Previous Lyme Disease Research Articles

Persistent Symptoms After Lyme Disease: Clinical Characteristics, Predictors, and Classification.

Persistent symptoms after an infection have been described for a number of infectious diseases, including Lyme disease. Studies have confirmed a moderate but consistent increase in the prevalence of such symptoms after Lyme disease, though the risk increase varies dependent on study design and the definition of persistent symptoms. Various possible predictors have been proposed, including a dysregulation of the immune system, metabolic changes, increased sensitization to pain signals, cognitive-behavioral factors, or-controversially-the persistence of the causative Borrelia bacteria or remnants thereof. Research on the precise roles of any of these factors is still ongoing. The lack of biological underpinning also makes it difficult to assess with certainty which patients' (generally nonspecific) persistent symptoms are etiologically related to the previous Lyme disease episode and which are not, particularly as these symptoms occur in the general population relatively frequently. The diagnostic criteria for posttreatment Lyme disease syndrome have shown their usefulness in both clinical and research settings but leave out a number of patients whose symptoms may fall just outside said criteria. Though the relationship between these symptoms and the previous Lyme disease episode may be very uncertain, we would argue that a uniform description and classification of these patients will aid in future research and patient management, regardless of the eventual underlying cause. Thus, we argue for an inclusive classification system for all persistent symptoms attributed to Lyme disease in order to promote validation of patient experiences and perspectives, while also maintaining scientific nuance regarding the very uncertain etiology of these patients' symptoms.

Does Biological Sex Matter in Lyme Disease? The Need for Sex-Disaggregated Data in Persistent Illness.

Biological sex should be included as an important variable in clinical research studies to identify outcome differences between men and women. Very few Lyme disease studies were designed to consider sex-based differences or gender bias as an important component of the research design. To assess sex-based differences in Lyme disease patients who were clinically diagnosed and reported remaining ill for six or more months after receiving antibiotic treatment, we analyzed self-reported clinical data from 2170 patients in the MyLymeData patient registry. We also reviewed previous Lyme disease studies for distribution of patients by biological sex according to stage of illness, data source, and definition of disease used as enrollment criteria. In MyLymeData, women reported more tick-borne coinfections, worse symptoms, longer diagnostic delays, more misdiagnoses, and worse functional impairment than men. No differences were reported in antibiotic treatment response or side effects. In our review, of clinical research trials and data sources, we identified a smaller percentage of women in studies of acute Lyme disease and a larger percentage of women in studies of persistent illness. Samples and data sources that were more reflective of patients seen in clinical practice had a higher percentage of women than randomized controlled trials and post-treatment Lyme disease studies. Our results indicate that biological sex should be integrated into Lyme disease research as a distinct variable. Future Lyme disease studies should include sex-based disaggregated data to illuminate differences that may exist between men and women with persistent illness.

Tick-Borne Disease Risk and Exposure among Vulnerable Populations in Perceived Non-Endemic Regions

Migrant and seasonal workers in the United States, among others in rural agricultural communities, may be at an elevated risk for tick-borne diseases (TBDs). This research included a survey of over 250 such workers, both women and men, in 13 locations across five eco-systems in Texas, which is generally perceived as a non-endemic state. Employing a modified Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire, a range of data was collected regarding living conditions, such as sleeping outside, along with queries about tick exposure, tick bite encounters, illnesses, and prior TBD diagnoses. Findings revealed that 67% of the respondents who scored highest on symptom severity suggestive of a TBD reported sleeping outdoors (compared to 29% of the lowest scoring), with 78% of the likely-to-highly-likely group also recalling tick-bite encounters (compared to 20% of the lowest scoring). Approximately 28% of those who reported severe symptoms also indicated previous Lyme disease diagnoses. This research serves as an initial investigation into the living conditions associated with increased risk of TBDs among vulnerable populations. It underscores the need for further assessments of TBD risk relative to vulnerable populations even in perceived non-endemic regions and highlights the paucity of actionable data as a critical public health issue.

Triangulating the New Frontier of Health Geo-Data: Assessing Tick-Borne Disease Risk as an Occupational Hazard among Vulnerable Populations.

