Rubella and Rubeola Infections

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Rubella and Rubeola Infections

Learning Objectives

At the conclusion of this chapter, the reader should be able to:

• Describe the etiology and epidemiology of rubella (German measles) infection.

• Explain the signs and symptoms of acquired and congenital rubella infection.

• Compare the immunologic manifestations of acquired and congenital rubella infection.

• Explain the laboratory diagnostic evaluation of rubella infection.

• Summarize the epidemiology and laboratory diagnosis of rubeola (measles).

• Analyze a representative case study.

• Correctly answer case study related multiple choice questions.

• Be prepared to participate in a discussion of critical thinking questions.

• Describe the principle, results, limitations, and clinical applications of the passive latex agglutination test for Rubella.

• Correctly answer end of chapter review questions.

Key Terms

Rubella

Etiology of Rubella

The rubella virus was first isolated in 1962. Acquired rubella, also known as German measles or 3-day measles, is caused by an enveloped, single-stranded RNA virus of the Togaviridae family. Because the virus is endemic to human beings, the disease is highly contagious and is transmitted through respiratory secretions. Before widespread rubella immunization, this viral infection usually occurred in childhood, although it also affected adults.

Epidemiology of Rubella

Three strains of live, attenuated rubella vaccine virus were developed and first licensed for use in the United States in 1969. Before widespread rubella immunization in the United States and Canada, rubella infections occurred in epidemic proportion at 6- to 9-year intervals. In 1964, more than 20,000 cases of congenital rubella syndrome and an unknown number of stillbirths occurred in the United States as the result of an epidemic that year.

The Pan American Health Organization (PAHO) has made historic achievements in the elimination of measles (rubeola) and has announced a new effort to eliminate (rubella) German Measles. Many countries in the regions of the Americas have already made great progress in reducing the incidence of congenital rubella syndrome (CRS) through accelerated rubella control programs. Costa Rica, Honduras, Brazil, and Chile, as well as the member countries of the Caribbean, have rubella elimination initiatives underway.

In countries where vaccination is uncommon, the incidence of rubella infection is high and epidemics are frequent. Because vaccination programs have prevented the rubella epidemics that once gave people naturally acquired immunity, individuals who have not been vaccinated have a higher level of susceptibility to rubella infection. Primarily, two types of outbreaks have occurred in the United States in the fairly recent past, affecting the following groups:

The epidemiology of measles reveals two major impediments to measles elimination: (1) unvaccinated preschool-age children, a factor that allows large outbreaks; and (2) vaccine failures, which account for outbreaks in highly vaccinated school-age populations. On U.S. college and university campuses, the susceptibility to rubella infection among students is estimated to be as high as 20%. Many cases of rubella infection have been unrecognized or unreported because these cases are mild or subclinical.

Contracting the infection and vaccinating against rubella are the only routes to developing immunity. Individuals should be immune to rubella if they have a dated record of rubella vaccination on or after their first birthday, or if they have demonstrable rubella antibody. Even when antibody titers fall to relatively low levels, previous infection or successful vaccination appears to confer permanent immunity to rubella, except in cases of congenital rubella. The only proof of immunity is a positive serologic screening test result for rubella antibody. A history of rubella infection, even if verified by a physician, is not acceptable evidence of immunity.

It is critical to continue to determine the rubella immune status of women of childbearing age and to vaccinate those who are not immune. Individuals requiring rubella immune status determination include those in the following groups:

If the woman is not rubella immune, she should be vaccinated and advised not to become pregnant for 3 months because of the remote possibility that the vaccination could lead to an infected fetus.

A positive test confirms immunity, but to rule out any possibility of unsuspected current infection, an immunoglobulin M (IgM) screening procedure may also be ordered. If the patient is not rubella-immune, she should be cautioned to avoid exposure to rubella infection. Vaccination is contraindicated in pregnant women; however, a woman should be vaccinated immediately after termination of the pregnancy.

Men and women should be vaccinated to prevent possible spread of nosocomial infection to pregnant patients.

Adverse reactions to rubella vaccine have been reported. The Institute of Medicine has determined that a causal relationship exists between rubella vaccine and acute arthritis in adult females. There is weak but consistent evidence for a causal relationship between rubella vaccine and chronic arthritis in adult females. Incidence rates are estimated to average 13% to 15% in adult females after vaccination. Much lower levels of arthritic adverse reactions were noted in children, adolescents, and adult males. Reliable estimates of excess risk of chronic arthritis after rubella vaccination are not available.

