Evaluation and 1-year follow-up of patients presenting at a Lyme borreliosis expertise centre: a prospective cohort study with validated questionnaires.

OBJECTIVES: To describe the course of symptoms reported by patients with symptoms attributed to Lyme borreliosis (LB) without being subsequently diagnosed with LB. METHODS: We performed a prospective cohort study with patients presenting at the outpatient clinic of two clinical LB centres. The primary outcome was the prevalence of persistent symptoms, which were defined as clinically relevant fatigue (CIS, subscale fatigue), pain (SF-36, subscale bodily pain), and cognitive impairment (CFQ) for ≥ 6 months and onset < 6 months over the first year of follow-up. Outcomes were compared with a longitudinal cohort of confirmed LB patients and a general population cohort. Prevalences were standardised to the distribution of pre-defined confounders in the confirmed LB cohort. RESULTS: Participants (n = 123) reported mostly fatigue, arthralgia, myalgia, and paraesthesia as symptoms. The primary outcome could be determined for 74.8% (92/123) of participants. The standardised prevalence of persistent symptoms in our participants was 58.6%, which was higher than in patients with confirmed LB at baseline (27.2%, p < 0.0001) and the population cohort (21.2%, p < 0.0001). Participants reported overall improvement of fatigue (p < 0.0001) and pain (p < 0.0001) but not for cognitive impairment (p = 0.062) during the follow-up, though symptom severity at the end of follow-up remained greater compared to confirmed LB patients (various comparisons p < 0.05). CONCLUSION: Patients with symptoms attributed to LB who present at clinical LB centres without physician-confirmed LB more often report persistent symptoms and report more severe symptoms compared to confirmed LB patients and a population cohort.

Assessment of three criteria to establish borrelial infection in suspected lyme neuroborreliosis.

PURPOSE: Diagnosis of (European) Lyme neuroborreliosis has been based on clinical presentation, cerebrospinal fluid (CSF) pleocytosis and demonstration of intrathecal borrelial antibody synthesis (ITBAS) to document Borrelia burgdorferi s. l. INFECTION: It is not known if other criteria to document Borrelia infection may contribute to the diagnosis. METHODS: We compared the sensitivity of three individual criteria (ITBAS, CSF Borrelia culture, and the presence of erythema migrans [EM]) to confirm the diagnosis of early Lyme neuroborreliosis in 280 patients ≥ 15 years of age evaluated at a Lyme borreliosis outpatient clinic in Slovenia. The patients had either radicular pain of new onset or involvement of a cranial nerve but without radicular pain, each in conjunction with CSF pleocytosis. Evaluation was of patients who had each of the three confirmatory criteria assessed, and for whom at least one criterion was positive. RESULTS: Analysis of 280 patients, 120 women and 160 men, median age 57 (range 15-84) years, revealed that ITBAS was the most frequently observed positive criterion (85.4%), followed by EM (52.9%), and by a positive CSF Borrelia culture (9.6%). Of the 280 patients, 154 (55%) met only one criterion (43.2% ITBAS only, 10.7% EM only, and 1.1% positive CSF culture only), whereas 42.1% met two criteria. Only 2.9% of patients were positive by all three criteria. CONCLUSION: Although ITBAS was the most frequent criterion for confirmation for Borrelia infection, the presence of EM alone confirmed an additional 10.7% of patients and a positive CSF Borrelia culture alone added another 1.1%.

Challenges of laboratory diagnosis of Lyme disease ‒ Questionnaire survey results.

Lyme disease. Our second goal was to identify bacterial and viral co-infections occurring concurrently with Lyme disease. Furthermore, it was our intention to also analyze the correlation of laboratory testing with the occurrence of erythema migrans (EM). BACKGROUND: The accuracy in diagnostic testing for Lyme disease in the early stages of infection is an important factor necessary for delivering proper treatment to patients. METHODS: A total of 173 individuals with confirmed Lyme disease or with laboratory testing underway participated in the quantitative survey. RESULTS: ELISA was the first test conducted in 51% of the respondents, 28% of whom yielded positive findings of both IgM and IgG antibody classes. The positivity of ELISA test findings was confirmed by Western blot in 100% of results. Negative results of ELISA were consistent with Western blot only in less than half of the patients. More than half of the respondents had not been tested for any bacterial or viral co-infections. The results of serological testing were not consistent with clinical findings in all cases, including those with clinically discernible skin manifestation of erythema migrans. CONCLUSION: The comparison of results obtained by ELISA and Western blot revealed significant discrepancies. Simultaneous infections by vectors with several pathogens were detected (Tab. 3, Fig. 2, Ref. 15).

