BACKGROUND: Ixodes ticks are pivotal in transmitting diseases like Lyme disease and human granulocytic anaplasmosis, caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. These pathogens not only affect humans through single or multiple tick bites but also pose risks to animal hosts, leading to potential coinfections. Despite regional studies indicating significant prevalence, their global coinfection data remain sparse. This study aims to bridge this gap through a systematic review and meta-analysis of B. burgdorferi and A. phagocytophilum coinfections in Ixodes ticks worldwide. Addressing data limitations and study variability, it seeks to provide a nuanced understanding of coinfection patterns, their epidemiological implications and inform targeted prevention strategies.
METHODS: Following Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015 guidelines and PROSPERO registration, this study will undertake a thorough database search without constraints on language or publication date, using standardised screening and data extraction protocols. The quality and bias of studies will be evaluated using Joanna Briggs Institute tools. In the statistical analysis phase, conducted in R, we will initially determine the use of fixed or random-effects models based on the assessment of data heterogeneity. This choice will guide the framework for subsequent analyses. Within the selected model\'s framework, we will perform subgroup analyses and meta-regression to investigate the effects of various factors, ensuring that each step is tailored to the initial model selection to maintain analytical consistency.
BACKGROUND: As this study does not involve clinical research or data collection from subjects, ethical approval is not required. We will uphold ethical standards in synthesising and reporting data. Study outcomes will be published in peer-reviewed journals, communicating findings to the scientific community and contributing to the understanding of Ixodes tickborne diseases.
UNASSIGNED: CRD42023449735.

The incidence or prevalence of Lyme arthritis (LA) in Denmark is unknown and assumed very low. No published cases of polymerase chain reaction (PCR)-confirmed LA from Denmark exist. Clinically, LA does not differ from other rheumatic oligoarthritic disorders posing a differential diagnostic challenge. To review the incidence and prevalence of LA to our knowledge and to present a case series of PCR-confirmed LA cases from Denmark. We conducted a systematic literature review via MEDLINE and EMBASE to explore incidence and prevalence rates of LA. Additionally, we present six cases of patients diagnosed with LA in Denmark. Our literature review identified 23 studies reporting prevalence or incidence, yet only ten studies provided estimates ranging from 1.1 to 280/100.000 in the general population. Our case series identified six patients with LA from a localized region in Southern Denmark; all confirmed by Borrelia-specific real-time PCR from synovial fluid. The diagnostic delay was up to 38 months. All patients except one had a history of previous tick bites; none had erythema migrans lesions. All presented with recurrent arthritis in the knee joint, and two had arthritis in the wrist. The literature review showed an incidence of LA ranging from 1.1 to 15.8 per 100.000 in Europe. Our case series suggests a potentially higher prevalence of LA in Denmark than previously believed. Lack of tick exposure history, antibody assessments and test of Borrelia burgdorferi sensu lato DNA in synovial fluid might lead to misdiagnosed cases potentially explaining the assumed low incidence of LA in Denmark.

Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone combination therapy (DDDCT) for 8 weeks, followed by one or several two-week courses of pulsed high-dose dapsone combination therapy (HDDCT). We discuss these patients\' cases to illustrate three important variables required for long-term remission. First, diagnosing and treating active co-infections, including Babesia and Bartonella were important. Babesia required rotations of multiple anti-malarial drug combinations and herbal therapies, and Bartonella required one or several 6-day HDDCT pulses to achieve clinical remission. Second, all prior oral, intramuscular (IM), and/or intravenous (IV) antibiotics used for chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDS), irrespective of the length of administration, were inferior in efficacy to short-term pulsed biofilm/persister drug combination therapy i.e., dapsone, rifampin, methylene blue, and pyrazinamide, which improved resistant fatigue, pain, headaches, insomnia, and neuropsychiatric symptoms. Lastly, addressing multiple factors on the 16-point multiple systemic infectious disease syndrome (MSIDS) model was important in achieving remission. In conclusion, DDDCT with one or several 6-7-day pulses of HDDCT, while addressing abnormalities on the 16-point MSIDS map, could represent a novel effective clinical and anti-infective strategy in CLD/PTLDS and associated co-infections including Bartonella.

