Prevalence and factors associated with a prescription of a Lyme borreliosis serology for erythema migrans diagnosis in general practice: a study from the French sentinel network, 2009-2020.

BACKGROUND: Serological testing of patients consulting for typical erythema migrans (EM) is not recommended in European recommendations for diagnosis of Lyme borreliosis (LB). Little is known on the level of adherence of French general practitioners to these recommendations. The objectives were to estimate the proportion of Lyme borreliosis serological test prescription in patients with erythema migrans seen in general practice consultations in France, and to study the factors associated with this prescription. METHODS: LB cases with an EM reported by the French general practitioners (GPs) of the Sentinelles network between January 2009 and December 2020 were included. To assess the associations with a prescription of a serological test, multilevel logistic regression models were used. RESULTS: Among the 1,831 EM cases included, a prescription for a LB serological test was requested in 24.0% of cases. This proportion decreased significantly over the study period, from 46.8% in 2009 to 15.8% in 2020. A LB serological prescription was associated with patients with no reported tick bite (Odds Ratio (OR): 1.95; 95% confidence interval [1.23-3.09]), multiple EM (OR: 3.82 [1.63-8.92]), EM of five centimeters or more (OR: 4.34 [2.33-8.08]), and GPs having diagnosed less than one EM case per year during the study period (OR: 5.28 [1.73-16.11]). CONCLUSIONS: Serological testing of patients consulting for EM is not recommended in European recommendations for diagnosis of Lyme borreliosis. Therefore, the significant decrease in the rate of LB serological test for EM over the study period is encouraging. The factors identified in this study can be used to improve messaging to GPs and patients. Further efforts are needed to continue to disseminate diagnostic recommendations for LB to GPs, especially those who rarely see patients with EM.

Incidence of Lyme Borreliosis in the Dutch General Practice Population: A Large-Scale Population-Based Cohort Study Across the Netherlands Between 2015 and 2019.

Background: There is a need for updated incidence rates (IRs) of Lyme borreliosis (LB) in Europe, including the Netherlands. We estimated LB IRs stratified by geographic area, year, age, sex, immunocompromised status, and socioeconomic status (SES). Methods: All subjects registered in the PHARMO General Practitioner (GP) Database without prior diagnosis of LB or disseminated LB and having ≥1 year of continuous database enrolment were included. IRs and corresponding confidence intervals (CIs) of GP-recorded LB, erythema migrans (EM), and disseminated LB were estimated during the period 2015‒2019. Results: We identified 14,794 events (suspected, probable, or confirmed) with a diagnostic code for LB that included 8219 with a recorded clinical manifestation: 7985 (97%) with EM and 234 (3%) with disseminated LB. National annual LB IRs were relatively consistent, ranging from 111 (95% CI 106‒115) in 2019 to 131 (95% CI 126‒136) in 2018 per 100,000 person-years. Incidence of LB showed a bimodal age distribution, with peak IRs observed among subjects aged 5‒14 and 60‒69 years in men and women. Higher LB incidence was found in subjects who were residents of the provinces of Drenthe and Overijssel, immunocompromised, or of lower SES. Similar patterns were observed for EM and disseminated LB. Conclusions: Our findings confirm that LB incidence remains substantial throughout the Netherlands with no indication of decline in the past 5 years. Foci in two provinces and among vulnerable populations suggest potential initial target groups for preventive strategies such as vaccination.

Treatment of erythema migrans with doxycycline for 7 days versus 14 days in Slovenia: a randomised open-label non-inferiority trial.

