July 7, 1997 |
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 Disease1,2
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.
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. |
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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