Rubella

Definition, Etiology, Pathogenesis Top

Rubella (German measles) is an acute systemic viral disease, typically accompanied by a generalized rash. Congenital rubella syndrome (CRS) is a constellation of congenital malformations in infants caused by maternal infection with rubella virus during the first 4 months of pregnancy. Congenital infection is possible after the first 4 months of pregnancy, but clinical manifestations are rare in this situation.

1. Etiologic agent: Rubella virus, which is a single-stranded RNA virus in the Togaviridae family. The virus infects the upper respiratory tract, spreads to the local lymph nodes, and replicates there, causing viremia. Rubella virus can infect the majority of cells and tissues (eg, lymphocytes, monocytes, conjunctiva, synovium, cervix, placenta).

2. Reservoir and transmission: Humans are the only reservoir for rubella virus. It is transmitted by respiratory droplets, direct contact with infectious material (particularly respiratory secretions, but also urine, blood, feces), and via the placenta (congenital infection).

3. Incubation and contagious period: The incubation period is from 14 to 23 days (usually 16-18 days). Rubella is most contagious from a few days before the appearance of rash until 7 days after the appearance of rash; however, viral shedding can occur up to 7 days before and 14 days after the appearance of rash. Congenitally infected infants can shed virus for a year or longer. Fetal infection occurs during primary viremia in the mother; the risk of infection is from 85% to 100% when the rash appears during the first 12 weeks of pregnancy; 54% when it appears in weeks 13 to 16; and 25% when it appears in weeks 17 to 22. Fetal involvement in the course of recurrent infection is possible, however the risk is very low.

Clinical Features Top

Rubella is frequently asymptomatic (in ~50% of patients) or manifests with minor symptoms. In other patients, the signs and symptoms appear in the following order (although some may be absent):

1. Prodromal signs and symptoms (persisting for a few days): Malaise, headache and myalgia, pharyngitis, rhinitis, dry cough, conjunctivitis (without photophobia), low-grade fever, loss of appetite.

2. Painful lymphadenopathy affecting the occipital, posterior auricular, posterior, or anterior cervical lymph nodes. It develops 1 day prior to the onset of rash and may be the only symptom of the disease. Lymphadenopathy persists for several weeks.

3. Rash: A variable generalized macular or maculopapular rash. Initially, it appears on the face (typically behind the ears) and trunk, then spreads to the extremities over 1 or 2 days. The rash on the face may look like that in measles (the lesions are confluent), but it also involves the skin between the nasolabial folds. The lesions on the trunk are similar to scarlet fever. The rash may be accompanied by pruritus. Lesions disappear after 2 to 3 days and do not leave discolorations; fine desquamation is possible.

4. Other (less common): Splenomegaly, pharyngitis, petechiae on the soft palate, transient hepatitis.

5. CRS: Clinical manifestations depend on the time of infection (the week of pregnancy), with more severe manifestations associated with infections early in gestation. Miscarriage is a frequent result of infection in the first few weeks. The following is a list of potential manifestations of CRS:

1) Intrauterine growth retardation.

2) Central nervous system: Meningoencephalitis, microcephaly, large anterior fontanelle, sensorineural hearing loss, developmental delays.

3) Ophthalmologic: Cataracts, infantile glaucoma, pigmentary retinopathy, microphthalmos.

4) Dermatologic: Dermal erythropoiesis (“blueberry muffin” syndrome).

5) Cardiac: Patent ductus arteriosus, peripheral pulmonary artery stenosis.

6) Respiratory: Interstitial pneumonitis.

7) Gastrointestinal: Hepatosplenomegaly, jaundice, hepatitis, diarrhea.

8) Other: Radiolucent bone lesions (in the long bones), adenopathy, hemolytic anemia, thrombocytopenia.

Diagnosis Top

Diagnosis of rubella made solely on the basis of the clinical presentation is highly unreliable. Therefore, laboratory diagnosis should be made particularly in suspected cases in pregnant women and newborn infants. In vaccinated patients (even with only 1 vaccine dose), rubella is unlikely.