BACKGROUND: Lyme borreliosis is the most prevalent vector-borne disease in Europe and the USA. Doxycycline for 10 days is the primary treatment recommendation for erythema migrans. To reduce potentially harmful antibiotic overuse by identifying shorter effective treatments, we aimed to assess whether oral doxycycline for 7 days is non-inferior to 14 days in adults with solitary erythema migrans. METHODS: In this randomised open-label non-inferiority trial, we enrolled patients with a solitary erythema at the University Medical Centre in Ljubljana, Slovenia. Patients were excluded if they were pregnant or lactating, immunosuppressed, allergic to doxycycline, or had received antibiotics with anti-borrelial activity within 10 days preceding enrolment or had additional manifestations of Lyme borreliosis Adults were randomly allocated 1:1 to receive oral doxycycline 100 mg twice a day for 7 days or 14 days. The primary efficacy endpoint was the difference in proportion of patients with treatment failure, defined as persistent erythema, new objective signs of Lyme borreliosis, or borrelial isolation on skin re-biopsy at 2 months, in a per-protocol analysis (the population that completed the assigned doxycycline regimen according to the study protocol and did not receive any other antibiotics with anti-borrelial activity until the 2-month visit). The non-inferiority margin was 6 percentage points. Safety was assessed in all randomly assigned patients who followed the study protocol and were evaluable at the 14-day visit. This study is registered with ClinicalTrials.gov, NCT03153267. FINDINGS: Between July 3, 2017, and Oct 2, 2018, we enrolled 300 patients (150 per group: median age 56 years [IQR 47-65]; 126 [45%] of 300 male; skin culture positive 72 [30%] of 239 assessed). 295 patients completed antibiotic therapy as per protocol and 294 (98%) patients were evaluable 2 months post-enrolment. Five (3%) of 147 patients from the 7-day group versus 3 (2%) of 147 patients from the 14-day group (one patient did not attend the 2-month visit and was unreachable by telephone) had treatment failure manifesting as persistence of erythema (difference 1·4 percentage points; upper limit of one-sided 95% CI 5·2 percentage points; p=0·64). No patients developed new objective manifestations of Lyme borreliosis during follow-up or had positive repeat skin biopsies. Two (1%) of 150 patients in the 7-day and one (1%) of 150 patients in the 14-day group discontinued therapy due to adverse events. INTERPRETATION: Our data support 7 days of oral doxycycline for adult European patients with solitary erythema migrans, permitting less antibiotic exposure than current guideline-driven therapy. FUNDING: Slovenian Research Agency and the University Medical Centre Ljubljana.

Lyme Disease in Children.

Lyme disease is now the most frequently reported vector-borne disease in the United States. The highest incidence is in children aged 5 to 9 years with a male predominance. The most common manifestation, erythema migrans, is sometimes not recognized, leading to risk of complications. Testing for Lyme disease should only be done if there is a consistent clinical syndrome with exposure in a Lyme-endemic area. Most forms of Lyme disease are successfully treated with short courses of oral therapy. Prevention and management of tick bites is important.

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.

Association between statin use and clinical course, microbiologic characteristics, and long-term outcome of early Lyme borreliosis. A post hoc analysis of prospective clinical trials of adult patients with erythema migrans.

BACKGROUND: Statins were shown to inhibit borrelial growth in vitro and promote clearance of spirochetes in a murine model of Lyme borreliosis (LB). We investigated the impact of statin use in patients with early LB. METHODS: In this post-hoc analysis, the association between statin use and clinical and microbiologic characteristics was investigated in 1520 adult patients with early LB manifesting as erythema migrans (EM), enrolled prospectively in several clinical trials between June 2006 and October 2019 at a single-center university hospital. Patients were assessed at enrollment and followed for 12 months. RESULTS: Statin users were older than patients not using statins, but statin use was not associated with Borrelia seropositivity rate, Borrelia skin culture positivity rate, or disease severity as assessed by erythema size or the presence of LB-associated symptoms. The time to resolution of EM was comparable in both groups. The odds for incomplete recovery decreased with time from enrollment, were higher in women, in patients with multiple EM, and in those reporting LB-associated symptoms at enrollment, but were unaffected by statin use. CONCLUSION: Statin use was not associated with clinical and microbiologic characteristics or long-term outcome in early LB.

Lyme borreliosis in Finland: a register-based linkage study.

BACKGROUND: In Finland, the routine surveillance of Lyme borreliosis (LB) is laboratory-based. In addition, we have well established national health care registers where countrywide data from patient visits in public health care units are collected. In our previous study based on these registers, we reported an increasing incidence of both microbiologically confirmed and clinically diagnosed LB cases in Finland during the past years. Here, we evaluated our register data, refined LB incidence estimates provided in our previous study, and evaluated treatment practices considering LB in the primary health care. METHODS: Three national health care registers were used. The Register for Primary Health Care Visits (Avohilmo) and the National Hospital Discharge Register (Hilmo) collect physician-recorded data from the outpatient and inpatient health care visits, respectively, whereas the National Infectious Diseases Register (NIDR) represents positive findings in LB diagnostics notified electronically by microbiological laboratories. We used a personal identification number in register-linkage to identify LB cases on an individual level in the study year 2014. In addition, antibiotic purchase data was retrieved from the Finnish Social Insurance Institution in order to evaluate the LB treatment practices in the primary health care in Finland. RESULTS: Avohilmo was found to be useful in monitoring clinically diagnosed LB (i.e. erythema migrans (EM) infections), whereas Hilmo did not add much value next to existing laboratory-based surveillance of disseminated LB. However, Hilmo gave valuable information about uncertainties related to physician-based surveillance of disseminated LB and the total annual number of EM infections in our country. Antibiotic purchases associated with the LB-related outpatient visits in the primary health care indicated a good compliance with the recommended treatment guidelines. CONCLUSIONS: Avohilmo and laboratory-based NIDR together are useful in monitoring LB incidence in Finland. A good compliance was observed with the recommended treatment guidelines of clinically diagnosed LB in the primary health care. In 2018, Avohilmo was introduced in the routine surveillance of LB in Finland next to laboratory-based surveillance of disseminated LB.

