Some Notes on Nonstandard
Lyme Disease Tests

Stephen Barrett, M.D.

Lyme disease is caused by infection with the bacterium Borrelia burgdorferi transmitted to humans by the bite of an infected tick. Patients usually have a history of exposure to ticks along with symptoms that include fever, fatigue, muscle, and joint aches, and a characteristic rash [1]. The U.S. Centers for Disease Control and Prevention (CDC) recommends a two-test process to detect antibodies against B. burgdorferi [2]. If an initial enzyme-linked immunosorbent assay test is positive or indeterminate, it is followed by a confirmatory Western Blot test. The FDA states that a laboratory-based diagnosis of Lyme disease is appropriate only if the Western Blot is positive [3]. So far, 85 initial and confirmatory diagnostic blood tests for Lyme disease have been cleared by the FDA [4].

The 9000-member Infectious Diseases Society of America (IDSA), which is the most prominent professional organization for infectious disease specialists, has issued evidence-based guidelines for diagnosing and treating Lyme disease [5]. The guidelines call for patients diagnosed with Lyme disease to be treated with oral or intravenous antibiotics for 10 to 28 days, which will relieve symptoms in 80%-90% of patients. CDC recommends following the IDSA guidelines [6].

A tiny minority of doctors reject the IDSA guidelines and assert that Lyme often becomes chronic and requires months or even years of antibiotic treatment. In 2011, a team of experts severely criticized this approach in a report that concluded:

At least 25 providers of nonstandard Lyme-related services have been subjected to disciplinary action, regulatory action, and/or criminal prosecution.

Questionable Tests

A false positive diagnosis of Lyme disease can lead to (a) harmful side effects without clinical benefit, (b) an increase in the risk of creating infectious organisms resistant to the antibiotics used to treat Lyme disease, and delay in diagnosing the patient's true condition. The questionable tests include the following.

Between 2000 and 2005, a "Dot Blot" test for urine antigens against Lyme disease was claimed to provide a 97% "true positive rate," although this term does not have a clear meaning in public health terms. An independent evaluation conducted in 2001 ran the test five times each for the same 10 healthy subjects and found that the test was consistently falsely positive for 2 subjects and gave contradictory results on at least two pairs of tests for 8 subjects (at least 16 false-positive tests), leading to the conclusion that at least half of all test results were incorrect or uninterpretable, and that this test should not be used for Lyme disease detection [8]. Further research indicated that because of lack of a clear correlation with clinical disease, urine tests in general are not appropriate for diagnosing Lyme disease [9].

Between 2003 and 2005,the Bowen Research and Training Institute of Lake Alfred, Florida, marketed a blood test for Lyme antigens thatr was prone to false-positives. Based on false-positive results, two couples underwent months of unnecessary treatment with antibiotics and other alternative medications. After litigation, a judge awarded them a total of $30 million in damages [10]. The Institute, founded in 1996, became licensed as a hematology laboratory in 2001 but relinquished the license a year later. In 2007, its director Jo Anne Whitaker, M.D., permanently surrendered her medical license to settle charges that she had continued to market her unlicensed Lyme test [11].

Californiapbased IGeneX offers a Western Blot test but does not follow CDC guidelines for interpretation. In 2005, the New York Department of Laboratories began investigating IGeneX after receiving eight complaints from doctors and patients who said that its Western Blot tests gave them positive results not confirmed by other labs' results [12]. IGeneX was eventually cleared to offer the test to New York State residents, but skeptics have expressed concern that it identifies people as Lyme-positive based on a Western Blot "far more liberally than CDC does." [13] Western Blot results are determined by the number of "antigenic bands" found in the specimen. To consider a test positive, CDC requires that at least 5 out of a list of 10 bands be found, but IGeneX asserts that 2 out of a slightly different list of 6 is enough [14].

In 2014, CDC warned against a Lyme disease culture test after conducting a review that "raised serious concerns about false-positive results caused by laboratory contamination and the potential for misdiagnosis," 15,16]. The warning did not name the lab, but a CDC official later said it was Advanced Laboratory Services of Sharon Hill, Pennsylvania [17]. The lab's medical director is Joseph J. Burrascano, Jr., M.D., who is prone to diagnose "chronic Lyme disease" and treat patients with months of antibiotic treatment [18].

Widely used diagnostic tests require FDA clearance or approval, but the agency has not attempted to regulate those done only within a single laboratory ("laboratory developed tests"), which can be marketed without having to prove that they are clinically valid. In a recent report, the FDA referred to the above as laboratory-developed tests that "yield many positive results when the disease is not actually present." [19] The FDA has expressed concern about this regulatory loophole and may close it [20].

