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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The incidence of tick-borne infections other than Lyme borreliosis and tick-borne encephalitis is rising in Europe, including the Netherlands. Nature management workers, being highly exposed to ticks, serve as valuable sentinels for seroprevalence studies on tick-borne pathogens (TBPs). This study assessed nature management workers' seropositivity to TBPs including Anaplasma phagocytophilum, Babesia divergens, B. microti, Borrelia burgdorferi s.l., Rickettsia conorii and R. typhi in the Netherlands. In addition, the study examined coexposure to multiple TBPs and identified risk factors for B. burgdorferi s.l.- and A. phagocytophilum-seropositivity. The study included 525 nature management workers who donated serum and completed a questionnaire. Sera were analysed for exposure to A. phagocytophilum, B. divergens, B. microti, R. conorii and R. typhi using immunofluorescence assays. For B. burgdorferi s.l. antibody detection, the recommended two-tier testing strategy was used. Risk factor analysis was performed using logistic regression modelling. Seropositivity was 30.9 % for B. burgdorferi s.l.; 16.4 % for A. phagocytophilum; 6.5 % for R. conorii; 2.3 % for R. typhi; 4.2 % for B. divergens; and 0.4 % for B. microti. Almost half (49.3 %) of the participants demonstrated seropositivity for one or more pathogens. Risk factors for B. burgdorferi s.l.-seropositivity included being male, increasing age and tick bite frequency. For A. phagocytophilum-seropositivity, increasing age and working in North Holland province were significant risk factors. This study illustrates the exposure to TBPs in the Netherlands, emphasizing the need for ongoing vigilance and international collaborations to better understand and address the growing threat of TBPs in regions with demonstrated environmental TBP circulation., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier GmbH.)

Objective: It is unclear how self-reported severe fatigue and difficulty concentrating after SARS-CoV-2 infection relate to objective neuropsychological functioning. The study aimed to compare neuropsychological functioning between individuals with and without these persistent subjective complaints. Method : Individuals with and without persistent severe fatigue (Checklist Individual Strength (CIS) fatigue ≥ 35) and difficulty concentrating (CIS concentration ≥ 18) at least 3 months after SARS-CoV-2 infection were included. Neuropsychological assessment was performed on overall cognitive functioning, attention, processing speed, executive functioning, memory, visuo-construction, and language (18 tests). T-scores -1.5 SD below population normative data ( T  ≤ 35) were classified as "impaired". Results: 230 participants were included in the study, of whom 22 were excluded from the analysis due to invalid performance. Of the participants included in the analysis, 111 reported persistent complaints of severe fatigue and difficulty concentrating and 97 did not. Median age was 54 years, 59% ( n  = 126) were female, and participants were assessed a median of 23 months after first infection (IQR: 16-28). With bivariate logistic regression, individuals with persistent complaints had an increased likelihood of slower information processing speed performance on the Stroop word reading (OR = 2.45, 95%CI = 1.02-5.84) compared to those without persistent complaints. Demographic or clinical covariates (e.g. hospitalization) did not influence this association. With linear regression techniques, persistent complaints were associated with lower t-scores on the D2 CP, TMT B, and TMT B|A. There were no differences in performance on the other neuropsychological tests. Conclusions: Individuals with subjective severe fatigue and difficulty concentrating after COVID-19 do not typically demonstrate cognitive impairment on extensive neuropsychological testing.

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource., (© 2024. The Author(s).)

Objectives: To describe the course of symptoms reported by patients with symptoms attributed to Lyme borreliosis (LB) without being subsequently diagnosed with LB., Methods: We performed a prospective cohort study with patients presenting at the outpatient clinic of two clinical LB centres. The primary outcome was the prevalence of persistent symptoms, which were defined as clinically relevant fatigue (CIS, subscale fatigue), pain (SF-36, subscale bodily pain), and cognitive impairment (CFQ) for ≥ 6 months and onset < 6 months over the first year of follow-up. Outcomes were compared with a longitudinal cohort of confirmed LB patients and a general population cohort. Prevalences were standardised to the distribution of pre-defined confounders in the confirmed LB cohort., Results: Participants (n = 123) reported mostly fatigue, arthralgia, myalgia, and paraesthesia as symptoms. The primary outcome could be determined for 74.8% (92/123) of participants. The standardised prevalence of persistent symptoms in our participants was 58.6%, which was higher than in patients with confirmed LB at baseline (27.2%, p < 0.0001) and the population cohort (21.2%, p < 0.0001). Participants reported overall improvement of fatigue (p < 0.0001) and pain (p < 0.0001) but not for cognitive impairment (p = 0.062) during the follow-up, though symptom severity at the end of follow-up remained greater compared to confirmed LB patients (various comparisons p < 0.05)., Conclusion: Patients with symptoms attributed to LB who present at clinical LB centres without physician-confirmed LB more often report persistent symptoms and report more severe symptoms compared to confirmed LB patients and a population cohort., (© 2024. The Author(s).)