Determining interventions to combat disease often requires complex analyses of spatial-temporal data to improve health outcomes. For some vulnerable populations, obtaining sufficient data for related analyses is especially difficult, thus exacerbating related healthcare, research, and public health efforts. In the United States (U.S.), migrant and seasonal workers are especially affected in this regard, with data on health interventions and outcomes largely absent from official sources. In response, this study offers a multi-modal approach that involves triangulating geographically specified health data that incorporate reports on canine tick species, Lyme disease (LD) incidence, and patient symptom severity indicating potential subsequent disease burden. Spatial alignment of data at the U.S. county level was used to reveal and better understand tick-borne disease (TBD) incidence and risk among the identified populations. Survey data from migrant and seasonal workers in Texas were employed to determine TBD risk based on symptoms, occupations, and locations. Respondents who were found to have a higher likelihood of a TBD were also considerably more likely to report the most common symptoms of LD and other TBDs on the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire. Those in the highly likely scoring group also reported more poor health and mental health days. Overall, a notable number of respondents (22%) were likely or highly likely to have a TBD, with particular relevance attributed to county of residence and living conditions. Also of note, almost a third of those reporting severe symptoms had received a previous Lyme disease diagnosis. These findings underscore the need for further surveillance among vulnerable populations at risk for TBDs.

Two-Tier Lyme Disease Serology in Children with Previous Lyme Disease

Background: A history of Lyme disease can complicate the interpretation of Lyme disease serology in acutely symptomatic patients. Materials and Methods: We prospectively enrolled children undergoing evaluation for Lyme disease in the emergency department of one of eight participating Pedi Lyme Net centers. We selected symptomatic children with a Lyme disease history (definite, probable, or none) as well as an available research biosample. We defined a Lyme disease case with either an erythema migrans (EM) lesion or positive two-tier serology with compatible symptoms. Using a generalized estimating equation, we examined the relationship between time from previous Lyme disease diagnosis and current Lyme disease after adjustment for patient demographics and symptoms as well as clustering by center. Results: Of 2501 prospectively enrolled study patients, 126 (5.0%) reported a history of definite or probable Lyme disease. Of these children with previous Lyme disease, 47 met diagnostic criteria for Lyme disease at the time of enrollment (37.3%; 95% confidence interval [CI] 29.1-45.7%); 2 had an EM lesion, and 45 had positive two-tier Lyme disease serology. Over time from the previous Lyme disease diagnosis, the less likely the patient met diagnostic criteria for Lyme disease (adjusted odds ratio 0.62 per time period; 95% CI 0.46-0.84). Conclusions: For children with a history of Lyme disease before enrollment, one-third met the diagnostic criteria for acute Lyme disease with a declining rate over time from previous Lyme disease diagnosis. Novel Lyme disease diagnostics are needed to help distinguish acute from previous Lyme disease.

Point-of-Care Serodiagnostic Test for Early-Stage Lyme Disease Using a Multiplexed Paper-Based Immunoassay and Machine Learning.

Caused by the tick-borne spirochete Borrelia burgdorferi, Lyme disease (LD) is the most common vector-borne infectious disease in North America and Europe. Though timely diagnosis and treatment are effective in preventing disease progression, current tests are insensitive in early stage LD, with a sensitivity of <50%. Additionally, the serological testing currently recommended by the U.S. Center for Disease Control has high costs (>$400/test) and extended sample-to-answer timelines (>24 h). To address these challenges, we created a cost-effective and rapid point-of-care (POC) test for early-stage LD that assays for antibodies specific to seven Borrelia antigens and a synthetic peptide in a paper-based multiplexed vertical flow assay (xVFA). We trained a deep-learning-based diagnostic algorithm to select an optimal subset of antigen/peptide targets and then blindly tested our xVFA using human samples (N(+) = 42, N(-) = 54), achieving an area-under-the-curve (AUC), sensitivity, and specificity of 0.950, 90.5%, and 87.0%, respectively, outperforming previous LD POC tests. With batch-specific standardization and threshold tuning, the specificity of our blind-testing performance improved to 96.3%, with an AUC and sensitivity of 0.963 and 85.7%, respectively.

