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.

[Clinical presentation and Treatment of Lyme Disease]. / Klinik und Therapie der Lyme-Borreliose.

Clinical presentation and Treatment of Lyme Disease Abstract. Lyme borreliosis is a tick-born disease caused by Borrelia burgdorferi sensu lato characteristically occurring in the northern hemisphere. Typically, the first manifestation is a localized infection of the skin with an expanding rash, commonly referred to as Erythema migrans. Early disseminated infections typically affect the central nervous system and, less commonly, the heart causing carditis. Late manifestations include arthritis and skin involvement, the so called "Acrodermatitis atrophicans". However, the chronology of signs and symptoms is not a necessity: late manifestations of the disease might also present as the first symptoms and need to be considered accordingly. With the exemption of Erythema migrans, which does not require serology, the diagnosis of infection with Borrelia relies on a synthesis of signs and symptoms and a positive serology. Infection with Borrelia can be treated with appropriate antibiotic regimens, especially beta-lactam derivatives and tetracyclines. Despite successful treatment, post-infectious symptoms may develop in a fraction of patients.

Oral Doxycycline Compared to Intravenous Ceftriaxone in the Treatment of Lyme Neuroborreliosis: A Multicenter, Equivalence, Randomized, Open-label Trial.

BACKGROUND: Lyme neuroborreliosis (LNB) is often treated with intravenous ceftriaxone even if doxycycline is suggested to be noninferior to ceftriaxone. We evaluated the efficacy of oral doxycycline in comparison to ceftriaxone in the treatment of LNB. METHODS: Patients with neurological symptoms suggestive of LNB without other obvious reasons were recruited. The inclusion criteria were (1) production of Borrelia burgdorferi-specific antibodies in cerebrospinal fluid (CSF) or serum; (2) B. burgdorferi DNA in the CSF; or (3) an erythema migrans during the past 3 months. Participants were randomized in a 1:1 ratio to receive either oral doxycycline 100 mg twice daily for 4 weeks, or intravenous ceftriaxone 2 g daily for 3 weeks. The participants described their subjective condition with a visual analogue scale (VAS) from 0 to 10 (0 = normal; 10 = worst) before the treatment, and 4 and 12 months after the treatment. The primary outcome was the change in the VAS score at 12 months. RESULTS: Between 14 September 2012 and 28 December 2017, 210 adults with suspected LNB were assigned to receive doxycycline (n = 104) or ceftriaxone (n = 106). The per-protocol analysis comprised 82 patients with doxycycline and 84 patients with ceftriaxone. The mean change in the VAS score was -3.9 in the doxycycline group and -3.8 in the ceftriaxone group (mean difference, 0.17 [95% confidence interval, -.59 to .92], which is within the prespecified equivalence margins of -1 to 1 units). Participants in both groups improved equally. CONCLUSIONS: Oral doxycycline is equally effective as intravenous ceftriaxone in the treatment of LNB. CLINICAL TRIALS REGISTRATION: NCT01635530 and EudraCT 2012-000313-37.

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.

Stages of Lyme Arthritis.

BACKGROUND/HISTORICAL PERSPECTIVE: Lyme arthritis was described in 1977, after an apparent outbreak of juvenile idiopathic arthritis in Lyme, Connecticut. The evolution of the disease has been meticulously described with presentation dependent on disease duration and previous therapy. SUMMARY INTEGRATING PUBLISHED LITERATURE: Erythema migrans is typically the first manifestation. Untreated patients often develop early disseminated disease, characterized by migratory polyarthralgia, potentially with cardiac and/or neurologic sequelae. If untreated, most patients develop late Lyme arthritis, characterized as a monoarthritis or oligoarthritis, typically involving the knees. Serologies are strongly positive at this stage; if positive, Lyme PCR from synovial fluid confirms the diagnosis. Doxycycline is recommended for late Lyme arthritis, although amoxicillin or ceftriaxone may be considered.Initial antibiotic therapy for late Lyme arthritis is insufficient for a subset of patients. However, serologies and synovial fluid PCR are not useful at determining whether infection persists after oral therapy. As such, ceftriaxone is recommended in patients with inadequate response to doxycycline or amoxicillin.Approximately 10% of patients have persistent arthritis despite antimicrobial therapy, termed postinfectious Lyme arthritis, which is thought to be related to prolonged inflammation and unique microbial and host interaction. Therapy at this stage relies on immunosuppression and/or synovectomy. MAJOR CONCLUSIONS AND FUTURE RESEARCH: Lyme arthritis provides unique insights into the complex interplay between microbes and host immunity. The progression from localized erythema migrans to early disseminated disease and late Lyme arthritis allows insight into arthritis initiation, and the study of postinfectious Lyme arthritis allows further insight into mechanisms of arthritis persistence.

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.

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.

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.

