Lyme Disease Endemic Area Research Articles

Lyme Borreliosis–Biology, Epidemiology and Control

Lyme borreliosis is the most common arthropod-borne disease in the United States and Europe, and cases are reported from nearly all regions of the Northern Hemisphere. As such, it is a particularly useful example of a zoonotic disease that should be considered not only from the perspective of the human patient but also from that of the vectors and reservoir hosts. This approach is the one adopted by the editors of Lyme Borreliosis–Biology, Epidemiology and Control. The first five chapters constitute a general review covering characteristics of the disease, molecular biology of the etiologic agent Borrelia burgdorferi sensu lato, and vector and host biology. Some of these chapters are not reviews in the truest sense. For example, chapter 2 is a primer on ecologic research; it provides important definitions and categorization of hosts and vectors. Likewise, a substantial portion of the chapter on B. burgdorferi in the vertebrate host is devoted to the role of complement in host specificity. Still, these chapters provide a good general description of the topics covered. Chapters 6–9 provide more specific detail on the unique aspects of ecology in Europe, Russia, Japan, and North America, respectively. Although these chapters do not follow the same format, all cover essentially identical topics, including description of the diversity of spirochete species, vectors, hosts, landscape ecology, and risk factors. The chapter on the ecology of B. burgdorferi in Russia is particularly worthwhile because many of the studies described have only been published to date in Russian-language journals. This information is now available to a broader audience. The final three chapters deal with epidemiology, prevention, and control. The chapter by Dennis and Hayes on epidemiology is outstanding and provides an excellent consideration of several controversial topics, including seronegative Lyme disease, persistent infection, chronic refractory Lyme disease, and problems of both underdiagnosis (in Lyme disease–endemic areas) and overdiagnosis. Hayes and Schriefer provide a comprehensive description of vaccine development. Unfortunately, the only commercially available vaccine, Lymerix, has been discontinued by the manufacturer, and little progress is reported on development of alternative vaccines. This leaves personal protective measures (e.g., avoiding tick-infested terrain, using appropriate clothing, checking for attached ticks), single-dose antimicrobial prophylaxis following selected tick bites, and tick control as the primary means of prevention. The last topic is covered in the book’s final chapter. The reader interested in details of the clinical aspects of Lyme disease will not find them here. Rather, the book focuses on vector and host wildlife ecology and epidemiology, as the title implies. There is an obvious effort to cover Lyme borreliosis from a global perspective rather than from a distinctly American one. This approach is one of the book’s strengths, although it does lead to some bias in the selected references in certain chapters. A comprehensive index is provided, and topics covered in multiple chapters are cross-referenced well, providing an integrated feel. The book will be quite useful for ecologists, epidemiologists, and public health workers, especially those interested in vector-borne infectious diseases. The book will be less informative for those interested in detailed descriptions of the molecular pathogenesis and clinical aspects of Lyme borreliosis.

Lyme disease.

To review the presentation, treatment, and prevention of Lyme disease in primary care. Selected articles from the scientific literature and the Centers for Disease Control. Lyme disease is a tick-borne, multisystem inflammatory disease with worldwide distribution caused by the spirochete Borrelia burgdorferi. Lyme disease is initially characterized by a spreading, annular erythema migrans skin rash and can disseminate to the musculoskeletal, neurologic, or cardiovascular system. Stages of the disease present with varying clinical manifestations. Treatment of Lyme disease with appropriate antimicrobial therapy should be prompt in order to avoid debilitating outcomes. Awareness of the many presentations of Lyme disease in endemic areas may facilitate a timely diagnosis and appropriate treatment.

Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis nymphs.

The effect of feeding duration on pathogen transmission was studied for individual ticks infected with either laboratory or field strains of the Lyme disease spirochete Borrelia burgdorferi and field strains of Ehrlichia phagocytophila, an agent of human granulocytic ehrlichiosis. Infected nymphal Ixodes scapularis were allowed to feed individually on mice, and equal numbers were removed at 24-h intervals for < or =96 h. Mice were assayed for infection by culture, serologic testing, and polymerase chain reaction (PCR) analysis. Fed ticks were assayed by culture or PCR analysis. Transmission of B. burgdorferi did not occur during the first 24 h among 66 attempts, with maximum transmission occurring between 48 and 72 h. A model estimating the probability of infection from individual ticks removed by patients in a Lyme disease-endemic area yielded an overall probability of 4.6%. Infected I. scapularis nymphs transmitted E. phagocytophila within 24 h in 2 of 3 attempts, which indicates that daily tick removal may not be adequate to prevent human infection with this agent.

