Rubella Virus

Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family and the Rubivirus genus. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Congenital rubella is particularly devastating and is associated with a classic triad of symptoms: cataracts, cardiac defects, and deafness. Infection in children and adults may be mild and present with constitutional symptoms along with a viral exanthem resembling the measles virus. Diagnosis is made clinically and confirmed with serum virus detection and serologic studies. Treatment is supportive and may be targeted depending on the organ system involved. Prevention is achieved through childhood vaccination with the measles, mumps, and rubella (MMR) vaccine.

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Classification

Rna viruses flowchart classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Serotypes, lineages, and strains:

  • Togaviridae family: Rubella is the only togavirus using humans as the sole, natural host.
  • Rubivirus genus: Rubella virus is the only member of the Rubivirus genus.
  • Serotype:
    • A serotype is defined by the number and type of surface antigens a microorganism possesses.
    • Only 1 genetically stable rubella serotype has been identified. 
  • Lineage:
    • A lineage is a collection of variants defined by novel mutations delineating a specific genetic line of the virus.
    • At least 3 distinct lineages have arisen from the single rubella serotype.
  • Strain:
    • A strain is a lineage acquiring new properties as a result of the mutations defining the lineage.
    • Multiple strains of the rubella virus are characterized by different antigenicities, which are the ability of antigens to bind to antigen receptors on an antibody or T cell.

Rubella virion

Structure:

  • Spherical
  • 40–80 nm in diameter
  • The lipoprotein envelope contains 2, spike-forming, membrane glycoproteins:
    • E1 mediates viral hemagglutination and neutralization.
    • E2 has 2 subtypes:
      • E2a and E2b
      • E2 glycoprotein variations confer the differences between rubella strains.
    • Spikes also contain hemagglutinin epitopes, which cause RBCs to clump together (hemagglutination).
  • A 30–35 nm electron-dense core:
    • Positive-sense, single-stranded RNA
    • Capsid protein C surrounds the RNA.

Rubella genome

  • Only a single, stable rubella serotype has been identified.
  • Very little variation between strains of rubella virus 
  • Suggestive of a low rate of mutation during viral replication
  • The strains are readily identified worldwide, which suggests constant cocirculation of lineages.
Electron micrograph of rubella virus

Electron micrograph of virions of the rubella virus

Image: “This transmission electron microscopic (TEM) image revealed the presence of rubella virus virions” by CDC. License: Public Domain

Epidemiology and Pathogenesis

Epidemiology

  • 1964–1965: Over 12 million cases of rubella and 20,000 cases of congenital rubella are recorded in the United States.
  • 1969: vaccine introduced in the United States → cases dropped to 0.5 cases per 100,000
  • 1990–1991: resurgence outbreaks in California and Pennsylvania
  • 2004: rubella eliminated from the United States due to the measles, mumps, rubella (MMR) vaccine
  • 2018: 14,621 cases globally
  • 2019: 168 countries with established vaccination programs

Transmission

  • Respiratory droplets:
    • Direct or droplet contact with respiratory secretions of infected patients
    • The virus replicates in the cells of the respiratory tract.
    • Viral shedding from the respiratory tract may continue for up to 6 weeks after the initial infection.
    • Relatively low infectivity and virulence
  • Vertical (mother to child):
    • During the 1st 3–4 months of pregnancy as one of the TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) infections:
      • TORCH infections may also include HIV or syphilis
      • Constitute the most common infections spread via vertical transmission
    • May occur during breastfeeding

Pathogenesis

Prenatal:

  • Direct viremia via placental transmission
  • Outcome depends on gestational age and is likely due to immature fetal host defenses.
  • Risk of infection and associated congenital defects decreases with gestational age:
    • 40%–60% chance if the mother is infected during the 1st 2 months of gestation
    • 30%–35% chance during the 3rd month of gestation
    • 10% chance during the 4th month of gestation
  • Virions may affect virtually any fetal organ system.

Postnatal:

Postnatal primary infections with rubella undergo a sequential pathogenic process:

  1. Inoculation through the respiratory tract
  2. Attachment to respiratory tract cell membranes (entry of the virion into the host cell occurs via transportation into endosomes)
  3. Multiplication in host cell cytoplasm over 2–3 weeks
  4. Exocytosis via an unclear mechanism
  5. Infiltration of local lymph nodes, causing constitutional symptoms and lymphadenopathy
  6. Development of viremia (virus is detected in the blood and respiratory secretions)
  7. Multiplication in the cells of other organs
  8. Development of fever and rash (rubella-specific IgM antibodies detected in the blood)
  9. Before rash resolution, disappearance of detectable virus in the blood as the antibodies surge
  10. IgG antibodies confer future immunity, but reinfection can occur.

Clinical Presentation

Congenital rubella

  • Congenital rubella syndrome with the classic triad:
    • Cataracts
    • Cardiac defects
    • Deafness
  • Congenital rubella infection (broader term to encompass all possible signs and symptoms of infection):
    • Ocular: cataracts, microphthalmia, glaucoma, and retinitis
    • Cardiovascular: patent ductus arteriosus, atrial septal defect, ventricular septal defect, and pulmonary artery stenosis
    • Central nervous system: intellectual disability, meningoencephalitis, microcephaly, and progressive rubella panencephalitis (rare)
    • Other: growth retardation, radiolucent bone disease, hepatosplenomegaly, thrombocytopenia, pneumonitis, diabetes mellitus, thyroiditis, petechiae, and purpura (a “blueberry muffin rash” due to extramedullary hematopoiesis in the skin)

Postnatal rubella

  • Incubation period of 2–3 weeks (may ultimately be asymptomatic (50% of cases))
  • Symptoms:
    • 1–2 weeks after exposure: headache, malaise, myalgias, lymphadenopathy, myalgias, and arthralgias
    • Up to 1 week after initial symptoms:
      • Fever and maculopapular rash
      • Exanthem: begins on the face and neck, spreads caudally
      • Resembles the exanthem of the measles virus
Exanthem of rubella virus infection

Typical exanthem of rubella infection:
Spread and distribution are similar to measles, however, the lesions are less intensely red and less confluent.