Integrated Assessment of Behavioral and Environmental Risk Factors for Lyme Disease Infection on Block Island, Rhode Island

Peridomestic exposure to Borrelia burgdorferi-infected Ixodes scapularis nymphs is considered the dominant means of infection with black-legged tick-borne pathogens in the eastern United States. Population level studies have detected a positive association between the density of infected nymphs and Lyme disease incidence. At a finer spatial scale within endemic communities, studies have focused on individual level risk behaviors, without accounting for differences in peridomestic nymphal density. This study simultaneously assessed the influence of peridomestic tick exposure risk and human behavior risk factors for Lyme disease infection on Block Island, Rhode Island. Tick exposure risk on Block Island properties was estimated using remotely sensed landscape metrics that strongly correlated with tick density at the individual property level. Behavioral risk factors and Lyme disease serology were assessed using a longitudinal serosurvey study. Significant factors associated with Lyme disease positive serology included one or more self-reported previous Lyme disease episodes, wearing protective clothing during outdoor activities, the average number of hours spent daily in tick habitat, the subject’s age and the density of shrub edges on the subject’s property. The best fit multivariate model included previous Lyme diagnoses and age. The strength of this association with previous Lyme disease suggests that the same sector of the population tends to be repeatedly infected. The second best multivariate model included a combination of environmental and behavioral factors, namely hours spent in vegetation, subject’s age, shrub edge density (increase risk) and wearing protective clothing (decrease risk). Our findings highlight the importance of concurrent evaluation of both environmental and behavioral factors to design interventions to reduce the risk of tick-borne infections.

Overdiagnosis and overtreatment of Lyme disease in children.

To determine the incidence of overdiagnosis and overtreatment of Lyme disease in children residing in endemic areas using standardized CDC diagnostic criteria. Case series, using data collected prospectively from patients referred for Lyme disease to a tertiary care center located in an area endemic for Lyme disease. Data were collected on all referred cases during a 30-month period from August, 1995, to February, 1998. We evaluated 216 patients with ages from birth to 18 years. Results of Lyme enzyme-linked immunosorbent assay and Western blot studies were available for all patients evaluated. Of these, 68 (31%) fulfilled the criteria for active Lyme disease, most commonly having arthritis, facial nerve palsy, aseptic meningitis or erythema migrans; 39 (18%) had a prior history of Lyme disease and were referred with an acute intercurrent illness or lower school grades attributed to the previous Lyme disease; 77% of these were receiving therapy at the time of referral; 109 (50%) of 216 had no past or current evidence of Lyme disease, yet 79% were receiving therapy at the time of referral. Overdiagnosis and overtreatment of Lyme disease is a major concern in areas endemic for Lyme disease, even after 1995 when standard criteria for diagnosis were published. The most common problem in diagnosis was misinterpretation of Western immunoblot results.

Outcomes of Lyme Disease.

Letters7 November 2000Outcomes of Lyme DiseaseNancy A. Shadick, MD, MPH, Robert A. Lew, PhD, and Matthew H. Liang, MD, MPHNancy A. Shadick, MD, MPHBrigham and Women's Hospital; Boston, MA 02115 (Shadick, Lew, Liang)Search for more papers by this author, Robert A. Lew, PhDBrigham and Women's Hospital; Boston, MA 02115 (Shadick, Lew, Liang)Search for more papers by this author, and Matthew H. Liang, MD, MPHBrigham and Women's Hospital; Boston, MA 02115 (Shadick, Lew, Liang)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-133-9-200011070-00023 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We appreciate Dr. Prybylski's insights. He interprets the findings as we do but arrives at them by way of a different path. We agree that it is striking that 14 self-reported symptoms were more prevalent in patients with previous Lyme disease than in those without. Among the 26 symptoms about which patients were queried, we chose these 14 symptoms to highlight in tabular form because they were more prevalent. We similarly noted the striking deficits in health-related quality of life, as measured by the SF-36, among patients with Lyme disease and believe this to be one of the ...

Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease.

