[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.

Multippel erythema migrans, borrelialymfocytom og nevroborreliose hos eit barn.

BACKGROUND: Lyme disease after a tick bite often presents as erythema migrans, yet less frequent variants of this disease, such as Borrelia lymphocytoma, multiple erythema migrans and neuroborreliosis, are also seen occasionally. CASE PRESENTATION: We report a case of a tick-bitten child who first presented with an indistinct macular erythema around the left eye and a more distinct macular erythema on and around the left ear. The next day, she developed a facial palsy. INTERPRETATION: The case was interpreted as facial multiple erythema migrans and Borrelia lymphocytoma on the ear, followed by neuroborreliosis. The diagnosis of lymphocytoma was made from clinical findings and PCR of skin biopsy. She recovered quickly after intravenous ceftriaxone and is now healthy.

Lyme borreliosis: diagnosis and management.

Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear. Persistent active infection in humans has not been identified as a cause of this syndrome, and randomized treatment trials have invariably failed to show any benefit of prolonged antibiotic treatment. For prevention of Lyme borreliosis, post-exposure prophylaxis may be indicated in specific cases, and novel vaccine strategies are under development.

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

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

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

Prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis: study protocol for an observational, prospective cohort study (LymeProspect).

BACKGROUND: After antibiotic treatment of Lyme borreliosis, a subset of patients report persistent symptoms, also referred to as post-treatment Lyme disease syndrome. The reported prevalence of persistent symptoms varies considerably, and its pathophysiology is under debate. The LymeProspect study has been designed to investigate the prevalence, severity, and a wide range of hypotheses on the etiology of persistent symptoms among patients treated for Lyme borreliosis in the Netherlands. METHODS: LymeProspect is a prospective, observational cohort study among adults with proven or probable Lyme borreliosis, either erythema migrans or disseminated manifestations, included at the start of antibiotic treatment. During one year of follow-up, participants are subjected to questionnaires every three months and blood is collected repeatedly during the first three months. The primary outcome is the prevalence of persistent symptoms after treatment, assessed by questionnaires online focusing on fatigue (CIS, subscale fatigue severity), pain (SF-36, subscale pain) and neurocognitive dysfunction (CFQ). Potential microbiological, immunological, genetic, epidemiological and cognitive-behavioral determinants for persistent symptoms are secondary outcome measures. Control cohorts include patients with long-lasting symptoms and unconfirmed Lyme disease, population controls, and subjects having reported a tick bite not followed by Lyme borreliosis. DISCUSSION: This article describes the background and design of the LymeProspect study protocol. This study is characterized by a prospective, explorative and multifaceted design. The results of this study will provide insights into the prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis, and may provide a rationale for preventive and treatment recommendations. TRIAL REGISTRATION: NTR4998 (Netherlands Trial Register). Date of registration: 13 February 2015.

Somatic symptoms and fatigue in a Norwegian population with high exposure to ticks.

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 Søgne 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.

Report of Non-Lyme, Erythema Migrans Rashes from New Jersey with a Review of Possible Role of Tick Salivary Toxins.

