Daniel W. Rahn

The Early Clinical Manifestations of Lyme Disease

Lyme disease, caused by a tick-transmitted spirochete, typically begins with a unique skin lesion, erythema chronicum migrans. Of 314 patients with this skin lesion, almost half developed multiple annular secondary lesions; some patients had evanescent red blotches or circles, malar or urticarial rash, conjunctivitis, periorbital edema, or diffuse erythema. Skin manifestations were often accompanied by malaise and fatigue, headache, fever and chills, generalized achiness, and regional lymphadenopathy. In addition, patients sometimes had evidence of meningeal irritation, mild encephalopathy, migratory musculoskeletal pain, hepatitis, generalized lymphadenopathy and splenomegaly, sore throat, nonproductive cough, or testicular swelling. These signs and symptoms were typically intermittent and changing during a period of several weeks. The commonest nonspecific laboratory abnormalities were a high sedimentation rate, an elevated serum IgM level, or an increased aspartate transaminase level. Early Lyme disease can be diagnosed by its dermatologic manifestations, rapidly changing system involvement, and if necessary, by serologic testing.

Treatment of the Early Manifestations of Lyme Disease

During 1980 and 1981, we compared antibiotic regimens in 108 adult patients with early Lyme disease. Erythema chronicum migrans and its associated symptoms resolved faster in penicillin- or tetracycline-treated patients than in those given erythromycin (mean duration, 5.4 and 5.7 versus 9.2 days, F = 3.38, p less than 0.05). None of 39 patients given tetracycline developed major late complications (meningoencephalitis, myocarditis, or recurrent attacks of arthritis) compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (chi square with 2 degrees of freedom = 5.33, p = 0.07). In 1982, all 49 adult patients were given tetracycline; again, none of them developed major complications. However, with all three antibiotic agents nearly half of the patients had minor late symptoms such as headache, musculoskeletal pain, and lethargy. These complications correlated significantly with the initial severity of illness. For patients with early Lyme disease, tetracycline appears to be the most effective drug, then penicillin, and finally erythromycin.

Successful Parenteral Penicillin Therapy of Established Lyme Arthritis

In a double-blind placebo-controlled trial carried out from 1980 to 1982, 20 patients with established Lyme arthritis were assigned treatment with 2.4 million U of intramuscular benzathine penicillin weekly for three weeks (total, 7.2 million U) and 20 patients received saline. Seven of the 20 penicillin-treated patients (35 per cent) had complete resolution of arthritis soon after the injections and have remained well during a mean follow-up period of 33 months. In contrast, all 20 patients given placebo continued to have attacks of arthritis (P less than 0.02). In 1983, of 20 patients treated with intravenous penicillin G, 20 million U a day for 10 days, 11 (55 per cent) had complete resolution of arthritis and have remained well since. As compared with nonresponders, penicillin-responsive patients in both studies were more likely to have previously received antibiotics for erythema chronicum migrans (P less than 0.02) and less likely to have been given intraarticular corticosteroids during or at the conclusion of parenteral therapy (P less than 0.1). The Lyme spirochete was not cultured from synovium or joint fluid. We conclude that established Lyme arthritis can often be treated successfully with parenteral penicillin. However, neither of the regimens that we tested is uniformly effective, and further experience will be needed to determine the optimal course of therapy.

Clinical Characteristics and Treatment Outcome of Early Lyme Disease in Patients with Microbiologically Confirmed Erythema Migrans

