Perspective

CDC OKs new two-tier testing algorithm for Lyme disease

Infectious Diseases in Children, September 2019

The CDC issued an updated recommendation for the serologic diagnosis of Lyme disease, endorsing the use of a two-tier testing algorithm that uses a second enzyme immunoassay, or EIA, in place of a western immunoblot assay.

The update, published in MMWR, followed the FDA’s clearance last month of four previously cleared Lyme disease tests manufactured by ZEUS Scientific with new indications for use in the modified two-tier testing process.

The CDC previously recommended a two-tier testing algorithm that included a sensitive first-tier test — either an EIA or immunofluorescence assay — followed by a supplemental immunoblot assay if the first test resulted in a positive or equivocal result. Under the new recommendation, when cleared by the FDA for Lyme disease testing, “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”

According to the update, “clinicians and laboratories should consider serologic tests cleared by FDA as CDC-recommended procedures for Lyme disease serodiagnosis” — a standard based on the criteria established at the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease.

Photo of a tick wanring in the woods 
The CDC updated its recommendation for the serologic diagnosis of Lyme disease to include a new two-tier testing algorithm that eliminates the need for a western immunoblot assay.
Source:Adobe Stock.

The report from that conference offered guidance on the development of future tests. It advised that “evaluation of new serologic assays include blind testing against a comprehensive challenge panel and that new assays should only be recommended if their specificity, sensitivity and precision equaled or surpassed the performance of tests used in the recommended two-test procedure,” the authors of the new recommendation wrote. – by Joe Gramigna

Disclosures: The authors report no relevant financial disclosures.

References:

FDA. FDA clears new indications for existing Lyme disease tests that may help streamline diagnoses. https://www.fda.gov/news-events/press-announcements/fda-clears-new-indications-existing-lyme-disease-tests-may-help-streamline-diagnoses. Accessed August 16, 2019.

Mead P, et al. MMWR Morb Mortal Wkly Rep. 2019;doi:10.15585/mmwr.mm6832a4external.

The CDC issued an updated recommendation for the serologic diagnosis of Lyme disease, endorsing the use of a two-tier testing algorithm that uses a second enzyme immunoassay, or EIA, in place of a western immunoblot assay.

The update, published in MMWR, followed the FDA’s clearance last month of four previously cleared Lyme disease tests manufactured by ZEUS Scientific with new indications for use in the modified two-tier testing process.

The CDC previously recommended a two-tier testing algorithm that included a sensitive first-tier test — either an EIA or immunofluorescence assay — followed by a supplemental immunoblot assay if the first test resulted in a positive or equivocal result. Under the new recommendation, when cleared by the FDA for Lyme disease testing, “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”

According to the update, “clinicians and laboratories should consider serologic tests cleared by FDA as CDC-recommended procedures for Lyme disease serodiagnosis” — a standard based on the criteria established at the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease.

Photo of a tick wanring in the woods 
The CDC updated its recommendation for the serologic diagnosis of Lyme disease to include a new two-tier testing algorithm that eliminates the need for a western immunoblot assay.
Source:Adobe Stock.

The report from that conference offered guidance on the development of future tests. It advised that “evaluation of new serologic assays include blind testing against a comprehensive challenge panel and that new assays should only be recommended if their specificity, sensitivity and precision equaled or surpassed the performance of tests used in the recommended two-test procedure,” the authors of the new recommendation wrote. – by Joe Gramigna

Disclosures: The authors report no relevant financial disclosures.

References:

FDA. FDA clears new indications for existing Lyme disease tests that may help streamline diagnoses. https://www.fda.gov/news-events/press-announcements/fda-clears-new-indications-existing-lyme-disease-tests-may-help-streamline-diagnoses. Accessed August 16, 2019.

Mead P, et al. MMWR Morb Mortal Wkly Rep. 2019;doi:10.15585/mmwr.mm6832a4external.

    Perspective
    Eugene Shapiro

    Eugene Shapiro

    Recommended testing for antibodies to Borrelia burgdorferi entails a two-tier algorithm. The first is a quantitative test, typically an enzyme-linked immunoassay (ELISA). If that result is either positive or equivocal, then a second-tier test, a western immunoblot, is performed. The result is positive only if both the ELISA and the western immunoblot results are positive. This testing algorithm has proved to be very good (except for early infection, because erythema migrans typically develops before antibodies are detectable). However, performing immunoblots is both time-consuming and expensive, and it is difficult to eliminate at least some degree of subjectivity in interpreting the blots.

    The newly approved diagnostic test system is a different two-tiered testing algorithm in which both the first-tier and second-tier tests are ELISAs that measure different antigens of B. burgdorferi. The new tests should be less expensive than testing with an ELISA and western blots, and the results should be available sooner. Although preliminary data on the sensitivity and the specificity of the new tests are promising, the true values will not be known until they have been used widely. Of course, the predictive value of a positive result (for either the old or the new tests) are highly dependent on the prior probability that the patient has Lyme disease. Neither test is meant to be a screening test, and they should not be ordered for patients with a low prior probability of Lyme disease, such as patients with only nonspecific symptoms.

    • Eugene Shapiro, MD
    • Infectious Disease News Editorial Board member
      Professor of pediatrics and epidemiology,
      Yale School of Public Health

    Disclosures: Shapiro reports royalties from UptoDate.

    Perspective
    Paul G. Auwaerter

    Paul G. Auwaerter

    The current serologic testing for Lyme disease is a so-called two-tier test. This includes a first-tier screen with an EIA. If that is positive, you then do immunoblots — a bit of an old-fashioned technology — to look for specific antibodies against antigens. That methodology in most clinical settings means you don't get a result back for 3 to 7 days after obtaining a blood test because immunoblots usually take time to be batched and run.

    In the newer, two-tier test, two EIAs are done either at the same time or sequentially. These are platforms that most labs can run in-house. You get results quickly the same day or the next day. Some of these modified two-tier tests use antigens that allow for earlier diagnosis after Lyme infection than standard tests. The reporting of positive or negative tests can usually be accomplished within a day or two, at most. Further, laboratories do not like doing immunoblots. They are a difficult technology and a bit more variable.

    This kind of approach, which has been approved by the FDA for one company (though I’m sure others will seek approval as well) ultimately allows for a faster and likely less expensive diagnostic approach to Lyme disease testing. It's important to note that it's really hard to culture Lyme disease or to find that bacteria by a molecular technique, so we currently remain reliant on serologic diagnosis.

    Clinicians should know that with modified two-tier testing used in a laboratory setting, you will still get a positive or a negative result. It is possible to still be in equivocal range on the first tier, and then have the second show as positive or negative. You will not see bands. As an infectious disease clinician, I find that patients and clinicians are often confused by reports that include bands.

    How your lab runs the modified two-tier test is important because you have options to report either positive immunoglobulin M or immunoglobulin G antibodies. For someone who has symptoms for several weeks who you think may have an acute infectious illness, the modified two-tier approach works very well. If you think someone has long-term symptoms for weeks or months, you may still wish to get an IgM and IgG determination of antibodies because there are still high rates of false-positive IgM antibodies. For anyone with long-term symptoms, the combined test that includes both IgM and IgG may give you a false impression of Lyme disease.

    As always, there are still, a couple of caveats with Lyme disease testing.

    • Paul G. Auwaerter, MD, MBA
    • Professor of medicine
      Clinical director, infectious diseases division
      Johns Hopkins University School of Medicine

    Disclosures: Auwaerter reports working as a consultant for DiaSorin.