The Consequences of Overdiagnosis and Overtreatment of Lyme Disease: An Observational Study

Lyme disease is a multisystem inflammatory disorder with signs and symptoms that include a characteristic rash (erythema migrans); flu-like indicators; and recognizable articular, neurologic, or cardiac manifestations [1, 2]. In most patients who develop Lyme disease, symptoms resolve completely after one course of antibiotic therapy [3, 4]. In as many as one third of cases [3, 5], however, objective disease manifestations resolve but fatigue, arthralgias, and myalgias persist for several months before dissipating. This condition is often called the post-Lyme syndrome. Previous studies [6-9] have shown that many patients who receive treatment for Lyme disease lack firm clinical or serologic evidence of disease. Persons at increased risk for inappropriate treatment include 1) patients who develop Lyme disease and receive appropriate antibiotic therapy but have persisting fatigue, arthralgias, and myalgias that are misinterpreted by patients or physicians as evidence of partially treated or recurrent Lyme disease and 2) patients who do not have Lyme disease but seek treatment for fatigue, arthralgias, and myalgias only or other non-specific symptoms (such as insomnia, chronic headache, or low energy). Reasons for inappropriate treatment in the latter group of patients include physician reliance on serologic rather than clinical evidence of disease (false-positive results on serologic tests for Lyme disease are common [10, 11]); unfamiliarity on the part of the physician with the signs and symptoms of Lyme disease; and patient demand for treatment because of anxiety about Lyme disease [12, 13]. Although the overdiagnosis and overtreatment of Lyme disease have been recognized [6-9], the adverse consequences associated with these practices have received inadequate attention [13]. We report on the clinical presentations, laboratory findings, and specific diagnoses of 209 patients evaluated for presumptive Lyme disease at a university-based Lyme disease clinic. We provide data on the use of health services, treatment-related illness, and levels of disability and psychological distress among patients who were inappropriately given a diagnosis of or treated for Lyme disease. Methods Study Patients All patients were evaluated by faculty physicians at the Yale University Lyme Disease Clinic (YLDC) between April 1994 and May 1995. Patients presented with a presumptive diagnosis of Lyme disease previously made by referring physicians, the patients themselves, or both. Data were obtained on all patients who spoke English, provided informed consent, completed a 50-item questionnaire, underwent a comprehensive physical examination and serologic testing for Lyme disease, and agreed to receive a follow-up telephone call. The human investigations committee at Yale University School of Medicine approved the study. Data Collection A 50-item questionnaire was mailed to all patients before their clinic appointments, along with a letter describing the purpose of the study. To ascertain the quantity of health services used, patients were asked to record the number of office visits and physicians seen for the evaluation and treatment of Lyme disease, the number of previously performed serologic tests for Lyme disease, and information about each previous treatment. To determine whether a patient had previously received a diagnosis of Lyme disease from a physician, we asked, Has a physician ever told you that you had Lyme disease? We also asked patients about the relative effectiveness of each antibiotic treatment previously received for Lyme disease. The number of work days lost and days during which normal activity was restricted were determined by using questions from the National Center for Health Statistics Limitations of Activities survey [14]. A score of 16 or more (range, 0 to 28) on the previously validated 7-item Center for Epidemiologic Studies of Depression scale [15] indicated the presence of depressive symptoms. Perceived stress was measured with the 10-item Perceived Stress Scale [16]. This index reliably measures the extent to which patients perceive situations in life as stressful [16-18]. A high level of perceived stress as measured by this index has been associated with clinically relevant outcomes, such as acute upper respiratory tract infections [18]. A score of 20 or greater (range, 0 to 40) was considered indicative of a high level of perceived stress. To identify adverse drug events, we asked patients to report the name of the drug used, the duration of therapy, the mode of administration, and whether any unanticipated reactions occurred with each course of antibiotic treatment received for Lyme disease. The last item was ascertained by asking, During or after treatment with this specific antibiotic, did you experience any of the following reactions? Response categories included common drug reactions caused by antibiotic medications currently used to treat Lyme