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FDA Public Health Advisory: Assays for Antibodies to Borrelia burgdorferi; Limitations, Use, and Interpretation for Supporting a Clinical Diagnosis of Lyme Disease

To:

Family practitioners Internists Infectious Disease Specialists Clinical pathologists

General Practitioners Pediatricians Dermatologists

FDA is advising you about the potential for misdiagnosis of Lyme disease. The results of commonly marketed assays for detecting antibody to Borrelia burgdorferi (anti-Bb), the organism that causes Lyme disease, may be easily misinterpreted. To reduce this risk of misdiagnosis we are providing guidance on the use and interpretation of these tests. It is important that clinicians understand the limitations of these tests. A positive result does not necessarily indicate current infection with B. burgdorferi, and patients with active Lyme disease may have a negative test result.^1-5

Assays for anti-Bb should be used only to support a clinical diagnosis of Lyme disease. Physicians are advised to base diagnosis on history (including symptoms and exposure to the tick vector), physical findings, and laboratory data other than anti-Bb results. The most definitive diagnostic procedure, biopsy and isolation in culture, frequently yields organism when collection and culture procedures are optimal but often is not practical. Assays for anti-Bb can provide evidence of previous or current infection; however, to improve reliability, results should be interpreted only in the context of a two-step testing algorithm (described below) and should not, by themselves, be used to establish a diagnosis of Lyme disease or to exclude Bb infection. The two-step algorithm, as opposed to using a single test, increases the specificity of laboratory testing.

Although package inserts for some commercial assays describe their intended use "to aid in the diagnosis of Lyme disease," this statement does not fully reflect current knowledge about Bb infections and many such assays yield potentially misleading results. FDA is applying the following recommendations as it works with manufacturers to change package inserts and as it evaluates new assays for anti-Bb.

The FDA Microbiology Advisory Panel has advised that package inserts of anti-Bb assays should promote the two-step testing algorithm recommended by the Second National Conference on Serologic Diagnosis of Lyme Disease^1,2 which included representatives from the Centers for Disease Control and Prevention (CDC), the Association of State and Territorial Public Health Laboratory Directors, manufacturers of assays, academic researchers, and FDA.

• The first step is to perform an assay that detects either total or class-specific antibodies (IgM or IgG) by using enzyme-linked immunosorbent technology ("ELISA" or "EIA") or indirect immunofluoresence microscopy ("IFA"). IgM levels usually peak 3-6 weeks after infection. IgG antibodies begin to be detectable several weeks after infection. The IgG response may continue to develop over the course of several months and generally persists for years.
  • A negative result indicates that there was not serologic evidence of infection with Bb at the time the specimen was collected. A negative result should not be the basis for excluding Bb as the cause of illness, especially if blood was collected within 2 weeks of when symptoms began. If Lyme disease is strongly suspected, a second specimen should be collected 2 to 4 weeks after the first specimen and then tested.

  • A positive or equivocal result is presumptive evidence of the presence of anti-Bb, should always be followed by second-step testing, and should not be reported until second-step testing is complete.

• The second step employs an assay that is more specific than that used for the first step. To date, Western-blot (immunoblot) assays have been used for second-step testing. This second test is more specific than ELISA or IFA because Western blot determines if serum contains antibodies (IgG or IgM) that react with appropriate Bb antigens separated by electrophoresis.
  • A negative result indicates that no reliable serologic evidence of Bb infection was present at the time the specimen was collected. A negative result should not be the sole basis for excluding Bb as the cause of illness. If Lyme disease is strongly suspected, a second specimen collected 2 to 4 weeks after the first specimen should be tested.

  • A positive result provides serologic evidence of past or current infection with Bb. Because the presence of even specific antibodies to Bb does not always indicate current infection, a positive result can support, but not establish, a clinical diagnosis of Lyme disease.

