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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.

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.

In North America, Lyme disease (LD) is caused predominantly by the spirochete Borrelia burgdorferisensu stricto, and is transmitted by blacklegged ticks. Long Island, New York, is highly endemic for the disease. The C6 peptide (C6P) is currently used as a screening test for LD in our institution. Our objective was to examine how screening with C6P concorded with diagnosis of LD at the Veterans Affairs Medical Center, Northport, Long Island. A retrospective chart-review of 2558 C6P tests was performed during the period of 1/1/2010 to 12/31/2016. Patients were categorized by Lyme Disease (LD) or no LD groups. LD group was defined as having an erythema migrans (EM) rash, or ≥ 2 IgM bands or ≥ 5 IgG bands on immunoblot. Out of the 409 patients with positive or equivocal C6P, 181 patients with LD were based on presence of EM, or Western blot IgM and IgG test results; 228 did not have LD. The positive predictive value of C6P was 44.5%. EM was the most common presentation. In the LD group, history of tick bite (P: 0.0001), headache (P: 0.0036), joint swelling (P: 0.0086) and myalgias (P: 0.0005) were more likely to be present. Zip code mapping of our cases mirrored those previously reported in the Suffolk County Department of Health. In our review we encountered a significant number of false positive C6 assays. False positive C6P tests were ordered by primary care physicians (PCP) (37%) followed by neurologists (33%). A history of tick exposure and clinical findings of early Lyme disease such as headaches or joint aches were more likely to denote a true positive C6 peptide test. Rigorous education of physicians about Lyme disease and pitfalls of our available diagnostic tests are needed for their proper utilization.

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 Sogne 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.

Whether infection with Borrelia burgdorferi sensu lato (sl) can cause nonspecific symptoms is a matter of controversy. We investigated whether individuals infected with B. burgdorferi sl develop unspecific symptoms more frequently than non-infected controls. Eighty-nine persons having presented with B. burgdorferi sl infection between 2015 and 2019 were asked to participate. The infection was defined as erythema migrans diagnosed either in the course of a previous study, during medical visits in the outpatient department, or as seroconversion in asymptomatic subjects. The control group consisted of 85 seronegative individuals without erythema migrans in the past. About two and a half years later, participants were asked to fill out a questionnaire with a list of nonspecific symptoms. The data of 37 persons with previous Borrelia infection and 49 uninfected controls were available for analysis. Muscle pain was significantly (P = 0.040) more frequent in the control group. Fatigue occurred more often in the infected group, but this was not statistically significant (P = 0.109). Likewise, the distribution of other symptoms did not differ considerably. The analysis revealed no difference in the frequency of symptoms of persons who had EM or asymptomatic Borrelia infection 2 years prior assessment in comparison to persons without Borrelia infection.

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.

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.

Both early localized and late disseminated forms of Lyme borreliosis are caused by Borrelia burgdorferi senso lato. Differentiating between the spirochetes that only cause localized skin infection from those that cause disseminated infection, and tracing the group of medically-important spirochetes to a specific vertebrate host species, are two critical issues in disease risk assessment and management. Borrelia burgdorferi senso lato isolates from Lyme borreliosis cases with distinct clinical manifestations (erythema migrans, neuroborreliosis, acrodermatitis chronica atrophicans, and Lyme arthritis) and isolates from Ixodes ricinus ticks feeding on rodents, birds and hedgehogs were typed to the genospecies level by sequencing part of the intergenic spacer region. In-depth molecular typing was performed by sequencing eight additional loci with different characteristics (plasmid-bound, regulatory, and housekeeping genes). The most abundant genospecies and genotypes in the clinical isolates were identified by using odds ratio as a measure of dominance. Borrelia afzelii was the most common genospecies in acrodermatitis patients and engorged ticks from rodents. Borrelia burgdorferi senso stricto was widespread in erythema migrans patients. Borrelia bavariensis was widespread in neuroborreliosis patients and in ticks from hedgehogs, but rare in erythema migrans patients. Borrelia garinii was the dominant genospecies in ticks feeding on birds. Spirochetes in ticks feeding on hedgehogs were overrepresented in genotypes of the plasmid gene ospC from spirochetes in erythema migrans patients. Spirochetes in ticks feeding on hedgehogs were overrepresented in genotypes of ospA from spirochetes in acrodermatitis patients. Spirochetes from ticks feeding on birds were overrepresented in genotypes of the plasmid and regulatory genes dbpA, rpoN and rpoS from spirochetes in neuroborreliosis patients. Overall, the analyses of our datasets support the existence of at least three transmission pathways from an enzootic cycle to a clinical manifestation of Lyme borreliosis. Based on the observations with these nine loci, it seems to be justified to consider the population structure of B. burgdorferi senso lato as being predominantly clonal.