Lyme Borreliosis, a public health concern in India: Findings of Borrelia burgdorferi serosurvey from two states.

Background: Lyme borreliosis is a public health concern in India. The prevalence of the disease is still undetermined with major entomological and epidemiological gaps. The present study was conducted to determine the seropositivity of Borrelia burgdorferi in Sikkim and Arunachal Pradesh, India. Methods: A cross-sectional serosurvey was conducted in Sikkim and Arunachal Pradesh. Data collection tools were developed and standardized for the collection of clinico-socio-demographic data. Sample size for each site was calculated using the formula for the estimation of a single proportion. Qualitative detection of IgG antibodies in serum samples was done using NovaLisa™ Lyme Borrelia IgG ELISA kit. Results: A total of 793 participants were enrolled, 484 (61%) from Arunachal Pradesh and 309 (39%) from Sikkim. Out of 793 participants, 21 (2.7%), 22 (2.8%), 6 (0.8%), 29 (3.7%), 44 (5.5%), and 16 (2.1%) gave history of tick bite, rash, erythema migrans, migratory muscle pain, migratory joint pain, and numbness, respectively, in the past one year. The adjusted seroprevalence (for sensitivity and specificity of kit) for the study is 3.7 (2.4-5.2). No signs or symptoms were found to be associated with IgG ELISA positivity. The state-wise distribution of seropositivity for Arunachal Pradesh and Sikkim was 4.1 (95% CI: 2.5-6.3) and 2.3 (95% CI: 0.9-4.6), respectively. Conclusion: This study establishes the state of Sikkim as a new endemic area in India of Lyme disease besides its already reported endemicity in Arunachal Pradesh. No association was conclusively established between symptoms of Lyme and IgG seropositivity emphasizing the need for detailed history taking and clinical suspicion in endemic areas.

Erythema Migrans Caused by Borrelia spielmanii, France.

We describe a rare case of early Lyme borreliosis in France caused by Borrelia spielmanii, which manifested as a large erythema chronicum migrans rash. The patient completely recovered after a 15-day course of amoxicillin. Absence of pathognomonic signs prevented distinguishing B. spielmanii from other etiologies as cause in this case-patient.

Lyme rashes disease classification using deep feature fusion technique.

Automatic classification of Lyme disease rashes on the skin helps clinicians and dermatologists' probe and investigate Lyme skin rashes effectively. This paper proposes a new in-depth features fusion system to classify Lyme disease rashes. The proposed method consists of two main steps. First, three different deep learning models, Densenet201, InceptionV3, and Exception, were trained independently to extract the deep features from the erythema migrans (EM) images. Second, a deep feature fusion mechanism (meta classifier) is developed to integrate the deep features before the final classification output layer. The meta classifier is a basic deep convolutional neural network trained on original images and features extracted from base level three deep learning models. In the feature fusion mechanism, the last three layers of base models are dropped out and connected to the meta classifier. The proposed deep feature fusion method significantly improved the classification process, where the classification accuracy was 98.97%, which is particularly impressive than the other state-of-the-art models.

Borrelia burgdorferi Is a Poor Inducer of Gamma Interferon: Amplification Induced by Interleukin-12.

