David T. Dennis

PROPHYLAXIS WITH SINGLE-DOSE DOXYCYCLINE FOR THE PREVENTION OF LYME DISEASE AFTER AN IXODES SCAPULARIS TICK BITE

BACKGROUND It is unclear whether antimicrobial treatment after an Ixodes scapularis tick bite will prevent Lyme disease. METHODS In an area of New York where Lyme disease is hyperendemic we conducted a randomized, double-blind, placebo-controlled trial of treatment with a single 200-mg dose of doxycycline in 482 subjects who had removed attached I. scapularis ticks from their bodies within the previous 72 hours. At base line, three weeks, and six weeks, subjects were interviewed and examined, and serum antibody tests were performed, along with blood cultures for Borrelia burgdorferi. Entomologists confirmed the species of the ticks and classified them according to sex, stage, and degree of engorgement. RESULTS Erythema migrans developed at the site of the tick bite in a significantly smaller proportion of the subjects in the doxycycline group than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of 247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87 percent (95 percent confidence interval, 25 to 98 percent). Objective extracutaneous signs of Lyme disease did not develop in any subject, and there were no asymptomatic seroconversions. Treatment with doxycycline was associated with more frequent adverse effects (in 30.1 percent of subjects, as compared with 11.1 percent of those assigned to placebo; P<0.001), primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent). Erythema migrans developed more frequently after untreated bites from nymphal ticks than after bites from adult female ticks (8 of 142 bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly after bites from nymphal ticks that were at least partially engorged with blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from unfed, or flat, nymphal ticks [0 percent]; P=0.02). CONCLUSIONS A single 200-mg dose of doxycycline given within 72 hours after an I. scapularis tick bite can prevent the development of Lyme disease.

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

Tularemia Outbreak Investigation in Kosovo: Case Control and Environmental Studies

A large outbreak of tularemia occurred in Kosovo in the early postwar period, 1999-2000. Epidemiologic and environmental investigations were conducted to identify sources of infection, modes of transmission, and household risk factors. Case and control status was verified by enzyme-linked immunosorbent assay, Western blot, and microagglutination assay. A total of 327 serologically confirmed cases of tularemia pharyngitis and cervical lymphadenitis were identified in 21 of 29 Kosovo municipalities. Matched analysis of 46 case households and 76 control households suggested that infection was transmitted through contaminated food or water and that the source of infection was rodents. Environmental circumstances in war-torn Kosovo led to epizootic rodent tularemia and its spread to resettled rural populations living under circumstances of substandard housing, hygiene, and sanitation.

Cases of Cat-Associated Human Plague in the Western US, 1977–1998

Exposure to cats infected with Yersinia pestis is a recently recognized risk for human plague in the US. Twenty-three cases of cat-associated human plague (5 of which were fatal) occurred in 8 western states from 1977 through 1998, which represent 7.7% of the total 297 cases reported in that period. Bites, scratches, or other contact with infectious materials while handling infected cats resulted in 17 cases of bubonic plague, 1 case of primary septicemic plague, and 5 cases of primary pneumonic plague. The 5 fatal cases were associated with misdiagnosis or delays in seeking treatment, which resulted in overwhelming infection and various manifestations of the systemic inflammatory response syndrome. Unlike infections acquired by flea bites, the occurrence of cat-associated human plague did not increase significantly during summer months. Plague epizootics in rodents also were observed less frequently at exposure sites for cases of cat-associated human plague than at exposure sites for other cases. The risk of cat-associated human plague is likely to increase as residential development continues in areas where plague foci exist in the western US. Enhanced awareness is needed for prompt diagnosis and treatment.

Plague as a Biological Weapon

Three well-documented plague pandemics have occurred in the past two millennia, resulting in more than 200 million deaths and great social and economic chaos (Perry and Fetherston, 1997; Pollitzer, 1954). The Justinian pandemic arose in northern Africa in the mid-6th century, and by the 7th century had spread throughout the Mediterranean and near-eastern regions—severely impacting both the Roman and Byzantine empires. The second pandemic, the Black Death or great pestilence, originated in Central Asia, was carried to Sicily in 1347 via ships from the Crimea, and rapidly swept through medieval Europe. By 1352, it had killed 30% or more of afflicted populations, slowly playing itself out in successive epidemics, including the Great Plague of London in 1665 (Perry and Fetherston, 1997). The third (Modern) pandemic began in southwestern China in the mid-19th, struck Hong Kong in 1894, and was soon carried by rat-infested steamships to port cities on all inhabited continents, including several in the United States (US) (Link, 1955; Pollitzer, 1954). By 1930, the third pandemic had caused more than 26 million cases and 12 million deaths. Plague in these three pandemics was predominantly the bubonic form, emanating from Yersinia pestis-infected rats and fleas, although terrifying outbreaks of the more virulent person-to-person spreading pneumonic form were recorded during the course of each. The explosive contagiousness and severity of pneumonic plague was most completely documented in Manchurian epidemics in the early 20th century, which involved tens of thousands of cases, virtually all of them fatal (Wu, 1926).

The Cost Effectiveness of Vaccinating against Lyme Disease

To determine the cost effectiveness of vaccinating against Lyme disease, we used a decision tree to examine the impact on society of six key components. The main measure of outcome was the cost per case averted. Assuming a 0.80 probability of diagnosing and treating early Lyme disease, a 0.005 probability of contracting Lyme disease, and a vaccination cost of

Coccidioidomycosis among workers at an archeological site, northeastern Utah.

50 per year, the mean cost of vaccination per case averted was

Test-treatment strategies for patients suspected of having Lyme disease: a cost-effectiveness analysis.

4,466. When we increased the probability of contracting Lyme disease to 0.03 and the cost of vaccination to

Gentamicin and Tetracyclines for the Treatment of Human Plague: Review of 75 Cases in New Mexico, 1985–1999

100 per year, the mean net savings per case averted was

First Reported Prairie Dog–to-Human Tularemia Transmission, Texas, 2002

3,377. Since few communities have average annual incidences of Lyme disease >0.005, economic benefits will be greatest when vaccination is used on the basis of individual risk, specifically, in persons whose probability of contracting Lyme disease is >0.01.