The aim of this study was to determine whether patients with antibodies against Borrelia burgdorferi sensu lato or who report a history of erythema migrans (EM) or tick bite are more likely to have non-specific symptoms such as musculoskeletal pain, fatigue, sensory disorder, and headache. The study group comprised 423 subjects with non-specific symptoms tested for antibodies against B. burgdorferi sensu lato between July 2012 and December 2014 because of suspicion of Lyme borreliosis (LB). Of these, 285 were females (67%) and 138 were males (33%); the median age was 53 years (range, 7–89 years). Patients with a confirmed diagnosis of LB and patients with a known underlying disease that could influence the development of the symptoms were excluded from the evaluation. Subjects were assigned to the seronegative group or to one of three seropositive groups, and the history of EM and tick bite was also recorded. Statistical analysis was performed with single chi-square tests of independence and multiple logistic regression models. No differences in the occurrence of non-specific symptoms were observed between patients grouped according to antibody status. A history of EM showed no significant effect on any of the non-specific symptoms. A history of tick bite was weakly correlated with joint pain and joint swelling (p

Clinical trials of oral penicillin preparations in the United States for treating Lyme disease patients with erythema migrans are limited to 2 studies. The results of these studies demonstrated a less than optimal outcome of this treatment. However, there were serious methodologic concerns in both studies precluding the interpretation that phenoxymethylpenicillin specifically should be regarded as ineffective. Therefore, additional clinical trials should be conducted in the United States with close attention to the dose and duration of treatment that have been used very successfully in Europe.

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.

Lyme disease/borreliosis (LD) is a well-known arthropod-transmitted entity in the northern hemisphere. The incidence of LD is reportedly rising throughout the world, although better diagnostic facilities may be contributory. The disease distribution is expanding in Europe, with its presence being now documented at higher altitudes and latitudes. Borrelia burgdorferi sensu lato is the most important genospecies leading to LD, although newer ones continue to be discovered. The variations in clinical spectrum with genospecies involved are an interesting feature. The alteration in gene expression while the organism cycles between two very different hosts is intriguing and has been described. The disease presents in three stages-namely, the early localized, early disseminated, and late stage. Erythema chronicum migrans is the pathognomic early lesion, and its diagnosis is purely clinical; however, laboratory diagnosis is essential for later manifestations. Two-tier serologic testing using an enzyme-linked immunosorbent assay (ELISA) as the first tier and immunoglobulin M (IgM) and IgG immunoblot as the second, if ELISA is positive or equivocal, is the mainstay of diagnosis. Doxycycline is the cornerstone of treatment, whereas parenteral therapy, mainly with ceftriaxone, is indicated in a few specific scenarios.

Background Lyme disease is the most common vector-borne infectious disease in North America. With nearly 2,500 Appalachian Trail (AT) hikers entering the endemic area for as long as 6 months, exposure to the disease is likely. The characteristic exanthem of erythema migrans (EM) should be a trigger for seeking medical treatment, and its recognition in this relatively isolated environment is important. Objective The purpose of this study was to determine the ability of AT hikers to identify EM, the exanthem of Lyme disease. Methods Hikers were administered a photographic stimulus in this Internal Review Board–approved pilot study. Historical hiking data, basic demographics, and self-reported treatment and diagnosis were collected. Results In all, 379 responses were collected by 4 researchers at 3 geographically separate locations at or proximate to the AT from June 2011 to May 2012. Fifty-four percent of respondents (206 of 379) were able to recognize the photographs of EM/Lyme disease; 46% could not. Of those who did recognize EM, 23 (6%) had seen it either on themselves or on another hiker while on the AT. A total of 37 hikers stated that they had been diagnosed with Lyme disease while hiking, and of these, 89% were treated with antibiotics. Thirteen of these 37 hikers (35%) diagnosed with Lyme disease had visualized an embedded tick. Nine percent of all respondents reported they had been diagnosed with Lyme disease by a healthcare practitioner, whether from EM, symptomatology, or by titer. Conclusions This study suggests that hikers are poorly able to recognize the characteristic exanthem of Lyme disease but have a high exposure risk.

To elucidate pathogen-host interactions during early Lyme disease, we developed a mathematical model that explains the spatiotemporal dynamics of the characteristic first sign of the disease, a large (≥5-cm diameter) rash, known as an erythema migrans. The model predicts that the bacterial replication and dissemination rates are the primary factors controlling the speed that the rash spreads, whereas the rate that active macrophages are cleared from the dermis is the principle determinant of rash morphology. In addition, the model supports the clinical observations that antibiotic treatment quickly clears spirochetes from the dermis and that the rash appearance is not indicative of the efficacy of the treatment. The quantitative agreement between our results and clinical data suggest that this model could be used to develop more efficient drug treatments and may form a basis for modeling pathogen-host interactions in other emerging infectious diseases.