Laboratory diagnosis of Lyme borreliosis (LB) is mainly based on serology, which has limitations, particularly in the early stages of the disease. In recent years there have been conflicting reports concerning a new diagnostic tool using the cytokine interferon-gamma (IFN-γ). Previous studies have generally found low concentrations of IFN-γ in early LB infection. The goal of this study is to investigate IFN-γ regulation during early LB and provide insights into the host response to B. burgdorferi. We performed in vitro experiments with whole blood assays and peripheral blood mononuclear cells (PBMCs) of LB patients and healthy volunteers exposed to B. burgdorferi and evaluated the IFN-γ response using ELISA and related interindividual variation in IFN-γ production to the presence of single nucleotide polymorphisms. IFN-γ production of B. burgdorferi-exposed PBMCs and whole blood was amplified by the addition of interleukin-12 (IL-12) to the stimulation system. This effect was observed after 24 h of B. burgdorferi stimulation in both healthy individuals and LB patients. The effect was highly variable between individuals, but was significantly higher in LB patients 6 weeks since the start of antibiotic treatment compared to healthy individuals. IL-12 p40 and IL-18 mRNA were upregulated upon exposure to B. burgdorferi, whereas IL-12 p35 and IFN-γ mRNA expression remained relatively unchanged. SNP Rs280520 in the downstream IL-12 pathway, Tyrosine Kinase 2, was associated with increased IFN-γ production. This study shows that IL-12 evokes an IFN-γ response in B. burgdorferi exposed cells, and that LB patients and healthy controls respond differently to this stimulation.

Colocalization of Radicular Pain and Erythema Migrans in Patients With Bannwarth Syndrome Suggests a Direct Spread of Borrelia Into the Central Nervous System.

BACKGROUND: There is a general assumption that after deposition into skin, Lyme borreliae disseminate hematogenously to other organs, resulting in extracutaneous manifestations of Lyme borreliosis, including Lyme neuroborreliosis. However, our experience over the past 40 years, along with several published case reports that observed colocalization of radicular pain and erythema migrans (EM) in patients with borrelial meningoradiculoneuritis (Bannwarth syndrome), argues against hematogenous dissemination in Lyme neuroborreliosis. METHODS: We compared the location of EM in 112 patients with Bannwarth syndrome to 12315 EM patients without neurological involvement. Moreover, we assessed the colocalization of EM and radicular pain in patients with Bannwarth syndrome. RESULTS: Compared to >12000 EM patients without neurological involvement, patients with Bannwarth syndrome had a significantly higher frequency of EM on head/neck (6% vs 1%; P=.0005) and trunk (47% vs 24%; P<.0001), similar frequency on arms (16% vs 16%; P=.91), but lower frequency on legs (30% vs 59%; P<.0001). Moreover, in 79% (89/112) of patients the site of EM matched the dermatomes of radicular pain. The odds for a congruent location of EM and radicular pain were highly significant with the highest odds ratios (OR) observed for head (OR=221), followed by neck (OR=159), legs (OR=69), arms (OR=48), and trunk (OR=33). CONCLUSIONS: The greater frequency of EM on head/neck and trunk and the colocalization of EM with radicular pain in patients with Bannwarth syndrome suggest that central nervous system involvement in Lyme neuroborreliosis is due to a retrograde spread of borrelia from skin to the spinal cord via peripheral nerves.

Non-specific symptoms and post-treatment Lyme disease syndrome in patients with Lyme borreliosis: a prospective cohort study in Belgium (2016-2020).

BACKGROUND: Patients with Lyme borreliosis (LB) may report persisting non-specific symptoms such as fatigue, widespread musculoskeletal pain or cognitive difficulties. When present for more than 6 months and causing a reduction in daily activities, this is often referred to as post-treatment Lyme disease syndrome (PTLDS). This study aimed to compare the occurrence of symptoms between LB patients and controls, to estimate the proportion of LB patients developing PTLDS and to identify risk factors. METHODS: A prospective cohort study was set up including three subpopulations: patients with an erythema migrans (EM) (i) or disseminated/late LB (ii) and a non-LB control group (iii). At 6- and 12-months follow-up, the occurrence of several symptoms, including six symptoms used to define PTLDS, i.e. muscle pain, joint pain, fatigue, memory problems, difficulties concentrating and problems finding words, and impact on daily activities, was compared between LB patients and controls. Finally, the proportion of LB patients developing PTLDS as defined by the Infectious Disease Society of America was estimated, including a time frame for symptoms to be present. RESULTS: Although the risk of presenting PTLDS-related symptoms was significantly higher in EM patients (n = 120) compared to controls (n = 128) at 6 months follow-up, the risk of presenting at least one of these symptoms combined with impact on daily activities was not significantly higher in EM patients, at either 6- or 12-months follow-up. A significant association was found between disseminated/late LB (n = 15) and the occurrence of any PTLDS-symptom with an impact on daily activities at both time points. The proportion of patients with PTLDS was estimated at 5.9% (95% CI 2.7-12.9) in EM patients and 20.9% (95% CI 6.8-64.4) in patients with disseminated/late LB (RR = 3.53, 95% CI 0.98-12.68, p = 0.053). No significant risk factors were identified, which may be explained by small sample sizes. CONCLUSIONS: In our study, PTLDS was present in both LB cohorts, yet with a higher percentage in disseminated/late LB patients. Additional research is needed into risk factors for and causes of this syndrome. In addition, development and validation of standardized methods to assess the PTLDS case definition, easily applicable in practice, is of great importance.