Erythema migrans (EM) rashes once considered pathognomonic of Lyme disease (LD) have been reported following bites of arthropods that do not transmit LD and in areas with no LD. Also, EM rashes have been reported in association with organisms other than members of Borrelia burgdorferi sensu lato complex. Arthropod saliva has chemicals that have effects on the host and pathogen transmission. Tick saliva has protein families similar to spiders and scorpions and even substances homologous to those found in snakes and other venomous animals. Ticks "invertebrate pharmacologists" have a sophisticated arsenal of chemicals that assist in blood feeding, pathogen transmission, and suppressing host defenses. No organisms have been isolated from many EM rashes. We propose that tick salivary toxins may play a role in the causation of rashes and laboratory abnormalities in tick-borne diseases. The role of tick salivary toxins needs further exploration. Cases of Lyme-like EM rashes referred to as STARI (Southern Tick-Associated Rash Illness) following bites of the lone star tick, Amblyomma americanum, in the United States have been reported predominantly in Southeastern Missouri and a few in South Carolina, North Carolina, Georgia, and one case each in Mississippi and Long Island, New York. Although there is one report of Borrelia lonestari in a patient with a rash, biopsies of 31 cases of STARI, with cultures and PCR, failed to show a relationship. Distribution of A. americanum, whose bites are associated with STARI, now extends along the East Coast of the United States, including New Jersey, up to the Canadian border. As far as we are aware, there have been no prior reports of Lyme-like rashes in New Jersey. In this study, we present case examples of 2 Lyme-like rashes, variations of EM rashes, and a brief review of studies that suggest a role of tick salivary toxins in tick-borne diseases.

Areolar lymphocytoma in a child: A rare cutaneous presentation of borreliosis.

Lyme disease is a common tick-borne infection caused by Borrelia burgdorferi in the United States, where infection is most prevalent in the northeastern and mid-Atlantic states. Although classically associated with erythema migrans, Lyme disease caused by Borrelia species found in Europe may also present with other cutaneous findings. Here we report the case of a girl who was clinically diagnosed with Lyme disease based on her history of recent travel and the appearance of an areolar lymphocytoma; this was confirmed by testing. Testing for European Lyme disease does not follow the testing algorithm that the Centers for Disease Control and Prevention recommends and may be easily missed. Our case serves as an important reminder that common infections can have varying presentations depending on their region of acquisition and may require specialized testing for accurate diagnosis.

Surveillance perspective on Lyme borreliosis across the European Union and European Economic Area.

Lyme borreliosis (LB) is the most prevalent tick-borne disease in Europe. Erythema migrans (EM), an early, localised skin rash, is its most common presentation. Dissemination of the bacteria can lead to more severe manifestations including skin, neurological, cardiac, musculoskeletal and ocular manifestations. Comparison of LB incidence rates in the European Union (EU)/European Economic Area (EEA) and Balkan countries are difficult in the absence of standardised surveillance and reporting procedures. We explored six surveillance scenarios for LB surveillance in the EU/EEA, based on the following key indicators: (i) erythema migrans, (ii) neuroborreliosis, (iii) all human LB manifestations, (iv) seroprevalence, (v) tick bites, and (vi) infected ticks and reservoir hosts. In our opinion, neuroborreliosis seems most feasible and useful as the standard key indicator, being one of the most frequent severe LB manifestations, with the possibility of a specific case definition. Additional surveillance with erythema migrans as key indicator would add value to the surveillance of neuroborreliosis and lead to a more complete picture of LB epidemiology in the EU/EEA. The other scenarios have less value as a basis for EU-level surveillance, but can be considered periodically and locally, as they could supply complementary insights.

[Evaluation of 10 cases of Lyme disease presenting with erythema migrans in Istanbul, Turkey]. / Istanbul'da eritema migrans ile basvuran 10 Lyme olgusunun degerlendirilmesi.