Prospective Evaluation of the Frequency and Severity of Symptoms in Lyme Disease Patients With Erythema Migrans Compared With Matched Controls at Baseline, 6 Months, and 12 Months.

BACKGROUND: Erythema migrans is the most common clinical manifestation of Lyme disease. Despite antibiotic therapy, typically at least 10% of adult patients with erythema migrans experience persistence of at least 1 subjective symptom for ≥6 months (posttreatment Lyme disease symptoms [PTLDS]). METHODS: This study was designed to determine whether the frequency and severity (based on a visual analogue scale) of 12 particular symptoms in patients with erythema migrans (n = 52) differed from matched control subjects (n = 104) followed prospectively for 12 months. RESULTS: At baseline, patients with Lyme disease were more likely than controls to have at least 1 symptom (P = .006). Among symptomatic subjects, Lyme disease patients had a higher mean number of symptoms (P < .001) and a higher mean total symptom severity score (P < .001). At both 6 and 12 months, however, there were no significant differences for these variables and no significant differences in the frequency or severity of any of the 12 individual symptoms assessed. However, 10 patients were clinically assessed as having possible PTLDS. CONCLUSIONS: Patients with erythema migrans were more likely than matched control subjects to be symptomatic at baseline with a greater symptom severity score, but this was not found at ≥6 months. Use of symptom survey data alone, however, was less likely to identify patients with possible PTLDS compared with individual clinical assessments. Because it is very challenging to be certain that the presence of long-term symptoms in a particular patient is correctly attributable to having had Lyme disease, an objective biomarker would be highly desirable.

Functional signs in patients consulting for presumed Lyme borreliosis.

INTRODUCTION: Little is known about the functional symptoms associated with Lyme borreliosis (LB) in Europe. We aimed to assess functional symptoms associated with presumed LB and to compare patients with and without confirmed LB. MATERIALS AND METHODS: We performed a retrospective monocenter study. Patients consulting for presumed LB were included. RESULTS: Between November 2015 and June 2018, 355patients were included (mean age: 51years, 52% of women) of which 48had LB: erythema migrans (42%), early disseminated LB (50%; 35% of neuroborreliosis cases), and late disseminated LB (8%). The most frequently reported functional symptoms were neuropathic pain (23%), arthralgia (23%), and asthenia (17%). Other functional symptoms were rare (≤10%). Three hundred and seven (86%) patients did not have LB. Patients with confirmed LB reported fewer functional symptoms than patients without LB (1.8 (±1.7) vs. 3.6 (±2.5), P<0.001) with a shorter duration of symptoms (< 3 months in 48% vs. 16% of cases, P<0.001). They less often reported asthenia (17% vs. 59%, P<0.001), widespread pain (10% vs. 31%, P=0.003), myalgia (10% vs. 32%, P=0.002), memory disorders (4% vs. 16%, P=0.03), irritability (2% vs. 23%, P±0.001), and sadness (0% vs. 16%, P=0.003). CONCLUSION: In patients consulting for presumed LB, patients diagnosed with LB had fewer and shorter functional symptoms than patients without LB.

Lyme snap: A feasibility study of on-line declarations of erythema migrans in a rural area of France.

