG be used only if a susceptible pregnant woman who has been exposed to rubella will not consider pregnancy termination under any circumstances.

Whether a higher dose of IG given intravenously is useful to prevent congenital rubella syndrome is unknown.
Consequence of RA 27/3 rubella vaccine administered inadvertently during the first trimester of pregnancy
Concern exists that RA 27/3 rubella vaccine, licensed in the United States in 1979, might have a greater teratogenic and fetotropic potential than earlier vaccines. However, no evidence indicates that the vaccine caused congenital rubella syndrome or any fetal abnormalities in the offspring of the 272 susceptible women who inadvertently received RA 27/3 vaccine within 3 months of their pregnancy from 1979-1988. Similarly, data collected before 1979 have shown no cases of congenital rubella syndrome in the offspring of women who were unknowingly immunized with other types of rubella vaccines during the first trimester of gestation.

Notwithstanding this evidence, recommended guidelines continue to state that pregnancy is a contraindication to the administration of rubella vaccines because vaccine viruses can cross the placenta barrier and infect the fetus.

Inadvertent vaccination of pregnant women during early pregnancy should not be a reason to consider interruption of pregnancy because no teratogenic effects attributable to rubella vaccines have been reported.
Rubella reinfection
Reinfection is a rubella infection occurring in an individual known to be immune to rubella either through naturally acquired disease or as a result of immunization against rubella infection. Rubella reinfection is estimated to occur in 5-10% of persons previously immune to rubella. It is usually subclinical but occasionally may be clinically apparent.

Maternal reinfection is uncommon but can occur, and, as noted above, congenital rubella syndrome occurring after maternal reinfection has been rarely been reported in the literature, especially after a clinically apparent rubella reinfection. Thus, all pregnant women should avoid rubella exposure.
Provided that appropriate sera are taken, a primary rubella infection can usually be distinguished from a reinfection on the basis of serologic response at the time of reinfection. In both primary infection and reinfection, a significant rise occurs in rubella-specific IgG antibody, but in a primary infection, a strong IgM antibody response also occurs and persists for approximately 4-12 weeks. In reinfection, IgM antibody either is not produced or found only in low concentrations. Thus, reinfection can be diagnosed if the initial sample taken at the moment of rubella exposure is IgG positive, implying rubella immunity, and a significant rise in rubella-specific IgG with a negative or low rubella-specific IgM antibody titer is demonstrated in a subsequent serum sample collected about 2 weeks later.
PICTURES Section 10 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography



Caption: Picture 1. Number of rubella cases per year.
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Caption: Picture 2. Number of congenital rubella syndrome cases per year.
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Caption: Picture 3. Deaths from rubella per year.
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BIBLIOGRAPHY Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography





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Rubella excerpt