Lyme disease (LD) is most often diagnosed clinically, and the differential diagnosis of erythema migrans may be challenging. Recent advances have raised questions about the efficacy of traditional diagnostic modalities, but may soon facilitate consistent identification of patients with Lyme borreliosis. Therapeutic recommendations vary with the stage of disease, and treatment usually leads to complete resolution. The management of patients with "chronic Lyme disease" is controversial. A number of preventative measures have been evaluated; those involving the avoidance of tick bites with protective clothing and insect repellents remain the simplest and most effective.

Lyme disease (LD) is an increasingly recognized multisystem, insect-borne zoonosis. Prevalent worldwide, it has a variety of presentations at different stages of infection. The characteristic rash with central clearing known as erythema chronicum migrans, or simply erythema migrans, appears in its first stage. Typical features may be absent, and important variations are evident among cases seen in different parts of the world. LD may be difficult to diagnose clinically; knowledge about its epidemiology and transmission may be of assistance when the diagnosis is unclear. Based upon our experience with LD and a comprehensive literature review, we provide an update of LD epidemiology, pathophysiology, and management. We also cover the three clinical stages of LD that parallel those of syphilis, another spirochetal disease.

In the present study, we report the occurrence of Lyme's borreliosis in patients from the Brazilian Amazon Region. Borreliosis was investigated by immunohistochemistry and focus floating microscopy for Borrelia burgdorferi in skin biopsy samples from 22 patients with both clinical and histopathology evidences compatible with Erythema Migrans. Spirochetes were detected by specific immunohistochemistry and focus floating microscopy for B. burgdorferi in samples from five patients. Clinical cure of the cutaneous lesions was observed in all the patients after treatment with doxycycline regimen as proposed by the Center Disease Control guidelines. A limitation of our study was the fact that we were not able to isolate and culture these organisms. These are the first known Brazilian cases of borreliosis to have Focus Floating Microscopy confirmation.

Erythema migrans (EM) is the most common objective manifestation of Lyme disease, accounting for about 90% of cases. Establishing the diagnosis of EM is important because appropriate treatment with oral antibiotics at an early stage of infection with Borrelia burgdorferi results in excellent outcomes. This article includes a discussion of the epidemiology of EM and its clinical, differential, and laboratory diagnosis. The treatment of EM and the prevention of Lyme disease are also discussed.

The antibody response of serum IgM and IgG of patients with neuroborreliosis and erythema migrans of Lyme borreliosis (LB) was examined against a 41-kDa flagellar antigen and an 8-mer synthetic OspC8 peptide (VAESPKKP) derived from the C-terminus of outer surface protein C (OspC) from Borrelia garinii. We developed a streptavidin-modified biochip-based immunodiagnosis and compared it with conventional methods such as enzyme-linked immunosorbent assay (ELISA) and Western blot (WB). The diagnostic sensitivity of the coated biochips was demonstrated to be identical, and the results of conventional assays such as ELISA and WB were confirmed. Flagellar antigens lead to better diagnosis because of a higher discriminative value. By contrast, OspC8, a peptide derived from the outer surface antigen, is less sensitive to identify immunity in LB. The inferior antigenicity of OspC8 may be due to epitope masking. Overall, this system is open to simultaneously analyze a larger family of peptides differing in length. Thus, an array approach is generally more advantageous to extend the pattern of antigens to be tested for antigenicity in LB. Serial analysis during ongoing disease may be valuable to learn more about the course of the disease and intermittent reactivation of infection. Protein biochip as a potential substitution of ELISA and WB method offers the opportunity to study serum immunity in a multiplicity of patients simultaneously.

The aim of this review was first to analyze the microbiological and pharmacological criteria used to choose a treatment for Lyme disease. The determination of Borrelia burgdorferi sensu lato susceptibility to antibiotics is difficult, especially because of the lack of standardization in the methods used. In vitro data is helpful to determine Lyme treatment but discrepancies between in vitro and in vivo results highlight the need to confirm this data by clinical trials. The second part is an analysis of the literature made to evaluate the current strategies of treatment and follow up of early Lyme disease characterized by erythema migrans (EM). beta-lactams (penicillin G and V, amoxicillin, cefuroxime axetil, ceftriaxone), tetracyclines (doxycycline), and macrolides (mainly azithromycin) are the drugs most frequently used during clinical trials. The comparison between treatments is difficult because of the lack of reliable clinical and biological criteria to identify complete recovery. However the prognosis of treated EM is good in most trials. If a clinical follow-up remains necessary after the treatment of an EM, prolonged antibody production among asymptomatic patients reduces the interest of a serological follow-up.