Aetna's Clinical Policy Bulletin on Lyme disease lists 24 tests as "experimental and investigational because there is inadequate evidence to prove their usefulness in clinical practice": antigen detection; Borrelia burgdorferi antibody index testing; Borrelia culture; C6 peptide ELISA assay (using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi); CD57+ lymphocyte counts; chemokine CXCL13; complement split products (e.g., C3a and C4a); cyst formation; cytokine analysis; Immune complexes; iSpot Lyme assay; lymphocyte markers; lymphocyte transformation test; measurement of natural killer (NK) cells; microscope-based assays; leuroadrenal expanded panel (including histamine, serotonin, and hydroxyindoleacetic acid); polymerase chain reaction (PCR) for identification or quantification of Lyme disease (B. burgdorferi) spirochetal DNA or RNA; positron emission tomography (PET) scanning; provocative testing (testing for B. burgdorferi after antibiotic provocation); serum borreliacidal assay; SPECT scanning; T-cell proliferation response assay; urine antigen assay; and xenodiagnosis using the natural tick vector, Ixodes scapularis [21].

Political Danger

Senator Richard Blumenthal, a long-time supporter of "chronic Lyme disease" activism [7], has introduced the Lyme and Tick-Borne Disease Prevention, Education, and Research Act of 2015 (S. 2015). This bill which calls for appointment of an advisory committee that would ensure that "a broad spectrum of scientific viewpoints are considered in public health policy decisions" and represent "a wide diversity of views." [22] Although these words may seem harmless, the bill aims to give (undeserved) political power to the advocates of unfounded Lyme theories and practices.

References

  1. Signs and symptoms of Lyme disease. CDC Web site, updated Aug 17, 2015.
  2. Two-step laboratory testing process. CDC Web site, updated March 26, 2015.
  3. FDA Office of in Vitro Diagnostics and Radiological Health. Guidance for industry and Food and Drug Administration staff - Establishing the performance characteristics of in vitro diagnostic devices for the detection of antibodies to Borrelia burgdorferi. FDA Web site, updated July 9, 2015.
  4. Tests can be located by searching Devices@FDA database for "LSR."
  5. Wormser GP and others. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:1089-1094, 2006.
  6. Lyme disease treatment. CDC Web site, updated July 6, 2015.
  7. Auwaerter PG and others. Antiscience and ethical concerns associated with advocacy of Lyme disease. The Lancet Infectious Diseases 11:713-719, 2011
  8. Klempner MS and others. Intralaboratory reliability of serologic and urine testing for Lyme disease. American Journal of Medicine 110:217-219, 2001.
  9. Critical evaluation of urine-based PCR assay for diagnosis of Lyme borreliosis. Clinical and Diagnostic Laboratory Immunology 12:910-917, 2005.
  10. Margolies D. Who's left to pay this big verdict? Kansas City Star, May 25, 2009.
  11. Administrative complaint. Florida Department of Health v. Jo Anne Whitaker, M.D. Case No., 2003-26295, filed Sept 25, 2006.
  12. Hurley D, Santora M. Unproved Lyme disease tests prompt warnings. New York Times. Aug 23, 2005.
  13. Daley B. Many tests to diagnose Lyme, but no proof they work: Unregulated procedures can be costly, sow confusion. Boston Globe, Oct 21, 2013.
  14. Western Blot. IGeneX Web site. To access the relevant article, click "Tick-Born Disease" in the left margin and then click "Western Blot."
  15. Nelson C and others. Concerns regarding a new culture method for Borrelia burgdorferi not approved for the diagnosis of Lyme disease. Morbidity and Mortality Weekly Report 63:333, 2014.
  16. Johnson BJ and others. Assessment of new culture method for detection of Borrelia species from serum of Lyme disease patients. Journal of Clinical Microbiology 52:721-7244, 2014.
  17. Kelly J. Lyme culture test causes uproar. Medscape, Jan 30, 2013.
  18. Burrascano JJ Jr. Advanced topics in Lyme disease: Diagnostic hints and treatment guidelines for Lyme and other tick-borne illnesses. October, 2008.
  19. The public health evidence for FDA oversight of laboratory developed tests: 20 case studies. Nov 16, 2015]
  20. Laboratory developed tests. FDA Web site, Nov 17, 2015
  21. Lyme disease and other tick-borne diseases . Aetna Clinical Policy Bulletin, May 17, 2016.
  22. Lyme and Tick-Borne Disease Prevention, Education, and Research Act of 2015.

This article was posted on May 30, 2016.

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