Objectives Systematic review and meta-analysis on shortening antibiotic therapy for Lyme borreliosis (LB) patients. Methods Data sources: Medline, Google, and Google Scholar (queried from January 2022-February 2024), following the PRISMA method and the Cochrane Handbook. Eligibility criteria: Randomized clinical trials, comparative studies; clear definitions of LB, duration of antibiotics and outcome; follow-up >= 6-12 months. Meta-analysis included studies that examined three outcomes: treatment failure; residual symptoms; adverse events. Intervention: Short vs. extended antibiotic therapy for erythema migrans (<= 10 days vs. > 10 days) and disseminated LB (<= 21 days vs. > 21 days). Assessment of risk of bias. Independently, using the Cochrane Tools. Methods of data synthesis. Estimation of treatment effects based on a fixed-effect model (Mantel-Haenszel or Peto method), with odds ratio (OR) and 95% confidence intervals (CI). Results Thirty-eight full-text articles were examined (850 patients): 29 were included in the qualitative analysis; six in the meta-analysis. Heterogeneity was low (I2 = 0%). At 12 months, short-term treatment did not differ from long-term treatment in terms of failures (OR1.50, 95%CI[0.43-5.22]) and residual symptoms (OR0.95, 95%CI[0.66-1.37]), albeit with small samples. Conclusion This meta-analysis was underpowered to prove non-inferiority of shorter treatment, but suggests its safety for EM. Studies focusing on antibiotics duration, with sufficient sample sizes and clear outcomes, are warranted.

Migratory birds play a dual role as potential reservoirs of tick-borne pathogens, and potential dispersers of pathogen-containing ticks during their migratory journeys. Ixodes ricinus, a prevalent tick species in Northern and Western Europe, serves as a primary vector for Anaplasma phagocytophilum-a bacterium with implications for human and animal health. There is limited information available regarding A. phagocytophilum in birds. Our investigation focused on A. phagocytophilum prevalence in ticks collected from migratory birds in southeastern Sweden. The identification of ticks involved both molecular analyses for species determination and morphological classification to ascertain the developmental stage. The presence of A. phagocytophilum was determined using real-time PCR. Of the 1115 ticks analyzed from 4601 birds, 0.9% (n = 10), including I. ricinus and Ixodes frontalis, tested positive for A. phagocytophilum. Notably, common blackbirds (Turdus merula) yielded the highest number of A. phagocytophilum-infected ticks. The findings suggest that A. phagocytophilum is present in a small proportion of ticks infesting migratory birds in southeastern Sweden. Consequently, the role of birds as hosts for ticks infected with A. phagocytophilum appears to be low, suggesting that birds seem to play a minor indirect role in the geographic dispersal of A. phagocytophilum.

Ixodes ricinus nymphs and adults removed from humans, and larvae and nymphs from birds, have been analysed for infection with Babesia species and Borrelia species previously in separately published studies. Here, we use the same data set to explore the coinfection pattern of Babesia and Borrelia species in the ticks. We also provide an overview of the ecology and potential public health importance in Sweden of I. ricinus infected both with zoonotic Babesia and Borrelia species. Among 1952 nymphs and adult ticks removed from humans, 3.1% were PCR-positive for Babesia spp. Of these Babesia-positive ticks, 43% were simultaneously Borrelia-positive. Among 1046 immatures of I. ricinus removed from birds, 2.5% were Babesia-positive, of which 38% were coinfected with Borrelia species. This study shows that in I. ricinus infesting humans or birds in Sweden, potentially zoonotic Babesia protozoa sometimes co-occur with human-pathogenic Borrelia spp. Diagnostic tests for Babesia spp. infection are rarely performed in Europe, and the medical significance of this pathogen in Europe could be underestimated.

The impact of the emerging tick-borne pathogen Borrelia miyamotoi is not fully understood. We utilised a protein array to investigate B. miyamotoi seroreactivity in various human populations in the Netherlands and Sweden. The IgM/IgG seroprevalence in Dutch healthy (2·5%, 95%CI 1·5–4·1) and population controls (2·0%, 95%CI 0·9–4·4) was lower (p = 0·01 and p = 0·01) compared to the tick-bite cohort (6·1%, 95%CI 3·9–9·5). In accordance, the Swedish healthy controls (1·0%, 95%CI 0·1–6·9) revealed a lower (p = 0·005 and p < 0·001) IgM/IgG seroprevalence compared to the tick-bite (8·9%, 95%CI 5·7–13·7) and fever after tick-bite cohort (16·5%, 95%CI 10·6–24·8). Altogether, 15 of 2175 individuals had serologic evidence of early B. miyamotoi infection. The risk of infection with B. miyamotoi was 0·7% (95%CI 0·3–1·4) in tick-bitten individuals, and of disease 7·3% (95%CI 2·6–12·8) in those with a febrile illness after tick-bite. Our findings provide insights into the risk of infection and disease with this pathogen in Europe.