Image: “This photograph shows the appearance of the German measles (rubella) rash.” by Parker N et al. License: CC BY 4.0, cropped by Lecturio.

Diagnosis, Management, and Prevention

Diagnosis

Diagnosis is made clinically and confirmed with serum virus detection and serologic studies. 

  • Congenital infection commonly involves a triad of cataracts, cardiac defects, and deafness, which are detected in the newborn period.
  • Congenital infection can be confirmed in a newborn by viral detection from cord blood, nasopharyngeal secretions, or urine.
  • Congenital infection is more commonly confirmed using RT-PCR to detect rubella RNA in the amniotic fluid prior to birth.
  • The virus can also be detected from nasopharyngeal secretions of pregnant patients.
  • For postnatal cases, rubella-specific IgM antibodies can be detected using enzyme immunoassay as early as 4 days after the rash onset.

Management and prevention

Treatment is supportive and targeted based on the organ system involved. Prevention is achieved through MMR or MMRV (measles, mumps, rubella, varicella) vaccination.

  • 1st dose at 12–15 months of age, 2nd dose at 4–6 years of age for either vaccine
  • Infection confers immunity; however, cases of reinfection have been documented.

Comparison of Common Childhood Rashes

Table: Comparison of common childhood rashes
Number Other names for the disease Etiology Description
1st disease
  • Measles
  • Rubeola
  • 14-day measles
  • Morbilli
Measles morbillivirus
  • Cough, coryza, conjunctivitis
  • Koplik’s spots (blue-white spots with a red halo) on the buccal membrane
  • Maculopapular rash begins on the face and behind the ears → spreads to trunk/extremities
2nd disease
  • Scarlet Fever
  • Scarlatina
Streptococcus pyogenes
  • Sandpaper-feeling maculopapular rash that begins on the neck and groin → spreads to trunk/extremities
  • Dark, hyperpigmented areas, especially in skin creases, called Pastia’s lines
  • Strawberry tongue: coated white membrane through which swollen, red papillae protrude
3rd disease
  • Rubella
  • German measles
  • 3-day measles
Rubella virus
  • Asymptomatic in 50% of cases
  • Fine macular rash on the face (behind the ears) → spreads to the neck, trunk, and extremities (spares palms/soles)
  • Forscheimer’s spots: Pinpoint red macules and petechiae can be seen over the soft palate/uvula.
  • Generalized tender lymphadenopathy
4th disease
  • Staphylococcal scalded skin syndrome
  • Filatow-Dukes’ disease
  • Ritter’s disease
Due to Staphylococcus aureus strains that make epidermolytic (exfoliative) toxin
  • Some believe that 4th disease is a misdiagnosis and, thus, nonexistent.
  • The term was dropped in the 1960s and is only used for medical trivia today.
  • Begins with a diffuse erythematous rash that usually starts around the mouth → fluid-filled bullae or cutaneous blisters → rupture and desquamate
  • Nikolsky’s sign: Applying pressure on the skin with a finger (stroking) results in sloughing off of upper layers.
5th disease Erythema infectiosum Erythrovirus or parvovirus B19 (Primate erythroparvovirus 1)
  • Facial erythema (“slapped-cheek” rash) that consist of red papules on the cheeks
  • Begins on the face → spreads to the extremities → extends to trunk/buttocks
  • Initially confluent, then becomes net-like or reticular as it clears
6th disease
  • Exanthem subitum
  • Roseola infantum
  • Rose rash of infants
  • 3-day fever
Human herpesvirus 6B or 7
  • Sudden onset of high fever
  • Nagayama spots: papular spots on the soft palate/uvula
  • Rash begins as fever resolves (the term “exanthem subitum” describes “surprise” of rash after the fever subsides).
  • Numerous rose-pink, almond-shaped macules on the trunk and neck → sometimes spreads to face/extremities

References:

  1. Parkman PD. (1996). Togaviruses: Rubella Virus. In Baron S (Ed). Medical Microbiology. (4th ed). https://www-ncbi-nlm-nih-gov.online.uchc.edu/books/NBK8200/
  2. Frey TK. (1994). Molecular biology of rubella virus. Advances in virus research, 44, 69–160. https://doi-org.online.uchc.edu/10.1016/s0065-3527(08)60328-0
  3. CDC. Rubella. In: Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th Ed, Atkinson W, Wolfe C, Hamborsky (Eds), Public Health Foundation, Washington, DC 2011.
  4. WHO fact sheet. Rubella. http://www.who.int/en/news-room/fact-sheets/detail/rubella
  5. Grant GB, Desai S, Dumolard L, Kretsinger K, & Reef SE. (2019). Progress Toward Rubella and Congenital Rubella Syndrome Control and Elimination – Worldwide, 2000-2018. MMWR. Morbidity and mortality weekly report, 68(39), 855–859. https://doi-org.online.uchc.edu/10.15585/mmwr.mm6839a5
  6. Miller S. (2015). Paramyxoviruses and Rubella Virus. In Brooks JE, et al. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology. (27th ed). [VitalSource Bookshelf 9.4.3]. 
  7. Edwards MS. (2021). Rubella. UpToDate. Retrieved April 26, 2021, from https://www.uptodate.com/contents/rubella

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