Context Lyme disease is the most common vector-borne disease in the United States. The traditional clinical presentation, an expanding erythematous rash with partial central clearing, sometimes accompanied by systemic symptoms, was described in patients who usually had clinically manifest Lyme disease for several days. Contribution This study describes 118 patients who acquired Lyme disease while under surveillance in a vaccine trial. Fifty-nine percent of rashes were homogeneous lesions, 32% had dense central erythema, and only 9% had classic central clearing. Signs and symptoms usually resolved within 3 weeks of antibiotic treatment. Implications Early Lyme disease may present with homogeneous or dense central erythematous lesions rather than classic erythema migrans. With antibiotic treatment, the prognosis is excellent. Early Lyme disease may present with homogeneous or dense central erythematous lesions rather than classic erythema migrans. With antibiotic treatment, the prognosis is excellent. The Editors Lyme disease in the United States is caused by the tick-transmitted spirochete Borrelia burgdorferi sensu stricto (1). This infection is the most common vector-borne disease in the country (2). The illness usually presents with localized infection of the skin, erythema migrans, which is often followed days to a few weeks later by dissemination of the spirochete to multiple sites, particularly to other skin sites, the nervous system, the heart, or the joints (3). Borrelia burgdorferi has been cultured readily from skin biopsy samples of erythema migrans early in the illness (4, 5), but later culture from other sites has been difficult. As a substitute for culture, B. burgdorferi DNA may be detected by polymerase chain reaction (PCR) in most patients with erythema migrans (6, 7) and in the joint fluid of patients with Lyme arthritis (8, 9). However, PCR has had low sensitivity in samples from other sites, including cerebrospinal fluid and blood. Serodiagnosis is not sensitive during the first several weeks of infection, but patients often seroconvert during convalescence (10). The initial clinical series of patients with early Lyme disease (11) was described before identification of the causative agent. Researchers used clinical criteria for study entry, particularly the classic appearance of erythema migrans, a slowly expanding erythema with partial central clearing. In that series of 314 patients, most had systemic symptoms and nearly half also had multiple annular erythemas, suggesting dissemination of the spirochete to multiple sites. In a subsequent study, 79 patients from Westchester County, New York, with early Lyme disease had erythema migrans from which B. burgdorferi was cultured (12). Most of the patients in this series, who were often seen earlier than those in the original study, had systemic symptoms, but only 18% had multiple erythemas. In Europe, where erythema migrans more often results from infection with B. afzelii or B. garinii rather than B. burgdorferi sensu stricto, inflammation of erythema migrans is less intense and migration is slower; in addition, patients generally have fewer systemic symptoms (13). In the southeastern United States, patients have been reported to have erythema migranslike skin lesions, but laboratory evidence of B. burgdorferi infection has been lacking. This suggests that another agent, perhaps even from the Borrelia genus, may cause the infection in this geographic area (14-16). Moreover, the same tick that transmits the Lyme disease agent may transmit other infectious agents, including the agent of human granulocytic ehrlichiosis and Babesia microti, and co-infection may influence the clinical presentation of Lyme disease (17, 18). Thus, microbiological confirmation is beneficial in describing the clinical features of Lyme disease in endemic areas in the United States. The recent phase III study of SmithKline Beechams Lyme disease vaccine provided an exceptional opportunity to assess the clinical picture of early Lyme disease in a large cohort of patients who acquired the infection in major endemic locations throughout the United States (19). As part of the protocol, patients who had symptoms of Lyme disease were extensively evaluated for that infection. We describe the clinical presentation, serologic results, and treatment outcome of early Lyme disease in 118 patients with microbiologically confirmed cases of erythema migrans. Methods Patients A total of 10 936 participants 15 to 70 years of age were enrolled in a double-blind, placebo-controlled study of the efficacy and safety of an outer surface protein A Lyme disease vaccine (LYMErix, recombinant outer surface protein A, SmithKline Beecham [now GlaxoSmithKline], Collegeville, Pennsylvania) at 31 sites in 10 endemic states. The Human Investigations Review Committees at all participating centers approved the study protocol. The complete protocol, as well as all members of the Lyme Disease Vaccine