Background Today only indirect fluorescent antibody assays (IFAs) are commercially available to detect antibodies against Babesia divergens in humans. IFA is subjective and requires highly experienced staff. We have therefore developed an enzyme-linked immunosorbent assay (ELISA)-based method for measuring anti-B. divergens immunoglobulin G antibodies in human blood samples.Methods Crude merozoite extract from in vitro cultures of a new B. divergens isolate was used in ELISA to detect antibodies in different sets of samples: Borrelia burgdorferi-positive samples, healthy individuals, tick-bitten individuals including follow-up samples 3 months later, positive control samples from patients with an active Babesia infection, and samples from malaria-endemic regions. As a reference, IFA was used to detect antibodies in the tick-bitten samples. Western blot was used to evaluate reactions against specific bands in extracts with/without parasites.Results Using IFA as the reference method, the sensitivity and specificity of the ELISA were 86% (12/14) and 100% (52/52). There was a very high correlation (r = -0.84; P = .0004) between IFA dilution factors and ELISA absorbances among the samples classified as positive. Five percent of the B. burgdorferi-positive samples were judged as weakly positive and 5% as strongly positive in our ELISA. Western blot showed that the immunodominant antigens (similar to 120 kDa) were from merozoites and not from erythrocytes.Conclusions This ELISA can detect antibodies directed against B. divergens, and it can be a useful and easy assay to handle compared with IFA. The ELISA can also measure high and low levels of antibodies, which could give insight into the recency of a B. divergens infection.

Background: Birds can cross geographical and environmental barriers and thereby facilitate dispersal of tick-borne pathogens both as carriers of infected ticks and as reservoirs of pathogenic microorganisms. Ixodes lividus (Ixodida: Ixodidae) is an endophilic tick in the Palearctic region that is highly specialized on its host, the European sand martin Riparia riparia. The purpose of this study was to determine whether I. lividus ticks sampled from sand martin nests in Sweden carry vector-borne pathogens.Materials and Methods: Fed ticks were collected in the autumns of 2017 and 2019 from the nests of a European sand martin colony in southern Sweden. Ticks were identified morphologically to developmental stage and species and were tested for tick-borne pathogens using PCR-based methods.Results: None of the 41 ticks tested positive for five tick-borne pathogens including Borrelia spp., tick-borne encephalitis virus (TBEV), Neoehrlichia mikurensis, Anaplasma phagocytophilum, and Babesia spp. Thirty-seven (13 females, 23 nymphs and 1 larva) of the 41 ticks tested positive for the gltA gene of Rickettsia spp. The sequences of the 17 kDa and gltA genes were most closely related to Candidatus Rickettsia vini.Conclusion: Our study confirms other reports that I. lividus ticks associated with the European sand martin have high infection prevalence of Ca. R. vini.

The aim of this study was to characterize the gene expression of host immune- and cellular responses to a Norwegian virulent strain of Anaplasma phagocytophilum, the cause of tick-borne fever in sheep. Ten sheep were intravenously inoculated with a live virulent strain of A. phagocytophilum. Clinical-, observational-, hematological data as well as bacterial load, flow cytometric cell count data from peripheral blood mononuclear cells and host's gene expression post infection was analysed. The transcriptomic data were assessed for pre-set time points over the course of 22 days following the inoculation. Briefly, all inoculated sheep responded with clinical signs of infection 3 days post inoculation and onwards with maximum bacterial load observed on day 6, consistent with tick-borne fever. On days, 3-8, the innate immune responses and effector processes such as IFN1 signaling pathways and cytokine mediated signaling pathways were observed. Several pathways associated with the adaptive immune responses, namely T-cell activation, humoral immune responses, B-cell activation, and T- and B-cell differentiation dominated on the days of 8, 10 and 14. Flow-cytometric analysis of the PBMCs showed a reduction in CD4+CD25+ cells on day 10 and 14 post-inoculation and a skewed CD4:CD8 ratio indicating a reduced activation and proliferation of CD4-T-cells. The genes of important co-stimulatory molecules such as CD28 and CD40LG, important in T- and B-cell activation and proliferation, did not significantly change or experienced downregulation throughout the study. The absence of upregulation of several co-stimulatory molecules might be one possible explanation for the low activation and proliferation of CD4-T-cells during A. phagocytophilum infection, indicating a suboptimal CD4-T-cell response. The upregulation of T-BET, EOMES and IFN-γ on days 8-14 post inoculation, indicates a favoured CD4 Th1- and CD8-response. The dynamics and interaction between CD4+CD25+ and co-stimulatory molecules such as CD28, CD80, CD40 and CD40LG during infection with A. phagocytophilum in sheep needs further investigation in the future.