Analysis of cases of Lyme arthritis in patients hospitalized in Infectious Diseases Department, University Hospital in Cracow.

Lyme disease is an emerging problem in Poland. Analysis has been undertaken of the medical documentation of 86 patients hospitalized in the Infectious Diseases Department, University Hospital in Cracow in 2013-2016, suspected of Lyme arthritis. It has especially considered medical history including potential exposure to the infection, detailed characteristics of the symptoms, diagnostic challenges and results of the treatment. Only some patients had a history of erythema migrans and not all of them recalled tick-bite. The majority of the patients had affected large joints, especially knee joints, and polyarthritis was rarely observed. Symptoms were resolved completely or partially after antibiotic treatment in most patients. The diagnosis of Lyme arthritis in areas endemic for Lyme disease is still a diagnostic challenge in patients with other rheumatic diseases, including osteoarthritis.

Doxycycline-induced photosensitivity in patients treated for erythema migrans.

BACKGROUND: Doxycycline is one of the recommended antibiotics for treating erythema migrans (EM). Since EM predominantly occurs during summer, the potential of doxycycline to induce photosensitivity is of concern. In studies on the efficacy of doxycycline for treating relatively small numbers of patients with EM, the reported frequency of photosensitivity has varied from none to 15%. The aim of this study was to elucidate the frequency and clinical symptoms of doxycycline-induced photosensitivity in a large cohort of patients with EM treated in a single medical centre. METHODS: Prospectively collected data on adverse events were analysed in adult patients with EM treated with doxycycline 100 mg twice daily for 10-15 days. RESULTS: Photosensitivity reactions ranging from itching and burning sensations to transient mild erythema of sun-exposed skin were documented in 16/858 (1.9, 95% CI 1.1-3.0%) patients and appeared from June to October with highest frequency in July. These adverse events were more frequent in patients treated for 14 or 15 days (16/750 [2.1%]; 95% CI 1.2-3.4%) than in those treated for 10 days (0/108 [0%]; 95% CI 0.0-3.4%); however, the difference was not significant (P = 0.24). Women were more often affected than men (13/475 [2.7%], 95% CI 1.5-4.6% versus 3/383 [0.8%], 95% CI 0.2-2.3%; P = 0.04). Of the 16 patients who developed photosensitivity, 13 did not adhere to the recommendation to avoid sun exposure. None of the patients had any long-term sequelae of photosensitivity. CONCLUSIONS: Photosensitivity reactions in adult patients with EM treated with doxycycline 100 mg twice daily for 10-15 days occurred rarely, were not severe, and had no long-term sequelae. TRIAL REGISTRATION: Registered at http://clinicaltrials.gov , Identifiers NCT00910715, May 28th 2009, NCT01163994, July 13th 2010 and NCT03584919, June 19th 2018 retrospectively registered.

[Amoxicillin-induced skin rash sparing a plaque of erythema migrans: Renbök phenomenon: Case report and literature review]. / Toxidermie à l'amoxicilline épargnant une plaque d'érythème migrant : phénomène de Renbök et revue de la littérature.

INTRODUCTION: Renbök phenomenon describes the inhibition of a lesion when a different one appears. We describe the first case of Renbök phenomenon occurring in a context of erythema migrans (EM) spared by an amoxicillin-induced skin rash and we also present a literature review. CASE REPORT: A 60-year-old patient was treated with amoxicillin for EM on the right knee and subsequently developed generalized erythema as a result of an antibiotic-induced skin rash, with sparing of the area previously affected by EM. Renbök phenomenon was diagnosed. DISCUSSION: In 1981, Cochran et al. first described a maculopapular drug reaction, which spared the sites of previous X irradiation for a tumor. Since then, nearly 40 cases have been reported, mostly describing patient with alopecia areata of the scalp with hair growth within plaques of psoriasis. One of the mechanisms suggested is a role played by cytokine cross-regulation in competition among distinct immune responses. CONCLUSION: We report the first case of Renbök phenomenon involving EM spared by a drug reaction. This phenomenon provides an insight into inflammatory response competition within a single patient.

Symptom load and general function among patients with erythema migrans: a prospective study with a 1-year follow-up after antibiotic treatment in Norwegian general practice.

