Measles, German (Rubella)

Cody D. Mead, DO and Jeffrey M. Milch, DO, CPT, MC, FS, USA Reviewed 06/2017
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Subject: Measles, German (Rubella)

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BASICS

DESCRIPTION

  • A generally self-limited viral infection of children and adults, characterized by a mild, maculopapular rash, lymphadenopathy, and slight fever. Complications in normal populations are rare; however, nonimmune women who become infected with rubella while pregnant may have devastating fetal effects.

  • 25-50% of all rubella infections are asymptomatic 1,2[A].

  • System(s) affected: hematologic; nervous; pulmonary; exocrine; ophthalmologic; skeletal

  • Synonym(s): German measles; 3-day measles

Pregnancy Considerations

  • Pregnancy-associated rubella infection may lead to congenital rubella syndrome (CRS) with potentially devastating fetal outcomes.

  • CRS is present in up to 90% of fetuses exposed during the 1st trimester 2[A].

  • Screening pregnant women for rubella immunity and vaccinating nonimmune women is the most effective means to prevent CRS 2[A].

  • Although no case of vaccine-associated CRS has been reported, women should not become pregnant for at least 28 days after vaccination because vaccine-type virus can cross the placenta 2[A].

  • Polymerase chain reaction (PCR) detection of viral RNA in amniotic fluid and fetal blood sampling allow for rapid diagnosis of fetal infection after 15 weeks' gestation 3[B].

EPIDEMIOLOGY

  • 50- to 70-nm RNA togavirus of genus Rubivirus1[A]

  • 13 genotypes have been identified 4[A].

  • A live attenuated vaccine has been available in United States since 1969—primarily to prevent CRS.

  • Since 2004, all cases of rubella in United States have been imported, typically in travelers with inadequate immunity 1[A].

  • Average incubation: 14 days; range 12 to 23 days

  • Infectious period between 7 days before and 5 to 7 days after rash onset

  • Transmitted primarily via respiratory droplets

  • Most common in late winter and early spring

  • Humans are only natural hosts 1[A].

Incidence

  • U.S. incidence: ≪10/100,000 since 2001

  • Declared eliminated (the absence of endemic transmission for 12 months or more) from the United States in 2004. However, primarily due to disease in international travelers, ≪10 cases are still reported in the United States annually 1[A].

  • Still occurs in developing countries with 100,000 cases of CRS reported annually worldwide

ETIOLOGY AND PATHOPHYSIOLOGY

  • Virus invades the respiratory epithelium, replicates in nasopharynx and regional lymph nodes, and spreads hematogenously. Infected patients shed virus from the nasopharynx 3 to 8 days after inoculation. Shedding lasts 7 or more days after onset of rash.

  • Disease typically progresses from a prodromal stage (1 to 5 days) to lymphadenopathy (5 to 10 days) to an exanthematous, pruritic, maculopapular rash. Petechiae on the soft palate (Forchheimer spots), may precede or accompany the rash. Rash starts on the face and spreads outward to the trunk and extremities, sparing the palms and soles (14 to 17 days after onset of prodromal symptoms). The rash typically lasts an average of 3 days.

  • Rubella first described by German scientists in the early 1800s as a variant of measles or scarlet fever

  • 1962 to 1965: global pandemic resulting in an estimated 12.5 million cases in the United States, with 2,000 cases of encephalitis; 11,250 cases of therapeutic or spontaneous abortions; 2,100 neonatal deaths; and 20,000 infants born with CRS 1[A]

Genetics

Children with CRS and children with type 1 diabetes share a high frequency of HLA-DR3 histocompatibility Ag and a high prevalence of islet cell Ab. 

RISK FACTORS

Inadequate immunization, inadequate immunity after prior vaccination, immunodeficiency states, immunosuppressive therapy, crowded living/working conditions, international travel 1[A

GENERAL PREVENTION

  • Vaccination is the most effective preventive strategy.

  • Available combined with measles and mumps (MMR) or with varicella (MMR-V). Isolated rubella vaccine is not available in the United States.