In the early stage of Lyme disease, atypical lesions of erythema migrans rash can develop and extend over the neck region, mimicking cervical cellulitis with deep neck infection. Here, we report a 9-year-old Taiwanese boy with a recent history of exposure to deer during his visit to Nanto County in central Taiwan. Cervical cellulitis with lymphadenitis was initially diagnosed. Erythema migrans developed in the following days and Lyme disease was finally diagnosed by a Western immunoblot test. Alertness to this unique clinical feature is required for prompt differential diagnosis of Lyme disease with a presentation of erythema migrans mimicking cervical cellulitis.

Different media have been utilized for borrelial cultivation. The aim of the present study was to evaluate the isolation rate of Borrelia burgdorferi sensu lato from two commonly used media, i.e. modified Kelly–Pettenkofer (MKP) and Barbour–Stoenner–Kelly II (BSK-II) medium, and to compare the isolated strains with regard to their phenotypic and genotypic characteristics. Skin biopsy specimens of 2×2×4 mm were taken from the peripheral site of human solitary erythema lesions and were divided in two pieces, one of which was inoculated into MKP and the other one into BSK-II medium. Species analysis of the obtained strains was performed and their plasmid and protein profiles were determined. Borrelia strains were isolated from 48/96 patients (50%) with erythema migrans. We obtained in 26/48 patients (54%) from MKP as well as from BSK-II, in 11 patients (23%) only from MKP, and in another 11 (23%) only from BSK-II medium a positive result. B. afzelii was isolated from 43 patients (23 were positive in both media, nine in MKP only and 11 in BSK-II medium only), while B. garinii was isolated from five patients (in three from both media, in two from MKP only). All strains of the obtained strain pairs were identical according to species and the type within the species. Plasmid profiles were identical in 17/21 B. afzelii strain pairs (81%) and in 1/3 B. garinii strain pairs; in 6/24 strain pairs, distinctions in the number of plasmids or in their molecular mass were present. Differences in the protein profile were found in 7/24 strain pairs (29%). The distinctions were uniform and were limited to the expression of OspC. In conclusion, our study showed comparable Borrelia isolation rates from MKP and BSK-II medium. The results of the present study indicate that human patients with Lyme borreliosis may simultaneously harbor heterogeneous B. burgdorferi s.l. strains.

Purpose To determine the long-term outcome of patients with culture-confirmed Lyme disease. Methods We analyzed data collected prospectively on adult patients from a highly endemic area in New York State who were diagnosed with early Lyme disease between 1991 and 1994. Patients with culture-confirmed erythema migrans were evaluated at baseline, 7 to 10 days, 21 to 28 days, 3 months, 6 months, 1 year, and annually thereafter. All patients were treated with antibiotics at the time of diagnosis. Results We evaluated 96 cases on 709 separate occasions (median, eight evaluations per case). The erythema migrans rash resolved within 3 weeks in all of the 94 evaluable cases, none of whom developed an objective extracutaneous manifestation of Lyme disease. Of the 81 cases who were followed for ≥1 year, all but 8 (10%) were asymptomatic at their last visit, a mean (± SD) of 5.6 ± 2.6 years into follow-up, and only 3 (4%) were symptomatic at every follow-up visit. Intercurrent tick bites were reported by 45 cases (47%), and 14 (15%) developed a second episode of erythema migrans. Four other cases who were asymptomatic seroconverted between years 2 and 5. Conclusion The long-term outcome of patients with erythema migrans after antibiotic therapy was excellent, but patients from a highly endemic area in New York State remained at high risk of re-exposure to ticks and reinfection. Subjective symptoms during follow-up evaluations tended to be mild to moderate, intermittent, and associated with more symptomatic illness at the time of initial diagnosis.

Erythema migrans, the characteristic skin manifestation of acute Lyme borreliosis, is a self-limited lesion. In contrast, acrodermatitis chronica atrophicans, the typical cutaneous manifestation of late Lyme borreliosis, is a chronic skin condition. In an effort to understand pathogenic factors that lead to different outcomes in dermatoborrelioses, skin biopsy samples from 42 patients with erythema migrans and 27 patients with acrodermatitis chronica atrophicans were analyzed for mRNA expression of five pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interferon-gamma, and interleukin-2) and two anti-inflammatory cytokines (interleukin-4 and interleukin-10) by in situ hybridization with cytokine-specific riboprobes. Among the 27 patients who had erythema migrans alone with no associated signs or symptoms, the major cytokines expressed in perivascular infiltrates of T cells and macrophages were the pro-inflammatory cytokine interferon-gamma and the anti-inflammatory cytokine interleukin-10. In the 15 erythema migrans patients who had associated signs and symptoms, including headache, elevated temperature, arthralgias, myalgias, or fatigue, a larger number of macrophages and greater expression of macrophage-derived pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6, were also found. In comparison, infiltrates of T cells and macrophages in the skin lesions of acrodermatitis chronica atrophicans patients had very little or no interferon-gamma expression. Instead, they usually expressed only the pro-inflammatory cytokine tumor necrosis factor alpha and the anti-inflammatory cytokine interleukin-4. Thus, the activation of pro-inflammatory cytokines in erythema migrans lesions, particularly interferon-gamma, seems to be important in the control of the spirochetal infection. In contrast, the restricted pattern of cytokine expression in acrodermatitis chronica atrophicans, including the lack of interferon-gamma, may be less effective in spirochetal killing, resulting in the chronicity of this skin lesion. J Invest Dermatol 115:1115-1123 2000