Previous follow-up studies of patients with Lyme disease suggest that disseminated infection may be associated with long-term neurologic and musculoskeletal morbidity. To determine clinical and functional outcomes in persons who were treated for Lyme disease in the late 1980s. Population-based, retrospective cohort study. Nantucket Island, Massachusetts. 186 persons who had a history of Lyme disease (case-patients) and 167 persons who did not (controls). Standardized medical history, physical examination, functional status measure (Medical Outcomes Study 36-item Short Form Health Survey [SF-36]), mood state assessment (Profile of Mood States), neurocognitive tests, and serologic examination. The prevalence of Lyme disease among adults on Nantucket Island was estimated to be 14.3% (95% CI, 9.3% to 19.1%). In multivariate analyses, persons with previous Lyme disease (mean time from infection to study evaluation, 6.0 years) had more joint pain (odds ratio for having joint pain in any joint, 2.1 [CI, 1.2 to 3.5]; P = 0.007), more symptoms of memory impairment (odds ratio for having any memory problem, 1.9 [CI, 1.1 to 3.5]; P = 0.003), and poorer functional status due to pain (odds ratio for 1 point on the SF-36 scale, 1.02 [CI, 1.01 to 1.03]; P < 0.001) than persons without previous Lyme disease. However, on physical examination, case-patients and controls did not differ in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance. Persons with previous Lyme disease who had persistent symptoms after receiving treatment (n = 67) were more likely than those who had completely recovered to have had fever, headache, photosensitivity, or neck stiffness during their acute illness (87% compared with 13%; odds ratio, 2.4 [CI, 1.0 to 5.5]; P = 0.045); however, the performance of the two groups on neurocognitive tests did not significantly differ. Because persons with previous Lyme disease exhibited no sequelae on physical examination and neurocognitive tests a mean of 6.0 years after infection, musculoskeletal and neurocognitive outcomes seem to be favorable. However, long-term impairment of functional status can occur.

Clinical evaluation of guidelines and two-test approach for lyme disease.

The diagnosis of Lyme disease should be based on objective clinical signs and symptoms. In a clinical study, we have evaluated whether the recommended two-step approach for serodiagnosis of Lyme disease is useful in daily clinical practice and can influence clinical decision making. The signs and symptoms of patients with ongoing musculoskeletal complaints, assumed by their referring physician or themselves to be attributable to active or chronic Lyme disease, and of patients diagnosed as having Lyme disease, were evaluated. On the basis of clinical evaluation only, patients were classified into three groups: previous Lyme disease, active Lyme disease and no Lyme disease. Antibodies to Borrelia burgdorferi were determined by means of an enzyme-linked immunosorbent assay (ELISA), followed, when positive, by immunoblotting. One hundred and three patients (41 males and 62 females, mean age 48.7 yr) participated in the study. Of the 49 patients classified as previous Lyme disease, 25 (51%) had antibodies to B. burgdorferi. All 10 patients with active Lyme disease had positive antibodies and 12 of the 44 patients (27%) classified as no Lyme disease had positive antibodies. No statistically significant differences were found between the percentage of positive immunoblots from patients with previous Lyme disease (72%) and patients with active Lyme disease (100%). In the group of no Lyme disease, five out of 12 patients had a negative immunoblot. Concerning serological testing, immunoblotting could have added additional information. However, immunoblotting did not influence clinical decision making in this group of patients. Immunoblotting did not influence clinical decision making for the 47 patients with antibodies to B. burgdorferi in this study.

The consequences of overdiagnosis and overtreatment of Lyme disease: an observational study.

The adverse consequences associated with overdiagnosis and overtreatment of Lyme disease, although previously recognized, have received inadequate attention. To determine the use of health services and occurrence of treatment-related illness, disability, and distress among patients in whom Lyme disease is inappropriately diagnosed or treated. Observational cohort study. University-based Lyme disease clinic. 209 patients with a presumptive diagnosis of Lyme disease previously assigned by referring physicians, the patients themselves, or both. Self-reported data, review of medical records, and standardized instruments were used to determine 1) use of health services in terms of number of outpatient visits, number of physicians seen, types of serologic tests, and days of antibiotic treatment; 2) occurrence of antibiotic-related adverse events; and 3) levels of disability, depression, and stress. Of the 209 patients, 44 (21%) met criteria for active Lyme disease, 40 (19%) had previous but not active Lyme disease, and 125 (60%) had no evidence of current or previous infection. In general, patients with active Lyme disease (who were not the focus of this study) had good outcomes. Patients with previous Lyme disease and patients with no evidence of Lyme disease used considerable health resources (median number of office visits, 11 and 7; median number of serologic tests, 4 and 4; and median days of antibiotic treatment, 75 and 42), had frequent minor adverse drug events (53% and 55%), reported significant disability (proportion of symptomatic days during which normal activities could not be performed, 16% and 18%), and had high rates of depression (38% and 42%) and stress (52% and 45%). Overdiagnosis and overtreatment of Lyme disease are associated with inappropriate use of health services, avoidable treatment-related illness, and substantial disability and distress.