BACKGROUND: Lyme disease (LD) is an emergent vector-borne disease caused by Borrelia spp. and transmitted through infected ticks, mainly Ixodes spp. Our objective was to determine meteorological and environmental factors associated with LD transmission in Europe and the effect of climate change on LD.
METHODS: A systematic review following the PRISMA guidelines was performed. We selected studies on LD transmission in the European Union (EU) and the European Economic Area (EEA) published between 2000 and 2022. The protocol was registered in the PROSPERO database.
RESULTS: We included 81 studies. The impact of environmental, meteorological or climate change factors on tick vectors was studied in 65 papers (80%), and the impact on human LD cases was studied in 16 papers (19%), whereas animal hosts were only addressed in one study (1%). A significant positive relationship was observed between temperature and precipitation and the epidemiology of LD, although contrasting results were found among studies. Other positive factors were humidity and the expansion of anthropized habitats.
CONCLUSIONS: The epidemiology of LD seems to be related to climatic factors that are changing globally due to ongoing climate change. Unfortunately, the complete zoonotic cycle was not systematically analyzed. It is important to adopt a One Health approach to understand LD epidemiology.

BACKGROUND: In the temperate world, Lyme disease (LD) is the most common vector-borne disease affecting humans. In North America, LD surveillance and research have revealed an increasing territorial expansion of hosts, bacteria and vectors that has accompanied an increasing incidence of the disease in humans. To better understand the factors driving disease spread, predictive models can use current and historical data to predict disease occurrence in populations across time and space. Various prediction methods have been used, including approaches to evaluate prediction accuracy and/or performance and a range of predictors in LD risk prediction research. With this scoping review, we aim to document the different modelling approaches including types of forecasting and/or prediction methods, predictors and approaches to evaluating model performance (eg, accuracy).
METHODS: This scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review guidelines. Electronic databases will be searched via keywords and subject headings (eg, Medical Subject Heading terms). The search will be performed in the following databases: PubMed/MEDLINE, EMBASE, CAB Abstracts, Global Health and SCOPUS. Studies reported in English or French investigating the risk of LD in humans through spatial prediction and temporal forecasting methodologies will be identified and screened. Eligibility criteria will be applied to the list of articles to identify which to retain. Two reviewers will screen titles and abstracts, followed by a full-text screening of the articles\' content. Data will be extracted and charted into a standard form, synthesised and interpreted.
BACKGROUND: This scoping review is based on published literature and does not require ethics approval. Findings will be published in peer-reviewed journals and presented at scientific conferences.

The diagnosis of Lyme disease is becoming more common in Turkey. Nonetheless, some physicians are not aware of the diagnostic principles that should be followed when faced with a suspected patient and could use tests that are not recommended, such as darkfield microscopy. Dark field microscopy is a diagnostic technique to visualize the spirochetes that cause Lyme disease; however, it is not recommended for the diagnosis of Lyme disease. One of the main limitations of dark field microscopy is its low sensitivity. Another limitation is its high false-positivity rate, as other microorganisms and cellular debris can be mistaken for spirochetes, leading to a misdiagnosis thatmay result in unnecessary treatment. Therefore, this study aimed to review the literature on the role of dark field microscopy as a diagnostic method for Lyme disease and inform physicians about recommended approaches in line with the recommendations of national or international guidelines. An electronic search of Pubmed, Scopus, and Web of Science was performed using the following medical subject headings (MeSH) search terms: Lyme borreliosis, Lyme disease, Borrelia burgdorferi, diagnosis, and microscopy. With this narrative review, we aimed to inform physicians better and improve patient care for patients with suspected Lyme disease.

OBJECTIVE: Residual symptoms after treatment of Lyme disease, sometimes called post-treatment Lyme disease symptoms (PTLDs), are a matter of ongoing controversy. To guide treatment recommendations, a systematic review was performed of the available literature on specific treatment for PTLDs.
METHODS: A systematic literature search of MEDLINE and CENTRAL was performed. No restrictions on case definitions, study types or specific interventions were applied to enable a comprehensive overview of the available literature. Risk of bias was assessed using the Cochrane risk of bias tools for randomized controlled trials. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Outcomes of interest were quality of life, fatigue, depression and cognition as well as adverse events.
RESULTS: After screening 1274 records, eight eligible randomized controlled trials were included. Heterogeneity was observed regarding inclusion criteria, intervention, length of treatment and outcome measures. For efficacy outcomes, results are presented narratively due to heterogeneity. Eligible studies show no statistically significant difference between antibiotics and placebo regarding quality of life, cognition and depression. Results for fatigue were inconsistent whilst studies with low risk of bias showed no statistically significant difference between antibiotics and placebo. Meta-analysis of safety outcomes showed statistically significantly more adverse events for antibiotics compared to placebo.
CONCLUSIONS: Available literature on treatment of PTLDs is heterogeneous, but overall shows evidence of no effect of antibiotics regarding quality of life, depression, cognition and fatigue whilst showing more adverse events. Patients with suspected PTLDs should not be treated with antibiotics.