Diagnostic Tests

1. Serology (enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence) is the key method of confirming the diagnosis of an acquired infection that is used in epidemiologic investigations:

1) Rubella-specific serum IgM antibodies (false-positive and false-negative results are possible) appear on day 2 after the onset of the rash, persist for ~1 month, and reappear in the case of reinfection.

2) A more than 4-fold increase in rubella-specific serum IgG antibodies over a period of 2 to 4 weeks or seroconversion between acute and convalescent serum titers are both diagnostic of postnatal infection. Stable IgG titers indicate a history of infection and a resulting immunity.

2. Isolation of the virus (culture) or viral RNA (reverse transcriptase–polymerase chain reaction [RT-PCR]) from various specimens: throat or nasopharynx, urine, blood, or cerebrospinal fluid; this is particularly useful in diagnosing CRS.

Differential Diagnosis

Other diseases associated with a generalized rash:

1) Infections: Measles, scarlet fever (group A streptococcus), enteroviruses, adenoviruses, parvovirus B19, Epstein-Barr virus, Mycoplasma.

2) Noninfectious diseases: Drug-induced and allergic reactions.

Congenital infections that can have similar presentations as CRS: Cytomegalovirus, toxoplasmosis, herpes simplex virus, HIV, syphilis, lymphocytic choriomeningitis virus, Chagas disease (Trypanosoma cruzi).

Treatment Top

Antiviral Treatment

No specific antiviral treatment is available.

Symptomatic Treatment

Treatment is symptomatic only:

1) Arthritis: Nonsteroidal anti-inflammatory drugs (NSAIDs).

2) Clinically significant thrombocytopenia: Prednisone (1 mg/kg) or platelet concentrates.

Complications Top

1. Arthritis: More common in adolescents and adults, particularly in girls and young women (prevalence, 1%-25%). Arthritis may develop at the end of the rash phase and up to several weeks after its resolution; it predominantly involves small joints of the hand and wrist, less commonly other joints (eg, the knee). The symptoms persist for 5 to 10 days (rarely extending to several weeks) and resolve spontaneously without sequelae.

2. Thrombocytopenia (incidence <1/3000): Persists for several days (rarely up to 6 months), resolves spontaneously.

3. Encephalitis (incidence, 1/5000): Develops within 7 days of the onset of rash and usually resolves within a week without sequelae. Prognosis is good. Mortality rates are low.

4. Other (rare): Myocarditis, optic neuritis, Guillain-Barré syndrome, bone marrow aplasia.

Prognosis Top

The prognosis in patients with acquired rubella is good; the vast majority acquires lifelong immunity. CRS is associated with worse outcomes (mortality rates are >15%; complications include psychomotor developmental delay, malformations, and other permanent sequelae).

Prevention Top

Specific Prevention

1. Vaccination is the key prevention method (see Vaccines: Measles, Mumps, and Rubella).

2. Passive immunoprophylaxis (immunoglobulin) is controversial and may be used in exceptional situations. In particular, immunoglobulin may be considered as postexposure prophylaxis for susceptible women who have had exposure early in pregnancy, although the efficacy of this intervention is not clear.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the lack of experimental studies. Peckham CS. Clinical and serological assessment of children exposed in utero to confirmed maternal rubella. Br Med J. 1974 Feb 16;1(5902):259-61. PubMed PMID: 4818181; PubMed Central PMCID: PMC1633174.

Nonspecific Prevention 

1. Isolation of hospitalized patients (particularly from women of childbearing age): Acquired rubella: droplet isolation for up to 7 days after the appearance of the rash; congenital rubella: contact isolation of children until at least 12 months of age, or until after 3 months of age if no virus was isolated from the nasopharynx and urine on 2 subsequent occasions.

2. Serologic screening of young unvaccinated women (for whom vaccination records are not available): Prompt vaccination of patients with negative specific IgG unless they are known to be pregnant.

3. Prenatal screening of women: If routine prenatal screening identifies a woman as nonimmune, she should be provided with vaccination immediately after birth (prior to discharge).