High-risk groups for alpha-gal sensitization.

BACKGROUND: Tick bite-induced IgE-mediated reactions to the oligosaccharide galactose α-1,3-galactose (alpha-gal) are increasingly recognized. This study investigated alpha-gal sensitization in three groups with different tick bite exposure. MATERIALS AND METHODS: Specific IgE antibodies to alpha-gal and total IgE were investigated in 485 patients with Lyme borreliosis with different disease manifestations and compared to a control group of 200 randomly selected patients without increased exposure to tick bites. A group of 232 hunters and forest workers served as a model for multiple tick bites. RESULTS: Specific IgE (sIgE) antibodies to alpha-gal (> 0.1 kU/L) were found in 12.6% of all borreliosis samples compared to the control group with 9% (relative risk 1.4; 95% CI 0.85 - 2.3; not significant (n.s.). The highest prevalence of sIgE to alpha-gal was observed in hunters and forest service employees (22.8%, relative risk 2.5; 95% CI 1.5 - 4.2; p < 0.001). Higher age and elevated total IgE were also associated with alpha-gal sensitization. CONCLUSION: IgE sensitization to alpha-gal tends to be more frequent in tick-exposed patients with borreliosis than in controls (n.s.). Moreover, hunters and forest workers show an even higher rate of elevated IgE to alpha-gal. Thus, frequent tick contact may result in alpha-gal sensitization. In the area of Munich, the prevalence of alpha-gal sensitization appears lower than in the state of Baden-Württemberg and lower than in the USA, which may be due to the difference in tick species or the frequency of tick exposure. This study could show that alpha-gal sensitization and presumably alpha-gal syndrome does not seem to be a modern problem but existed already more than 30 years ago.

Guidelines for diagnosis and treatment in neurology - Lyme neuroborreliosis.

Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3-15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults. Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany). The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.

[Lyme Borreliosis: Cutaneous and Neurologic Manifestations, Case Definitions and Therapy]. / Lyme-Borreliose: Kutane und neurologische Manifestationen, Falldefinitionen und Therapie.

Lyme borreliosis is the most common zoonosis in Germany with an incidence of up to 138/100 000. More than 90 % of all cases show dermatological manifestations. Early manifestations are erythema migrans, multiple erythemata migrantia, and (less frequently) borrelial lymphocytoma. A typical late manifestation is acrodermatitis chronica atrophicans. Lyme neuroborreliosis is much less common with an incidence of about 0.8/100 000 inhabitants in Germany. Bannwarth's syndrome (painful radiculoneuritis) is the most common manifestation of Lyme neuroborreliosis in adults followed by meningitis. International case definitions exist regarding the likelihood of Lyme neuroborreliosis on the basis of diagnostic test results. A CSF analysis should be performed in patients with suspected Lyme neuroborreliosis. The first line treatment for dermatological manifestations of Lyme borreliosis is doxycycline, in children and pregnant women amoxicillin. Doxycycline and beta-lactam antibiotics show similar efficacy regarding neurological symptoms and adverse effects for treatment of neurological manifestations. Treatment duration for early manifestations is 10 to 14 days, in Lyme neuroborreliosis it should not exceed 21 days. All manifestations, also Lyme neuroborreliosis, usually show a favourable prognosis after antibiotic treatment. Antibiotic treatment does not show any efficacy in patients with unspecific symptoms and concurrent positive anti-borrelial serology.

Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis.

Importance: Controversies about the choice of antibiotic agent and treatment modality exist in the management of erythema migrans in early cutaneous Lyme borreliosis (LB). Objective: To conduct a network meta-analysis (NMA) of all randomized clinical trials on various antibiotic agents and treatment modalities in early cutaneous LB. Data Sources: Electronic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception until July 2017. The reference lists of the included studies were hand searched, authors were contacted, and ongoing trials were searched at ClinicalTrials.gov. Study Selection: One reviewer screened the titles and abstracts of the 9975 reports identified by the electronic searches. Full-text copies of 161 potentially relevant articles were obtained, and 2 reviewers independently assessed those articles for inclusion. Adults with a physician-confirmed early localized skin infection who were treated with antibiotics of any dose or duration were included. Data Extraction and Synthesis: Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analyses on treatment effects and adverse outcomes were calculated with a frequentist approach using the R package netmeta. The Grading of Recommendations Assessment, Development and Evaluation guidance for NMA was used to assess the certainty of evidence. Main Outcomes and Measures: Treatment effects for response to treatment (resolution of symptoms) and treatment-related adverse events. Results: Overall, 19 studies (2532 patients) were included. The mean patient age ranged between 37 and 56 years, and the percentage of female patients ranged from 36% to 60%. The antibiotics investigated were doxycycline, cefuroxime axetil, ceftriaxone, amoxicillin, azithromycin, penicillin V, and minocycline. Pooled effect sizes from NMAs did not suggest any significant differences in treatment response by antibiotic agent (eg, amoxicillin vs doxycycline odds ratio, 1.26; 95% CI, 0.41-3.87), dose, or duration (eg, doxycycline, 200 mg/d for 3 weeks, vs doxycycline, 200 mg/d for 2 weeks, odds ratio, 1.28; 95% CI, 0.49-3.34). Treatment failures were rare at both 2 months (4%; 95% CI, 2%-5%) and 12 months (2%, 95% CI, 1%-3%) after treatment initiation. There were also no differences in the effect sizes among antibiotic agents and treatment modalities for treatment-related adverse outcomes, which were generally mild to moderate. Certainty of evidence was categorized as low and very low mostly because of imprecision, indirectness, and study limitations (high risk of bias) of the included studies. Conclusions and Relevance: This NMA suggests that neither the antibiotic agent nor treatment modality contributed to comparative effectiveness or drug-related adverse outcomes. This finding is relevant for physicians treating patients with LB and for patient decision making.