The incidence of Lyme borreliosis remains a matter of debate, but it can be estimated using the incidence of erythema migrans (EM), which is pathognomonic of the first phase. The aim of this prospective pilot study was to assess the feasibility of the on-line declaration of EM in rural areas where the incidence of Lyme borreliosis was previously estimated at 85 per 100,000 inhabitants per year. The study was limited to a rural area (Les Combrailles, Auvergne) of approximately 52,800 inhabitants and was preceded by an information campaign for the inhabitants and the healthcare professionals. Patients who sent a photo of the suspected EM by email or MMS message between April 2017 and April 2018 and who accepted to answer a questionnaire were included in the study. Two physicians then evaluated the quality of the photographs and the probability of EM. In parallel, the number of EM seen by physicians and pharmacists in the area over the given period was recorded. Out of the 113 emails and MMS messages received, 73 people were outside of the trial area or period and 9 did not complete the questionnaire. The photos of the remaining 31 people were analysed. The median age was 51.5 years old ([38-58] IQR) and 18 (58%) were women. Seven people (25%) stated that they did not have a smartphone and in 9 cases (29%) the photo was sent by a third party. The quality of the photos was considered very good in 22 (71%) cases, good in 7 (23%) cases, and average in 2 (6%) cases. The probability of EM was determined to be strong or possible in 12 (38%) cases, i.e. an estimated incidence of 22.7 per 100,000 inhabitants. Over the study period, 40 physicians and 20 pharmacists were contacted on a monthly basis. A median of 5 physicians [3;7] and 4 pharmacists [3 ;7] answered each month for a total of 18 and 36 declared EM respectively. The EM (strong probability/possible) collected by on-line declaration and those declared by healthcare professionals were all sent between April and October 2017. The total time spent on the information campaign and collection has been estimated at 265 h (divided between 10 people) for an overall cost of 10,669 Euros. The incidence of EM recorded by on-line self-declaration in our study seems to be lower than in previous studies, the under-reporting was probably linked to the low use of new technologies in the rural areas. Increasing the human resources and finances appears difficult to achieve in practice over a longer time period but the development of an application for the automatic recognition of EM could be one method for a more exhaustive collection in the long term and at lower cost.

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.

Combining primary care surveillance and a meta-analysis to estimate the incidence of the clinical manifestations of Lyme borreliosis in Belgium, 2015-2017.

Lyme borreliosis (LB) is an important tick-borne disease which can cause a broad range of symptoms mainly affecting the skin, the nervous system and the joints. This study aims to estimate the incidence of the different clinical manifestations of LB in Belgium. The incidence of erythema migrans (EM) was estimated through the network of sentinel general practices at 97.6/100,000 inhabitants (uncertainty interval [UI] 82.0-113.0) for the period 2015-2017. This result was used to estimate the incidence of other LB manifestations based on their proportional distribution (ratios) to EM reported in the neighboring countries of Belgium. To estimate these ratios, we performed a systematic review of studies published between February 1, 2008 and January 31, 2018 and pooled the results using a random effects meta-analysis. Six studies were retained in the systematic review, and the meta-analysis estimated the occurrence ratios for Lyme neuroborreliosis/EM, Lyme arthritis/EM and other manifestations/EM at 0.024 (95% confidence interval [CI] 0.016-0.037), 0.022 (95% CI 0.020-0.024) and 0.014 (95% CI 0.012-0.016) respectively. Applying these ratios to the EM incidence in Belgium resulted in an incidence estimation of 2.4/100,000 inhabitants (95% UI 1.5-3.7) for Lyme neuroborreliosis, 2.1/100,000 (95% UI 1.7-2.6) for Lyme arthritis and 1.4/100,000 (95% UI 1.1-1.7) for other less frequent manifestations. Some of these LB manifestations, other than EM, are more severe, hence these estimates are essential to assess the health burden and economic cost of LB which would be highly relevant for patients, healthcare providers and policymakers. As both over- and underestimation of different clinical LB manifestations remain possible due to characteristics of the primary surveillance systems and the disease itself, future studies to validate these estimates would be of great value.

Somatic symptoms and fatigue in a Norwegian population with high exposure to ticks.