Lyme borreliosis in Belgium: a cost-of-illness analysis.

BACKGROUND: Lyme borreliosis (LB) is the most common tick-borne disease in Europe and North America, yet its economic burden remains largely unknown. This study aimed to estimate the economic cost associated with the different clinical manifestations of LB in Belgium. METHODS: An incidence approach and societal perspective were used to estimate the total cost-of-illness for LB in Belgium. Costs were calculated for patients with erythema migrans (EM) or disseminated/late LB, including patients who developed post-treatment Lyme disease syndrome (PTLDS). Direct medical, direct non-medical (transportation & paid help) and indirect non-medical costs (productivity losses) were included in the analysis. Ambulatory cost data were collected through a prospective cohort study from June 2016 to March 2020, in which patients with LB were followed up 6 to 12 months after diagnosis. Hospitalization costs were retrieved from the Minimal Clinical Data registry, a mandatory registry for all Belgian hospitals, linked to the Minimal Financial Data registry. Costs were expressed in 2019 euros. RESULTS: The total annual cost associated with clinical manifestations of LB in Belgium was estimated at €5.59 million (95% UI 3.82-7.98). Of these, €3.44 million (95% UI 2.05-5.48) or 62% was related to disseminated/late LB diagnoses and €2.15 million (95% UI 1.30-3.26) to EM. In general, direct medical costs and productivity losses accounted for 49.8% and 46.4% of the total costs, respectively, while direct non-medical costs accounted for only 3.8%. The estimated mean costs were €193 per EM patient and €5,148 per disseminated/late LB patient. While patients with PTLDS seemed to have somewhat higher costs compared to patients without PTLDS, the number of patients was too small to have representative estimates. CONCLUSIONS: We estimate the total annual direct medical costs, direct non-medical and indirect non-medical costs associated with LB to exceed €5.5 million per year, almost evenly distributed between EM (40%) and disseminated/late LB (60%). EM costs 26 times less per patient but occurs also 16 times more frequently than disseminated/late LB. The cost burden remains limited by comparison to other infectious diseases due to the relative lower incidence.

The clinical presentation, treatment and outcome of serologically confirmed paediatric Lyme disease in the Republic of Ireland over a 5-year period: a retrospective cohort study.

Lyme disease (LD) is the most common tick-borne illness in Europe. Population-based studies in European children are few. This study aimed to assess the incidence, clinical presentation, treatment and outcome of serologically confirmed paediatric LD in the Republic of Ireland over a 5-year period. A retrospective review of records from accredited laboratories performing Borrelia burgdorferi serological testing was undertaken. Proformas were distributed to clinicians of children and adolescents with positive Lyme serology. Data were requested regarding clinical presentation, treatment and outcome. Updated NICE guidelines were used to classify clinical cases. Serology testing for B. burgdorferi was performed on 2908 samples. Sixty-three (2.2%) children were two-tier positive, generating a crude annual incidence rate of 1.15/100,000. Proformas were returned for 55 (87%) and 47 met clinical and laboratory criteria for LD. Twenty-seven (57%) presented with non-focal symptoms (erythema migrans and/or influenza-like symptoms), and 20 (43%) with focal symptoms (cranial nerve involvement, 11; CNS involvement, 8; arthritis, 1). Median age at presentation was 8.2 (2.5-17.9) years. Seventeen (36%) acquired LD overseas. Twenty-five (83%) of the remaining 30 children acquired infection in the West/Northwest of Ireland. Full resolution of symptoms was reported in 97% of those with available data. Serologically confirmed LD in children is relatively rare in the Republic of Ireland. Ninety-eight percent of children tested were seronegative. Of the seropositive cases, 40% could have been diagnosed based on clinical findings alone. Neurological presentations (40%) were common. Full resolution of symptoms occurred in almost all (97%) where data were available.

