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February 2, 2000

Long-term Outcomes and Management of Patients With Lyme Disease

Author Affiliations

Author Affiliation: Department of Medicine, Infectious Disease Division, State University of New York at Stony Brook School of Medicine.

JAMA. 2000;283(5):658-659. doi:10.1001/jama.283.5.658

Although Lyme disease was first recognized 25 years ago, serologic methods of diagnosis have not been well standardized, and there is significant variability between laboratories.1-3 In the absence of a criterion standard blood test, the diagnosis of Lyme disease is based on a characteristic clinical picture in the appropriate epidemiologic setting (often supported by serologic data). Because the initial IgM response to the causative spirochete Borrelia burgdorferi characteristically begins 1 to 2 weeks after infection, patients with early classic Lyme disease may be antibody-negative.4 Conversely, B burgdorferi expresses cross-reactive antigens and false-positive test results may occur, even using the recommended 2-step system of enzyme-linked immunosorbent assay (ELISA) screening (high sensitivity) followed by Western immunoblot (high specificity).5 To further complicate the issue, all the currently licensed ELISA tests contain the OspA surface antigen and, therefore, are invalid for individuals who have received the Lyme disease vaccine (composed of purified OspA).6

For patients with classic presentations of Lyme disease, there is widespread agreement about the initial diagnosis and antibiotic management. However, without a serologic criterion standard, there is no valid way to address issues of asymptomatic or atypical infection for long-term outcomes. The situation is analogous to the early years of the acquired immunodeficiency syndrome, when the case definition was entirely clinical and only patients with the most classic presentations (eg, Pneumocystis carinii pneumonia or Kaposi sarcoma) were considered to represent acquired immunodeficiency syndrome cases. With the advent of reliable human immunodeficiency virus testing in 1985, the case definition was broadened to include a variety of additional presentations (eg, recurrent Candida or Mycobacterium avium-intracellulare infection), and studies of the epidemiology and natural history of the infection quickly followed.

Uncertainty breeds strong disparate opinions. As long as Lyme disease is defined primarily by its clinical characteristics, legitimate disagreement will exist between those who accept only the narrow case definition, limited to those patients with well recognized Lyme disease manifestations, and those who believe that B burgdorferi also may be an important contributor to other, less well-defined illnesses, particularly when accompanied by positive (albeit imperfect) serologic test results. Physicians who accept less stringent criteria argue that the full spectrum of Lyme disease is not known and that the strict diagnostic criteria may recognize only the tip of the iceberg. Concern about inadequately diagnosed or treated B burgdorferi infection is heightened by comparisons to syphilis, another disease caused by a spirochete, in which subtle, protean signs and symptoms may progress insidiously if not treated effectively. For the highly motivated patient seeking a diagnostic label for persistent symptoms, it is not difficult to find a physician who, reasoning that the response to a course of antibiotics represents a diagnostic trial, is willing to treat for the unlikely possibility of Lyme disease.

This "doctor's dilemma" is addressed in this issue of THE JOURNAL by Seltzer and colleagues7 in their assessment of long-term outcomes of patients who were diagnosed as having Lyme disease and reported to the Connecticut Department of Public Health from 1984 to 1991. Their random subsample of 8764 patients with reported Lyme disease netted 678 enrollable study patients, the largest group of patients with Lyme disease followed up in a longitudinal study. It is reassuring that after a median follow-up of 51 months, patients with a diagnosis of Lyme disease that met the national surveillance case definition developed by the Centers for Disease Control and Prevention (CDC)8 had the same profile of symptoms and the same quality-of-life indicators as age-matched controls without Lyme disease. Thus, recognition and treatment of clear-cut Lyme disease resulted in a return to baseline with no measurable sequelae. On the other hand, patients who were reported to have Lyme disease but who did not meet the CDC's case definition of Lyme disease had increased symptoms and worsening quality-of-life indicators. The implication is that many of these individuals really did not have Lyme disease and therefore did not respond to the treatment.

Although this study used accepted epidemiologic methods and analyses, it is surprising that only 64.3% of cases reported to the state met the current CDC national surveillance definition of Lyme disease. Moreover, not all patients diagnosed as having Lyme disease were treated with antibiotic agents. Among patients for whom treatment information was available, those who met the CDC case definition for Lyme disease were more likely to have received antibiotic treatment than were those who did not meet the same case definition (98% vs 82%; P<.001). This difference raises the question of whether the difference in observed outcomes was due, in part, to antibiotic treatment rather than simply to more accurate diagnosis, and it lessens the power of the authors' conclusions.

Nevertheless, this study adds support to the champions of evidence-based medicine and validates the position paper of the American College of Rheumatology and Infectious Diseases Society of America,9 both of which try to discourage the use of antibiotics for the patient whose clinical presentation is nonspecific and who does not meet the accepted case definition standard. In particular, the practice of empirically treating patients who have common, frustrating illnesses such as fibromyalgia and chronic fatigue syndrome (even those with positive serologic test results for B burgdorferi) with prolonged courses of parenteral antibiotics can be condemned as unwarranted, expensive, and contributing to the problem of antimicrobial resistance.

Despite these general directives to be more stringent in diagnosing and treating Lyme disease, physicians will continue to deal with the troublesome fact that there is no test that will rule out Lyme disease and that some patients will be persistent in their search for physicians willing to treat their chronic symptoms empirically. Physicians faced with a symptomatic patient rather than a practice guideline will continue to ask themselves, "What if the patient is right and really has an atypical presentation of Lyme disease?"

Help may come in the form of a new generation of tests for serum antibodies to B burgdorferi. The most promising of these is the use of recombinant chimeric Borrelia proteins (RCBPs) in an ELISA.6 By enhancing and combining specific portions of key proteins from multiple variants into unique recombinant proteins, the sensitivity and specificity of the RCBP ELISA assay are improved. Test sensitivity in late-stage Lyme disease approaches 100%, although in early Lyme disease (prior to full antibody response), the test sensitivity is only 57%.6 Also, by omitting OspA, RCBP ELISAs can be used for the diagnosis of B burgdorferi infections regardless of Lyme disease vaccine status. If additional validation studies confirm these promising results, epidemiologists and clinicians will be able to explore a variety of important questions regarding the clinical scope and natural history of Lyme disease with much greater precision. In turn, improvement in the diagnosis of Lyme disease—even for patients with asymptomatic infection or atypical presentations—will better inform treatment decisions.

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