Lyme borreliosis (Lyme disease) is often said to be associated with "protean" manifestations, a reference to the ancient god Proteus, who could assume many forms and thus elude his pursuers. This legendary quality has clouded our understanding of Lyme borreliosis by giving Borrelia burgdorferi infection a mythical aura of its own. This review shows that this illness, while incompletely understood, is far more palpable than Proteus and is (in most cases) much more readily subdued. The clinical presentations of Lyme borreliosis do differ in North America and Eurasia, possibly due to the differing pathogenicity of distinct genospecies of Borrelia burgdorferi. The most common manifestation, however, in both continents is erythema migrans. Diagnosis should rest on a careful history and objective clinical findings, supported by appropriately chosen laboratory tests. Reports of coinfection with other tick-borne diseases should prompt a fresh look at Lyme borreliosis. Assertions about "protean manifestations" of B burgdorferi infection should be reappraised. Advances in laboratory techniques are welcome but culture remains the gold standard for the diagnosis--and no laboratory test result should substitute for careful clinical observation and critical analysis.

Serological testing for Lyme borreliosis was compared in 5 European reference laboratories with a total of 79 sera in order to determine variations in laboratory performance. A considerable range of methods were used and several laboratories employed 2 or 3 genomospecies of Borrelia burgdorferi sensu lato. No laboratory relied routinely on a single test and each weighted the significance of the findings of the various tests differently. A difference in strategy between laboratories in high and low prevalence areas was apparent in that laboratories in low prevalence areas emphasised specificity more than sensitivity and therefore produced fewer false positives, but also missed some cases. Overall agreement between the laboratories was poor and it was concluded that there is a need for a quality assurance scheme within Europe.

A skin biopsy from a patient with erythema migrans was inoculated into C3H/He mice and into culture medium. A Borrelia garinii strain named Rio1 was isolated from both a direct BSK medium culture and a mouse ear-punch biopsy culture. Inoculating human tissue into mice produced a disease resulting in severe inflammation of the left tibio-tarsal joint, development of perivascular infiltrates as seen in ear-punch biopsies and the spread of spirochaetes along the skin, far from the inoculation site. The isolation of this strain confirms the circulation of this Borrelia species in Spain as a human pathogen, as well as its arthrogenicity in an animal model. The method used to recover strain Rio1 from human tissue is described as rapid and sensitive compared to direct inoculation of tissue into BSK medium.

Background: Interstitial granulomatous dermatitis with arthritis is an uncommon systemic disorder involving the cutaneous and musculoskeletal systems. The eruption may mimic other dermatoses including granuloma annulare, erythema chronicum migrans, and the inflammatory stage of morphea. Key histopathologic characteristics, along with clinical correlation, allow accurate diagnosis. Objective: We describe the clinical, serologic, and histologic features in three patients with interstitial granulomatous dermatitis with arthritis. Methods: Skin biopsy specimens were examined and correlated with the clinical and laboratory findings. Results: Erythematous, annular, indurated plaques on the extremities were present in two women. An erythematous, papular eruption on the head and neck was present in a third patient. All patients had myalgia and migratory polyarthralgias of the extremities along with various serologic abnormalities. Histologic examination revealed a dense lymphohistiocytic interstitial infiltrate involving primarily the reticular dermis. Foci of necrobiotic collagen were present. Vasculitis was absent. Conclusion: Interstitial granulomatous dermatitis with arthritis is a unique multisystem disease with variable cutaneous expression. Abnormal serologic findings indicate a possible connection to collagen vascular disease.