The presenting characteristics of erythema migrans vary by age, sex, duration, and body location.

PURPOSE: The erythema migrans (EM) skin lesion is often the first clinical sign of Lyme disease. Significant variability in EM presenting characteristics such as shape, color, pattern, and homogeneity, has been reported. We studied associations between these presenting characteristics, as well as whether they were associated with age, sex, EM duration, body location, and initiation of antibiotics. METHODS: Two hundred and seventy one adult participants with early Lyme disease who had a physician-diagnosed EM skin lesion of ≥ 5 cm in diameter and ≤ 72 h of antibiotic treatment were enrolled. Participant demographics, clinical characteristics, and characteristics of their primary EM lesion were recorded. RESULTS: After adjusting for potential confounders, EM size increased along with increasing EM duration to a peak of 14 days. Male EM were found to be on average 2.18 cm larger than female EM. The odds of a red (vs blue/red) EM were 65% lower in males compared to females, and were over 3 times as high for EM found on the pelvis, torso, or arm compared to the leg. Age remained a significant predictor of central clearing in adjusted models; for every 10-year increase in age, the odds of central clearing decreased 25%. CONCLUSIONS: Given that EM remains a clinical diagnosis, it is essential that both physicians and the general public are aware of its varied manifestations. Our findings suggest possible patterns within this variability, with implications for prompt diagnosis and treatment initiation, as well as an understanding of the clinical spectrum of EM.

Three cases diagnosed not Lyme disease but "tick-associated rash illness (TARI)" in Japan.

We report three cases of tick-associated rash illness (TARI) in Japan that presented with erythema migrans (EM) after a tick bite. Although EM is considered to be a characteristic finding of Lyme disease, EM can occur even if patient is not affected by Lyme disease and if it is bitten by a tick. In Japan, the vector of Lyme disease pathogens are not distributed in most areas, and patients with EM are unlikely to have Lyme disease. We aim to raise TARI awareness among physicians.

Migrating Swollen Joint and Lyme Disease: A Case Report.

This article discusses a case involving a pediatric patient who presented to a large urban children's hospital in the Northeastern United States with complaints of migratory monoarticular joint swelling. The patient had presented with a swollen and painful left knee but with no other associated symptoms. He was nontoxic appearing, afebrile, and had normal vital signs. On examination, he was noted to have a tender and swollen left knee that was not erythematous, bruised, or warm to the touch. There was a history of fevers over the summer after returning home from a camping trip in a park located in the northeastern United States. A plain film knee x-ray showed signs of joint effusion but no osseous abnormalities. A bedside ultrasonography of the knee showed a pocket of fluid in the joint space. With parental consent, the left knee joint was aspirated under direct ultrasound guidance, with collection of dark yellow synovial fluid. This was sent for analysis that included cultures, Gram stain, crystal analysis, and Lyme antigens. The patient was admitted, and his symptoms improved during his hospitalization. The results were positive for Lyme and he was discharged home on a 3-week course of Amoxicillin with complete resolution of his symptoms.

Lyme Disease among Patients at an Ambulatory Unit in a Highly Endemic Country: Lithuania.