disease. Patients were instructed to check off any reaction they had during or after each course of treatment. If patients thought that an antibiotic treatment had caused a reaction that was not listed, they were instructed to record those reactions as well. Diagnostic Criteria A diagnosis of active Lyme disease required the presence of erythema migrans or characteristic articular, neurologic, or cardiac manifestations [1, 2] with confirmation by serologic testing. Patients with previous Lyme disease fulfilled criteria for active Lyme disease in the past, had completed recommended antibiotic therapy appropriate for their stage of disease [19], and did not meet the criteria for active Lyme disease at the time of evaluation. Patients were considered to have no evidence of Lyme disease if no current or previous physician had documented erythema migrans, the medical history was inconsistent with previous infection, and the criteria for active Lyme disease were not met. All patients who met the criteria for active Lyme disease were informed that they had Lyme disease, whereas all patients with previous Lyme disease or no evidence of Lyme disease were told that they did not currently have Lyme disease. Alternative diagnoses for patients in the latter two groups were made on the basis of the clinical judgment of YLDC physicians. Classification of Adverse Drug Events A reported drug reaction was counted as a probable adverse drug event if the antibiotic in question had been previously cited [20, 21] as causing the putative reaction, the patient was not taking other medications that may have caused the adverse event, and a temporal association could be seen between the antibiotic treatment and the adverse event (for example, the reaction occurred while the patient was taking the antibiotic or within 2 weeks of discontinuing therapy with the drug). We also required that major adverse events be documented in the patient medical record. We classified adverse drug events as minor or major. A minor event was defined as a reaction that was self-limited and did not require discontinuation of antibiotic therapy (such as epigastric distress) or that required physician intervention (such as treatment for vaginal yeast infection) but was not serious or life-threatening. A major event was defined as any drug reaction that was potentially serious or life-threatening (such as neutropenia or septic thrombophlebitis). Reliability of Determinations of Adverse Drug Events and Patient Survey Responses To ascertain the reliability of determinations of adverse drug events, surveys from 23 patients (5 with active Lyme disease, 6 with previous Lyme disease, and 12 with no evidence of Lyme disease) were randomly selected and independently rated by a second investigator. The proportion of observed agreement between raters was 89% ( = 0.73), indicating excellent overall agreement in the classification of adverse drug events. To assess the reliability of patient survey responses, a second questionnaire consisting of 12 items randomly selected from the original 50-item survey was administered to 18 consecutive patients at the time of their YLDC visit. The abbreviated questionnaire contained 2 items pertinent to the results in this report (number of previous physician visits and serologic tests performed for Lyme disease). The proportions for observed agreement for these items were 72% and 83%, respectively, with corresponding intraclass correlation coefficients of 0.80 and 0.81. These results indicate substantial intrapatient reliability. Clinical and Serologic Evaluation For all patients, a comprehensive history was taken, medical records were reviewed, and a complete physical examination was performed. Serologic testing for Borrelia burgdorferi antibodies was done in all patients by enzyme-linked immunosorbent assay (ELISA) at the YLDC laboratory as described elsewhere [22]. A titer of 1:200 or greater for IgM or IgG was considered a positive result. All specimens with positive ELISA results were subsequently tested for IgM and IgG antibodies in our laboratory by doing Western blot analysis using a two-step procedure [23] and were evaluated according to Centers for Disease Control and Prevention criteria [24]. The most common reasons for conducting Western blot tests were suspicion of a false-positive result on ELISA (n = 88) or Western blot done at outside laboratories (n = 21). Symptom Duration We defined symptom duration as the time from the initial onset of symptoms to the patients' initial YLDC visit. We ascertained the time of initial onset of symptoms by asking patients, When did you first develop signs or symptoms that suggested a diagnosis of Lyme disease? Because some patients reported multiple episodes of Lyme disease interspersed with symptom-free periods, all patients were asked to estimate the number of symptom-free days from the time of their initial physician evaluation. We subtracted the total number of symptom-free days before calculating the symptom duration for all patie