[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.

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.

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.

Sensitivity of Two-Tiered Lyme Disease Serology in Children With an Erythema Migrans Lesion.

In our prospective cohort of 192 children with a physician-diagnosed erythema migrans (EM) lesion, two-tier Lyme disease serology had higher sensitivity in children with multiple EM lesions (76.8% multiple lesions vs. 38.1% single EM; difference 38.7%, 95% confidence interval 24.8%-50.4%). The diagnosis of cutaneous Lyme disease should be based on careful physical examination rather than laboratory testing.

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.

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.

Initial Presentation and Time to Treatment in Early Lyme Disease.

The erythema migrans (EM) rash is an important initial diagnostic sign of early Lyme disease. We tested the hypothesis that patients who noticed EM first differed from those who noticed viral-like symptoms first. "EM First" participants (167/271, 61.6%) had shorter illness duration before treatment (5.0 versus 6.2 days, P = 0.019), were more likely to have seen or removed a tick (P = 0.048) and to be non-Hispanic White (P = 0.025), and were less likely to present with disseminated lesions at the time of diagnosis (P = 0.003) than "Symptoms First" participants (104/271, 38.4%). In multivariate analyses, EM First participants had a 22% decrease in time to treatment (P = 0.012) compared with Symptoms First participants, suggesting that initial presentation affects time to treatment. In a large minority of patients, EM may not be the initial sign or symptom of early Lyme disease. There is a need for rapid diagnostics and improved physician awareness of the varied manifestations of early Lyme disease.

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.

First-degree atrioventricular block in 14-year-old child due to Lyme disease.

Lyme disease is an infectious disease caused by bacteria of the Borrelia burgdorferi sensu lato (Bbsl) complex and is characterized by predominant lesions of the skin, cardiovascular system, nervous system and musculoskeletal system. We have described a clinical case of first-degree atrioventricular block in a 14-year-old boy caused by Lyme borreliosis. The disease started with the manifestations of cardiovascular system involvement. The patient and his parents did not recall observing a tick bite or manifestation of erythema migrans (EM). The boy was prescribed doxycycline. Three weeks after antibiotic therapy a second ECG examination was performed and showed no abnormalities.

Annular infectious dermatoses.

Annular configuration is conspicuous in the clinical manifestation of many skin diseases and can be helpful for the diagnosis and differential diagnosis. Variations may include arciform, ring-form, annular, circinate, serpiginous, gyrated, polycyclic, targeted or figurate forms, in different colors, sizes, and numbers, with various textures and surfaces. In infectious dermatoses, the annular reactions can be specific or nonspecific, while the underlying mechanisms remain largely unknown. In the specific reactions caused by direct invasion of the pathogens, the contest between the centrifugal outspread of the infectious agents and the centripetal impedance of the host immune response is supposed to determine the final conformation. Examples include erythema infectiosum, orf, erythema multiforme, and pityriasis rosea of viral origin. Bacterial infections that may display annular lesions include erythrasma, erythema (chronicum) migrans of Lyme borreliosis, secondary syphilis, cutaneous tuberculosis, and leprosy. Superficial mycosis, such as dermatophytosis, candida intertrigo, tinea imbricata, and subcutaneous mycosis, such as chromoblastomycosis, and algae infection protothecosis, are characterized by annular progression of the skin lesions. The creeping serpiginous extension is an alarming sign for the diagnosis of cutaneous larva migrans. A better understanding of the virulence and pathogenicity of the pathogens and the way and type of immune response will help to clarify the pathogenesis.

Early Erythema Migrans: Do Not Count on Plasma Cells.

ABSTRACT: Three hundred thousand new cases of Lyme disease are diagnosed annually in the United States. The earliest manifestation of the disease, erythema migrans, occurs earlier than serologic conversion, and skin biopsies can be very helpful in suggesting the diagnosis. Histopathologic findings vary depending on where in the lesion the specimen is taken, but typically consist of a superficial and deep perivascular and interstitial lymphocytic infiltrate with eosinophils centrally and with histiocytes and plasma cells at the periphery. Rare cases with interstitial histiocytes and rare-to-sparse plasma cells exist. We present a 67-year-old man whose skin biopsy, taken on day 2 of his eruption, demonstrated a subtle perivascular and interstitial infiltrate of histiocytes without plasma cells. Dermatopathologists need to be aware of this pattern and consider the diagnosis of erythema migrans, despite negative initial serologic testing.

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.

A comprehensive clinical and laboratory evaluation of 224 patients with persistent symptoms attributed to presumed tick-bite exposure.

BACKGROUND: Persistent symptoms attributed to presumed tick-bite exposure constitute an unresolved medical controversy. We evaluated whether Swedish adults who met the criteria for post-treatment Lyme disease syndrome (PTLDS) exhibited characteristics distinguishable from adults who did not, but who displayed similar symptoms and disease course after suspected previous tick-bite infection (TBI). METHODS AND FINDINGS: During 2015-2018, 255 patients-referred to the Centre for Vector-borne Infections, Uppsala University Hospital, Sweden with symptoms lasting longer than six months-were recruited. Of this group, 224 completed the study. Each patient was examined by an infectious disease specialist and, besides a full medical history, underwent a panel of blood and cerebrospinal fluid laboratory tests including hematological, biochemical, microbiological and immunological analyses, and the RAND-36 scale to measure quality of life. For analysis purposes, patients were divided into five subgroups, of which one represented PTLDS. According to serological results indicating TBI and documented/ reported objective signs of Lyme disease, 85 (38%) patients fulfilled the criteria for PTLDS and were compared with the other 139 (62%) serologically classified patients. In the PTLDS group, erythema chronicum migrans (ECM) was documented/reported in 86% of patients, previous neuroborreliosis in 15%, and acrodermatitis chronica atroficans (ACA) in 3.5%. However, there were no significant differences regarding symptoms, laboratory results or disease course between patients with PTLDS and those without laboratory evidence of Borrelia exposition. Most reported symptoms were fatigue-related (70%), musculoskeletal (79%), neurological (82%) and neurocognitive (57%). Tick bites were recalled by 74%. The RAND-36 score was significantly below that of the general Swedish population. Signs of immunological/inflammatory reactivity with myositis antibodies were detected in 20% of patients, fibrinogen levels were moderately increased in 21% and elevated rheumatoid factor in 6%. CONCLUSIONS: The PTLDS group did not differ exclusively in any respect from the other subgroups, which either lacked previously documented/reported evidence of borreliosis or even lacked detectable serological signs of exposure to Lyme disease. The results suggest that symptoms often categorized as Chronic-Lyme-Disease (CLD) in the general debate, cannot be uniquely linked to Lyme disease. However, approximately 20% of the total group of patients showed signs of autoimmunity. Further studies are needed to elucidate the underlying causes and mechanisms of PTLDS and there is reason to consider a multifactorial approach.