Background and objectives: Lyme disease is the most common tick-borne infectious disease in Europe, caused by the spirocheta bacteria of Borrelia burgdorferi. Several genospecies of B. burgdorferi are pathogenic to humans. B. burgdorferi sensu stricto, which is prevalent in North America, causes reactive arthritis, whereas B. garinii and B. afzelii, common in Europe, can affect the skin, heart, or nervous system; it has been shown that the clinical symptoms of the disease may be very different. The objective of this study was to identify the baseline characteristics of Lyme disease and to elucidate the frequency of different Lyme disease syndromes in Lithuania. Materials and Methods: Patients who were diagnosed with Lyme disease during an ambulatory visit to the Center of Infectious Diseases, Vilnius University Santaros clinics, from 2014 to 2016, were enrolled in this study. A retrospective material analysis was conducted. Results: In total, 1005 patients were enrolled with the following prevalence of clinical syndromes: erythema migrans (EM), 945 (94.02%); Lyme arthritis, 32 (3.18%); neuroborreliosis, 23 (2.28%); Lyme carditis, 4 (0.39%); and acrodermatitis, 1 (0.09%). Erythema migrans was dominant among middle-aged women, with a rash appearing mainly on the lower extremities. Lyme arthritis mainly manifested among middle-aged women as an oligoarthritis, mostly affecting the knee joint. Neuroborreliosis was seen more often in middle-aged women than men and the main symptom was nervus facialis neuropathy. Lyme carditis, manifested as an atrioventricular block, with a male/female ratio of 3:1, and the median age was 51. Acrodermatitis was diagnosed in a 61-year-old woman, as a painful, red rash on the hand. Conclusions: According to the prevalence of B. garinii and B. afzelii in Europe, previously it was thought that Lyme disease presented as erythema migrans, and less frequently as neuroborreliosis; however, this study revealed that other syndromes may also be seen. In addition, we revealed that the longer it takes for erythema migrans to appear, the greater the likelihood of Lyme arthritis developing.

Patients with Erythema Migrans: Characterizing the Impact of Initiation of Antibiotic Therapy Prior to Study Enrollment.

Erythema migrans is the most common clinical manifestation of Lyme disease, with concomitant subjective symptoms occurring in ∼65% of cases in the United States. We evaluated the impact of having been started on antibiotic treatment before study enrollment on 12 particular symptoms for 38 subjects with erythema migrans versus 52 untreated subjects. There were no significant differences in the frequency of having at least one symptom or in the symptom severity score on study entry. However, the frequency of having at least one symptom was significantly greater for those who had received <7 days of antibiotic treatment than for those who had been treated for ≥7 days (23/24 [95.8%] versus 8/14 [57.1%], P = 0.006). In addition, the percentage of subjects who were males was significantly lower among the group on treatment than among the untreated study subjects (13/38 [34.2%] versus 34/52 [65.4%], P = 0.005). In conclusion, based on these findings, combining untreated and treated groups of patients with erythema migrans for research study analyses may have limitations and, depending on the study objectives, might not be preferred. Additional studies are warranted to better understand the day-to-day impact of antibiotic treatment on the presence, type, and severity of symptoms in patients with early Lyme disease.

Epidemiology of Lyme Disease in a Highly Endemic European Zone.

Background and objective: Lyme disease, also known as Lyme borreliosis (LB), is a tick-borne infectious disease caused by the spirochete bacteria Borrelia. The risk of infection depends on the geographical area, ecological factors, and human behavior. Clinical manifestations of Lyme borreliosis have a wide range, but the most frequent clinical symptom, which is also a diagnostic symptom, is a skin rash called erythema migrans (EM). The disease is very common worldwide. In Lithuania, the disease frequency is 99.9 cases per 100,000 population (Centre for Communicable Diseases and AIDS, Lithuania, 2017). The main aim of this study was to obtain the baseline characteristics of the disease regarding the infected Lithuanian population. Materials and Methods: We analyzed data from the Centre for Communicable Diseases and AIDS about all Lyme disease (A69.2) diagnosed patients over a three-year period (from 2014 to 2016) in Lithuania. Results: In 2014-2016, 7424 (crude incidence rate 85.4) cases with LB were diagnosed in Lithuania. Most of them (4633 (62.4%)) were identified in women. Older people were more likely to suffer from LB. Urban residents were 2.6 times more often affected that those living in villages. Tick bites were primarily observed in high season months, from May to September (90%), with the highest peak in July. There was a higher number of observed tick bites (p = 0.003) in the urban residents. Erythema migrans occurred in 75.6% LB cases, while other symptoms did not exceed a quarter of all LB cases. There were 7353 (99.6%) cases where LB was confirmed via clinical symptoms and/or laboratory tests. Also, 1720 (23.2%) patients were tested for LB immunoglobulins. Conclusions: This study found a high incidence of Lyme disease in Lithuania. We elucidated the baseline characteristics regarding the infected Lithuanian population which may ease medical clinicians' work on new Lyme diagnoses.

