The Diagnosis of Lyme Disease: Good News, Bad News

Early Lyme disease usually presents with a characteristic rash— erythema migrans. However, in as many as one fourth of cases, patients may have a nonspecific febrile syndrome without a rash being noted. Most rashes occur after a history of exposure to ticks within an endemic area. Because serologic testing is positive in only approximately half of these patients, even when bloodstream dissemination is present (1–3), diagnosis and therapy need to be based primarily on clinical grounds. Given the slow development of an antibody response, there remains a need for better early diagnostic tools, such as more sensitive antibody detection or direct detection of the nucleic acids or antigens of the pathogen itself (3,4). Unfortunately, these tests have not yet shown sufficient sensitivity or practicality to be useful clinically. The diagnosis of late Lyme disease, when most patients have had months of infection during which to develop measurable antibody, is still a controversial matter. Wellconducted studies of patients with clear-cut Lyme arthritis or neurologic disease (2,5,6) generally document that at least 90% of patients have IgG antibodies in their sera that are detected by readily available tests such as enzyme immunoassay or indirect immunofluorescence. Rarely, patients have late “seronegative Lyme disease” (7), probably as a result of inadequate treatment for early Lyme disease, which is thought to blunt the level of antibody production. Borderline results of enzyme immunoassay or indirect immunofluorescence assay tests may be associated with disease, because false-positive tests can occur, evaluation of all borderline and positive tests with the more specific Western immunoblot assay, so-called twostep testing, is recommended (8). The controversy lies in the evaluation and treatment of patients who have symptoms that seem to defy medical explanation and that they or their physicians have ascribed to Lyme disease. Although some of the patients have a history of Lyme disease (9), most do not, and these patients are usually seronegative. Their symptoms, which include fatigue, muscle and joint aching without objective findings, cognitive difficulties, and nonspecific neurologic complaints may be severe (10,11). It is not known whether some of these patients are infected with Borellia burgdorferi but have failed to make antibody or whether most have other conditions. Some afflicted patients may note improvement, which is often transient or difficult to maintain, after antimicrobial therapy. There are important caveats, however, to drawing conclusions from the individual experiences of these patients and physicians. First, the placebo effect may be a powerful factor, leading to clinical responses even in chronically ill patients (12,13). Second, other infectious diseases or inflammatory processes may also respond to antibiotics. For these reasons, only carefully controlled clinical studies, with objective clinical or laboratory endpoints, can determine whether some patients benefit from antibiotic therapy and, if so, who those patients are. Nonetheless, because of an unproven belief that chronic seronegative Lyme disease may be common and undetectable by current methods, and because of the severity of symptoms, patients and physicians may undertake or recommend long courses of antibiotic therapy. These are costly and can cause adverse effects such as biliary stasis (14), catheterrelated infections, and allergic reactions. This issue of the Green Journal contains both good and bad news about testing in the later stages of Lyme disease. First, Klempner et al (15) show that results of an available IgG Western blot assay are highly reproducible in a single laboratory. This finding does not address concerns raised by early studies, which were mostly performed before to the development of well-standardized assays, that results of commonly available Lyme disease serologic tests (usually performed by enzyme immunoassay or indirect immunofluorescense assay) vary among laboratories. However, it does support the use of a wellstandardized IgG Western blot to help clarify or confirm a borderline or positive initial serology. The bad news concerns the specificity of a commercially available urine antigen test, the LUAT (Lyme urine antigen testing). Why should one consider examining the urine for tracks of the Lyme disease spirochete? First, the urinary bladder is commonly and persistently involved in experimental B. burgdorferi infection (16). Second, B. burgdorferi antigens or nucleic acids may be shed into the urine in some patients with active Lyme disease (17,18). However, none of these assays has yet been demonstrated to be useful clinically or reliable. The urine antigen assay reevaluated by Klempner et al (15) is a proprietary assay performed by IgeneX Inc., a Am J Med. 2001;110:236 –238. From The Division of Infectious Diseases, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, and the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland. Requests for reprints should be addressed to Jesse L. Goodman, MD, MPH, Box 250 Mayo, 420 Delaware St., Minneapolis, Minnesota 55455.