    • ▪ Adults: 1- or 2-dose MMR vaccine schedule is recommended for those born after 1957. When 2 doses are used, each must be ≥28 days apart.
    • ▪ Pediatric: A 2-dose MMR vaccine schedule is recommended with the 1st dose given at ages 12 to 15 months; 2nd dose recommended either at 4 to 6 years or at 11 to 12 years of age.
    • ▪ Special pediatric cases: In special circumstances (e.g., upcoming international travel), the second dose may be given prior to 4 years of age, but no sooner than 28 days since the initial dose. Children 6 to 11 months of age may also receive a single dose prior to international travel but should be revaccinated with full 2-dose schedule starting at 12 months of age. Children with HIV should receive MMR vaccine at 12 months of age if no contraindications exist. In the event of an outbreak, immediate vaccination of infants 6 to 11 months old is also recommended 2[A].
    • ▪ Vaccination is recommended for nonimmune people in the following groups: prepubertal boys and girls, all women of reproductive age, college students, daycare personnel, health care workers, and military personnel.
  • Contraindicated: pregnancy, immunodeficiency (except HIV infection), within 3 months of IVIG or blood administration, severe febrile illness, or hypersensitivity to vaccine components. Patients who receive rubella vaccine do not transmit rubella to others, although the virus can be isolated from the pharynx. Breastfeeding is not a contraindication to vaccination 1[A].

  • During outbreaks, serologic screening before vaccination is NOT recommended because rapid mass vaccination is necessary to stop disease spread 2[A].

  • The MMR vaccine is not associated with autism4[A],5[B].

  • Children who receive the MMR-V vaccine have a 2-fold increase in risk of febrile seizures compared with those who receive MMR and varicella vaccines separately 5[B].

  • Routine rubella antibody (IgG) screening is recommended during pregnancy 4[A].

DIAGNOSIS

Council of State and Territorial Epidemiologists (CSTE) Case Definition Classifications of Rubella 1[A
  • Clinical case definition

    • ▪ Acute onset of pink, coalescent macules on the face spreading to the trunk and extremities, becoming discrete macules then fading in previously affected areas, on average, within 3 days
    • ▪ Temperature >99ºF (37.2ºC; if measured)
    • ▪ Arthralgia or arthritis, lymphadenopathy, or conjunctivitis
  • Laboratory criteria for diagnosis

    • ▪ Isolation of virus from throat or nasopharynx, serum, CSF, urine, or cataracts (postmortem)
    • ▪ 4-fold rise in acute- and convalescent-phase titers of serum IgG Ab
    • ▪ Positive serologic test for IgM Ab
    • ▪ PCR positive for virus

HISTORY

  • Most cases of postnatal rubella are due to inadequately immunized travelers returning from endemic areas.

  • Rubella can spread quickly among persons residing in close quarters.

  • Postnatal rubella: low-grade fever, lymphadenopathy (postcervical, occipital, and postauricular), sore throat, nausea, anorexia, arthritis, arthralgia, malaise. 25-50% are asymptomatic.

  • CRS: parental concerns about hearing or vision impairment, jaundice, or developmental delay

  • Deafness could be the only manifestation and not be noticed until 2nd year of life 2[A].

PHYSICAL EXAM

  • Postnatal rubella: low-grade fever, lymphadenopathy (posterior auricular, occipital, posterior cervical), exanthem (mild, pink, discrete 1- to 4-mm maculopapular rash), soft palate petechiae (Forchheimer sign) (20%) 1[A]

  • CRS: microcephaly, large anterior fontanelle, sensorineural hearing loss (58%), cataracts, glaucoma, microphthalmia, pigmentary retinopathy, purpuric (“blueberry muffin”) skin lesions, murmur (50%) consistent with patent ductus arteriosus (PDA), hepatosplenomegaly, jaundice, cryptorchidism, inguinal hernia, radiolucent bone disease 2[A]

DIFFERENTIAL DIAGNOSIS

  • Postnatal rubella

    • ▪ Measles virus (rubeola)
    • ▪ Scarlet fever (strep A)
    • ▪ Infectious mononucleosis
    • ▪ Erythema infectiosum (parvovirus B19)
    • ▪ Roseola infantum (i.e., exanthem subitum)
    • ▪ Toxoplasmosis
    • ▪ Drug eruptions
    • ▪ Other exanthematous enteroviral infections
  • Congenital rubella

    • ▪ Measles
    • ▪ Parvovirus B19
    • ▪ Human herpesvirus 6
    • ▪ Other exanthematous entero- or arboviruses

DIAGNOSTIC TESTS & INTERPRETATION

  • Because 50% of cases are subclinical, laboratory testing is preferred to confirm the diagnosis 1,2[A].