Study Group, have been reported elsewhere (19). Briefly, study participants received a packet with information about Lyme disease. Participants were requested to report promptly to their clinician-investigator any symptoms that suggested infection, including onset of a new rash or flu-like illness (without predominant respiratory or gastrointestinal symptoms), arthralgias or arthritis, facial palsy, radiculopathy, or syncope. All participants who were thought to have possible Lyme disease underwent a focused history, physical examination, and laboratory testing. All clinical data were entered on an electronic data form for central analysis. Antibiotic treatment was prescribed according to recommended guidelines (20), but the actual antibiotic and the duration of treatment were at the discretion of the investigator or the patients personal physician. Of the 10 936 participants, 146 met study criteria for definite Lyme disease and 118 had an acute illness with culture-proven or PCR-confirmed erythema migrans. Two clinicians independently reviewed photographs of erythema migrans from case-patients. Laboratory Methods Serologic testing was done at the New England Medical Center exclusively by Western blot (MarDx, San Diego, California), since the standard enzyme-linked immunosorbent assay would be expected to yield positive results in patients vaccinated with outer surface protein A (21). A baseline sample was obtained at study entry, and acute and convalescent samples were obtained when the patient had symptoms suggestive of Lyme disease. The diagnosis of Lyme disease was serologically supported by IgM or IgG seroconversion, or both, between baseline and the acute phase of the illness or between the acute and convalescent phases of the illness. Samples from the same participant were always tested together in the same assay. Western blot results were interpreted according to the criteria of the Centers for Disease Control and Prevention and of the Association of State and Territorial Public Health Laboratory Directors (22). On Western blot, outer surface protein A antibodies bind to a 31-kilodalton band; this is not included in the Centers for Disease Control and Prevention criteria. Following local anesthesia, skin biopsy specimens from erythema migrans were obtained by using 2-mm punch biopsy. Half of each sample was placed directly into a 15-mL tube of BarbourStoennerKelly medium (BSK-H medium, Sigma-Aldrich, St. Louis, Missouri) with ciprofloxacin (0.4 g/mL) and rifampin (40 g/mL); the other half was placed in a 2-mL polypropylene plastic tube for PCR testing. Specimens were shipped the same day by Federal Express to New England Medical Center. On arrival at the laboratory, half of the medium was replaced with fresh medium. Skin samples for culture were placed in an incubator at 33 C and were examined weekly for 1 month by darkfield microscopy for motile spirochetes. Polymerase chain reaction assays of skin biopsy samples were performed as described elsewhere (8). Role of the Funding Source SmithKline Beecham provided data and gave the authors permission to review them, compile them, and independently present results. Dr. Parenti was employed as a research physician with SmithKline Beecham during the early phases of the study. Results During the 20-month study period, which covered two summers of Lyme disease transmission, 1917 of the 10 936 study participants were evaluated for possible Lyme disease (19). Of the 1917 patients, 146 (7.6%) met study criteria for definite Lyme disease, and 118 (6.2%) had microbiological confirmation of this infection by culture or PCR testing of erythema migrans. The mean age of these 118 patients was 51 years (range, 17 to 71 years); 53% were men, and 47% were women. Forty-seven percent were from New England, 51% were from mid-Atlantic states, and 2% were from Wisconsin, reflecting the locations of the study sites. June and July were the peak months of disease onset, which correlated with the expected peak questing period of nymphal Ixodes scapularis ticks. However, cases occurred from March through October, suggesting that adult ticks may also transmit the disease. Vaccine and placebo recipients did not differ in the size of erythema migrans, persistence of symptoms after treatment, and morphologic characteristics of the lesions. In addition, no clinical differences were noted in different geographic areas. Therefore, we present data from vaccine and placebo recipients and from different geographic areas together. Characteristics of Erythema Migrans One hundred eighteen patients had erythema migrans in which B. burgdorferi was detected by culture (88%); by PCR testing (72%); or, in most instances, by both methods (60%). Rashes, which were evaluated a median of 3 days after onset (range, 1 to 30 days), were a median of 10 cm in diameter (range, 5 to 37 cm) at the time of diagnosis. In this adult population, nearly half of the lesions were located on the groin, buttocks, or lo