Lyme disease is the most-common tick-borne disease in the United States, and its incidence is increasing, especially after the damp winter of 1993–1994 in the Northeast. In 1982, investigators discovered that Lyme disease was caused by the spirochete, Borrelia burgdorferi. Since then, several strains of that organism have been described, possibly explaining differing clinical presentations in Europe and the United States. It is crucial to diagnose Lyme disease in its earliest phases, as treatment with antibiotics usually results in a complete cure. Failure to make an early diagnosis and certain genetic factors contribute to a pattern of chronic disease in some patients. Diagnosis is made difficult by lack of a history or finding of a tick bite and by the fact that the pathognomonic finding, the rash of erythema chronicum migrans, is seen in only a minority of cases. Serologic diagnosis depends on the enzyme-linked immunosorbent assay, which is neither specific nor reliable, and the Western blot, which is not yet standardized. Particularly vexing is the confusion of Lyme disease with fibromyalgia, a common rheumatic disease of uncertain etiology with many overlapping symptoms. This confusion often leads to prolonged, unnecessary, and expensive treatments with dubious results. In general, Lyme disease responds well to a variety of oral and parenteral antibiotics. Special problems arise in the treatment of Lyme disease in pregnancy and in the choice of antibiotics in growing children. A vaccine for Lyme prophylaxis is expected for high-risk individuals.

Stomatitis areata migrans, unlike its analogue on the tongue, migratory glossitis, is not easily recognized and is so uncommon and varied in appearance that it may escape definitive diagnosis. It may be so puzzling to the clinician that the patient's credibility may be questioned. A detailed report of a case is presented in which an atypical migratory stomatitis went undiagnosed. Bizarre patient behavior followed in the form of self-inflicted injury (Munchausen syndrome) as the patient attempted to convince the care providers of the true existence of lesions in order to maintain their interest and to obtain relief from discomfort.

We studied retrospectively the cases of neurological forms of Lyme disease observed in two internal and two neurological departments from 1986 till 1993. Twenty five cases have been collected among 15 men and ten women whose mean age was 61 years. Tick bites were previously noticed in 11 cases. Erythema chronicum migrans (ECM) was mentioned in 16 cases mostly on lower limbs. The mean time between ECM and the onset of neurological symptoms was less than 1 month in 11 cases, 2 months in three cases, and 6 months in two cases. Neurological abnormalities were often associated in the same patient. Hyperalgic radiculitis (n = 16), mainly noticed in the ECM territory (n = 10) was only sensitive in six cases and associated with motor deficit in ten. Atypical polyradiculoneuritis was achieved in six cases. Clinical (n = 5) or biological (n = 22) meningitis could occur: CSF was clear with pleiocytosis (132 per mm3), mainly lymphocytic, and hyperproteinorachia (1.2 g/l) with normoglycorachia. An increase of the CSF immunoglobulins G with oligoclonal fragmentation was noticed in 11 cases. Cranial neuropathy was frequent: VII (n = 8), VI (n = 2), III, IV, VIII (n = 1). Encephalitis (with white matter demyelination) resolved partially in two cases. Diagnosis was always confirmed by Borrelia burgdorferi serology (indirect immunofluorescence) with a significant increase of the antibodies titer (n = 17) or a CSF titer > 1/4 (n = 11). Syphilitic serology was always negative. All patients were treated with parenteral beta lactamins and four with corticosteroids. Outcome was favorable in 20 patients with incomplete resolution of neurological symptoms in two patients.

Resume Les manifestations cliniques des infections a Borrelia burgdorferi sont variees selon le stade evolutif: cutanees, articulaires, neurologiques et cardiaques. Certaines manifestations cutanees sont plus evocatrices lorsqu'elles sont associees entre elles. Observation. — Une fille agee de 8 ans a ete examinee pour une lesion nodalaire de l'areole mamelonnaire gauche apparue 3 mois plus tot. Cette lesion etait associee a un erytheme annulaire centre par le mamelon gauche et s'etendant a la face anterieure du thorax et dans le creux axillaire gauche, sans adenopathie. L'association de ce qui a paru etre un lymphocytome cutane et d'un erytheme chronique migrateur a oriente vers la possibilite d'une infection a Borellia malgre l'absence d'antecedent de morsure de tique. Les tests serologiques (immunofluorescence indirecte) ont ete negatifs mais les manifestations cutanees ont disparu en moins de 2 semaines sous ceftriaxone, a la dose de 50 mg/kg/j. Conclusions. — L'erytheme chronique migrateur apparait habituellement plus tot que le lymphocytome cutane benin. L'association des deux manifestations est pathognomonique d'une borreliose; la negativite de l'etude serologique peut s'expliquer par la precocite du diagnostic et du traitement.