Lack of cardiac manifestations among patients with previously treated Lyme disease.

Cardiac involvement is common in acute Lyme disease, and case reports suggest that cardiac abnormalities might also occur years after the primary infection. To determine the prevalence of cardiac abnormalities in persons with previously treated Lyme disease. Population-based, retrospective cohort study with controls. Nantucket Island, Massachusetts. From among 3703 adult respondents to a total-population (n = 6046) mail survey, 336 (176 case-patients and 160 controls) were randomly selected for clinical evaluation. Current cardiac symptoms and major or minor abnormal electrocardiographic features, including heart rate; rhythm; axis; PR, QRS, and QT intervals; QRS structure; atrioventricular blocks; and ST-segment and T-wave changes. Persons with Lyme disease (case-patients, n = 176) (mean duration from disease onset to study evaluation, 5.2 years) and persons without evidence of previous Lyme disease (controls, n = 160) did not differ significantly in their patterns of current cardiac symptoms and electrocardiographic findings, including heart rate (P > 0.2), PR interval (P = 0.15), QRS interval (P > 0.2), QT interval (P > 0.2), axis (P > 0.2), presence of arrhythmias (P > 0.2), first-degree heart block (P = 0.12), bundle-branch block (P > 0.2), and ST-segment abnormalities (P > 0.2). In multivariate analyses that adjusted for age, sex, and previous heart disease, a history of previously treated Lyme disease was not associated with either major (odds ratio, 0.78; P > 0.2) or minor (odds ratio, 1.09; P > 0.2) electrocardiographic abnormalities. Persons with a history of previously treated Lyme disease do not have a higher prevalence of cardiac abnormalities than persons without a history of Lyme disease.

Lyme disease.

In the United States, there was an increase in the number of reported cases of Lyme disease in 1994 compared with previous years. The majority of cases occurred in the Northeast and Midwest, which are areas with established foci of Borrelia burgdorferi. Advances in the understanding of the epidemiology and ecology of ixodes ticks, the established vector for transmission of Lyme disease, provided strategies for reducing tick populations and the risk of acquiring disease. Dissemination of B. burgdorferi from the site of a tick bite likely occurs, in part, via attachment to host plasmin and subsequent degradation of glycoproteins. Analysis of T cell immune responses in mice contributed to our understanding of differences in disease susceptibility. Vaccination of patients with previous Lyme disease has been found to be safe, and clinical trials of vaccine efficacy are currently under way.

The Overdiagnosis of Lyme Disease

To analyze the diagnoses, serological test results, and treatment results of the patients evaluated in a Lyme disease clinic, both prior to referral and from current evaluation. Retrospective case survey of prescreened patients. Research and diagnostic Lyme disease clinic in a university hospital. All 788 patients referred to the clinic during a 4.5-year period who were thought by the referring physician or the patient to have a diagnosis of Lyme disease. Symptoms and signs of disease, immunodiagnostic tests of Lyme disease, and tests of neurological function. Of the 788 patients, 180 (23%) had active Lyme disease, usually arthritis, encephalopathy, or polyneuropathy. One hundred fifty-six patients (20%) had previous Lyme disease and another current illness, most commonly chronic fatigue syndrome or fibromyalgia; and in 49 patients, these symptoms began soon after objective manifestations of Lyme disease. The remaining 452 patients (57%) did not have Lyme disease. The majority of these patients also had the chronic fatigue syndrome or fibromyalgia; the others usually had rheumatic or neurological diseases. Of the patients who did not have Lyme disease, 45% had had positive serological test results for Lyme disease in other laboratories, but all were seronegative in our laboratory. Prior to referral, 409 of the 788 patients had been treated with antibiotic therapy. In 322 (79%) of these patients, the reason for lack of response was incorrect diagnosis. Only a minority of the patients referred to the clinic met diagnostic criteria for Lyme disease. The most common reason for lack of response to antibiotic therapy was misdiagnosis.