Lyme Disease: Recommendations for Diagnosis and Treatment

The incidence and the endemic range of Lyme disease in the United States have increased steadily since the disease was originally recognized in Lyme, Connecticut, in 1975. Because of the varied clinical manifestations of this illness and the use of unstandardized serologic testing methods, diagnosis is often uncertain and treatment outcomes are often difficult to evaluate. The antibiotic regimens that are commonly used in clinical practice have changed rapidly. They show much regional variation with little critical comparison of treatment results. The clinical diagnosis and the literature on the treatment of the various stages of Lyme disease are reviewed. The reported data are supplemented with recommendations based on 15 years of clinical experience with this illness.

Azithromycin compared with amoxicillin in the treatment of erythema migrans : A double-blind, randomized, controlled trial

Lyme borreliosis is the most common vectorborne disease in the United States and Europe [1]. Infection begins as a local process after Borrelia burgdorferi is inoculated into the skin by a feeding tick. In most persons, the initial sign of infection is the development of erythema migrans, which is characterized by an annular erythematous skin lesion. Amoxicillin and doxycycline have been advocated as the treatments of choice, primarily on the basis of small, often unblinded, randomized trials and retrospective analyses [2-4]. Azithromycin, an azalide (a new subclass of macrolide antibiotics), has been shown to have excellent in vitro and in vivo activity against B. burgdorferi in the laboratory [5, 6]. In a small, randomized, open study on the treatment of erythema migrans, a 5-day course of azithromycin was reported to be as effective as a 10-to 20-day course of doxycycline or amoxicillin with probenecid [7]. To more thoroughly assess the efficacy of azithromycin and further define the treatment of erythema migrans, we conducted this large, multicenter, double-blind, randomized trial. Amoxicillin rather than doxycycline was chosen as the comparative agent to circumvent the problems associated with sun-related hypersensitivity reactions. During the study, we clarified important clinical questions about the natural history of this disease, its manifestations, and the usefulness of enzyme-linked immunosorbent assay (ELISA) for serologic testing. Methods Patients Adult patients who had had erythema migrans diagnosed by a physician were recruited between June 1990 and October 1991 from 12 centers in eight states: New York (83 patients), Connecticut (85 patients), Missouri (35 patients), Wisconsin (23 patients), New Jersey (10 patients), Minnesota (6 patients), California (2 patients), and Rhode Island (2 patients). To be eligible for the study, patients had to be at least 12 years of age and had to weigh at least 45 kg. Erythema migrans lesions at least 5 cm in diameter were photographed for documentation. Pregnant or nursing women were not enrolled. Exclusion criteria included frank arthritis or objective evidence of central nervous system or cardiac (second- or third-degree block) involvement at time of presentation; evidence of meningismus or Bell palsy with pleocytosis [more than 7 cells/mm3]; and history of 1) nervous system, cardiac, rheumatic, or collagen vascular disease, 2) an immediate hypersensitivity reaction to -lactam antibiotics or macrolides, 3) any antibiotic therapy within 72 hours before enrollment or use of any antibiotic during the study other than those supplied, or 4) antibiotic treatment for Lyme disease during the preceding 12 months. The study protocol was approved by the Institutional Review Board of each study center, and all participants gave written informed consent. Clinical Diagnostic Evaluations Patients were evaluated by a physician at baseline and 8, 20, 30, 90, and 180 days after initiation of therapy. Subjective symptom scores for 11 key symptoms (fatigue, joint pain, headache, muscle pain, anorexia, stiff neck, fevers, paresthesias, dizziness, cough, and nausea and vomiting) were recorded on a visual analog scale at each evaluation. Blood samples were obtained for B. burgdorferi serologic testing (IgG and IgM), hepatitis B serologic tests, and liver function tests. Electrocardiography was done. All tests except for the hepatitis B serologic test were repeated on days 8, 20, and 30. In addition, blood samples for B. burgdorferi serologic testing and electrocardiograms were obtained at the 90- and 180-day evaluations. All ELISAs for Lyme disease were done at the University of Minnesota as previously described [8]. Patients were seen at unscheduled visits if indicated by their clinical condition. Treatment and Study Design Patients were stratified by the presence of flu-like constitutional symptoms (such as fever, chills, headache, malaise, fatigue, arthralgias, and myalgias) and then randomly assigned to one of the two treatment arms. Each center was given a randomization schedule for two types of presenting symptoms: erythema migrans alone and erythema migrans with flu-like symptoms. These randomization schedules consisted of sequential numbers to which the following study drug regimens were allocated: 500 mg of azithromycin once daily and placebo doses twice daily (to match the three-times-daily dosing regimen of amoxicillin); or amoxicillin, 500 mg three times daily. The drugs were provided by Pfizer