Arthur Weinstein

Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease

BACKGROUNDnIt is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease.nnnMETHODSnWe conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study.nnnRESULTSnAfter a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients.nnnCONCLUSIONSnThere is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

Laboratory Evaluation in the Diagnosis of Lyme Disease

1. Introduction 1.1 Lyme disease is the most common tick-borne disease in North America. From 1982 through 1994, more than 70 000 cases were reported in North America; most of these cases were in the United States [1]. It is important that clinicians diagnose Lyme disease correctly because efficacious therapy is available and delayed or inadequate treatment can lead to many morbid sequelae. Lyme disease is a complex multisystem disease caused by the spirochete Borrelia burgdorferi [2]. It affects persons of all ages and both sexes. Since the disease was recognized in Connecticut in 1975 [3], endemic areas have been identified in several regions in North America. In more restricted areas in some northeastern and upper midwestern U.S. states, the disease has assumed the characteristics of an emerging epidemic [4-9]. The true incidence is almost certainly underestimated because of under-reporting [10, 11]. 1.2 Most patients develop a distinctive rash, erythema migrans, that is accompanied by such flu-like symptoms as fatigue, headache, mild stiff neck, joint and muscle aches, and fever [12]. Some weeks or months after the initial exposure, symptoms and signs of disseminated disease (particularly neurologic, cardiac, or articular disease) may develop in untreated patients [13, 14]. 1.3 Case definitions of Lyme disease have been developed in the United States for national disease surveillance purposes. A positive serologic test result was initially required for patients who had erythema migrans alone and had not been exposed to Lyme disease in endemic areas [15], but the 1990 criteria established in the Centers for Disease Control and Preventions (CDCs) U.S. Lyme disease national surveillance definition reduced this requirement to a recommendation (Table 1) [16]. These criteria were developed for an epidemiologic case definition intended for surveillance purposes only. However, previous national disease surveillance criteria have been used in clinical studies [17, 18], and such definitions do provide standardization. Standardization allows comparisons of clinical studies and permits the performance of meta-analysis to facilitate development of clinically useful guidelines. Table 1. Criteria for Confirmed Lyme Disease 1.4 Requests for laboratory testing for Lyme disease have increased rapidly. In Wisconsin, for example, it was reported that more than 60 000 tests were being done annually [19]; in New Jersey, 5000 tests were done in 1 week in 1989 [20]. According to market projections for the United States, 2.79 million rapid tests were to have been done for Lyme disease in 1995 [21]. Testing is often done in persons who have only nonspecific signs and symptoms of illness, such as headache, fatigue, myalgia, or arthralgia. Even in highly endemic areas, the pretest probability of Lyme disease in such patients is less than 0.20 (usually much lower). Thus, even when highly experienced laboratories are used, the probability of a false-positive test result is higher than that of a true-positive result. This problem is compounded by the lack of standardized serologic tests for Lyme disease. Comparisons of the test results from different laboratories have shown poor reliability and accuracy; up to 21% of standardized positive samples are missed, and up to 7% of samples from persons with no known exposure are incorrectly identified as positive [22]. 1.5 This background paper provides a quantitative and qualitative evaluation of the predictive value of the laboratory diagnosis of Lyme disease. This evaluation forms the basis for guidelines on clinical diagnosis. Practitioners have been confused by the lack of consensus on diagnostic criteria for Lyme disease. The causes of this controversy arise from a combination of factors: the use of different tests in different laboratories, the use of different criteria to set positive and negative cutoff values for the same tests, different degrees of quality control in different laboratories, and differences in the community prevalence of Lyme disease. 1.6 We address each of these factors and make recommendations for the diagnostic workup of patients suspected of having Lyme disease. 2. Methods 2.1 Data Sources Relevant articles from the medical literature were identified by searching the MEDLINE database for English-language articles or articles with English-language abstracts published from 1982 (when the spirochetal cause of Lyme disease was established [23, 24]) to 1996. The keywords used were Lyme disease, Borrelia burgdorferi, diagnosis, ELISA, Western blot, immunofluorescence assay, polymerase chain reaction, urinary antigen detection, and culture. The computerized literature search was complemented by citations from authorities in the field. 