  • Detection of wild-type virus is gold standard 1[A].

  • Enzyme immunoassay (EIA): preferred testing for IgM antibodies, which may not be detectable before 5 days after the onset of rash 1[A]

  • Hemagglutination inhibition (HAI) test: A 4-fold increase of IgG Ab levels from acute to convalescent phase is diagnostic for recent infection 1[A].

  • Latex agglutination (LA) test: sensitive and specific but dependent on experience of lab personnel 1[A]

  • Immunofluorescent antibody (IFA) assay: used for detection of viral IgG and IgM Ab 1[A]

  • Avidity test: not routinely used. Should only be performed in reference labs. Used to distinguish between recent and past infections 1[A]

  • Most rubella cases are virus positive on the day of the rash onset and remain positive for the following 7 to 10 days. Serum collection should be performed during this period. When testing for IgM, repeat collection may be necessary if the sample was taken before day 5. When testing for seroconversion, a 2nd IgG sample should be collected 2 to 3 weeks after the first (acute to convalescent phase). In most cases, IgG is detectable 8 days after rash onset 1[A].

  • Virus may also be isolated from 1 week prior to 2 weeks after the onset of rash. Maximal viral shedding occurs up to day 4 after rash onset. Best results are from throat swab samples 1[A].

  • Epidemiologically, viral genotyping by reverse transcription (RT)-PCR helps determine the country of origin. Throat swabs should be collected 4 days after the rash onset and sent to the CDC 1[A].

  • Viral cultures of CSF are reserved for suspected cases of CRS or rubella encephalitis 1[A].

  • If a pregnant female is exposed, amniotic fluid PCR or fetal blood sampling may be done at 15 weeks' gestation for viral detection. Placental biopsy (less common) may be done at 12 weeks' gestation. If positive, offer genetic counseling 1[A].

  • As the incidence of rubella decreases, the positive predictive value (PPV) of IgM results decreases. False-positive findings occur in patients with parvovirus B19, mononucleosis, and positive rheumatoid factor 1[A].

  • After reexposure, a person with a low level of Ab from past infection or prior vaccination may experience an acute, small rise in Ab levels. This is not associated with a high risk of contagion to others or fetal complications 1[A].

Initial Tests (lab, imaging)

Follow-Up Tests & Special Considerations
  • Reporting: state-dependent. Samples should be sent to the CDC for genotyping. Cases of CRS are reported to the National Congenital Rubella Syndrome Registry 1,2[A].

  • Infants with CRS may shed virus up to 1 year. Observe contact isolation during all hospitalizations until child turns 1 year old (unless child has two negative throat cultures and urine specimens a month apart after 3 months of age) 2[A].

TREATMENT

  • Supportive for mild cases

  • Isolate patients for 5 to 7 days after rash onset.

  • Postnatal rubella: mild and self-limited; treat symptomatically. Hospitalize for complications: idiopathic thrombocytopenic purpura (ITP) or encephalitis 1[A].

  • CRS: supportive care unless neurologic or hemorrhagic complications develop; phototherapy may be indicated for jaundice; multidisciplinary management of long-term complications 2[A]

MEDICATION

No specific therapy available for mild cases. 

First Line

  • Age- and dose-appropriate antipyretics

  • NSAIDs can be used for arthritis and arthralgias in adults and infants age >6 months.

  • IVIG can be given for severe thrombocytopenia; most cases, however, are self-limited.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Individuals immune to rubella through natural infection or vaccine may be reinfected when reexposed; such infection is usually asymptomatic and detectable only by serology. Those who have received the vaccine have lower measurable IgG levels than those who had the natural disease.

  • In CRS, it is important to detect auditory and visual impairment early 2[A].

  • 2/3 of internationally adopted children have no written record of immunizations 4[A].

PATIENT EDUCATION

http://www.cdc.gov/rubella/ 

PROGNOSIS

  • Postnatal rubella: Complete recovery is typical.