Isolation and morphological characterization of mosquito spirochetes from a Lyme disease endemic area.

Isolation and morphological characterization of mosquito spirochetes from a Lyme disease endemic area.

Safety and immunogenicity profile of a recombinant outer-surface protein a Lyme disease vaccine: Clinical trial of a 3-dose schedule at 0, 1, and 2 months

Objectives This study compared the tolerability of a Lyme disease vaccine administered intramuscularly at 0 and 1 months with that of a vaccine administered at 0, 1, and 2 months to determine (1) whether adding a third dose of vaccine 1 month after the second would affect the safety profile, and (2) whether a shortened vaccination schedule of 0, 1, and 2 months would provide an immune response similar to that obtained with vaccine administered at 0, 1, and 12 months. Background An efficacy trial of a Lyme disease vaccine had demonstrated safety and efficacy against definite (clinically manifested and laboratory-confirmed) Lyme disease after 3 doses at 0, 1, and 12 months and resulted in 90% of subjects having titers ≥1400 enzyme-linked immunosorbent assay units (EL.U)/mL (the proposed seroprotective level for 1 tick season). Methods This multicenter, open-label, prospective, randomized study assessed the safety and efficacy of different doses of a recombinant outer-surface protein A (OspA) vaccine in 956 volunteers aged 17 to 72 years from 3 Lyme disease-endemic sites. Blood samples were collected at months 0, 2, 3, 12, and 13 to assess total immunoglobulin-G anti-OspA titers. Results Most adverse events were transient and mild to moderate. The geometric mean antibody titer increased 2.8-fold from month 2 (1786 EL.U/mL to 4842 EL.U/mL), and ~90% of the volunteers had a titer ≥1400 and 99% had a titer ≥400 EL.U/mL (the minimum seroprotective level at any given time) after the third dose. An antibody kinetics model predicts that protection would last for a typical tick-transmission season. Conclusions In volunteers aged 17 to 72 years, 3 doses of vaccine administered in 2 months was well tolerated, more immunogenic than 2 doses, and provided a higher probability of protection before exposure or travel to Lyme disease-endemic areas.

Estimation of the Transmission Probability of Lyme Borreliosis

Whether physicians should prophylactically treat tick bites in areas endemic for Lyme disease has been debated. The high rates of tick infection (10–50%) found in Lyme disease-endemic areas suggest that tick bites should be treated; conversely, the low rates of Lyme disease (1–4%) found in recent clinical trials of untreated tick-bite victims suggest caution in treatment. Medical advice given from Lyme-disease World Wide Web sites is equally contradictory, ranging from suggesting that all tick bites should be treated to suggesting that no tick bites be treated. To clarify this issue, we estimate the transmission probability of the causative agent of Lyme disease, Borrelia burgdorferi, for different durations of tick attachment. The data used to estimate this transmission probability is obtained from previously published animal studies. The accuracy of these estimates is assessed by comparing model predictions of the number of Lyme disease cases to that actually observed in clinical studies of Lyme disease. Our results suggest that tick bites should be treated only when it is known that the duration of tick attachment is longer than 48 hours.

Density of deer in relation to the prevalence of Borrelia burgdorferi s.l. in Ixodes ricinus nymphs in Rambouillet forest, France.

