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Serologic Testing for Rubella

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Published: July 2008

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Dr. Binnicker reviews the epidemiology of rubella and a patient case. Dr. Binnicker discusses how the conclusion that rubella is no longer endemic in the United States has changed the laboratory approach to diagnosis. As a result of these changes, Mayo Medical Laboratories has discontinued IgM-class antibody testing for rubella.

Presenter: Matt Binnicker, PhD, D(ABMM)) from the Division of Clinical Microbiology at Mayo Clinic

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Transcript

Introduction

Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this presentation is Dr. Matthew Binnicker from the Division of Clinical Microbiology at Mayo Clinic. Dr. B will be discussing the conclusion that Rubella is no longer endemic in the United States has changed the laboratory approach to diagnosis.

Patient Case

I’d like to present a patient case that I think will illustrate several key points regarding Rubella serologic testing as we move through the presentation.

This is the case of 23-year-old, pregnant female who was seen by her obstetrician at 7 weeks gestation. A blood specimen was obtained for routine first tri testing. A review of the patient’s history indicates that she is currently employed as an elementary teacher, and has been in her regular state of good health. Several days later, her obstetrician calls to speak with her regarding the results of her blood test. The results of testing are as follows:

The syphilis and HIV antibody screens were reported as negative, as was the Hepatitis B screen. The Rubella IgG was reported as positive, and this would generally indicate immunity to Rubella. However, a Rubella IgM was also ordered, and this was reported as positive.

The patient’s obstetrician is concerned about the positive Rubella IgM result and asked the following question: What is the appropriate follow-up action and how should this be interpreted?

Before we proceed with the case and discuss Rubella serologic testing in more detail, I’d like to briefly review some key points regarding acute Rubella infection.

Background

Rubella is also commonly referred to as German, or three-day, measles and is caused by Rubella virus. It’s important to emphasize that Rubella should not be confused with classic measles, which is a separate viral exanthem is caused by rubeola virus.

Post-natal Rubella is transmitted primarily through direct or droplet contact with nasopharyngeal secretions. The incubation period is typically 14 to 21 days. In most cases, Rubella causes a subclinical or mild disease characterized by a generalized erythematousmaculopapular rash with lymphadenopathy and a low-grade fever. A picture of a typical Rubella rash is shown on the right side of the screen.

Despite most cases being mild and resolving spontaneously, serious complications can occur following intrauterine infection, especially when a susceptible pregnant female is infected during her first trimester. This can result in Congenital Rubella Syndrome (CRS), which can cause serious neo-natal manifestations including cataracts, congenital glaucoma, hearing impairment, behavioral disorders, growth retardation, and in some cases, fetal demise.

Serologic Testing

Historically, laboratory testing for Rubella has consisted primarily of serology. Rubella IgG is often used as a marker of past infection or response to vaccination. This test is especially important in women of childbearing age and is included in the recommended prenatal blood tests. The presence of IgG typically indicates immunity to acute Rubella infection.

In contrast, testing for IgM class antibodies to Rubella virus has historically been used as a marker of acute phase Rubella infection. IgM antibodies can be detected in serum 2 to 7 days after onset of the rash, but importantly, Rubella IgM levels can persist at low levels for up to 12 months after acute infection, so its presence is not always a marker of recent infection.

Now that we’ve reviewed the conventional laboratory approach for determining immunity and diagnosing acute Rubella infection, I’d like to change gears and discuss a significant change in the epidemiology of the disease that has occurred over the past 40 years. I think this change has a tremendous impact on the approach that we should take when testing for Rubella.

Timeline to Elimination

In the early- to mid-20th century, Rubella continued to be an important public health concern, causing hundreds of thousands of cases in the United States, and millions of cases of acute Rubella and Congenital Rubella Syndrome worldwide.

However, in 1969, a Rubella vaccine was licensed for use with the target population of children aged 1 year to puberty. Implementation of this vaccine resulted in a 78% reduction in cases from 1969-1976. In 1978, the target population was expanded to include adolescents and postpubertal females in an attempt to further decrease the number of cases of Congenital Rubella Syndrome. In 1979, a new formulation of the vaccine was introduced and this formulation yielded a more pronounced and prolonged immune response. A decade later, the U.S. Department of Health and Human Services established a goal, and this goal was to eliminate indigenous Rubella and CRS in the United States. This initiative was accompanied by the routine implementation of the 2-dose MMR vaccination series in the United States.