Co-infections in Persons with Early Lyme Disease, New York, USA.

In certain regions of New York state, USA, Ixodes scapularis ticks can potentially transmit 4 pathogens in addition to Borrelia burgdorferi: Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and the deer tick virus subtype of Powassan virus. In a prospective study, we systematically evaluated 52 adult patients with erythema migrans, the most common clinical manifestation of B. burgdorferi infection (Lyme disease), who had not received treatment for Lyme disease. We used serologic testing to evaluate these patients for evidence of co-infection with any of the 4 other tickborne pathogens. Evidence of co-infection was found for B. microti only; 4-6 patients were co-infected with Babesia microti. Nearly 90% of the patients evaluated had no evidence of co-infection. Our finding of B. microti co-infection documents the increasing clinical relevance of this emerging infection.

Clinical spectrum of Lyme disease.

Lyme disease (borreliosis) is one of the most common vector-borne diseases worldwide. Its incidence and geographic expansion has been steadily increasing in the last decades. Lyme disease is caused by Borrelia burgdorferi sensu lato, a heterogeneous group of which three genospecies have been systematically associated to Lyme disease: B. burgdorferi sensu stricto Borrelia afzelii and Borrelia garinii. Geographical distribution and clinical manifestations vary according to the species involved. Lyme disease clinical manifestations may be divided into three stages. Early localized stage is characterized by erythema migrans in the tick bite site. Early disseminated stage may present multiple erythema migrans lesions, borrelial lymphocytoma, lyme neuroborreliosis, carditis, or arthritis. The late disseminated stage manifests with acordermatitis chronica atrophicans, lyme arthritis, and neurological symptoms. Diagnosis is challenging due to the varied clinical manifestations it may present and usually involves a two-step serological approach. In the current review, we present a thorough revision of the clinical manifestations Lyme disease may present. Additionally, history, microbiology, diagnosis, post-treatment Lyme disease syndrome, treatment, and prognosis are discussed.

Prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis: study protocol for an observational, prospective cohort study (LymeProspect).

BACKGROUND: After antibiotic treatment of Lyme borreliosis, a subset of patients report persistent symptoms, also referred to as post-treatment Lyme disease syndrome. The reported prevalence of persistent symptoms varies considerably, and its pathophysiology is under debate. The LymeProspect study has been designed to investigate the prevalence, severity, and a wide range of hypotheses on the etiology of persistent symptoms among patients treated for Lyme borreliosis in the Netherlands. METHODS: LymeProspect is a prospective, observational cohort study among adults with proven or probable Lyme borreliosis, either erythema migrans or disseminated manifestations, included at the start of antibiotic treatment. During one year of follow-up, participants are subjected to questionnaires every three months and blood is collected repeatedly during the first three months. The primary outcome is the prevalence of persistent symptoms after treatment, assessed by questionnaires online focusing on fatigue (CIS, subscale fatigue severity), pain (SF-36, subscale pain) and neurocognitive dysfunction (CFQ). Potential microbiological, immunological, genetic, epidemiological and cognitive-behavioral determinants for persistent symptoms are secondary outcome measures. Control cohorts include patients with long-lasting symptoms and unconfirmed Lyme disease, population controls, and subjects having reported a tick bite not followed by Lyme borreliosis. DISCUSSION: This article describes the background and design of the LymeProspect study protocol. This study is characterized by a prospective, explorative and multifaceted design. The results of this study will provide insights into the prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis, and may provide a rationale for preventive and treatment recommendations. TRIAL REGISTRATION: NTR4998 (Netherlands Trial Register). Date of registration: 13 February 2015.