Superficial radiation therapy in peyronie's disease: An effective and well-tolerated therapy.

PURPOSE: This study aimed to assess the safety, efficacy, and patient satisfaction of superficial radiation therapy in the treatment of Peyronie's disease (PD) in a retrospective analysis. METHODS AND MATERIALS: We performed a retrospective analysis of 83 patients who underwent radiation therapy between 1999 and 2008 with 8 fractions of 4 Gy over a period of 6 months. With a mean follow-up time of 52 months, patients responded to a comprehensive questionnaire that covered patient characteristics, disease duration before radiation therapy, course of disease, treatment response, side effects, and patient satisfaction. RESULTS: After a mean follow-up time of 52 months, 78% of the treated patients reported that PD progression had stopped. Furthermore 47% of patients had a symptom regression. Only 7% of patients reported PD progression. The penile curvature was improved in 49% of patients, and plaque induration could be reduced in 42% of patients. Moreover, 71% of patients reported substantial pain relief, as measured by a visual analogue scale (1 = not satisfied; 10 = very satisfied). Treatment satisfaction was rated with a median of 8 in a visual analogue scale out of 10. Side effects included transient erythema in 38.6% of patients and 9.6% reported of transient or chronic dryness. No severe side effects were observed. CONCLUSIONS: Radiation therapy for PD in the disease's early stages proved to be a safe and well-tolerated method with good results in pain relief, especially in patients aged <62 years. No serious adverse events or malign transformations are expected using doses up to 32 Gy.

Cutaneous Lyme borreliosis: Guideline of the German Dermatology Society.

This guideline of the German Dermatology Society primarily focuses on the diagnosis and treatment of cutaneous manifestations of Lyme borreliosis. It has received consensus from 22 German medical societies and 2 German patient organisations. It is the first part of an AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.) interdisciplinary guideline: "Lyme Borreliosis - Diagnosis and Treatment, development stage S3". The guideline is directed at physicians in private practices and clinics who treat Lyme borreliosis. Objectives of this guideline are recommendations for confirming a clinical diagnosis, recommendations for a stage-related laboratory diagnosis (serological detection of IgM and IgG Borrelia antibodies using the 2-tiered ELISA/immunoblot process, sensible use of molecular diagnostic and culture procedures) and recommendations for the treatment of the localised, early-stage infection (erythema migrans, erythema chronicum migrans, and borrelial lymphocytoma), the disseminated early-stage infection (multiple erythemata migrantia, flu-like symptoms) and treatment of the late-stage infection (acrodermatitis chronica atrophicans with and without neurological manifestations). In addition, an information sheet for patients containing recommendations for the prevention of Lyme borreliosis is attached to the guideline.

Efficacy and safety of pharmacological agents in the treatment of erythema migrans in early Lyme borreliosis-systematic review protocol.

BACKGROUND: Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment. METHODS: To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach. DISCUSSION: Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care. PROSPERO: CRD42016037932.

Patients with "organically unexplained symptoms" presenting to a borreliosis clinic: clinical and psychobehavioral characteristics and quality of life.

OBJECTIVE: This study explores the prevalence of patients with "organically unexplained symptoms" presenting to a Lyme borreliosis clinic and describes their clinical and psychobehavioral characteristics as well as health-related quality of life. METHODS: Study instruments consisted of a set of self-rating questionnaires and an organicity rating of presenting symptoms by an acknowledged expert. Participants included 125 patients presenting with symptoms attributed to borreliosis. Clinical and psychobehavioral characteristics as well as health-related quality of life for patients whose symptoms were rated as "organically unexplained" were compared with those of patients whose symptoms were rated as "organically explained." RESULTS: Symptoms of 37 (30%) patients were rated as "organically unexplained" (ORG-) and symptoms of 88 (70%) patients were rated as "organically explained" (ORG+). ORG- differed from ORG+ in various clinical and psychobehavioral characteristics and in health-related quality of life. For example, ORG- reported a higher number of symptoms, more illness consequences and negative emotional illness representations, and felt less reassured in the medical context, more dissatisfied with medical care, and more convinced of having a serious illness. CONCLUSIONS: Our results suggest that patients with "organically unexplained symptoms" inadequately attributed to Lyme borreliosis reveal many clinical and psychobehavioral characteristics that indicate significant somatic and mental distress. An early focus on all of the patients' mental and bodily symptoms, as well as on subjective illness perceptions and consequences allows for a more specific plan.

Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22.

Chronic mucocutaneous candidiasis (CMC) constitutes a selective inability to clear infection with the yeast Candida, resulting in persistent debilitating inflammation of skin, nails, and mucous membranes. The underlying defect is unknown. Only recently, IL-17-producing T cells have been reported to be involved in clearing Candida infections. In order to characterize T cellular immune response to Candida, we analyzed T-cell cytokine secretion to Candida antigen and mitogenic stimuli in CMC patients, immunocompetent patients suffering from acute Candida infection, and healthy volunteers. Peripheral blood mononuclear cells (PBMCs) from CMC patients produced significantly lower amounts of IL-17 and IL-22 mRNA and protein when stimulated with Candida albicans or mitogen in vitro compared with that in matched healthy individuals. Additionally, PBMCs from immunocompetent Candida-infected patients secreted more IL-17 and IL-22 than those of both CMC patients and healthy, non-infected controls. Flow cytometry revealed a decreased number of CCR6+ IL-17-producing T cells in CMC patients, whereas the amount of CCR6+/CCR4+ cells was not altered. Levels of differentiating cytokines for human Th17 cells, IL-1beta and IL-6, tended to be higher in CMC patients. The inability to clear C. albicans in CMC patients could be due to a defect in the immune response of IL-17-producing T cells.

Epidemiological aspects and molecular characterization of Borrelia burgdorferi s.l. from southern Germany with special respect to the new species Borrelia spielmanii sp. nov.

In 475 Borrelia-infected Ixodes ricinus (2155 ticks investigated) from southern Germany the most common Borrelia burgdorferi sensu lato species was B. garinii (34.3%) followed by B. afzelii (25.1%), B. burgdorferi sensu stricto (22.0%), and B. valaisiana (12.7%). B. spielmanii sp. nov. was detected in 5.9% of the 475 infected ticks. Hints for a focal distribution were found for B. spielmanii sp. nov. and B. garinii OspA type 4. In 242 patient isolates, dominance (66.9%) of B. afzelii for skin could be confirmed, while frequency of B. garinii in cerebrospinal fluid (CSF) isolates (51.1%) was comparable to the frequency in nymphal ticks (51.6%). Four patient isolates from southern Germany and two from Slovenia, all isolated from erythema migrans, could be assigned to B. spielmanii sp. nov. Within this new species high sequence identities were found for rrs, fla, and ospA while rrf-rrl, ospC, and dbpA were less conserved: three new ospC and two new dbpA sequence types were found. This genetic heterogeneity reveals that B. spielmanii sp. nov. did not evolve just recently.

Altered, but not diminished specific T cell response in chronic mucocutaneous candidiasis patients.

Patients suffering from chronic mucocutaneous infections with the yeast Candida albicans (CMC) are discussed to have an underlying primary cellular immunodeficiency. In order to characterise cellular immunity in CMC patients, we analysed chemotaxis and myeloperoxidase (MPO) releases of neutrophils and T cell proliferation and cytokine production to Candida albicans. Patients with chronic mucocutaneous candidiasis (n = 4) and healthy volunteers of same sex and similar age (n = 14) were enrolled into the study. Neutrophil chemotaxis was assessed by transwell migration assay, and MPO release by ELISA. T cell proliferation capacity was investigated by thymidine incorporation and cytokine secretion in supernatants by ELISA. Neither neutrophil migration nor MPO release differed between CMC patients and healthy controls. The relative lymphocyte stimulation index (SI Candida/SI PHA) was heterogenous, but overall it was higher in CMC patients compared to controls. However, Candida-specific IFN-gamma production was significantly reduced in CMC patients. Notably, Candida-specific T cell IL-10 production was markedly higher in CMC patients. The inability to clear the yeast Candida albicans in our CMC patients does not seem to be due to an impaired neutrophil function or reduced antigen specific proliferation of lymphocytes. In fact, our patients tended to proliferate stronger to Candida antigen relative to PHA than healthy controls. However, the impaired Th1 cytokine production with an enhanced IL-10 production could play an important role in the pathogenesis of chronic mucocutaneous Candida infections.

Borrelia burgdorferi complement regulator-acquiring surface protein 1 of the Lyme disease spirochetes is expressed in humans and induces antibody responses restricted to nondenatured structural determinants.

Borrelia burgdorferi complement regulator-acquiring surface protein 1 (CRASP-1), the dominant factor H and FHL-1-binding protein of the Lyme disease spirochete B. burgdorferi, is implicated in pathogen persistence and was recently reported to be nonimmunogenic in humans. Here we show that serum samples from Lyme disease patients contain antibodies with exclusive specificity for nondenatured structural determinants of CRASP-1.