The Rambouillet Forest, a Lyme disease-endemic area near Paris, France, was surveyed from September 1994 to October 1995 to determine the risk periods and zones for humans. Firstly, during the period of Ixodes ricinus activity, abundance of nymphs is greater in spring than in autumn. Secondly, we observed significant variation in nymphal abundance between zones according to the density of cervids. The polymerase chain reaction (PCR) was used to detect DNA of Borrelia burgdorferi sensu lato in 461 unfed nymphs. DNA was detected in 38 nymphs (8.2%). By genospecific PCR based on the OspA gene, we detected the three pathogenic spirochetes with occurrences of 10.3, 31.1 and 58.6 for B. burgdorferi s.s., Borrelia garinii and Borrelia afzelii, respectively, indicating that B. afzelii is probably the main Borrelia species in the Rambouillet Forest. Finally, 11.5% of positive nymphs exhibited a double infection. Infection rates of I. ricinus nymphs by B. burgdorferi s.l. were not significantly different throughout the year for a given area, indicating that the risk periods of acquiring Lyme disease are mainly linked to nymph activity and correspond to spring and autumn. Likewise infection rates of nymphs were not significantly different between zones with a high density of deer (more than 100 animals per 100 ha) and zones with lower deer density (less than 20 animals per 100 ha). In addition to the role of deer as an amplifier of tick populations, these data indicate that zones with a high density of cervids should be considered as higher risk areas.

Landscape features associated with lyme disease risk in a suburban residential environment

The landscape features of residential properties within two communities were studied in relation to the abundance of the tick vector Ixodes scapularis. Habitat types of 400 properties, located in a Lyme disease endemic area of Westchester Co., New York, USA, were categorized into lawn, ornamental, ecotone, woods, and stone wall as measured from aerial photographs and sampled for nymphal-stage ticks. Logistic regression results indicate that presence or absence of ticks is influenced by the proportion of either lawn or woodland, and total woodland area. Poisson regression results indicate the abundance of nymphs is negatively associated with proportion, area, and patch frequency of lawn, and positively associated with proportion, area, and patch frequency of woodland. Predictions of tick presence and abundance from landscape features at the scale of individual property is useful for implementing disease prevention measures.

Morphologic, immunohistochemical, and ultrastructural characterization of a distinctive renal lesion in dogs putatively associated with Borrelia burgdorferi infection: 49 cases (1987-1992).

A distinctive renal lesion consisting of glomerulonephritis, diffuse tubular necrosis with regeneration, and interstitial inflammation was found in 49 biopsy/necropsy cases obtained from 1987 to 1992. This lesion is manifested clinically as a rapidly progressive glomerular disease that was uniformly fatal. Immune-mediated membranoproliferative glomerulonephritis predominated (43/49, 88%). Membranous glomerulonephritis (5/49, 10%) and amyloidosis (1/49, 2%) were also noted. Subendothelial deposits, IgG, IgM, and C3 were present along glomerular basement membranes. IgA was absent. The exact cause of the tubular necrosis is unknown. Affected dogs were significantly younger (5.6 +/- 2.6 years) than dogs with other forms of glomerulonephritis (7.1 +/- 3.6 years) and amyloidosis (7.8 +/- 3.5 years) both in the studied population for the same period and in the reported canine population. Labrador and Golden retrievers were 6.4 and 4.9 times more likely, respectively, to develop this lesion. This is the first report of a breed predilection for spontaneous canine glomerulonephritis. Previous reports have associated this lesion with Borrelia burgdorferi exposure. All dogs in this study were from Lyme disease-endemic areas. Of 18 dogs serologically tested, all were positive for exposure. Silver stain examination of kidneys revealed rare spirochetes, suggesting that the presence of spirochetes in the kidney is apparently unrelated to lesion development. The role of vaccination in development of the renal lesion is undetermined. The association of this histologically and clinically unique lesion, Lyme nephritis, with Borrelia burgdorferi infection is significant because it is the only fatal form of canine Lyme borreliosis.

Seasonal and long-term variations in abundance of adult Ixodes scapularis (Acari:Ixodidae) in different coastal plain habitats of New Jersey.

Fifteen sites in 4 different vegetation types in a Lyme disease endemic area were surveyed during times of peak tick activity in fall of 1982, 1984, and 1992, and subsequent spring activity periods to determine seasonal and year-to-year differences in habitat use by the blacklegged tick, Ixodes scapularis Say. Populations of I. scapularis adults varied significantly among the 3 yr surveyed, although this variability tended to be more pronounced in fall. I. scapularis adults were consistently more abundant in the fall than spring. Significant seasonal and year-to-year differences in adult populations were observed between and within vegetation types. However, the variability in habitat use was generally lower in spring compared with fall. In most of the surveys, the 5 sites yielding the greatest number of adults were represented by 3 or 4 of the vegetation types. Explanations for this variability and implications for tick surveillance and reducing risk of Lyme disease transmission are discussed.

