Pediatric Rubella: Background, Etiology, Pathophysiology (original) (raw)

Overview

Background

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. (See the image below.) For example, infection in younger children is characterized by mild constitutional symptoms, rash, and suboccipital adenopathy; however, 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.

Image in a 4-year-old girl with a 4-day history of low-grade fever, symptoms of an upper respiratory tract infection, and rash. Courtesy of Pamela L. Dyne, MD.

The major complication of rubella is its teratogenic effects when pregnant individuals 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.

Etiology

Rubella and congenital rubella syndrome are caused by rubella virus. Only one antigenic type of rubella virus is available, 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 RNA.

Its outer envelope is made up of glycosylated lipoprotein, which contains two virus-specific polypeptides (E1, E2) and a host-cell–derived lipid. These two envelope proteins comprise the spiked 5-nm 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-inhibiting 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°C to -20°C). It is resistant to thimerosal and is stable at temperatures of -60°C or less.

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 (CSF), 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.

Epidemiology

United States statistics

During the 1962-1965 worldwide epidemic, an estimated 12.5 million rubella cases occurred in the United States, 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. For the 2024-2025 school year, the estimated vaccination coverage for measles, mumps, and rubella (MMR) among kindergartners in the United States is 92.5%. [1]

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 reported in the United States. (See the image below.) In 1969, a total of 57,686 cases of rubella and 31 cases of congenital rubella syndrome were recorded. In contrast, from 2005 to 2022, the median number of rubella cases reported each year in the United States was six. [2]

Number of rubella and congenital rubella syndrome (CRS) cases — United States, 1966–2011. Courtesy of Centers for Disease Control (CDC).

An independent panel convened by the Centers for Disease Control and Prevention (CDC) in 2004 to assess progress toward elimination of rubella and congenital rubella syndrome 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. Furthermore, an expert panel reviewed available data and unanimously agreed in 2011 that rubella elimination has been maintained in the United States. Rubella elimination is defined as the absence of endemic rubella transmission. [3]

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 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.

International statistics

Rubella occurs worldwide. The number of reported cases is highest in countries where routine rubella immunization is either not available or was recently introduced.

In 2020, global rubella vaccine coverage was estimated to be 70%, and by 2022, 51% of countries had eliminated rubella. [4, 5] However, about 100,000 cases of congenital rubella syndrome are estimated to occur each year in low- and middle-income countries, particularly in Africa and Southeast Asia. [6]

Race-, sex-, and age-related demographics

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

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.

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.

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.

Morbidity/mortality

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 the image below).

Deaths from rubella per year.

In contrast to postnatal rubella, which is not a debilitating disease, congenital rubella infection may result in growth delay, learning disability, intellectual disability, 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 in the United States From 1969-2007 [7, 8, 9, 10] (Open Table in a new window)

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 complication is rare, occurring in 1 per 3000 cases. Children are affected more frequently than adults, and girls are affected more often than boys. The thrombocytopenia 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 (CSF) examination usually reveals mild pleocytosis (20-100 white blood cells [WBCs]/μL) with a predominance of lymphocytes. Glucose level is usually normal, whereas protein levels may be normal or slightly elevated. Rubella encephalitis usually resolves with little or no significant neurologic sequelae.

Hepatitis

Mild hepatitis is a rarely reported complication of acquired rubella.

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• Number of rubella cases per year.

• Number of congenital rubella syndrome cases per year.

• Deaths from rubella per year.

• Image in a 4-year-old girl with a 4-day history of low-grade fever, symptoms of an upper respiratory tract infection, and rash. Courtesy of Pamela L. Dyne, MD.

• Number of rubella and congenital rubella syndrome (CRS) cases — United States, 1966–2011. Courtesy of Centers for Disease Control (CDC).

• Congenital rubella syndrome. Newborn with blueberry muffin lesions on the forehead.

• Table 1. Reported Cases of Rubella, Deaths From Rubella, and Number of Cases of Congenital Rubella Syndrome in the United States From 1969-2007 [7, 8, 9, 10]

• Table 2. Clinicopathologic Abnormalities in Congenital Rubella

• Table 3. Age-Specific CD4+ T-lymphocyte Count and Percentage of Total Lymphocytes as a Criteria for Severe Immunosuppression in Persons with HIV

Table 1. Reported Cases of Rubella, Deaths From Rubella, and Number of Cases of Congenital Rubella Syndrome in the United States From 1969-2007 [7, 8, 9, 10]

Table 2. Clinicopathologic Abnormalities in Congenital Rubella

Table 3. Age-Specific CD4+ T-lymphocyte Count and Percentage of Total Lymphocytes as a Criteria for Severe Immunosuppression in Persons with HIV

Author

Elias Ezike, MD Consulting Staff, Beaumont Pediatric Center, PLLC

Elias Ezike, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Jocelyn Y Ang, MD, FAAP, FIDSA, FPIDS Clinical Professor of Pediatrics, Wayne State University School of Medicine; Professor of Pediatrics, Central Michigan University College of Medicine; Consulting Staff, Division of Infectious Diseases, Children's Hospital of Michigan

Jocelyn Y Ang, MD, FAAP, FIDSA, FPIDS is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Pfizer
Serve(d) as a speaker or a member of a speakers bureau for: Astellas
Received research grant from: JYA's institution (Central Michigan University) has received research grants from Astellas Pharma Global Development, Inc,Eli Lilly and Company and F. Hoffmann-LaRoche Ltd.

Pharmacy Editor

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Winthrop University Hospital; Professor of Pediatrics, Stony Brook University School of Medicine

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Peter C Lombardo, MD Associate Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Private Practice, Sutton Place Dermatology, PC

Peter C Lombardo, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Dermatologic Society of Greater New York, New York Academy of Medicine, New York State Society of Dermatology and Dermatological Surgery

Disclosure: Nothing to disclose.

Acknowledgements

Leslie L Barton, MD Professor Emerita of Pediatrics, University of Arizona College of Medicine

Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.