Signs and Symptoms of Rubella Infection

A diagnosis of acquired rubella is not based solely on clinical manifestations. The signs and symptoms of rubella vary widely from person to person and may not be recognized in some cases, especially if the characteristic rash is light or absent, as may occur in a substantial number of cases. Rubella infection also may resemble other disorders, such as infectious mononucleosis and drug-induced rashes.

Acquired Rubella Infection

The incubation period of acquired rubella infection varies from 10 to 21 days, and 12 to 14 days is typical. Infected persons are usually contagious for 12 to 15 days, beginning 5 to 7 days before the appearance (if present) of a rash. Acute rubella infection lasts from 3 to 5 days and generally requires minimal treatment. Permanent effects are extremely rare in acquired infections.

The clinical presentation of acquired rubella is usually mild. The clinical manifestations of infection usually begin with a prodromal period of catarrhal symptoms, followed by involvement of the retroauricular, posterior cervical, and postoccipital lymph nodes, and finally by the emergence of a maculopapular rash on the face and then on the neck and trunk (Figs. 24-1 and 24-2). A temperature less than 34.4° C (94° F) is usually present. In older children and adults, self-limiting arthralgia and arthritis are common.

image
Figure 24-1 Rubella. (From Odom RB, James WD, Berger TG: Andrews’ diseases of the skin: clinical dermatology, ed 9, St Louis, 2000, Saunders.)
image
Figure 24-2 Rubella rash. (From Krugman S et al: Infectious diseases of children, ed 8, St Louis, 1985, Mosby.)

Congenital Rubella Infection

Rubella infection is usually a mild, self-limiting disease with only rare complications in children and adults. In pregnant women, however, especially those infected in the first trimester, rubella can have devastating effects on the fetus (Fig. 24-3). In utero infection can result in fetal death or manifest as rubella syndrome, a spectrum of congenital defects. About 10% to 20% of infants infected in utero fail to survive beyond 18 months.

image
Figure 24-3 Congenital malformations of rubella. (From Krugman S et al: Infectious diseases of children, ed 8, St Louis, 1985, Mosby.)

The point in the gestation cycle at which maternal rubella infection occurs greatly influences the severity of congenital rubella syndrome (Table 24-1); the extent of congenital anomalies varies from one infant to another. Some infants manifest almost all the defects associated with rubella, whereas others exhibit few, if any, consequences of infection. Clinical evidence of congenital rubella infection may not be recognized for months or even years after birth.

Table 24-1

Manifestation of Anomalies in Maternal Rubella

Period of Gestation Risk of Anomaly
Prospective Studies
First trimester ≈25%
Second trimester  
First month Less than (>)1%
Second month ≥25%
Third month ≥10%
Serologically Confirmed Cases of Maternal Infection
Before 11 wk 90%
11-12 wk 33%
13-14 wk 11%
15-16 wk 24%
After 16 wk 0%

image

Rubella syndrome encompasses a number of congenital anomalies. In addition to stillbirth, fetal abnormalities associated with maternal rubella infection include encephalitis, hepatomegaly, bone defects, mental retardation, cataracts, thrombocytopenic purpura, cardiovascular defects, splenomegaly, and microcephaly. Severely affected children are likely to have multiple defects in different organ systems. In neonates with congenital rubella syndrome, low birth weight and failure to thrive are common.

Rubella immunity develops in almost all children who have had congenital rubella. In late childhood, however, about one third of these patients lose antibody and become susceptible to acquired rubella. If acquired rubella occurs, it follows a typically benign course. Children with congenital rubella should be screened for rubella immunity in late childhood and vaccinated if necessary.

Immunologic Manifestations

Acquired Rubella Infection

In a patient with primary rubella infection, the appearance of both immunoglobulin G (IgG) and IgM antibodies is associated with the appearance of clinical signs and symptoms, when present.

The IgM antibodies become detectable a few days after the onset of signs and symptoms and reach peak levels at 7 to 10 days. These antibodies persist but rapidly diminish in concentration over the next 4 to 5 weeks, until antibody is no longer clinically detectable. The presence of IgM antibody in a single specimen suggests that the patient has recently experienced a rubella infection. In most cases, the infection probably occurred in the preceding month.

Production of IgG is also associated with the appearance of clinical signs and symptoms. Antibody levels increase rapidly for the next 7 to 21 days and then level off or even decrease in strength. IgG antibodies, however, remain present and protective indefinitely. Detection of IgG antibody is a useful indicator of rubella infection only when the acute and convalescent blood specimens are drawn several weeks apart. Optimum timing for paired testing in the diagnosis of a recent infection is 2 or more weeks apart, with the first (acute) specimen taken before or at the time signs and symptoms appear, or within 2 weeks of exposure.