Risk of Human Exposure to Vector Ticks (Acari: Ixodidae) in a Heavily Used Recreational Area in Northern California

The risk of humans encountering vector ticks along hiking trails or in picnic grounds in a Lyme disease-endemic area was evaluated in a multipurpose recreational area (Tilden Regional Park) in the populous San Francisco Bay region of California. Four hillside hiking trails (two high-use, two low-use) were sampled by dragging and walking through low vegetation biweekly for one year; four heavily used picnic areas were sampled concurrently by dragging. Adults of three human-biting ticks were enumerated (n = 1,911) along all trials: Dermacentor occidentalis (63.6% of total), Ixodes pacificus (26.2%), and D. variabilis (0.2%). Subadults (n = 1,669) of D. occidentalis (0.06% of total) and two nonhuman-biters, D. albipictus (70.3%) and Haemaphysalis leporispalustris (29.7%), also were collected. Dragging yielded many more adult ticks than walking year-round for all trials. These methods were significantly correlated during periods of peak tick abundance, but the associations were not sufficiently strong or consistent to allow prediction of captures for either method based on the other. Adult ticks were distributed largely in clusters along the uphill sides of trails. Several adult ticks collected adjacent to trails were found to contain spirochetes identified with polyclonal antibodies as Borrelia burgdorferi (D. occidentalis, 0 of 861; D. variabilis, 2 of 126 [1.6%]; I. pacificus, 1 of 609 [0.2%]). Picnic areas produced low numbers of adult D. occidentalis and I. pacificus, which prohibited testing them for spirochetes. Two measures for evaluating risk were calculated, the encounter distance (= mean number of meters traveled before encountering a vector tick by either dragging or walking) and the mean number of spirochete-infected ticks encountered by these methods per kilometer of trial. These measures revealed that the risk of exposure to spirochete-infected adult ticks along trails was low year-round irrespective of usage, and risk was even lower in picnic areas. Future studies evaluating human exposure to vector ticks in recreational areas should incorporate, whenever possible, testing for multiple pathogens because most ixodid ticks that commonly bite people in the United States are capable of transmitting two or more microbial disease agents.

Efficacy of antibiotic prophylaxis for prevention of Lyme disease.

To determine if antibiotic prophylaxis following a dear tick bite is effective in reducing the risk of developing Lyme disease. Meta-analysis of published trials. Clinical trials were identified by a computerised literature search of MEDLINE and by an assessment of the bibliographies of published studies. Trials were included in the analysis if their patients were randomly allocated to a treatment or control group, enrolled within 72 hours following an Ixodes tick bite, and had no clinical evidence of Lyme disease at enrollment. Three trials were selected for review after inclusion criteria were applied. Data were extracted for details of study design, patient characteristics, interventions, duration of therapy, and number of adverse events in each arm of therapy. Among the 600 patients with Ixodes tick bites, the rate of infection in the placebo group was 1.4%. In contrast, patients who received antibiotic prophylaxis had a 0% infection rate. The pooled odds ratio, comparing prophylaxis to placebo, was 0.0 (95% confidence interval 0.0, 1.5) (p = .12). The available evidence to date suggests that the routine use of antibiotic prophylaxis for the prevention of Lyme disease remains uncertain. Meta-analysis of the controlled trials failed to establish definitive treatment efficacy owing to the small sample size of the combined trials and the low rates of infection following a deer tick bite. A larger randomized trial is needed to demonstrate definitively that prophylaxis is more effective than placebo in reducing the risk of early Lyme disease in endemic areas.

Physician preferences in the diagnosis and treatment of Lyme disease in the United States.