While this algorithm is a consensus approach for detecting serologic evidence of infection with Bb, the sensitivity and specificity of both steps are less than optimal. Physicians may be familiar with other two-step testing algorithms, such as that for antibodies to human immunodeficiency virus, in which a highly sensitive first-step assay is sometimes referred to as a "screening" test and a highly specific second-step assay, as "confirmatory." Because assays for anti-Bb should be used only for supporting a clinical diagnosis of Lyme disease and not for "screening" asymptomatic individuals, "initial" is preferred for describing the first step. Second-step Western-blot assays are "supplemental" rather than "confirmatory" because of suboptimal specificity, particularly for detecting IgM anti-Bb. Thus, a positive IgM anti-Bb result alone is not recommended for supporting a diagnosis of Lyme disease in persons with illness of greater than one month duration.^1,2

Several important factors contribute to the limitations of using ELISA, IFA, or Western-blot tests for supporting Lyme disease diagnosis. The stage of disease in which the specimen was taken is critical. First, many patients with active or recent infections do not have detectable anti-Bb in a single specimen. This happens because such antibodies often develop subsequent to manifestations of early infection (the majority of patients' sera are negative for IgM anti-Bb at presentation, whereas most will have detectable IgM and/or IgG anti-Bb if sera are collected and tested at both presentation and 2-4 weeks later) or because detectable anti-Bb may diminish or never develop in patients treated with antibacterial drugs. Secondly, it is not possible to make a definite temporal association between detectable anti-Bb and an illness because these antibodies do not indicate when infection with Bb occurred or if there is active Lyme disease. Serologic assays can detect anti-Bb for many years after infection. Thus, a positive result can be true evidence of previous infection with Bb, unrelated to current illness. Finally, assays for anti-Bb frequently yield false-positive results because of cross-reactive antibodies associated with autoimmune diseases or from infection with other spirochetes, rickettsia, ehrlichia, or other bacteria such as Helicobacter pylori.^5-7

Physicians are encouraged to report adverse events related to medical devices, including clinical laboratory assays, to MedWatch, the voluntary program for reporting to FDA. Pertinent adverse events could include anti-Bb results that led to inappropriate management or a problem with quality control of an assay. Submit these reports by telephone to 1-800-FDA-1088, by fax to 1-800-FDA-0178, by mail to: MedWatch, Food and Drug Administration, HF-2, 5600 Fishers Lane, Rockville, MD 20857

If you have any questions regarding this Advisory, please contact John Ticehurst, M.D. or Roxanne Shively, CDRH, Office of Device Evaluation, HFZ-440, 2098 Gaither Road, Rockville, MD 20850, or FAX 301-594-5941. Please include your phone number with any correspondence.

Sincerely yours, D. Bruce Burlington, M.D. Director Center for Devices and    Radiological Health

References

1. Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the second national conference on serologic diagnosis of Lyme disease. MMWR 1995; 44:590-591.

2. Association of State and Territorial Public Health Laboratory Directors and the Centers for Disease Control and Prevention. Recommendations. In: Proceedings of the Second National Conference on Serologic Diagnosis of Lyme Disease (Dearborn, Michigan). Washington, DC: Association of State and Territorial Public Health Laboratory Directors 1995; 1­5.

3. Craven RB, Quan TJ, Bailey RE, Dattwyler R-J, Ryan RW, Sigal LH, Steere AC, Sullivan B, Johnson BJB, Dennis, DT, Gubler DJ. Improved serodiagnostic testing for Lyme disease; results of a multi center serologic evaluation. Emerging Infect Dis 1996; 2: 136-140.

4. Bakken LL, Callister SM, Wand PJ, Schell RF. Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene / College of American Pathologists proficiency testing program. J Clin Microbiol 1997; 35:537-543.

5. Johnson RC, Johnson BJB. Lyme disease: serodiagnosis of Borrelia burgdorferi sensu lato infection. In:Rose NR, Macario EC, Fahey JL, Freidman H, Penn GM, eds. Manual of Clinical Laboratory Immunology, 5th ed. Washington, DC: American Society for Microbiology, 1997:526-533.

6. Magnarelli LA, Miller JN, Anderson JF, Riviere GR. Cross-reactivity of nonspecific treponemal antibody in serologic tests for Lyme disease. J Clin Microbiol 1990; 28:1276-1279.

7. Schwan TG, Burgdorfer W, Rosa PA. Borrelia. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology, 6th ed. Washington DC: American Society for Microbiology, 1995:626-635.

Updated July 11, 1997

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