Lyme disease (LD) is a tick-borne, multisystemic infection caused by Borrelia burgdorferi. Although variable rates of seropositivity for B.burgdorferi have been reported between 2% to 44% in Turkey, its actual prevalence is not well-understood. The aim of this retrospective study was to evaluate the characteristics of 10 cases of LD presenting as erythema migrans (EM) between 2009 and 2013 from Istanbul which is one of the metropolitan cities of Turkey. Of the patients, five were male and five were female, ages between 9-51 years (mean age: 34.5 years). Five of the patients were admitted in June, three in October, one in November and two in December and all have the history of tick bite in last 1-2 weeks. There were no clinical symptoms for systemic infection among the patients with normal level routine laboratory test (whole blood count and biochemical tests) results. Five of the cases had EM lesions in the trunk, three in the upper extremities, and two in the lower extremities. Four patients presented with annular, three with solitary macular, and three with target-like EM lesions. In all cases, the biopsy specimens were positive for B.burgdorferi sensu lato DNA with polymerase chain reaction and all were also positive in terms of B.burgdorferi IgM antibodies with ELISA. Nine patients were treated with oral doxycycline, 100 mg twice daily and one child patient was treated with oral amoxicillin 500 mg twice daily for 21 days. EM lesions disappeared within 2-4 weeks in all patients. There was no clinical evidence for systemic involvement in any of the patients like neurologic, cardiac, and joint involvement at the follow-ups on the third, sixth and 12(th) months. To our best knowledge, 10 patients in this study are the largest EM series reported from Turkey. The increase in the number of LD cases may be associated with increased tick bite and increased awareness due to the emergence of concurrent Crimean-Congo hemorrhagic fever epidemic in Turkey. As a result, when enlarged erythematous lesions on the skin were observed, LH must also be considered in differential diagnosis, history of tick bite should be questioned and etiological diagnostic test should be performed.

[Clinical and Laboratory Predictors for Forecasting the Outcomes of Ixodes Tick-Borne Borreliosis].

OBJECTIVE: Our aim was to identify the most informative clinical and laboratory predictors of chronicity of Ixodes tick-borne borreliosis in the acute phase of the disease based on the "optimal cut-off values" (COV) and the predicted probability of the outcomes. METHODS: A retrospective cohort controlled study was carried out. We used the technique of ROC-analysis to estimate the information content of the clinical and laboratory indicators in patients with Ixodes tick-borne borreliosis in the acute phase of the disease with erythemal (n =16), non-erythemal (n = 77) forms of Ixodes tick-borne borreliosis and co-infection with the tick-borne encephalitis (n = 68) for the prediction of the outcomes: recovery or chronization. RESULTS: A retrospective analysis of clinical and laboratory parameters recorded in the acute phase of the disease in 161 patients with chronic Ixodes tick-borne borreliosis. The calculations were performed for the informative clinical and laboratory prognostic predictors of the outcomes for the intervals above and below the COVvalues are defined probabilities of recovery or chronization of Ixodes tick-borne borreliosis. A general predictor of outcomes for all clinicalforms of the disease--the interleukin 8--was established: the probability of chronization after erythemal form is 100.0% at the level of its production over 107.89 pg/ml (AUC = 1.0), after non-erythemal form is 54.63 ± 0.23% at serum concentrations above 94.64 pg/ml (AUC = 0.770), after co-infection with the tick-borne encephalitis is 52.69 ± 0.27% at the level of interleukin 8 above 84.96 pg/ml (AUC = 0.780). CONCLUSION: The results of the study suggest the possibility of predicting the outcomes of infection in the acute phase, which allows to optimize the etiopathogenic therapy of the disease in a timely manner.

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

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

Lyme chondritis presenting as painless ear erythema.

Erythema of the ear lobe in the context of Lyme disease is caused by either borrelial lymphocytoma or localized erythema migrans. Here we present a case of chondritis limited to the ear cartilage caused by Lyme disease. The patient was treated with ceftriaxone with complete resolution of symptoms.

Common misconceptions about Lyme disease.

Lyme disease, infection with Borrelia burgdorferi, is a focally endemic tick-transmitted zoonosis. During the 3 decades since the responsible spirochete was identified, a series of misconceptions and misunderstandings have become widely prevalent, leading to frequent misdiagnosis and inappropriate treatment. Persistent misconceptions concern the reliability of available diagnostic tools, the signs and symptoms of nervous system involvement, the appropriate choice and duration of antimicrobial therapy, the curability of the infection, and the cause of symptoms that may persist in some patients after treatment. Concern about disparate perspectives led the Institute of Medicine to review the subject. In this article we review the principal misconceptions, discussing their origins and the best currently available scientific evidence related to each one.