Cutaneous borreliosis in children - a challenging problem.

Borreliosis, also known as Lyme disease, is a vector-borne disease caused by different species of the Borrelia burgdorferi complex. It is frequent in Europe and Northern America. The major vectors are ixodoid ticks. Paediatric borreliosis is common and peaks in children between five to nine years. In Europe, the leading symptom of early infection is erythema migrans, in contrast to Northern America where arthritis is the dominating clinical finding. In this review, we focus on Europe, where cutaneous borreliosis is mainly caused by infection with B. afzelii. The cutaneous symptoms include erythema migrans, lymphocytoma, chronic atrophic dermatitis and juxta-articular nodules. In children, lymphocytoma is very common but chronic atrophic dermatitis is rare. Clinical symptoms, diagnosis, peculiarities of childhood disease and treatment are also reviewed. It is important to note that after haematogeneic spread, signs of infection may be non-specific, and this is a challenge for diagnosis.

[Cutaneous Lyme disease: not always a rash with a central clearing]. / Cutane lymeziekte: lang niet altijd een rode ring.

During the past four decades the number of reported Lyme disease diagnoses in the Netherlands has increased to 27.000 a year, with a yearly incidence of Lyme disease between 111 (95% CI 106-115) to 131 (95% CI 126-136) per 100,000 person years. A large part of all Lyme disease diagnoses concern the skin; in the Netherlands, 77-89% erythema migrans, 2-3% borrelia lymfocytoom and 1-3% acrodermatitis chronica atrophicans. These skin manifestations have a variable clinical expression, reason why they can be difficult to diagnose. Early recognition and treatment is important to prevent the development of systemic manifestations.

Dermatoscopic Features of Early Erythema Chronicum Migrans.

Dear Editors, A 37-year-old man from a Lyme disease-endemic area presented with a one-week old rapidly expanding rash on his right calf. He lacked other comorbidities or symptoms such as fever, weakness, lack of appetite, or joint pain, but recalled removing a tick from the same region three weeks earlier. Inspection revealed a round, bluish-red erythematous patch with a central clearing (Figure 1). The patient experienced no discomfort, but the rash was warm and faded easily when palpated. Dermatoscopic inspection revealed collarette-shaped white scales encircling the punctum of the tick bite in the center (Figure 2, left inset). There were three distinct background zones towards the periphery: skin-colored, bluish-red, and bright red. The transitions between the zones were not fully discernable. Red purpuric dots and clods were randomly distributed over these backgrounds, gradually increasing towards the periphery (Figure 2). The rash was diagnosed as erythema chronicum migrans (ECM), and the patient was started on doxycycline 100 mg BID. The expansion of the rash was stopped, while the speed of central clearing was increased. Half of the rash had healed by the third day (Figure 1, left inset), and it had completely disappeared by the seventh (Figure 1, right inset). Anti-Borrelia burgdorferi antibodies were initially negative for IgM and positive for IgG, but both tested positive two weeks later. ECM is the hallmark of early-stage lyme disease, but it is not always present. In addition to the classically described bull's eye appearance, ECM may appear as homogenous erythematous patches, interrupted annular patches, or patches with hemorrhagic or purpuric components (1). It can manifest anywhere except in the palmoplantar region, but it is more common around large joints. Despite the morphological variations of ECM, the clinical presentation is often clear and distinct enough for dermatologists to correctly diagnose more than 90% of patients (1). Diagnostic procedures such as ELISA or Western blot are employed in cases when the ECM is absent or atypical. However, their reliability is low due to the lack of standardization, limited coverage of Borrelia spp., and significant false-positive and false-negative rates (1). Seropositivity owing to previous asymptomatic infection in individuals residing in endemic areas may result in incidental positive findings. Alternative methods, including isolating the pathogen or PCR testing from biopsy samples have similar drawbacks (1). Histopathological investigations are another practical method that yields supportive findings. ECM exhibits diffuse perivascular and interstitial inflammation, including lymphocytes, eosinophils, and plasma cells (2), which corresponds to background erythema in dermatoscopy. As the inflammation develops, the newly-developed regions are superficial and brilliant red, but the surface inflammation fades over time, leaving bluish erythema, which correlates to deeper inflammation (2,3) dermoscopy is gaining appreciation in assisting the diagnosis of nonneoplastic diseases, especially inflammatory dermatoses (inflammoscopy). Extravasated erythrocytes combined with perivascular inflammation (2) generate purpuric pinkish-red dots and clods. Given the greater efficacy of early treatment and the ambiguity surrounding diagnostic methods, clinical findings should be deemed adequate to commence therapy, particularly in endemic regions (1). Dermatoscopic examination of ECM offers a quick and low-cost alternative approach for supporting the diagnosis. However, as emphasized by Errichetti, dermatoscopic examination in non-neoplastic diseases should be regarded as the second step of a "2-step procedure", with differential diagnoses established first by history and clinical examination (3). A systematic investigation of early and late, typical and atypical lesions would improve the reliability and utility of this method.