Background: Doxycycline is widely used to treat Lyme disease associated with erythema migrans. Whether it is comparable to tetracycline is unknown. Objective: We conducted a two-part retrospective analysis of (1) the safety and efficacy of doxycycline compared with tetracycline and (2) the safety and efficacy of a 14-day versus a 20-day course of doxycycline. Methods: Twenty-seven patients given tetracycline (500 mg four times a day for 14 days [group 1]) were compared retrospectively with 21 patients who received doxycycline (100 mg two or three times a day for 14 days [group 2]). The results for group 2 were also compared with that of 38 patients who received doxycycline for 20 days (100 mg three times daily) in a prospective treatment trial (group 3). Results: There was no significant difference in the incidence of adverse drug effects or in efficacy at 1 month, but at 1 year there was a trend toward a better outcome in the group treated with tetracycline ( p = 0.08). A 14-day course of doxycycline was comparable to a 20-day course in the incidence of adverse drug effects and in clinical outcome. Conclusion: The principal advantage of doxycycline over tetracycline for the treatment of Lyme disease associated with erythema migrans is the convenience of less frequent dosing, not enhanced efficacy or safety. There appears to be no advantage in extending treatment with doxycycline from 14 to 20 days.

Background: The risk of acquiring Lyme disease has been evaluated by xenodiagnostic procedures with laboratory strains of Borrelia burgdorferi and laboratory-reared Ixodes ticks, or by clinical trials in which diagnosis was based on clinical findings, culture, or serologic tests. Objective: Our purpose was to determine the risk of infection from tick bites in a natural setting in which wild strains of B. burgdorferi were involved, by a biopsy culture technique. Methods: Skin biopsy specimens were obtained from Ixodes scapularis tick bite sites, processed, and examined for the presence of B. burgdorferi . Results: B. burgdorferi was cultivated from only 2 of 48 skin biopsy specimens. In both instances duration of tick attachment was approximately 24 hours. Conclusion: In a hyperendemic region for Lyme disease the risk of infection after a deer tick bite appears to be low, particularly if the tick has been attached for less than 24 hours.

Lyme borreliosis is a cutaneous-systemic infection that is generally transmitted by a hard-bodied tick and caused by some species of Borrelia, Borrelia burgdorferi (sensu stricto), B. garini, and B. afzelii. Lyme borreliosis is a widespread disease, present in all continents. It can be divided into an early disease, corresponding to the primary stage, and a late disease, including the secondary and tertiary stages. The typical cutaneous lesions are erythema (chronicum) migrans, lymphadenosis benigna cutis, and acrodermatitis chronica atrophicans. The course of Lyme borreliosis depends on the timeliness of both diagnosis and antibiotic treatment.

Early diagnosis of Borrelia burgdorferi infection, hampered by the absence of detectable antibodies in most patients with erythema chronicum migrans is important to prevent late-stage neurologic, rheumatologic, and skin disorders. Furthermore, B. burgdorferi has been claimed to be the causative agent in localized scleroderma (morphea). We used PCR amplification to search for B. burgdorferi outer surface protein OspA-specific sequences in DNA obtained from lesional skin biopsies on Finnish patients with clinically suspect erythema chronicum migrans, lymphocytoma, morphea, or with diverse skin manifestations and persistent high antibodies to B. burgdorferi flagellar antigen. Seronegative patients with other skin lesions served as controls. The amplicons obtained with primers specific for B. burgdorferi type strain B31 ospA sequence did not hybridize to the corresponding probes, and thus the DNA amplified from a Finnish B. burgdorferi erythema chronicum migrans skin isolate was sequenced. This 98-nucleotide sequence of ospA (332-429) showed 11% to 14% nucleotide divergence compared with the North American type strain (B31), several European strains, and an East Siberian tick strain. The sequence was almost identical (99%) to a Swedish isolate from acrodermatitis chronica atrophicans. Using oligonucleotides specific for the Finnish strain, a positive polymerase chain reaction-based hybridization was obtained in six of seven untreated erythema chronicum migrans patients infected in Finland or in Estonia, and in the lymphocytoma patient. Only two of the erythema chronicum migrans patients had IgG or IgM antibodies to flagellin. However, all seven morphea lesions as well as the other lesions were polymerase chain reaction negative. Polymerase chain reaction-based hybridization of B. burgdorferi OspA gene from skin-derived DNA thus provides a sensitive and specific diagnostic tool. In conditions not unequivocally known to be caused by B. burgdorferi, like in morphea, this assay was negative. We also demonstrate that peri-Baltic B. burgdorferi isolates show homology in their OspA genes but differ from geographically more distant isolates.

Background: We recently demonstrated that cultivation of Borrelia burgdorferi from skin biopsy specimens obtained from erythema migrans lesions was an efficacious procedure to confirm the diagnosis of Lyme disease. Objective: Our purpose was to investigate the efficacy of our microbiologic technique on blood samples obtained from patients with Lyme disease and erythema migrans. Methods: Whole blood samples were obtained from 52 patients with erythema migrans and early localized or early disseminated Lyme disease and placed into polystyrene tubes containing 6 ml of modified Barbour-Stoenner-Kelly medium, processed, and examined for B. burgdorferi by dark-field microscopy. Results: B. burgdorferi was cultured from the blood of two of our 52 patients (4%). Clinically, both of these patients were considered to have early localized Lyme disease. Conclusion: The culture of B. burgdorferi from the blood of patients with early Lyme disease does not appear to be an efficacious procedure to confirm the diagnosis of Lyme disease. However, the demonstration of spirochetemia in patients with erythema migrans without any extracutaneous evidence of disseminated illness does have therapeutic significance.