  • CRS

    • ▪ Varied and unpredictable spectrum, ranging from stillbirth to normal infancy/childhood 1,2[A]
    • ▪ Detectable levels of IgG persist for years and then may decline (does not drop at the expected 2-fold dilution/month). By age 5 years, 20% have no detectable antibody 2[A].
    • ▪ IgM may not be detectable until 1 month after birth and may persist for 6 to 12 months 2[A].
    • ▪ Overall mortality (up to 10%) is greatest during first 6 months.
    • ▪ 70% of encephalitis cases develop residual neurologic defects, including autistic syndrome.
    • ▪ Prognosis is excellent if only minor congenital defects are present.

COMPLICATIONS

  • Frequently leads to arthralgia/arthritis in women (up to 70%) 6

  • Postinfectious encephalitis (1/5,000 cases)

  • Thrombocytopenic purpura (1/3,000 cases)

  • CRS: incidence dependent on trimester exposed

  • Rubella vaccine may rarely cause encephalitis or ITP.

    • ▪ ITP is self-limited and is not a contraindication to vaccination.

REFERENCES

Centers for Disease Control and Prevention. Chapter 14: rubella. In: McLean  H, Redd  S, Abernathy  E, et al, eds. Manual for the Surveillance of Vaccine-Preventable Diseases. 5th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/vaccines/pubs/surv-manual/chpt14-rubella.html. Accessed July 29, 2016.
Centers for Disease Control and Prevention. Chapter 15: congenital rubella syndrome. In: McLean  H, Redd  S, Abernathy  E, et al, eds. Manual for Surveillance of Vaccine—Preventable Diseases. 5th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html. Accessed July 29, 2016.
Abernathy  ES, Hubschen  JM, Muller  CP, et al. Status of global virologic surveillance for rubella viruses. J Infect Dis.  2011;204(Suppl 1):S524–S532.  [View Abstract]
McLean  HQ, Fiebelkorn  AP, Temte  JL, et al. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep.  2013;62(RR-04):1–34.  [View Abstract]
Lai  J, Fay  KE, Bocchini  JA. Update on childhood and adolescent immunizations: selected review of US recommendations and literature: part 2. Curr Opin Pediatr.  2011;23(4):470–481.  [View Abstract]
White  SJ, Boldt  KL, Holditch  SJ, et al. Measles, mumps, and rubella. Clin Obstet Gynecol.  2012;55(2):550–559.  [View Abstract]

ADDITIONAL READING

  • Centers for Disease Control and Prevention. Rubella. In: Atkinson W, Wolfe C, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2012:325–340. www.cdc.gov/vaccines/pubs/pinkbook/rubella.html. Accessed January 21, 2016.

  • Mongua-Rodriguez N, Díaz-Ortega JL, García-García L, et al. A systematic review of rubella vaccination strategies implemented in the Americas: impact on the incidence and seroprevalence rates of rubella and congenital rubella syndrome. Vaccine.  2013;31(17):2145–2151.

CODES

ICD10

  • B06.9 Rubella without complication

  • B06.00 Rubella with neurological complication, unspecified

  • P35.0 Congenital rubella syndrome

  • B06.89 Other rubella complications

  • O35.3XX1 Maternal care for (suspected) damage to fetus from viral disease in mother, fetus 1

  • B06.01 Rubella encephalitis

  • B06.82 Rubella arthritis

ICD9

  • 056.9 Rubella without mention of complication

  • 056.00 Rubella with unspecified neurological complication

  • 771.0 Congenital rubella

  • 056.79 Rubella with other specified complications

  • 655.30 Suspected damage to fetus from viral disease in the mother, affecting management of mother, unspecified as to episode of care or not applicable

SNOMED

  • 36653000 Rubella (disorder)

  • 111868009 Rubella infection of central nervous system

  • 1857005 Congenital rubella syndrome (disorder)

  • 84611003 Rubella with complication (disorder)

  • 312657007 Maternal care for damage to fetus from maternal rubella (disorder)

CLINICAL PEARLS

  • Rubella is typically a self-limited viral exanthematous infection of children and adults.

  • Nonimmune women who are infected with rubella while pregnant may have devastating fetal effects (CRS).

  • Immunization is the key prevention strategy.

 
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