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.

A Prospective Study to Characterize Symptoms and Symptom Severity in Adult Patients with Extracutaneous Manifestations of Lyme Disease.

BACKGROUND: Systematic assessments of the presence and severity of particular symptoms over time are relatively uncommon for Lyme disease patients in the United States, and especially for Lyme disease patients with extracutaneous manifestations (ECLD). METHODS: Symptoms and symptom severity of 12 particular symptoms were evaluated in a prospective study at baseline and at 12 months for 35 adult Lyme disease patients with ECLD, 91.4% of whom were already started on antibiotic therapy, and compared with 52 adult Lyme disease patients with erythema migrans, who were untreated at study entry. RESULTS: No significant difference in the frequency of having at least 1 symptom of the 12 evaluated was found between the 2 groups at either the baseline visit or the 12-month evaluation. Demographic variables were also similar between the 2 study groups, except that the ECLD patients were significantly less likely to be Caucasian: 24/35 (68.6%) of the ECLD cases vs 48/52 (92.3%) of the erythema migrans cases; P = .008. CONCLUSION: Lyme disease patients with ECLD had a similar frequency of symptoms at baseline compared with patients with erythema migrans. ECLD subjects, however, were significantly less likely to be Caucasian, raising the question of whether a preceding erythema migrans skin lesion may have been missed in persons with a darker skin color. An important limitation of our study, however, is that we did not record skin color per se, which should be considered for future studies.

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.

[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.

[CME: Neuroborreliosis]. / CME: Neuroborreliose CME-Fragen.

CME: Neuroborreliosis Abstract. Lyme disease is the most common infectious disease transmitted by ticks throughout Europe. Bacteria of the Borrelia burgdorferi complex are transmitted via tick bites to humans. The typical initial presentation is a localized infection of the skin (Erythema migrans). If the patient is not treated with antibiotics, a disseminated infection might occur, presenting as neurological Lyme disease, Lyme carditis, Lyme arthritis or Acrodermatitis chronica atrophicans. A neuroborreliosis occurs in 3-15% of the cases. It may present as polyradiculitis, meningitis or - in rare cases - as encephalomyelitis. The antimicrobial therapy of neuroborreliosis is doxycyclin, ceftriaxone or penicillin G. Prevention is defined by exposure prophylaxis. A vaccination is currently under development in Europe.

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.

Characteristics of spirochetemic patients with a solitary erythema migrans skin lesion in Europe.

Neither pre-treatment characteristics, nor the outcome after antibiotic therapy, have been reported for spirochetemic European patients with Lyme borreliosis. In the present study, patients with a solitary erythema migrans (EM) who had a positive blood culture for either Borrelia afzelii (n = 116) or Borrelia garinii (n = 37) were compared with age- and sex-matched patients who had a negative blood culture, but were culture positive for the corresponding Borrelia species from skin. Collectively, spirochetemic patients significantly more often recalled a tick bite at the site of the EM skin lesion, had a shorter time interval from the bite to the onset of EM, had a shorter duration of the skin lesion prior to diagnosis, and had a smaller EM skin lesion that was more often homogeneous in appearance. Similar results were found for the subset of spirochetemic patients infected with B. afzelii but not for those infected with B. garinii. However, patients with B. garinii bacteremia had faster-spreading and larger EM skin lesions, and more often reported itching at the site of the lesion than patients with B. afzelii bacteremia. Treatment failures were rare (7/306 patients, 2.3%) and were not associated with having spirochetemia or with which Borrelia species was causing the infection.

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.

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.

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.

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.

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.

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.