The AxBioTick Study: Borrelia Species and Tick-Borne Encephalitis Virus in Ticks, and Clinical Responses in Tick-Bitten Individuals on the Aland Islands, Finlandby  Nellie Carlströmer Berthén 1,2,*,† , Eszter Tompa 3,† , Susanne Olausson 1,2, Clara Nyberg 1, Dag Nyman 1,2, Malin Ringbom 1,4, Linda Perander 1,4, Joel Svärd 3, Per-Eric Lindgren 3,5, Pia Forsberg 3, Peter Wilhelmsson 3,5,‡, Johanna Sjöwall 3,6,‡  and Marika Nordberg 1,4,‡  1Borrelia Research Group of the Aland Islands, 22100 Mariehamn, The Aland Islands, Finland2Bimelix AB, 22100 Mariehamn, The Aland Islands, Finland3Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linkoping University, 581 83 Linkoping, Sweden4The Aland Islands Healthcare Services, 22100 Mariehamn, The Aland Islands, Finland5Clinical Microbiology, Laboratory Medicine, County Hospital Ryhov, 551 85 Jonkoping, Sweden6Department of Infectious Diseases, Vrinnevi Hospital, 603 79 Norrkoping, Sweden*Author to whom correspondence should be addressed.†These authors contributed equally to the study.‡These authors contributed equally to the study.Microorganisms 2023, 11(5), 1100; https://doi.org/10.3390/microorganisms11051100Received: 30 March 2023 / Revised: 17 April 2023 / Accepted: 19 April 2023 / Published: 22 April 2023(This article belongs to the Special Issue Research on Ticks and Tick-Borne Pathogens)

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AbstractThe AxBioTick study was initiated to investigate the prevalence of ticks and tick-borne pathogens and their impact on antibody and clinical responses in tick-bitten individuals on the Aland Islands. This geographical area is hyperendemic for both Lyme borreliosis (LB) and Tick-borne encephalitis (TBE). Blood samples and ticks were collected from 100 tick-bitten volunteers. A total of 425 ticks was collected, all determined to Ixodes ricinus using molecular tools. Of them 20% contained Borrelia species, of which B. garinii and B. afzelii were most common. None contained the TBE virus (TBEV). Blood samples were drawn in conjunction with the tick bite, and eight weeks later. Sera were analyzed for Borrelia- and TBEV-specific antibodies using an ELISA and a semiquantitative antibody assay. In total 14% seroconverted in Borrelia C6IgG1, 3% in TBEV IgG, and 2% in TBEV IgM. Five participants developed clinical manifestations of LB. The high seroprevalence of both Borrelia (57%) and TBEV (52%) antibodies are likely attributed to the endemic status of the corresponding infections as well as the TBE vaccination program. Despite the similar prevalence of Borrelia spp. detected in ticks in other parts of Europe, the infection rate in this population is high. The AxBioTick study is continuing to investigate more participants and ticks for co-infections, and to characterize the dermal immune response following a tick bite.

Purpose

The tick-borne bacterium Neoehrlichia mikurensis causes the infectious disease neoehrlichiosis in humans. Vascular endothelium is one of the target cells of the infection. Neoehrlichiosis patients with compromised B cell immunity present with more severe inflammation than immunocompetent patients. The aim of this study was to compare the cytokine profiles of immunocompetent and immunosuppressed patients with neoehrlichiosis.

Methods

Blood samples from Swedish and Norwegian immunosuppressed (N = 30) and immunocompetent (N = 16) patients with neoehrlichiosis were analyzed for the levels of 30 cytokines, using a multiplex cytokine assay and ELISA. A gender-matched healthy control group (N = 14) was analyzed in parallel. Data were analyzed using the multivariate method OPLS-DA.

Results

The multiplex cytokine analyses generated more cytokine results than did the uniplex ELISA analyses. Multivariate analysis of the multiplex cytokine results established that increased levels of FGF2, GM-CSF, CXCL10, and IFNγ were associated with immunosuppressed patients, whereas increased levels of IL-15 and VEGF were associated with immunocompetent neoehrlichiosis patients. When multivariate analysis findings were confirmed with uniplex ELISA, it was found that both groups of patients had similarly elevated levels of VEGF, FGF2 and IFNγ. In contrast, the immunosuppressed patients had clearly elevated levels of CXCL10, CXCL13 and BAFF, whereas the immunocompetent patients had the same levels as healthy controls.

Conclusion

Pro-angiogenic and type 1 cytokines were produced as part of the host response of neoehrlichiosis independent of immune status, whereas immunosuppressed neoehrlichiosis patients produced cytokines required for B cell-mediated defense.