Raymond J. Dattwyler

The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi.

The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia burgdorferi, the spirochete that causes this disorder. Although prompt treatment with antibiotics may abrogate the antibody response to the infection, symptoms persist in some patients. We studied 17 patients who had presented with acute Lyme disease and received prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently developed. Although these patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls. The patients had a vigorous T-cell proliferative response to whole B. burgdorferi, with a mean ( +/- SEM) stimulation index of 17.8 +/- 3.3, similar to that (15.8 +/- 3.2) in 18 patients with chronic Lyme disease who had detectable antibodies. The T-cell response of both groups was greater than that of a control group of healthy subjects (3.1 +/- 0.5; P less than 0.001). We conclude that the presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to B. burgdorferi is evidence of infection in seronegative patients with clinical indications of chronic Lyme disease.

Lyme neuroborreliosis: Central nervous system manifestations

We evaluated 85 patients with serologic evidence of Borrelia burgdorferi infection. Manifestations included encephalopathy (41), neuropathy (27), meningitis (2), multiple sclerosis (MS) (6), and psychiatric disorders (3). We performed lumbar punctures in 53, brain MRI in 33, and evoked potentials (EPs) in 33. Only patients with an MS-like illness had abnormal EPs, elevated IgG index, and oligoclonal bands in the cerebrospinal fluid. Twelve of 18 patients with encephalopathy, meningitis, or focal CNS disease had evidence of intrathecal synthesis of anti-B burgdorferi antibody, compared with no patients with either MS-like or psychiatric illnesses, and only 2/24 patients with neuropathy. MRIs were abnormal in 7/17 patients with encephalopathy, 5/6 patients with an MS-like illness, and no others. We conclude that (1) intrathecal concentration of specific antibody is a useful marker of CNS B burgdorferi infection; (2) Lyme disease causes an encephalopathy, probably due to infection of the CNS; (3) MS patients with serum immunoreactivity against B burgdorferi lack evidence of CNS infection with this organism.

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,

CEFTRIAXONE COMPARED WITH DOXYCYCLINE FOR THE TREATMENT OF ACUTE DISSEMINATED LYME DISEASE

BACKGROUND Localized Lyme disease, manifested by erythema migrans, is usually treated with oral doxycycline or amoxicillin. Whether acute disseminated Borrelia burgdorferi infection should be treated differently from localized infection is unknown. METHODS We conducted a prospective, open-label, randomized, multicenter study comparing parenteral ceftriaxone (2 g once daily for 14 days) with oral doxycycline (100 mg twice daily for 21 days) in patients with acute disseminated B. burgdorferi infection but without meningitis. The erythema migrans skin lesion was required for study entry, and disseminated disease had to be indicated by either multiple erythema migrans lesions or objective evidence of organ involvement. RESULTS Of 140 patients enrolled, 133 had multiple erythema migrans lesions. Both treatments were highly effective. Rates of clinical cure at the last evaluation were similar among the patients treated with ceftriaxone (85 percent) and those treated with doxycycline (88 percent); treatment was considered to have failed in only one patient in each group. Among patients whose infections were cured, 18 of 67 patients in the ceftriaxone group (27 percent) reported one or more residual symptoms at the last follow-up visit, as did 10 of 71 patients in the doxycycline group (14 percent, P > or = 0.05). Mild arthralgia was the most common persistent symptom. Both regimens were well tolerated; only four patients (6 percent) in each group withdrew because of adverse events. CONCLUSIONS In patients with acute disseminated Lyme disease but without meningitis, oral doxycycline and parenterally administered ceftriaxone were equally effective in preventing the late manifestations of disease.

Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis

72 adults with erythema migrans (early Lyme borreliosis) were enrolled in a randomised prospective trial comparing amoxycillin 500 mg plus probenecid 500 mg three times a day with doxycycline 100 mg twice a day for 21 days. These antibiotic regimens were chosen because of the known in-vitro sensitivity of Borrelia burgdorferi, the antibiotic tissue penetration, the pharmacokinetics of the drugs, and because the organism can disseminate early in the course of infection. 72 patients were evaluable (35 in the doxycycline group and 37 in the amoxycillin/probenecid group). The two regimens were equally effective for treatment of erythema migrans. Mild fatigue or arthralgia were the only post-treatment complaints, which resolved within 6 months. None of the patients needed further antibiotic treatment for Lyme borreliosis.

Lyme disease Cause of a treatable peripheral neuropathy

Peripheral nerve dysfunction was demonstrated in 36% of patients with late Lyme disease. Of 36 patients evaluated, 14 had prominent limb paresthesias. Thirteen of these had neurophysiologic evidence of peripheral neuropathy; neurologic examinations were normal in most. Repeat testing following treatment documented rapid improvement in 11 of 12. We conclude that this neuropathy, which is quite different from the infrequent peripheral nerve syndromes previously described in this illness, is commonly present in late Lyme disease. This neuropathy presents with intermittent paresthesias without significant deficits on clinical examination and is reversible with appropriate antibiotic treatment. Neurophysiologic testing provides a useful diagnostic tool and an important measure of response to treatment.

Neurologic manifestations in children with North American Lyme disease

To delineate the spectrum of neurologic manifestations and the relative frequencies of different syndromes associated with North American Lyme disease, we describe 96 children referred for neurologic problems in the setting of Borrelia burgdorferi infection. The most frequent neurologic symptom was headache, and the most common sign was facial palsy. Less common manifestations were sleep disturbance, and papilledema associated with increased intracranial pressure. Signs and symptoms of peripheral nervous system involvement were infrequent. The most common clinical syndromes were mild encephalopathy, lymphocytic meningitis, and cranial neuropathy (facial nerve palsy). In contrast with adult patients with neurologic Lyme disease, meningoradiculitis (Bannwarths syndrome) and peripheral neuropathy syndromes were rare. However, a “pseudotumor cerebri-like” syndrome seems to be unique to North American pediatric Lyme disease.

Antiscience and ethical concerns associated with advocacy of Lyme disease.

Advocacy for Lyme disease has become an increasingly important part of an antiscience movement that denies both the viral cause of AIDS and the benefits of vaccines and that supports unproven (sometimes dangerous) alternative medical treatments. Some activists portray Lyme disease, a geographically limited tick-borne infection, as a disease that is insidious, ubiquitous, difficult to diagnose, and almost incurable; they also propose that the disease causes mainly non-specific symptoms that can be treated only with long-term antibiotics and other unorthodox and unvalidated treatments. Similar to other antiscience groups, these advocates have created a pseudoscientific and alternative selection of practitioners, research, and publications and have coordinated public protests, accused opponents of both corruption and conspiracy, and spurred legislative efforts to subvert evidence-based medicine and peer-reviewed science. The relations and actions of some activists, medical practitioners, and commercial bodies involved in Lyme disease advocacy pose a threat to public health.

Treatment Trials for Post-Lyme Disease Symptoms Revisited

The authors of 4 National Institutes of Health-sponsored antibiotic treatment trials of patients with persistent unexplained symptoms despite previous antibiotic treatment of Lyme disease determined that retreatment provides little if any benefit and carries significant risk. Two groups recently provided an independent reassessment of these trials and concluded that prolonged courses of antibiotics are likely to be helpful. We have carefully considered the points raised by these groups, along with our own critical review of the treatment trials. On the basis of this analysis, the conclusion that there is a meaningful clinical benefit to be gained from retreatment of such patients with parenteral antibiotic therapy cannot be justified.