Borrelia burgdorferi, the etiologic agent of Lyme borreliosis, has occasionally been isolated from tissues or body fluids of patients after antimicrobial treatment. A prospective study of patients with Lyme borreliosis associated with erythema migrans (EM) was initiated in Westchester County, New York, to determine: (1) the clinical and laboratory parameters associated with culture positivity, and (2) the microbiologic response to treatment.Skin biopsies were performed in patients with EM and cultured for B. burgdorferi in modified Barbour-Stoenner-Kelly medium at 33 degrees C. Subsequent biopsies for culture were performed adjacent to the original biopsy site for culture-positive patients after the completion of antimicrobial therapy.Initial biopsy cultures were performed for 44 patients; 6 were unevaluable due to culture contamination with other bacteria. Cultures were positive in 21 of 29 patients prior to treatment (72%), but in none of 9 patients during treatment (p0.001). The only other identified factor associated with successful recovery of B. burgdorferi was shorter duration of EM. When patients who had received prior antimicrobial therapy were excluded, the mean duration of the EM lesion for those with positive cultures was 5.0 +/- 5.2 days compared with 14.6 +/- 9.9 days for those with negative cultures (p0.01). B. burgdorferi could not be reisolated from any of 18 evaluable subsequent biopsies of skin from 13 culture-positive patients 4 to 209 days after completion of a course of antimicrobial therapy. Five patients had negative subsequent biopsy cultures on two separate occasions 3 to 5 months apart.After brief courses of antibiotics, B. burgdorferi appears to be rapidly eliminated from the skin at EM sites. The ability to recover B. burgdorferi from skin biopsy cultures of untreated patients with EM lesions wanes with increasing duration of EM, suggesting that this organism may also be spontaneously cleared from skin over time.

We present further evidence in support of the notion that Borrelia burgdorferi is possibly involved in the pathogenesis of morphea and lichen sclerosus et atrophicus (LSA). Running a nested polymerase chain reaction (PCR) with a primer set specific for the flagellin gene of B. burgdorferi enabled us to demonstrate the presence of Borrelia DNA in skin biopsies of patients with morphea (nine of nine) of LSA (six of six). Biopsy specimens obtained from patients with erythema chronicum migrans (two patients, four of four samples) and acrodermatitis chronica atrophicans (one patient, one of one sample) also showed positive PCR results. By contrast, there was no amplification of Borrelia DNA in control biopsies either from patients with chronic eczema (three of three) or psoriasis (two of two) or from normal skin (three of three). Antibodies directed against B. burgdorferi were only detected in the serum of patients with erythema chronicum migrans (two of two) and acrodermatitis chronica atrophicans (one of one) but were not present in cases of morphea (five of five), LSA (three of three), or in control subjects (three of three). These data suggest that B. burgdorferi may play a role in the pathogenesis of both morphea and LSA. Furthermore, we conclude that PCR analysis provides an important diagnostic tool, even in seronegative Borrelia infections.

Eighty-two patients who were treated at the Department of Dermatology, Innsbruck, Austria, from 1980 to 1987 for cutaneous manifestations of Lyme disease were subjected to a clinical follow-up investigation aimed at detecting dermatologic, neurologic, and internal late complications of borreliosis. Only 54 of these patients had received adequate antibiotic treatment according to current standards. Also, their sera were investigated for the presence of immunoglobulin O (IgG) and IgM Borrelia burgdorferi antibodies by an indirect immunofluorescence assay, three different enzyme-linked immunosorbent assays, and immunoblotting. As a control, the sera of 126 healthy blood donors were investigated with the same assays. Results showed no unambiguous clinical late complications of Lyme borreliosis, even in inadequately treated or untreated patients. Seropositivity varied considerably according to the assay used; the indirect immunofluorescence assay, yielded the highest scores. The proportion of seropositive results (immunofluorescence assay)was 59% in patients with erythema chronicum migrans, 69% in those with lymphocytoma cutis, and 100% in those with acrodermatitis chronica atrophicans (overall 63%); in contrast, only 31% of the blood donor control group were found to be seropositive. Seropositivity did not correlate with adequacy of treatment, interval between onset of symptoms and treatment, time span since treatment, age of patients, and presence of antinuclear antibodies. Immunoblot-pattern showed high incidence of antibodies against the 29/51-kD (outer surface proteins OspA and OspB) and 55/58-kD antigens in general and against the 41-kD protein (flagellin) in patients with acrodermatitis chronica atrophicans only.