To assess physician preferences in the diagnosis and treatment of Lyme disease, questionnaires were sent to physicians in various Lyme disease endemic areas in the U.S. Seventy-eight responses were analyzed. Both ELISA and Western blot were ordered by 86% of responders. Fifty percent of responders believed that 25% or more of patients who have Lyme disease were seronegative. The treatment was influenced by physician specialty. Antibiotic treatment for tick bite was prescribed by 20% of responders. Erythema migrans rash was treated by all responders without serologic confirmation. The median treatment duration of erythema migrans was 4 weeks. For post-erythema migrans Lyme disease, 43% of responders treat 3 months or more; for chronic Lyme disease, 57% of responders treat 3 months or more. Our survey documents significant differences between published recommendations and actual practices. Physician education and clinical trials are needed to clarify the reasons for these differences.

Duration of Tick Bites in a Lyme Disease-endemic Area

Regression equations, based on scutal index (body length/scutal width), were developed to determine the duration of attachment for nymphal and adult female lxodes scapularis ticks. Feeding times were calculated for 444 nymphal and 300 female ticks submitted by bite victims between 1985 and 1989 in Westchester County, New York, an area where Lyme disease is highly endemic. Nymphs were attached for a mean of 34.7 hours, with 26.8% removed after 48 hours, the critical time for transmission of Borrelia burgdorferi. Attachment times increased with victim age class (Kruskal-Wallis test, p < 0.05). Mean duration of attachment for female ticks (28.7 hours) was significantly less (Kruskal-Wallis test, p < 0.05) than that for nymphs, with 23.3% attached for more than 48 hours. The 0- to 9-year age class had the highest proportion (37.1%) of females attached for more than 48 hours. Nymphs remain attached to adult tick-bite victims longer than they remain attached to children. However, children have a high risk of acquiring Lyme disease because they receive more nymphal bites and also because they are less likely to have female ticks removed in time to prevent transmission.

Increase in Abundance of Immature Ixodes scapularis (Acari: Ixodidae) in an Emergent Lyme Disease Endemic Area

Changes in the abundance of immature Ixodes scapularis Say, the primary vector of Lyme disease, were assessed over a 7-yr period in Westchester County, New York, where the disease is endemic. In total, 4,000 m2 were drag sampled at each of 6 study sites in June and July of 1984 and 1991. The abundance of nymphs collected from all sites was 2.6-fold greater in 1991 than in 1984. Four of the 6 sites had significantly more nymphs in 1991, with increases ranging from 1.1- to 46.5-fold. The abundance of larvae collected from all sites was 34.2-fold higher in 1991 than in 1984. Five of the sites sampled had significantly more larvae in 1991, with increases ranging from 2.7- to 681-fold. These data demonstrate that populations of immature I. scapularis in Westchester County have, overall, increased during the 7-yr period from 1984 to 1991. However, the magnitude of increase is not uniform from site to site.

Prevalence of Borrelia burgdorferi in host-seeking ticks (Acari: Ixodidae) from a Lyme disease endemic area in northern Michigan.

The Lyme disease spirochete, Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner, was recovered from the guts of questing Ixodes scapularis Say adults and nymphs and adult Dermacentor variabilis (Say), collected in Menominee County, Michigan, in 1992. Spirochetes were cultured successfully from guts placed in modified Barbour-Stoenner-Kelly II medium held in 5-ml cultures tubes or in 0.3-ml wells of microtiter plates. Most isolates were recovered within 2 wk of culturing at an incubation temperature of 34 degrees C. Spirochetes were recovered more rapidly in culture tubes than in microtiter plates. For determination of tick infection with B. burgdorferi, culturing was equivalent to examination of gut smears by immunofluorescence. We found the following infection rates: 57/179 I. scapularis females (31.8%), 62/204 I. scapularis males (30.4%), 9/54 I. scapularis nymphs (16.7%), and 5/383 D. variabilis adults (1.3%).

The distribution of canine exposure to Borrelia burgdorferi in a Lyme-Disease endemic area.