Hemophagocytic lymphohistiocytosis (HLH) secondary to tick-borne infections is a rare but potentially life-threatening syndrome. We performed a scoping review according to PRISMA guidelines to systematically analyze the existing literature on the topic. A total of 98 patients were included, with a mean age of 43.7 years, of which 64% were men. Most cases, 31%, were reported from the USA. Immunosuppression was present in 21.4%, with the most common cause being previous solid organ transplantation. Constitutional symptoms were the most common, observed in 83.7% of the patients, while fever was reported in 70.4% of cases. Sepsis was present in 27.6%. The most common laboratory abnormalities in this cohort were thrombocytopenia in 81.6% of patients, while anemia, leukopenia, and leukocytosis were observed in 75.5%, 55.1%, and 10.2%, respectively. Liver enzyme elevation was noted in 63.3% of cases. The H-score was analyzed in 64 patients, with the mean value being 209, and bone marrow analysis was performed in 61.2% of patients. Ehrlichia spp. was the main isolated agent associated with HLH in 45.9%, followed by Rickettsia spp. in 14.3% and Anaplasma phagocytophilum in 12.2%. Notably, no patient with Powassan virus infection or Lyme borreliosis developed HLH. The most common complications were acute kidney injury (AKI) in 35.7% of patients, shock with multiple organ dysfunction in 22.5%, encephalopathy/seizure in 20.4%, respiratory failure in 16.3%, and cardiac complications in 7.1% of patients. Treatment included antibiotic therapy alone in 43.9%, while 5.1% of patients were treated with immunosuppressants alone. Treatment with both antibiotics and immunosuppressants was used in 51% of patients. Appropriate empiric antibiotics were used in 62.2%. In 43.9% of cases of HLH due to tick-borne disease, patients received only antimicrobial therapy, and 88.4% of those recovered completely without the need for immunosuppressive therapy. The mortality rate in our review was 16.3%, and patients who received inappropriate or delayed empiric therapy had a worse outcome. Hence, we suggest empiric antibiotic treatment in patients who are suspected of having HLH due to tick-borne disease or in whom diagnostic uncertainty persists due to diagnostic delay in order to minimize mortality.

BACKGROUND: Antibiotic therapy for patients with early Lyme disease is necessary to prevent later-stage Lyme disease complications. This systematic review and meta-analysis compares shorter versus longer antibiotic regimens in treating early Lyme disease.
METHODS: A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted up to November 2023. We examined treatment failure, complete response, and photosensitivity. Short vs. long therapy was defined as ≤10 days vs. >10 days. Subgroup analyses included antibiotic type and varying treatment durations. Analysis utilized RStudio 4.1.2. PROSPERO registration: CRD42023423876.
RESULTS: Seven studies, encompassing 1,462 patients, were analyzed. No significant differences in treatment failure, 12-month complete response, final visit complete response were found between short and long durations of antibiotic therapy. Subgroup and sensitivity analyses corroborated these findings.
CONCLUSIONS: Shorter and longer antibiotic regimens for early Lyme disease show similar efficacy, highlighting the potential of ≤10-day courses, as effective treatment options.

Lyme disease is caused by Borrelia burgdorferi (B. burgdorferi), which is a spirochete transmitted by ticks of the genus Ixodes. Complications related to the cardiovascular system usually occur in the early phase of infection, and the most common cardiovascular complication of Lyme disease is atrioventricular block, especially third-degree heart block. We report a case of a young Caucasian male patient who presented to the emergency department (ED) with complaints of chest pain and shortness of breath. Initial investigations, including chest X-ray, were negative. An EKG revealed ST elevation and PR depression with troponin elevation. The echocardiogram showed a normal ejection fraction with no pericardial effusion. Skin examination was positive for erythema migrans concerning Lyme. Initial Lyme testing was negative in the patient and it should be repeated after four to six weeks, according to the guidelines. This case report highlights the importance of keeping the differentials broad in these patients even if the initial testing is negative, especially since misdiagnosis or delayed diagnosis can cause cardiac complications.