Number of Rubella Cases

The graph on this slide illustrates the significant impact that each of these initiatives has had on reducing the incidence of Rubella and CRS in this country. The number of Rubella cases from 1966-2004 is indicated by the solid blue line. The number of cases of CRS is depicted by the yellow dash line. Due to the trends depicted in this graph, the CDC and an independent panel of experts convened in 2004 to review the data regarding Rubella infection and transmission. Based on the data, the group  unanimously concluded that Rubella is no longer endemic in the United States.

This conclusion was based on several factors, including the high level of immunity to Rubella, adequate surveillance, and the fact that fewer than 10 cases of Rubella were reported in 2004. Interestingly, the majority of these cases reported in 2004 occurred in individuals born outside of the United States.

Reported Rubella Incidence Rates

The graph on this slide further emphasizes the significant decrease in the incidence of Rubella. This graph shows that as of 2003, the incidence was well below the 1 case per million population threshold in the United States. As I’ve mentioned, this public health achievement has a significant impact on the way that we should approach laboratory testing for Rubella and importantly how results should be interpreted. Let’s return to our patient case to illustrate this point.

Patient case (continued)

Due to the concern of the initial positive Rubella IgM result, the obstetrician appropriately ordered follow-up testing. A second serum sample was collected and submitted for Rubella serology. The results from this specimen were reported as positive for IgG, but negative for IgM.

In addition, a throat swab and urine specimen were forwarded to the state health laboratory for viral culture, and this was found to be negative. Despite these follow-up results, I think an ordering physician would still be left to answer the question, How should the initial positive Rubella IgM be interpreted?

Rubella IgM

I think this question can be answered if we take a look at several factors that are key in properly interpreting results, but may be overlooked when a laboratory test is ordered. These factors are number one, the prevalence of the disease, which is simply the number of cases of disease at a given time in a certain population. The second factor is the positive predictive value (PPV) of the laboratory test, which is the proportion of patients with positive test results who are correctly diagnosed.

As this graph depicts, the PPV of a laboratory test is highly dependent on the prevalence of the disease. In other words, if the disease has a very low prevalence, the PPV of a laboratory test will also be very low. This is the case even if the laboratory test demonstrates excellent specificity.

So let’s focus in on the example of IgM testing for Rubella to drive this point home. The current estimated prevalence of Rubella is well below 1 case per 1 million population. Because of this, the PPV of testing is extremely low. This point is critical to the proper interpretation of test results, because given the situation, virtually all positive Rubella IgM results are false positive results.

Serologic Testing

Because of this, Mayo Medical Laboratories has discontinued all serologic testing for IgM-class antibodies to Rubella. This decision was based on several factors, including:

  • The absence of endemic transmission of the disease in the United States as determined by the CDC;
  • The high rate of vaccine coverage (>95%) among school-aged children;
  • The high level of immunity in this country; and finally,
  • The potential negative impact of false-positive Rubella IgM result.

Although it’s not recommended, Rubella IgM testing is often performed prenatally in asymptomatic pregnant women. In this setting, a false-positive result may generate substantial worry to parents, needless follow-up testing, needless expenditure of resources, and potentially the termination of healthy pregnancies.

This change results in the following tests have been discontinued at Mayo Medical Laboratories:

  • #83264 Rubella Antibodies, IgG and IgM, Serum
  • #8317 Rubella Antibodies, IgM, Serum
  • #80804 (Rubella component only) TORCH Profile IgM

I just want to stress that the toxoplasma, CMV and HSV components of the TORCH profile will continue to be available. It’s also important that I emphasize that Mayo Medical Laboratories will continue to offer testing for IgG-class antibodies to Rubella as a mechanism of determining immunity and response to vaccination.

Conclusion

I’d like to close by clarifying that it is possible that outbreaks of Rubella can still occur in the United States if the virus is imported from countries with low vaccine coverage or where the disease is still endemic. If a case of acute Rubella or CRS is suspected, it’s recommended that you contact your state health department or the CDC. These institutions are equipped to screen cases based on clinical findings and potential exposure histories and can arrange appropriate follow-up testing if clinically indicated.


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