A serosurvey of canine exposure to Borrelia burgdorferi, the causative agent of human Lyme disease, was conducted in Westchester County, New York, to determine the distribution of exposure in an area endemic for Lyme disease. A total of 1446 blood samples was collected from resident dogs and tested by modified enzyme-linked immunosorbent assay. Equivocal samples were further tested by immunoblot. A mean number of 57.8 samples was collected from each of 25 towns and cities. Seroprevalence rates for municipalities ranged from 6.5% to 85.2%. County seroprevalence was 49.2%. There was a significant difference among the rates for the northern (67.3%), central (45.2%), and southern (17.3%) regions. Multiple range analysis indicated homogeneity between the southern and central regions and the central and northern regions. Canine exposure to B burgdorferi increases in a south to north gradient within the county. Intensity of exposure, measured by enzyme-linked immunosorbent assay titers, indicates a similar pattern. The close association between dogs and humans suggests that human risk of acquiring Lyme disease within Westchester County is equally disparate and is inversely related to the degree of urbanization.

The 12-lead electrocardiogram of “healthy” ambulatory subjects with positive lyme immunoserology

First described as a distinct clinical entity by Steere et al 1 in 1977, Lyme disease is now known to result from human infection with the spirochete Borrelia burgdorferi, an organism predominantly transmitted by Ixodes ticks. 2 Serologic testing for the presence of antibodies to B. burgdorferi, although imperfect, remains the single best, widely available, laboratory method to demonstrate exposure to the offending organism. 3 The most frequently reported cardiac manifestation of early (stage II) Lyme disease consists of variable degrees of atrioventricular block, including complete heart block. These conduction abnormalities have been documented by 12-lead electrocardiography and invasive electrophysiologic testing. 4,5 Despite advances in characterizing the acute expressions of this spirochetal infection in patients with definite disease, little has been learned regarding the significance of previous subclinical infection, specifically a “positive” Lyme test in an untreated asymptomatic person in an endemic area, with no history of clinically apparent Lyme disease. The aim of this study was to identify any electrocardiographic abnormalities that may be attributable to exposure to the Lyme spirochete in “healthy” seropositive subjects in a Lyme disease endemic area.

Early Lyme Disease: A Flu-Like Illness Without Erythema Migrans

The existence of a form of early Lyme disease characterized by a flu-like illness without erythema migrans is controversial. To confirm the existence and define the clinical characteristics of the flu-like illness without erythema migrans of localized Lyme disease, the authors studied patients from a Lyme disease endemic area of Connecticut who visited their primary care physicians with an undefined flu-like illness. Patients kept a diary of their symptoms. Acute and convalescent sera were obtained. The diagnosis of Lyme disease was based on the appearance of IgM or IgG antibodies to Borrelia burgdorferi as demonstrated by both enzyme-linked immunosorbent assay and immunoblot assay. Twenty-four untreated patients were studied. In five patients acute serologic evidence of Lyme disease developed. The flu-like illness in these five patients was characterized by fever and fatigue and resolved spontaneously in 5 to 21 days. Symptoms recurred in three of these five patients. The existence of a flu-like illness without erythema migrans of early Lyme disease has been clearly established. Prospective, controlled studies are needed to better define its incidence, characteristics, and prognosis so that appropriate diagnostic and therapeutic strategies can be developed.

Canine exposure to Borrelia burgdorferi and prevalence of Ixodes dammini (Acari: Ixodidae) on deer as a measure of Lyme disease risk in the northeastern United States.

Surveillance programs that identify areas where both the vector (Ixodes dammini) and etiologic agent (Borrelia burgdorferi) are present may identify the risk of Lyme disease and its spread earlier and more accurately than do programs relying on any single method, particularly human case reports. Hunter-killed deer (n = 1,204) from 22 counties in Maryland, Massachusetts, New Hampshire, New York, and Pennsylvania were examined in fall 1989 and all ectoparasites were identified. The following spring, canine sera (n = 884) were obtained from these sites, which included known endemic areas and those where Lyme disease is uncommon, and tested by enzyme-linked immunosorbent assay. Regression analysis of canine seroprevalence versus tick prevalence on deer from the same counties demonstrate a significant positive linear relationship. Sites were designated as low-, moderate-, or high-risk counties based upon their position on the regression curve. The geographic distribution of the sites correlated well with the distribution of known Lyme disease endemic and nonendemic areas. Locations were also identified where Lyme disease may be emerging. The positive relationship between measures of vector and pathogen abundance determined in this study permits public health workers to identify endemic and potentially endemic areas independently of human case reports.