2.2 Study Selection All identified articles were reviewed by using a modification of the methodologic criteria for evaluating diagnostic tests developed by Irwig and colleagues [25]. The included studies had to provide the following material: a clear statement on the test of interest, a description of the study characteristics that used a design that permitted the calculation of sensitivity and specificity, reproducible information on the sampling and clinical details of patients with the disease of interest and on controls (that is, data on the presence or absence of the criteria for Lyme disease described in the U.S. Lyme disease national surveillance case definition) (Table 1), and reproducible information on the reference standard (that is, cases diagnosed by experts who were blinded to the results of the diagnostic tests being evaluated). Because there are systematic differences in the strains of B. burgdorferi in different parts of the world, studies were excluded if they described results in patients outside of North America. When the same cohort of patients was described in more than one report, the results for individual patients were included only once. 2.3 Data Extraction Sensitivity, specificity, and likelihood ratios were calculated by using established methods [26]; a random-effects model was used to combine the proportions from the eligible studies [27]. 2.4 Estimates of Prevalence and Incidence Levels of the endemicity of Lyme disease in the United States can be estimated by using the annual incidence of Lyme disease reported to the CDC [1] (Figure 1). Figure 1. Rates of Lyme disease cases in the United States in 1993 as reported by states to the Centers for Disease Control and Prevention. 2.5 Epidemiologic studies of Lyme disease in communities in the eastern United States provide important information on the emergence of the disease in populations newly at risk, as well as some estimates of incidence and prevalence [29]. In two clusters of cases in New Jersey, risk was related to residence in new suburban housing developments and to occupational exposures among outdoor workers at a military reservation [6, 7]. A study on Fire Island, a barrier island off the southern coast of Long Island, New York, reported a seasonal incidence of 1% to 3% and a cumulative prevalence of 7.5% among residents of this summer vacation site [5]. A longitudinal study of a community of about 160 persons on Great Island, Massachusetts, found a slow build-up of incidence to a peak of 3 cases per 100 persons per year and a total cumulative prevalence of 16% over a 20-year period [9]. Two population-based studies in highly endemic suburban communities in Westchester, New York, reported seasonal attack rates of 2.6% and 3% and cumulative prevalences of 8.8% and 17%, respectively [30, 31]. On the basis of these data, we considered four categories of endemicity: low (incidence estimate, 0.01%), moderate (incidence estimate, 0.1%), high (incidence estimate, 1%), and very high (incidence estimate, 3%). 2.6 Likelihood Ratios and Treatment Thresholds of Tests Three of the authors constructed scenarios that describe three hypothetical patients. One had diffuse nonspecific muscle pain (scenario A), one had a rash resembling erythema migrans (scenario B), and one had episodic oligoarticular arthritis (scenario C) (Table 2). These models were used to compute the change in the probability of disease using likelihood ratios (likelihood ratio for positive test result = sensitivity [100 specificity]; likelihood ratio for negative test result = [100 sensitivity] specificity) [26] resulting from the use of enzyme-linked immunosorbent assay (ELISA) and Western blotting. Decision analysis was used to assess the relative cost-effectiveness of the management options in these clinical situations when the clinician must decide whether to perform laboratory testing for Lyme disease [32]. Incremental cost-effectiveness ratios were calculated as costs per quality-adjusted life-year for each scenario. This cost-effectiveness study is described in detail in a forthcoming paper [33]. Table 2. Hypothetical Patient Scenarios 3. Data Synthesis 3.1 Microbial Isolation Cultural isolation of B. burgdorferi is the best diagnostic evidence of Lyme disease. Borrelia burgdorferi grows well in Barbour, Stoenner, Kelly (BSK) medium, but it is difficult to obtain isolates from clinical specimens other than biopsy samples from erythema migrans lesions. 3.2 Thirty-four papers were identified by the literature search. None met the criteria formal analysis, but some case reports were worth noting. In the presence of erythema migrans, material has been collected from cutaneous lesions with various techniques, including direct aspiration of involved skin, aspiration after saline instillation, and skin biopsy. Wormser and colleagues [34] reported success rates of 29% with saline-lavage needle aspiration and 60% with 2-mm punch biopsies of the advancing edge of suspected primary erythema migrans lesions. Berger and colleagues [35] reported a success rate of more than 80% with biopsy specimens obtained from the leading edge of erythema migrans lesions. 3.3 Culture from sites other than the erythem

Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus.