BACKGROUND: It is heavily debated whether tick-borne infections cause chronic subjective health complaints. If the hypothesis of a major causal connection is true, one would expect to find more subjective health complaints in a population with high exposure to ticks than in a population with less exposure. In the current study we aimed to assess somatic symptoms and fatigue in a Norwegian population with high exposure to ticks, compare our findings to normative data, and assess predictors of somatic symptom load. MATERIAL AND METHODS: All individuals aged 18-69 years with residential address in Søgne municipality in southern Norway were in the period June 2015 to June 2016 invited to participate in the study. Somatic symptoms were assessed by the Patient Health Questionnaire-15 (PHQ-15) and fatigue by the Fatigue Severity Scale (FSS). A multivariable regression analysis was performed to assess predictors of somatic symptom load. RESULTS: Out of 7424 invited individuals, 2971 (40.0%) returned the questionnaire. 85.1% of 2950 responders reported exposure to tick-bite. PHQ-15 mean sum score was 5.3, and 16.5% reported moderate to severe somatic symptom load (i.e. ≥ 10). FSS mean score was 3.2, and 29.8% scored above the cut-off value for fatigue (i.e. ≥ 4.0). All gender and age groups in our study population had equal or lower mean sum score on PHQ-15 than reported in Swedish normative data, and lower mean score on FSS than reported in Norwegian normative data. In multivariable regression the following factors were associated with higher somatic symptom load (listed in order of descending beta coefficient): Anxiety and depression, number of other diseases, female gender, younger age, recruitment when visiting general practitioner's office, ≤ 6 years education after primary school, tick-bite earlier in life, erythema migrans earlier in life, less physical activity, and modern health worries. CONCLUSION: The study population reported high exposure to tick-bites, but less or equal level of somatic symptoms and less fatigue than found in normative data. There was a weak association between somatic symptom load and exposure to tick-bite and erythema migrans, possibly related to selection bias. Our findings do not support the hypothesis of a major causal connection between tick-borne infections and subjective health complaints.

Report of Non-Lyme, Erythema Migrans Rashes from New Jersey with a Review of Possible Role of Tick Salivary Toxins.

Erythema migrans (EM) rashes once considered pathognomonic of Lyme disease (LD) have been reported following bites of arthropods that do not transmit LD and in areas with no LD. Also, EM rashes have been reported in association with organisms other than members of Borrelia burgdorferi sensu lato complex. Arthropod saliva has chemicals that have effects on the host and pathogen transmission. Tick saliva has protein families similar to spiders and scorpions and even substances homologous to those found in snakes and other venomous animals. Ticks "invertebrate pharmacologists" have a sophisticated arsenal of chemicals that assist in blood feeding, pathogen transmission, and suppressing host defenses. No organisms have been isolated from many EM rashes. We propose that tick salivary toxins may play a role in the causation of rashes and laboratory abnormalities in tick-borne diseases. The role of tick salivary toxins needs further exploration. Cases of Lyme-like EM rashes referred to as STARI (Southern Tick-Associated Rash Illness) following bites of the lone star tick, Amblyomma americanum, in the United States have been reported predominantly in Southeastern Missouri and a few in South Carolina, North Carolina, Georgia, and one case each in Mississippi and Long Island, New York. Although there is one report of Borrelia lonestari in a patient with a rash, biopsies of 31 cases of STARI, with cultures and PCR, failed to show a relationship. Distribution of A. americanum, whose bites are associated with STARI, now extends along the East Coast of the United States, including New Jersey, up to the Canadian border. As far as we are aware, there have been no prior reports of Lyme-like rashes in New Jersey. In this study, we present case examples of 2 Lyme-like rashes, variations of EM rashes, and a brief review of studies that suggest a role of tick salivary toxins in tick-borne diseases.

Comparison of phenoxymethylpenicillin, amoxicillin, and doxycycline for erythema migrans in general practice. A randomized controlled trial with a 1-year follow-up.

OBJECTIVES: To compare the three most commonly used antibiotics for erythema migrans (EM) in Norwegian primary care. METHODS: A randomized, parallel, controlled trial was carried out. Treatments were open to the patients, but blinded for the GPs and investigators. Patients eligible for inclusion were aged ≥18 years and clinically diagnosed with EM. Block randomization was processed in blocks of six. Patients were assigned to receive one of three antibiotic treatments for 14 days: phenoxymethylpenicillin (PCV), amoxicillin, or doxycycline. The primary outcome was the duration of EM in days in the three treatment groups. Patients kept a diary for the 14 days of treatment, in which they registered concomitant symptoms and side effects. The patients consulted their GP after 14 days of treatment and had a 1-year follow-up to monitor any development of disseminated Lyme borreliosis (LB). EMs with a duration of more than 14 days were followed until resolution. ClinicalTrials.govNCT01368341 and EU Clinical Trials Register 2010-023747-15. RESULTS: One hundred and eighty eight patients (PCV: n = 56, amoxicillin: n = 64, doxycycline: n = 68) were included by 44 Norwegian general practitioners (GPs) from June 2011 to November 2013. Follow-up was completed by December 2014. The median duration of EM was altogether 14 days (range 3-293). For the PCV group median duration was 14 days (range 5-91), for amoxicillin 13 days (range 4-179) and for doxycycline 14 days (range 3-293). The duration of EM did not differ significantly between the three antibiotic groups (p 0.277). None of the patients developed disseminated LB within the 1-year follow-up. CONCLUSIONS: We did not find 14 days of PCV, doxycycline, and amoxicillin treatments to differ in effectiveness or safety in the treatment of clinically diagnosed EM in primary care.