Central Research in a double-matching (dummy) form so that all pills for both groups of patients were identical. All patients received the oral (active or placebo) medication for 20 days, but those in the azithromycin group received active drug for only 7 days. Both the clinical investigator and the patient were blinded to treatment assignments. Efficacy was evaluated in the patients who returned for an examination on day 20 and had taken at least one half of their medication. Patients who withdrew from the study because of adverse events and who took less than one half of their medication were considered nonevaluable for efficacy analysis. Response was assessed by clearance or persistence of erythema migrans and presenting objective signs and by relief of symptoms (assessed using the visual analog scale), and was then graded according to the following criteria. 1. Complete response: complete clearance of erythema migrans and all objective signs and greater than 75% relief of presenting symptoms. 2. Partial response: 1) complete clearance of erythema migrans with persistent signs and 50% to 75% relief of symptoms or 2) persistent erythema migrans with complete clearance of signs and greater than 75% relief of symptoms. 3. Treatment failure: 1) persistent erythema migrans, persistent signs, and less than 50% relief of symptoms or 2) development of new signs and symptoms of disease before the examination on day 20. Symptom relief was calculated as a percent reduction from baseline in the sum of the symptom scores on the visual analog scale. On subsequent examinations up to 180 days, patients were evaluated for relapse, which was defined as any objective evidence of arthritis, evanescent skin lesions, facial palsies, atrioventricular heart block, or peripheral or central nervous system disease, including meningitis. Toleration of treatment was determined from treatment-related adverse events and laboratory abnormalities. Statistical Analysis To compare responses to therapy, we used chisquare analysis or the Fisher exact test (two-tailed) for ordinal data and the t-test (two-tailed) for interval data. Confidence intervals on percentages were calculated using a normal approximation with are sine transformation. Results Study Population The baseline demographic and clinical characteristics of the patients are shown in Table 1. The mean diameter of the largest erythema migrans lesion, the distribution of single and multiple erythema migrans lesions, the presence of concomitant flu-like illness, and the seropositivity rate did not differ significantly between the treatment groups. The baseline characteristics were similar, except that the azithromycin group had more patients with multiple erythema migrans lesions. Table 1. Baseline Demographic and Clinical Characteristics of Evaluable Patients On physical examination at study entry, the most common signs of disease included lymphadenopathy (18%; lymphadenopathy was regional in 40 patients and generalized in 3), pain on neck flexion (13%), muscle tenderness (12%), and joint tenderness (11%) (Table 2). Of the 11 self-reported symptoms, the most frequent were fatigue (52%), joint pain (34%), headache (29%), muscle pain (26%), anorexia (24%), fever (22%), and stiff neck (21%) (Table 2). Electrocardiographic abnormalities (first-degree block) attributed to Lyme disease were present in four patients (2%); none had cardiac abnormalities by day 20. Although one patient, who had first-degree heart block, had a relapse (joint pain) at 180 days, his electrocardiogram continued to be normal. Mild liver function abnormalities were noted in more than 20% of patients; increases in aminotransferase levels occurred most frequently. Table 2. Clinical Manifestations of Erythema Migrans in Evaluable Patients Of the 246 patients enrolled, 217 (88%) were evaluable for efficacy at day 20. Seven patients (2 receiving azithromycin and 5 receiving amoxicillin) were excluded because they had received less than 50% of their study medication as a result of adverse events; 17 patients (8 receiving azithromycin and 9 receiving amoxicillin) did not return for the follow-up examination at day 20; 2 patients (both receiving amoxicillin) were noncompliant; and 3 patients (all receiving azithromycin) did not meet entry criteria. The baseline signs of disease in the nonevaluable patients were regional lymphadenopathy (9 patients [31%]), muscle tenderness (1 patient [3%]), neck pain (2 patients [7%]), pharyngitis (4 patients [14%]), evanescent erythema migrans (3 patients [10%]), right upper quadrant tenderness (1 patients [3%]), and first-degree atrioventricular block (1 patient [3%]). The baseline symptoms of these patients were fatigue (13 patients [45%]), joint pain (8 patients [28%]), headache (7 patients [24%]), muscle pain (7 patients [24%]), anorexia (5 patients [17%]), stiff neck (11 patients [38%]), fever (4 patients [14%]), paresthesia (4 patients [14%]), dizziness (3 patients [10%]), and cough (2 patients [7%]). Response to Therapy Twenty days after the initiation of therapy, 93 of 106 patients treated with amoxicillin (88% [95% CI, 80% to 93%]) had had a complete response to therapy compared with 84 of 111 patients treated with azithromycin (76% [CI, 67% to 83%]) (P = 0.024) (Table 3). Furthermore, 3 patients treated with azithromycin had not responded or had worsened within the first 20 days (for example, they had persistent erythema migrans, joint tenderness,