Paired-specimen testing may demonstrate that the antibody levels are the same. In these cases, either the patient was previously immunized or the acute sample was taken after the antibody had already reached maximum levels. Demonstration of an unequivocal increase in IgG antibody concentration between the acute and convalescent specimens suggests a recent primary infection or a secondary (anamnestic) antibody response to rubella in an immune individual. In cases of an anamnestic response, IgM antibodies are not demonstrable, but IgG production begins quickly. No other signs or symptoms of disease are exhibited.

If both IgM and IgG test results are negative, the patient has never had rubella infection or been vaccinated. Such patients are susceptible to infection. If no IgM is demonstrable but IgG is present in paired specimens, the patient is immune.

When evaluating of the immune status of patients, IgG antibodies present in a dilution of 1:8 or higher indicate past infection with rubella virus and clinical protection against future rubella infection. The clinical significance of lower levels is not currently known. Titers of 1:16, 1:64, 1:512, or higher may be found in acute and past infections; however, the diagnosis of acute infection requires an IgM antibody titer on the same specimen or a paired-specimen comparison. It should be noted that IgM also appears for a transient period after vaccination.

Congenital Rubella Syndrome

Because IgG antibody is capable of crossing the placental barrier, there is no way of distinguishing between IgG antibody of fetal origin and IgG antibody of maternal origin in a neonatal blood specimen (Fig. 24-4).

image
Figure 24-4 Natural history of congenital rubella: pattern of virus excretion and antibody response. (Adapted from Krugman S et al: Infectious diseases of children, ed 9, St Louis, 1992, Mosby.)

Testing for IgM antibody is invaluable for the diagnosis of congenital rubella syndrome in the neonate. IgM does not cross an intact placental barrier; therefore, demonstration of IgM in a single neonatal specimen is diagnostic of congenital rubella syndrome. In the newborn, serologic confirmation of rubella infection can be made by testing for IgM antibody for at least the first 6 months of life. This is especially useful when clinical evidence of congenital rubella is slow in emerging or is of uncertain origin.

Diagnostic Evaluation

Several screening methods are available, including the TORCH (Toxoplasma, other [viruses], rubella, cytomegalovirus [CMV], and herpes) procedure (see Chapter 15). The assays for the determination of immune status and evidence of recent infection are presented in Table 24-2.

Table 24-2

Tests for Rubella Antibodies

Method Antibody Detected
TORCH antibodies IgM
TORCH antibodies IgG
Chemiluminescent immunoassay IgM
Chemiluminescent Immunoassay IgG
Immunochromatographic assay IgG
Indirect immunofluorescence assay (IFA) Monoclonal antibody (antibodies) to rubella virus virion proteins, E2 and C

Persons with infectious mononucleosis sometimes have rubella-specific IgM in low concentrations. Cross-reactions of rubella IgM-positive sera can result from parvovirus IgM. Occasionally, pregnant women will demonstrate IgM antibodies not only to rubella but also to CMV, varicella-zoster virus, and measles virus. In these patients, diagnosis of rubella can be made only by the assessment of rubella-specific IgG antibodies supported by a detailed clinical history.

Rubeola (Measles)

Rubella and Rubeola are two distinctly different infections. Rubeola is referred to as measles.

Measles is a highly contagious disease caused by the rubeola virus.

Epidemiology

Endemic or sustained measles transmission has not occurred in the United States since the late 1990s. The minimal number of cases yearly in the United States is due to the high rate of vaccination. Occasional small outbreaks from imported cases of measles primarily infects unvaccinated individuals.

Even though the ongoing transmission of endemic (native) measles was declared to be eliminated in the United States in 2000, the disease is still common in many other countries and can be imported into the United States by foreign visitors or returning travelers who are not fully protected against the disease. During 2001 to 2008, a median of 56 cases of measles were reported to the Centers for Disease Control and Prevention (CDC) annually. However, during the first 19 weeks of 2011, 118 cases of measles were reported, the highest number reported for this period since 1996. Of these cases, 87% were imported from the World Health Organization (WHO) European and Southeast Asia regions; 89% of these patients were unvaccinated.

Measles are caused by a single-stranded RNA virus, the only member of the genus Morbillivirus (Paramyxoviridae family). Human beings are the only natural reservoirs of this virus, which is spread by respiratory droplets. It is highly contagious, with more than a 90% transmission rate among non-immunized individuals.