Is the risk of early neurologic Lyme borreliosis reduced by preferentially treating patients with erythema migrans with doxycycline?

Doxycycline is highly effective treatment for early neurologic Lyme borreliosis (NLB). Nineteen studies were reviewed to determine if treatment of patients with erythema migrans with other oral antibiotics would increase the risk for developing NLB. In the eight studies that directly compared doxycycline to another antibiotic, the pooled difference indicated a 0.2% greater risk of developing NLB in doxycycline-treated patients (95% CI: -1.0%, +1.4%; P = 0.77), with an estimated heterogeneity of 0.0%, P = 0.58. Overall, in the 19 studies, NLB was reported in 8/828 (1.0%; 95% CI: 0.42%, 1.89%) doxycycline-treated patients versus 6/1022 (0.6%; 95% CI: 0.22%, 1.27%) patients treated with other antibiotics (P = 0.42). Based on the 95% CI calculation (-0.5%, +1.40%), patients receiving nondoxycycline treatment regimens collectively might have at most a 0.5% greater risk for developing NLB. Available data suggest that oral doxycycline is not superior to comparators for preventing NLB in patients receiving treatment for erythema migrans.

Surveillance perspective on Lyme borreliosis across the European Union and European Economic Area.

Lyme borreliosis (LB) is the most prevalent tick-borne disease in Europe. Erythema migrans (EM), an early, localised skin rash, is its most common presentation. Dissemination of the bacteria can lead to more severe manifestations including skin, neurological, cardiac, musculoskeletal and ocular manifestations. Comparison of LB incidence rates in the European Union (EU)/European Economic Area (EEA) and Balkan countries are difficult in the absence of standardised surveillance and reporting procedures. We explored six surveillance scenarios for LB surveillance in the EU/EEA, based on the following key indicators: (i) erythema migrans, (ii) neuroborreliosis, (iii) all human LB manifestations, (iv) seroprevalence, (v) tick bites, and (vi) infected ticks and reservoir hosts. In our opinion, neuroborreliosis seems most feasible and useful as the standard key indicator, being one of the most frequent severe LB manifestations, with the possibility of a specific case definition. Additional surveillance with erythema migrans as key indicator would add value to the surveillance of neuroborreliosis and lead to a more complete picture of LB epidemiology in the EU/EEA. The other scenarios have less value as a basis for EU-level surveillance, but can be considered periodically and locally, as they could supply complementary insights.

Candidatus Neoehrlichia mikurensis and Borrelia burgdorferi sensu lato detected in the blood of Norwegian patients with erythema migrans.

The most common tick-borne human disease in Norway is Lyme borreliosis. Ticks in Norway also harbour less known disease-causing agents such as Candidatus Neoehrlichia mikurensis, Borrelia miyamotoi and Rickettsia helvetica. However, human infections caused by these pathogens have never been described in Norway. The main aims of the study were to evaluate the contribution of several tick-borne bacterial agents, other than Borrelia burgdorferi sensu lato, to zoonotic diseases in Norway and to determine their clinical pictures. Blood samples from 70 symptomatic tick-bitten adults from the Agder counties in southern Norway were screened for seven tick-borne pathogens by using a commercial multiplex PCR-based method and by singleplex real-time PCR protocols. Most patients (65/70) presented with a rash clinically diagnosed as erythema migrans (EM). The most frequently detected pathogen DNA was from Ca. N. mikurensis and was found in the blood of 10% (7/70) of the patients. The Ca. N. mikurensis-infected patients presented with an EM-like rash as the only symptom. B. burgdorferi s.l. DNA was present in the blood of 4% (3/70) of the study participants. None had detectable Anaplasma phagocytophilum, B. miyamotoi, Rickettsia typhus group or spotted fever group, Francisella tularensis, Coxiella burnetii or Bartonella spp. DNA in the blood. The commercially available multiplex PCR bacteria flow chip system failed to identify half of the infected patients detected by corresponding real-time PCR protocols. The recovery of Ca. N. mikurensis DNA was higher in the pellet/plasma fraction of blood than from whole blood. To conclude, Ca. N. mikurensis appeared to be the etiological agent in patients with EM in a surprisingly large fraction of tick-bitten persons in the southern part of Norway.