Treatment of early lyme disease

PURPOSE To compare the safety and efficacy of azithromycin, amoxicillin/probenecid, and doxycycline for the treatment of early Lyme disease, to identify risk factors for treatment failure, and to describe the serologic response in treated patients. PATIENTS AND METHODS Fifty-five patients with erythema migrans and two patients with flu-like symptoms alone and fourfold changes in antibody titers to Borrelia burgdorferi were randomized to receive (1) oral azithromycin, 500 mg on the first day followed by 250 mg once a day for 4 days; (2) oral amoxicillin 500 mg and probenecid 500 mg, three times a day for each for 10 days; or (3) doxcycline, 100 mg twice a day for 10 days. If symptoms were still present at 10 days, treatment was extended with amoxicillin/probenecid or doxycycline for 10 more days. Evaluations were done at study entry and 10, 30, and 180 days later. RESULTS Three of the patients who initially had symptoms suggestive of spread of the spirochete to the nervous system, one from each antibiotic treatment group, subsequently developed neurologic abnormalities, but symptoms in the other 54 patients resolved within 3 to 30 days after study entry. Six of the 19 patients (32%) (95% confidence interval, 13% to 57%) given amoxicillin/probenecid developed a drug eruption, whereas none of the patients given azithromycin or doxycycline had this complication. The presence of dysesthesias at study entry was the only risk factor significantly associated with treatment failure (p less than 0.001). By convalescence, 72% of the patients were seropositive, and 56% still had detectable IgM responses to the spirochete 6 months later. CONCLUSIONS The three antibiotic regimens tested in this study were generally effective for the treatment of early Lyme disease, but the regimens differ in the frequency of side effects and in ease of administration.

Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive serologic result for Lyme disease : a cost-effectiveness analysis