Laboratory Testing

Laboratory confirmation of measles is made by the detection measles-specific immunoglobulin M antibodies in serum of, isolation of measles virus, or detection of measles virus RNA by nucleic acid amplification in an appropriate clinical specimen (e.g., nasopharyngeal or oropharyngeal swabs, nasal aspirates, throat washes, or urine; Table 24-3).

Table 24-3

Measles (Rubeola) Antibody Testing

Test Name Recommended Use Comments
Viral culture method—cell culture, immunofluorescence Gold standard procedure Nasopharyngeal aspirate, washing, throat swab, lung tissue, CSF or urine samples
Enzyme-linked immunosorbent assay (ELISA) Measles (rubeola) antibody IgG and IgM; semiquantitative
Measles (rubeola) antibody, IgG; semiquantitative
Measles (rubeola) antibody, IgM or IgG, CSF; semiquantitative		 Low IgM antibody levels occasionally persist >12 mo postinfection or immunization ; residual IgM response may be distinguished from early IgM response by testing patient sera 2-3 wk later for changes in specific IgM antibody levels.
Screen for vaccination responses.
Diagnose rare but fatal subacute sclerosing panencephalitis (SSPE) in CSF samples; rubeola CSF antibody detection may indicate central nervous system infection; possible contamination by blood or transfer of serum antibodies across blood-brain barrier can affect the results.

Adapted from ARUP Laboratories: Measles virus—rubeola, 2012 (http://www.arupconsult.com/Topics/Rubeola.html).

Serum testing for antibodies is done for the following reasons:

The reverse transcription polymerase chain reaction (RT-PCR) assay is not widely available, but is useful for testing CSF.

CASE STUDY

image Passive Latex Rubella Agglutination Test

Principle

Latex particles are sensitized with solubilized rubella virus antigens. When the latex reagent is mixed with serum containing sufficient rubella antibodies, the antigen-antibody complex will form visible clumps. In the absence of antibody, or if the concentration is too low to react, the latex particles will remain smooth and evenly dispersed.

Procedure Notes

A single specimen can be used to estimate the immune status of the individual, because any detectable antibody is indicative of immunity and protection against subsequent viral infection. The CLSI has advised that the specimen should not be frozen in a frost-free freezer because the freeze-thaw cycle may be detrimental to serum proteins. These guidelines further suggest that frozen specimens be retained for at least 1 year for later follow-up examination, especially for women of childbearing age who are inadvertently exposed to the rubella virus.

The acute-phase specimen should be collected as closely as possible to the time of exposure, and no later than 3 days after the onset of rash. The convalescent-phase specimen should be taken 7 to 21 days after the onset of the rash or at least 30 days after exposure if no clinical symptoms appear because of a possible inapparent infection. Both specimens should be tested simultaneously.

See the image website for the procedural protocol.

Chapter Highlights

• Acquired rubella (German or 3-day measles) is caused by an enveloped, single-stranded RNA virus of the Togaviridae family. It is endemic to human beings, highly contagious, and transmitted through respiratory secretions.

• Contracting rubella infection and vaccinating against rubella are the only ways to develop immunity.

• A diagnosis of acquired rubella is not based solely on clinical manifestations; signs and symptoms vary widely. Although usually mild and self-limiting, with rare complications in children and adults, rubella infections in pregnant women, especially in the first trimester, can result in fetal death or congenital rubella syndrome.

• In primary rubella infection, the appearance of IgG and IgM antibodies is associated with clinical signs and symptoms, when present. IgM antibodies are detectable a few days after onset of symptoms, reach peak levels at 7 to 10 days, and persist but decrease rapidly in concentration over the next 4 to 5 weeks, until no longer clinically detectable.

• IgM antibody in a single specimen suggests a recent rubella infection.

• An unequivocal increase in IgG antibody concentration between the acute and convalescent specimens suggests a recent primary infection or an anamnestic antibody response to rubella in an immune individual.

• Negative IgM and IgG test results indicate that the patient has never had rubella infection or been vaccinated. These patients are susceptible to infection. If no IgM is demonstrable but IgG is present in paired specimens, the patient is immune.

• IgM does not cross an intact placental barrier, so its demonstration in a single neonatal specimen is diagnostic of congenital rubella syndrome. Rubella infection can be confirmed serologically by IgM antibody testing for at least the first 6 months of life, especially when clinical evidence of congenital rubella is slow in emerging or has an uncertain origin.

• Laboratory confirmation of (rubeola) measles is made by the detection of measles-specific immunoglobulin M antibodies in serum, isolation of measles virus, or detection of measles virus RNA by nucleic acid amplification in an appropriate clinical specimen.

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