Molecular Detection of Tick-Borne Pathogens in Humans with Tick Bites and Erythema Migrans, in the Netherlands.

BACKGROUND: Tick-borne diseases are the most prevalent vector-borne diseases in Europe. Knowledge on the incidence and clinical presentation of other tick-borne diseases than Lyme borreliosis and tick-borne encephalitis is minimal, despite the high human exposure to these pathogens through tick bites. Using molecular detection techniques, the frequency of tick-borne infections after exposure through tick bites was estimated. METHODS: Ticks, blood samples and questionnaires on health status were collected from patients that visited their general practitioner with a tick bite or erythema migrans in 2007 and 2008. The presence of several tick-borne pathogens in 314 ticks and 626 blood samples of this cohort were analyzed using PCR-based methods. Using multivariate logistic regression, associations were explored between pathogens detected in blood and self-reported symptoms at enrolment and during a three-month follow-up period. RESULTS: Half of the ticks removed from humans tested positive for Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, Candidatus Neoehrlichia mikurensis, Rickettsia helvetica, Rickettsia monacensis, Borrelia miyamotoi and several Babesia species. Among 92 Borrelia burgdorferi s. l. positive ticks, 33% carried another pathogen from a different genus. In blood of sixteen out of 626 persons with tick bites or erythema migrans, DNA was detected from Candidatus Neoehrlichia mikurensis (n = 7), Anaplasma phagocytophilum (n = 5), Babesia divergens (n = 3), Borrelia miyamotoi (n = 1) and Borrelia burgdorferi s. l. (n = 1). None of these sixteen individuals reported any overt symptoms that would indicate a corresponding illness during the three-month follow-up period. No associations were found between the presence of pathogen DNA in blood and; self-reported symptoms, with pathogen DNA in the corresponding ticks (n = 8), reported tick attachment duration, tick engorgement, or antibiotic treatment at enrolment. CONCLUSIONS: Based on molecular detection techniques, the probability of infection with a tick-borne pathogen other than Lyme spirochetes after a tick bite is roughly 2.4%, in the Netherlands. Similarly, among patients with erythema migrans, the probability of a co-infection with another tick-borne pathogen is approximately 2.7%. How often these infections cause disease symptoms or to what extend co-infections affect the course of Lyme borreliosis needs further investigations.

Borrelial Lymphocytoma in Adult Patients.

BACKGROUND: Information on the course and outcome of borrelial lymphocytoma (BL) is limited. METHODS: The study comprised 144 adult patients (75 female, 69 male; median age, 49 years) who had BL diagnosed at a single center between 1986 and 2014 and were followed up for 1 year. RESULTS: BL was located on the breast in 106 patients (73.6%), on the ear lobe in 27 (18.8%), and elsewhere in 11 (7.6%). The median duration of BL before diagnosis was 27 days (interquartile range [IQR], 9-68 days). Concomitant erythema migrans was registered in 104 of 144 patients (72.2%); other objective manifestations of Lyme borreliosis (LB) were present in 11 (7.6%). Immunoglobulin M and/or G borrelial serum antibodies were present in 72 patients (50%). Borreliae were isolated from BL lesions in 14 of 42 patients (33.3%) who had not received antibiotics before skin biopsy. Of 13 typed Borrelia strains, 11 were B. afzelii, 1 was B. garinii, and 1 was B. bissettii The median duration of BL after starting antibiotic treatment was 21 days ([IQR], 10-30 days); the average duration was longer in patients who were older, had longer BL duration before treatment, or had signs of disseminated LB. Treatment failure occurred in 14 of 144 patients (9.7%). Patients with signs or symptoms of disseminated LB before treatment had nearly 4 times higher odds of treatment failure (95% confidence interval, 1.22-13.07) than those without such symptoms. All patients with treatment failure had uneventful outcome after retreatment. CONCLUSIONS: BL is a rare manifestation of early localized LB. Fourteen-day antibiotic treatment, as used for erythema migrans, is effective.