The importance of microbial infection as a trigger for the induction of systemic lupus erythematosus is frequently debated. Clinical observations indicate that anti‐viral and anti‐bacterial responses are often accompanied by self reactivity, and anti‐pneumococcal antibodies elicited in non‐autoimmune individuals by pneumococcal vaccine express lupus‐associated anti‐DNA idiotypes. To explore the relationship between protective and pathogenic antibodies in humans, we have used the phage display immunoglobulin expression system to generate a combinatorial library from spleen cells of a lupus patient immunized with a polyvalent pneumococcal polysaccharide vaccine prior to splenectomy. From this library, monovalent antigen‐binding fragments expressing the 3I Vκ1‐associated idiotype were isolated. This idiotype is expressed on up to 90u2009% of anti‐DNA antibodies in the serum of lupus patients and on anti‐pneumococcal antibodies in the serum of non‐autoimmune individuals. Eight 3I+ monovalent antigen‐binding fragments reacting with pneumococcal polysaccharide, DNA or both were analyzed. Four of these fragments were cross‐reactive with both foreign and self antigen, demonstrating that a high percentage of anti‐bacterial antibodies produced in a patient with lupus bind double‐stranded DNA. These studies provide support at the molecular level for a potential role of molecular mimicry in the generation of anti‐DNA antibodies. In addition, this is, to our knowledge, the first panel of fully sequenced human anti‐pneumococcal antibodies.

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.

Acute Adrenal Insufficiency and the Antiphospholipid Syndrome

Excerpt To the Editor:A few cases (1, 2) of massive adrenal hemorrhage associated with the lupus anticoagulant have been reported. We report a patient who had an arterial thrombosis and subsequent ...

The fibromyalgia impact questionnaire: A useful tool in evaluating patients with post–Lyme disease syndrome

OBJECTIVEnTo determine the reliability and validity of a modified version of the Fibromyalgia Impact Questionnaire (FIQ) in evaluating patients with post-Lyme disease syndrome (PLDS).nnnMETHODSnIn this cross-sectional analysis 13 PLDS, 18 fibromyalgia (FM), and 16 healthy controls (n = 47) completed a modified FIQ containing items to evaluate physical impairment, symptom severity, and global well-being. Comparisons between groups were done using analysis of variance with a significance level set at 0.05.nnnRESULTSnPLDS patients demonstrated statistically significantly greater levels of impairment than controls in physical functioning, FIQ total score, global well-being, joint pain, fatigue, depression, ability to perform activities of daily living, and memory/concentration. FM patients demonstrated a statistically significantly greater level of impairment than the control group in all categories, and the scores were significantly higher than the PLDS group in the measurement of physical impairment, FIQ total score, muscle pain, and joint pain. Overall, the instrument possesses good reliability and validity, although adequacy of this instrument to measure impairment in the male PLDS population needs further elucidation.nnnCONCLUSIONnThe results of this study suggest that the modified FIQ may be a useful tool in evaluating PLDS patients. The findings suggest that there may be some differences in the etiopathology of the symptoms experienced by PLDS and FM patients.

Reflex Sympathetic Dystrophy Syndrome Following Air-Bag Inflation

To the Editor: Reflex sympathetic dystrophy syndrome is commonly precipitated by trauma and is characterized by pain and swelling with signs of vasomotor instability in a distal extremity.1 We describe a case of air-bag–induced trauma followed by the reflex sympathetic dystrophy syndrome. A 44-year-old woman had an accident while driving in December 1996. When the air bag inflated, her left and right hands, which were initially on the steering wheel, were pushed back against the window and the seat, respectively. Both carpometacarpal joints were dislocated, causing severe pain. After closed reduction, casts were applied for four weeks. Although the right .xa0.xa0.