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Lyme Disease

Diagnosis of Lyme Disease

by
National Institute of Allergy and Infectious Diseases
Division of Microbiology & Infectious Diseases
Date: pre April 17, 2004
The links above do no longer work at least as of September 24, 2012

All would agree that the successful management and treatment of any infectious disease ? including Lyme disease ? rests mainly upon early and accurate diagnosis. However, since the tests now being used for the diagnosis of Lyme disease are not as sensitive and specific as one would like, their results must be viewed with some reservations.

Obviously, the only way one can be absolutely sure that a disease is in fact caused by a particular infectious agent is to isolate and culture that agent from the blood or tissues of those suspected of having the disease.

In most cases, it is not possible to isolate and culture Borrelia burgdorferi, the spirochete that causes Lyme disease, from patients suspected of having Lyme disease.

Therefore, one is forced to rely upon indirect serological tests (e.g., Western blot and ELISA assays) that detect the presence of serum antibodies specific for the antigens against B. burgdorferi. The presence of such antibodies, which are likely to persist for long periods of time even after infection has been eliminated after successful antibiotic therapy,

is presumptive and
does not necessarily prove that an individual is actively infected.

To be sure, the polymerase chain reaction (PCR) is an extremely sensitive laboratory test that is capable of detecting very few molecules of bacterial DNA. However, the numbers of Borrelia likely to be present -- if at all -- in patients suspected of having Lyme disease are too small to generate sufficient amounts of bacterial DNA to be detected by this procedure.

Western blot and ELISA assays are the two most widely used serological tests for the diagnosis of Lyme disease. Although these tests have been improved considerably during the past few years,

they are not quantitative and do not enable one to assess the severity of an infection. Furthermore,
they have problems related to standardization and reproducibility of the results obtained, not only within the same laboratory but also between different laboratories.
Both tests can yield a high number of false-positive - or false-negative - results, depending on the particular patient population considered.

For example, if these tests are done on populations where the likelihood of having Lyme disease is low, the probability of obtaining a false-positive result is greater than that of obtaining an unequivocal true positive result.
Although an individual may be positive for both tests, others may be positive for one - but not the other - test, and individuals with clinical symptoms associated with Lyme disease may be negative for both tests.

Neither the Western blot nor the ELISA tests are sufficiently quantitative to enable one to monitor and evaluate the efficacy of antibiotic therapy during the course of treatment.

Because of these and other considerations, some have expressed the view that Lyme disease is either under or over diagnosed and treated, and that current estimates of the incidence of this disease in the United States are inaccurate.

Consequently, a history of having had a deer tick bite, followed by the characteristic "bulls eye" lesion (erythema migrans rash) with flu-like symptoms is considered to be the most reliable diagnostic indicator of Lyme disease; such a history is sufficient to justify antibiotic therapy in the absence of further serological tests, since only about 30 percent of such individuals would usually be seropositive by Western blot and ELISA assays.

The development of a rapid, sensitive and specific diagnostic test to distinguish those who were infected in the past but are no longer infected from those who are now actively infected would be a significant advance for many infectious diseases, including Lyme disease.

Such a test is needed, especially for patients with those symptoms (e.g., fatigue, muscular or neurological aches and pains, cognitive difficulties) that are usually associated with chronic Lyme disease, but which are not unique for Lyme disease and thus could be attributed to a variety of other illnesses or medical conditions.

The availability of a test that is both sensitive and indicative of active infection with B. burgdorferi also would enable one to identify those patients who would benefit from antibiotic therapy, as well as to judge the effectiveness of such therapy on the resolution of infection.

Since the genome of B. burgdorferi has now been sequenced, the application of novel approaches, such as microarray technology and proteomics, to address this issue holds much promise, and

NIAID is now encouraging and supporting basic research in that regard.

NIAID also is supporting research

to improve the sensitivity and specificity of existing diagnostic methods, as well as

to identify virulence-associated antigens generated during the course of infection. The latter would have great potential for use in the development of new diagnostic procedures and may also serve as indicators of active infection.

Until better tests are available, the diagnosis of Lyme disease must be based on characteristic clinical findings in which the results of laboratory tests play a supportive role. Consequently, primary care physicians in endemic areas must be familiar with all aspects of this disease and understand both the characteristics and limitations of laboratory tests commonly used for the diagnosis of Lyme disease.

The American College of Physicians has published a position paper evaluating the limitations and performance of various laboratory tests now being used for the diagnosis of Lyme disease.

Several mechanisms also are available to instruct both the medical community and the general public on the prevention, diagnosis, and treatment of Lyme disease. These include NIH- and CDC-sponsored Web sites and publications, as well as Web sites, publications, and newsletters developed by local public health agencies as well as patient advocate organizations.

Both the CDC and the Infectious Disease Society of America (IDSA) have published specific guidelines, which are updated periodically, on the diagnosis and treatment of Lyme disease.

Treatment indications for previously untreated acute or chronic disease are relatively straightforward and standards of care exist. The most current standard of care guidelines have been prepared and published by the IDSA.
Treatment standards for individuals who remain symptomatic after completing a generally accepted standard course of antibiotic therapy for either acute or chronic Lyme disease have not been defined.

In the absence of a consensus on the treatment of such individuals, NIAID initiated both intramural and extramural clinical treatment trials on Chronic Lyme.
The intramural clinical study of Lyme disease is assembling a well-characterized cohort of patients with chronic Lyme disease and relevant controls. Multiple research projects are being developed based on the findings derived from these studies.

Ongoing research on the development of new or improved diagnostic tests for Lyme disease include:

a new PCR and a RT-PCR assay for Borrelia;
evaluation of a new culture medium for the isolation of Borrelia from blood and/or tissue specimens;
research on the basis for variability of the Western blot and ELISA assays, as well as the
use of well-defined and specific recombinant protein antigens in such assays;
collaborative studies on the application of a newly developed ELISA test;
research on the application of the Western blot assay for use with cerebrospinal fluid; and
evaluation of the use of specific immune complexes testing for the diagnosis and treatment of chronic Lyme disease.

NIAID, in collaboration with the CDC and the Office of Rare Diseases, sponsored a conference on the laboratory diagnosis of Lyme disease in August 1998.

At this conference, the strengths and weaknesses of all laboratory tests routinely used for the diagnosis of Lyme disease were evaluated and examined in great detail.

Many recommendations were made as to how diagnosis could be improved and some of these now are in the process of being implemented.

NIAID, in collaboration with the CDC, plays a major role in encouraging the development of novel approaches to improve the diagnosis of Lyme disease in the presence of co-infecting agents (e.g., Babesia microti, and Ehrlichia species) that could comlicate or interfere with diagnosis, as well as in individuals previously immunized with the recently licensed LYMErix^(R) vaccine for Lyme disease.

A significant development is the use of a synthetic peptide, composed of 26 amino acid residues derived from a variable surface antigen (VlsE) of B. burgdorferi, in a new, rapid, and extremely sensitive ELISA test for the diagnosis of Lyme disease. Since this test does not detect antibodies specific for Osp-A, it can be used even in those who have been immunized with the recently licensed Osp-A-based LYMErix^(R) vaccine.

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