Since the original observation of Lyme disease in 1975 in the United States [1], an increase has occurred in the number of articles in the lay and medical press defining its cause, epidemiology, clinical features, and response to therapy, which has resulted in increased awareness of Lyme disease by both physicians and the lay public. Conventionally, the clinical expressions of Lyme disease have been divided into three stages [2]. The first stage begins up to 1 month after a tick bite and is characterized by a pathognomonic skin lesion, erythema chronicum migrans, and associated flu-like symptoms [3]. With dissemination of the infection, prominent systemic symptoms (fever, myalgia, arthralgia, headache, stiff neck) and multiple, secondary skin lesions may occur. In this second stage of Lyme disease, other systemic features may occur, including objective neurologic abnormalities (cranial neuropathies, radiculopathies, meningitis, meningoencephalitis), cardiac manifestations (myocarditis or abnormalities of atrioventricular conduction) [4, 5], and a skin condition known as lymphadenosis benigna cutis. Intermittent oligoarticular and asymmetrical arthritis may also begin during this stage of illness. The third or chronic stage occurs months to years after the initial tick bite and may be expressed by oligoarticular arthritis, particularly affecting the knees. In a small percentage of patients, the arthritis may become chronic, with erosion of cartilage and bone [6]. In addition, this stage can include a chronic skin lesion (acrodermatitis chronica atrophicans, seen predominantly in Europe) [7] and chronic neurologic abnormalities (including subtle encephalopathy and peripheral neuropathies), sometimes called tertiary neuroborreliosis [8-10]. Nonspecific symptoms such as headache, fatigue, and arthralgias can occur during any of the three stages. Approximately 20% of patients with later manifestations of Lyme disease recall no history of tick bite or erythema chronicum migrans [11]. Similarly, patients with Lyme disease arthritis may have no history of earlier symptoms [6]. Although the skin rash and flu-like symptoms of early Lyme disease (stage 1) can be adequately treated in most instances with oral antibiotics [12, 13], later disease symptoms clearly require more aggressive antibiotic therapy [2, 4, 10, 14, 15]. Because the etiologic agent, Borrelia burgdorferi, is difficult to culture, the diagnosis of Lyme disease is based on the occurrence of [1] one or more of the classical features and [2] serum antibodies to the etiologic spirochete after the first 4 to 6 weeks of illness. This has resulted in increased testing for antibodies to B. burgdorferi, the causative agent of Lyme disease, in many patients with nonspecific somatic complaints or fatigue. Increasing numbers of such patients, who completely lack any of the classic clinical features for Lyme disease, are receiving empirical, parenteral antibiotic treatment for suspected late-stage, chronic Lyme disease [16-21]. This treatment consists of 2 to 3 weeks of daily intravenous cephalosporin (ceftriaxone, Rocephin; Roche Laboratories, Nutley, New Jersey) therapy costing between

Clinical manifestations of Lyme disease.

3000 and

Lyme disease: clinical manifestations, diagnosis, and treatment.