OBJECTIVE: Promptly treated erythema migrans (EM) has good prognosis. However, some patients report persistent symptoms. Do patients with EM have more symptoms than the general population? We describe individual symptoms and general function in EM-patients at time of diagnosis and one year after treatment. DESIGN: Prospective study with 1-year follow up after treatment. Questionnaires included a modified version of the Subjective Health Complaints Inventory, comprising three additional Lyme borreliosis (LB) related symptoms. General function was assessed using a five-point scale modified from the COOP/WONCA charts. SETTING: Norwegian general practice. SUBJECTS: A total of 188 patients were included in a randomized controlled trial comparing three antibiotic regimens for EM, of whom 139 had complete data for this study. MAIN OUTCOME MEASURES: Individual symptoms, symptom load and general function. RESULTS: Mild symptoms were common, reported by 84.9% at baseline and by 85.6% at follow-up. At baseline, patients reported a mean of 5.4 symptoms, compared with 6.2 after one year. Severely bothersome symptoms and severely impaired general function were rare. Tiredness was the most reported symptom both at baseline and at follow-up. Palsy (other than facial) was the least reported symptom, but the only one with a significant increase. However, this was not associated to the EM. CONCLUSION: The symptom load was comparable to that reported in the general population. We found an increase in symptom load at follow-up that did not significantly affect general function. IMPLICATION: Monitoring patients' symptom loads prior to treatment reduce the probability of attributing follow-up symptoms to LB. Key points Erythema migrans has a good prognosis.Patients treated for erythema migrans have a slight increase in symptom load one year after treatment. This increase does not affect general function. The levels of subjective health complaints in patients treated for erythema migrans are comparable to the background population.

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.

Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis.

In this study, autoantibody responses to annexin A2 were found in 11-15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.

Clinical spectrum of skin manifestations of Lyme borreliosis in 204 children in Austria.

The spectrum of skin manifestations of Lyme borreliosis in children is not well characterized. We conducted a retrospective study to analyze the clinical characteristics, seroreactivity to Borrelia burgdorferi sensu lato, and outcome after treatment in 204 children with skin manifestations of Lyme borreliosis seen in 1996-2011. Solitary erythema migrans was the most common manifestation (44.6%), followed by erythema migrans with multiple lesions (27%), borrelial lymphocytoma (21.6%), and acrodermatitis chronica atrophicans (0.9%). A collision lesion of a primary borrelial lymphocytoma and a surrounding secondary erythema migrans was diagnosed in 5.9% of children. Rate of seroreactivity to B. burgdorferi s.l. was lower in solitary erythema migrans compared to other diagnosis groups. Amoxicillin or phenoxymethylpenicillin led to complete resolution of erythema migrans within a median of 6 (solitary) and 14 days (multiple lesions), respectively, and of borrelia lymphocytoma within a median of 56 days. In conclusion, erythema migrans with multiple lesions and borrelial lymphocytoma appear to be more frequent in children than in adults, whereas acrodermatitis chronica atrophicans is a rarity in childhood. The outcome after antibiotic therapy was excellent in children, and appears to be better than in adults.

Delayed onset of the Jarisch-Herxheimer reaction in doxycycline-treated disease: a case report and review of its histopathology and implications for pathogenesis.

The Jarisch-Herxheimer reaction (JHR) is a transient inflammatory syndrome triggered hours after the start of antibiotic treatment of spirochete infections, namely syphilis. Clinically, JHR manifests as an abrupt onset of constitutional symptoms and exacerbation of cutaneous lesions that resolve without intervention. JHR's pathogenesis is unclear and it is histopathologically rarely reported. Herein, the authors report a 47-year-old woman, with solitary erythema migrans and positive Lyme disease serology, who presented for medical care 14 days after commencement of doxycycline therapy. She complained of malaise, facial flushing, gingival erythema, and acquisition of additional plaques characterized by swelling, increased erythema, pruritus, and exfoliative scale. Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate. By Borrelia-specific immunohistochemistry, spirochetes were found in the deep dermis, unassociated with inflammation, and focally in the upper spinous layer, associated with spongiosis. Borrelia burgdorferi DNA was detected by nested polymerase chain reaction. Doxycycline was discontinued, and symptoms and signs resolved within a few days. Liberation of endotoxin-like materials (eg, lipoproteins) from degenerating spirochetes and concomitant cytokine production is the suspected cause of JHR and supported by the finding of lesional spirochetes. Alternatively, a reversal reaction with a delayed-type hypersensitivity reaction is also a plausible cause based on spirochetes found in the lymphocytic spongiotic dermatitis.

Vesicular erythema migrans: an atypical and easily misdiagnosed form of Lyme disease.

Erythema migrans is the initial sign in the majority of patients infected with Borrelia, the genus of spirochetes that causes Lyme disease. Early identification and treatment decrease the risk of progression to later stages of disease. Although a "bull's eye" appearance owing to lesional clearing is considered classic for erythema migrans, this feature is surprisingly often lacking among patients in the United States. Furthermore, cutaneous Lyme disease can exhibit a wide range of morphologic variability in a minority of patients. Herein, we describe the case of a patient with Lyme disease in which the presence of atypical vesicular features, in conjunction with the initial absence of clearing, resulted in multiple misdiagnoses and delayed treatment. We also review the literature on the epidemiology and management of erythema migrans for cases in which the diagnosis may pose a challenge.