5000. Although little doubt exists that a 2- to 4-week course of intravenous antibiotic therapy can often cure unequivocal, objective symptoms of disseminated (second-stage) and chronic (third-stage) Lyme disease, we found no reports in the peer-reviewed literature suggesting effectiveness of empirical, intravenous antibiotic treatment in patients with nonspecific complaints and a positive antibody titer for Lyme disease. Several reports exist indicating a lack of efficacy of this therapy [16-21]. Nonetheless, many patients with only nonspecific symptoms are given therapy empirically for months. A most striking example is the report of Genese and colleagues [20] of patients given as many as seven courses of intravenous antibiotic therapy. Twenty-five patients who received this therapy for as long as 170 days developed biliary disease, and 14 of these patients needed cholecystectomy. Twenty-two patients in the same cohort developed 29 bloodstream infections associated with intravenous catheter use after a median of 152.5 days of catheterization (range, 16 to 764 days) [20]. Our report examines the risks and benefits of two alternative therapeutic interventions: 1) empirical intravenous antibiotic treatment of the nonspecifically symptomatic patient who has a positive Lyme antibody titer or 2) no antibiotic treatment of such a patient. The analysis indicates that even in a best-case scenario, the risks and dollar costs of empirical therapy are substantially greater than the benefits. Methods To evaluate the relative benefits and costs of the above two alternatives, the following procedures were developed. Data on the epidemiology of Lyme disease, the performance of serologic tests for the disease and the response to parenteral therapy were obtained by computerized search of peer-reviewed literature. Serologic Tests for Lyme Disease No standardized method exists for titering serum antibodies to B. burgdorferi. The two most commonly used methods include enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescent assay using crude homogenates of the etiologic organism [19-26]. Because the ELISA method was developed using standards from the indirect immunofluorescence assay, it behaves similarly to the latter, and it is the method typically used now, we have not considered the latter assay in this analysis. Most investigators have considered a titer by ELISA to be positive if it exceeds by two standard deviations the mean for a group of normal sera [22-26]. Because the serologic test essentially defines the patients affected by this analysis, it is appropriate to examine both the sensitivity and the specificity of this test in different groups of patients. If one assumes a relatively normal distribution of titers in the normal population, then 2.5% of that normal population would be expected to exceed the mean by two standard deviations and thus would have false-positive results. If properly done, the test will detect cross-reactive antibody in patients with other spirochetal diseases. False-positive results have also been reported in varicella infections, infectious mononucleosis, rheumatoid arthritis, and systemic lupus erythematosus. However, after eliminating positive results due to cross-reactivity, published reports indicate a specificity in the ELISA assay of between 97% and 100%. In our baseline analysis, we assumed 100% sensitivity (because it is a positive titer that identifies patients for inclusion in this analysis in the first place) and a specificity of 98% (that is, 2% false positivity). Although investigators anticipate that using purified spirochetal epitopes as antigen in the ELISA in the future will greatly increase specificity, these epitopes are not available. Although Western blot testing is available for a nominal sum, it has not been standardized, and its specificity is only 95%. The specificity of antibody reactivity with any of the several possible epitopes has not been established, and considerable disagreement exists about whether the number of lines, the position of lines, or the intensity of lines in Western blots distinguish true- from false-positive results [27, 28]. In Western blots, many of the antibodies in sera from true-positive patients recognize antigenic epitopes shared by other bacteria. Thus, persons with neither classical Lyme disease nor positive ELISA results have sera that can react with many lines on Western blots, so the specificity of this method and its role in diagnosis is undefined [27, 28]. Therefore, it is the current ELISA technology that is most relevant to our policy statement. Regional Incidences of Lyme Disease and the Fatigue and Myalgia Syndrome A major consideration in attempting to calculate the likelihood of risks and benefits of the parenteral antibiotic intervention is the prior likelihood or incidence of Lyme disease in a given area. Town-specific incidences in the state in which the disease was first defined were 815 per 100 000 (0.8%) in the most endemic area, with a county-specific incidence of 114 per 100 000 (0.1%) and a statewide incidence of 23 per 100 000 (0.02%) [29]. A national surveillance study by Tsai and colleagues [30] from 1987 to 1988 indicated the incidences shown in Table 1. Table 1. Regional Incidence of Lyme Disease It should be noted that the incidence, even within states known to be endemic, can vary greatly. Epidemiologic studies have suggested that the rate of subclinical infection in endemic areas may vary from none to about the same rate as clinically apparent infections [11, 31, 32]. To bias this analysis in favor of antibiotic therapy, we have assumed the latter, that is, for every person contracting Lyme disease in Table 1, one infected asymptomatic seroconverter was at risk for having fatigue and myalgia as the sole symptom of Lyme disease. No data exist on the prevalence of Lyme disease in these areas; however, a period prevalence can be calculated by multiplying the incidence by the duration of the disease. We have assumed that a patient with the fatigue and myalgia syndrome will seek medical attention well within the first 2 years of symptom onset. Thus, in the mid-Atlantic region (where our assumption assumes an incidence rate of 6 nontypical/asymptomatic seroconverters per 100 000 population per year), the prevalence of seroconverters at the end of 2 years will be 12/100 000, which we have used as the baseline assumption for the prevalence of true-positive seroconverters in this analysis. In one report from a small island community in New York State, 9.7% of 176 persons had positive Lyme serologic results. We have examined the implications of this prevalence in our sensitivity analysis. As mentioned earlier, the prevalence of the fatigue and myalgia syndrome, custo