Objectives: Different SARS-CoV-2 variants can differentially affect the prevalence of Post Covid-19 Condition (PCC). This prospective study assesses prevalence and severity of symptoms three months after an Omicron infection, compared to Delta, test-negative and population controls. This study also assesses symptomology after reinfection and breakthrough infections., Methods: After a positive SARS-CoV-2 test, cases were classified as Omicron or Delta based on ≥ 85% surveillance prevalence. Three months after enrolment, participants indicated point prevalence for 41 symptoms and severity, using validated questionnaires for four symptoms. PCC prevalence was estimated as the difference in prevalence of at least one significantly elevated symptom, identified by permutation test, in cases compared to population controls., Results: At three months follow-up, five symptoms and severe dyspnea were significantly elevated in Omicron cases (n = 4138) compared to test-negative (n = 1672) and population controls (n = 2762). PCC prevalence was 10·4% for Omicron cases and 17·7% for Delta cases (n = 6855). In Omicron cases, severe fatigue and dyspnea were more prevalent in reinfected than primary infected, while severity of symptoms did not significantly differ between cases with a booster or primary vaccination course., Conclusions: Prevalence of PCC is 41% lower after Omicron than Delta at three months. Reinfection seems associated with more severe long-term symptoms compared to first infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms., Methods: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments., Results: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses., Conclusions: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures., Trial Registration: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13)., (© 2024. The Author(s).)

Background: Patients treated for Lyme borreliosis (LB) frequently report persistent symptoms. Little is known about risk factors and etiology., Methods: In a prospective observational cohort study with a follow-up of one year, we assessed a range of microbiological, immunological, genetic, clinical, functional, epidemiological, psychosocial and cognitive-behavioral variables as determinants of persistent symptoms after treatment for LB. Between 2015 and 2018 we included 1135 physician-confirmed LB patients at initiation of antibiotic therapy, through clinical LB centers and online self-registration. Two reference cohorts of individuals without LB (n = 4000 and n = 2405) served as a control. Prediction analyses and association studies were used to identify determinants, as collected from online questionnaires (three-monthly) and laboratory tests (twice)., Findings: Main predictors of persistent symptoms were baseline poorer physical and social functioning, higher depression and anxiety scores, more negative illness perceptions, comorbidity, as well as fatigue, cognitive impairment, and pain in 295 patients with persistent symptoms. The primary prediction model correctly indicated persistent symptoms in 71.0% of predictions (AUC 0.79). In patients with symptoms at baseline, cognitive-behavioral responses to symptoms predicted symptom persistence. Of various microbiological, immunological and genetic factors, only lower IL-10 concentrations in ex vivo stimulation experiments were associated with persistent symptoms. Clinical LB characteristics did not contribute to the prediction of persistent symptoms., Interpretation: Determinants of persistent symptoms after LB were mainly generic, including baseline functioning, symptoms and cognitive-behavioral responses. A potential role of host immune responses remains to be investigated., Funding: Netherlands Organisation for Health Research and Development (ZonMw); the Dutch Ministry of Health, Welfare and Sport (VWS)., Competing Interests: Declaration of interests MEB, FRvdS and JWH report collaborations on LB diagnostics with Pfizer, Antigen Discovery Inc., Oxford Immunotec, AID/GenID, and InVitaLab; funding to institution and/or material supplied for research free of charge, no personal financial compensation. MEB reports support for travel expenses related to LB symposium at Massachusetts General Hospital. LABJ and BJK are co-inventor of Spirofind, an experimental in-house assay for Lyme borreliosis, which is owned by Radboudumc and will not be developed further as potential diagnostic test. CCvdW is a consortium partner and partner in sub-project in the NMCB consortium (The Dutch ME/CFS Cohort and Biobank Consortium) funded by Netherlands Organization for Health Research and Development (ZonMw, project numbers 10091012110027 and 10091012110018). The other authors report no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [ 18 F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI., Methods and Analysis: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [ 18 F]DPA-714 PET, and brain functioning and structure using (f)MRI., Ethics and Dissemination: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population., Competing Interests: Competing interests: FB: Steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This prospective study assesses symptoms 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection compared to test-negative and population controls, and the effect of vaccination prior to infection., Methods: Participants enrolled after a positive (cases) or negative (test-negative controls) SARS-CoV-2 test, or after invitation from the general population (population controls). After 3 months, participants indicated presence of 41 symptoms and severity of 4 symptoms. Permutation tests were used to select symptoms significantly elevated in cases compared to controls and to compare symptoms between cases that were vaccinated or unvaccinated prior to infection., Results: In total, 9166 cases, 1698 symptomatic but test-negative controls, and 3708 population controls enrolled. At 3 months, 13 symptoms, and severity of fatigue, cognitive impairment, and dyspnea were significantly elevated incases compared to controls. Of cases, 48.5% reported ≥1 significantly elevated symptom compared to 29.8% of test-negative controls and 26.0% of population controls. Effect of vaccination could be determined for cases aged <65 years, and was significantly protective for loss of smell and taste but not for other symptoms., Discussion: Three months after SARS-CoV-2 infection, almost half of cases report symptoms, which was higher than background prevalence and test-negative prevalence. Vaccination prior to infection was protective against loss of smell and taste in cases aged <65 years., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lyme borreliosis (LB) is not notifiable in many European countries, and accurate data on the incidence are often lacking. This study aimed to determine the seroprevalence of Borrelia burgdorferi sensu lato (s.l.)-specific antibodies in the general population of The Netherlands, and to determine risk factors associated with seropositivity. Sera and questionnaires were obtained from participants (n = 5592, aged 0-88 years) enrolled in a nationwide serosurveillance study. The sera were tested for B. burgdorferi s.l.-specific IgM and IgG antibodies using ELISA and immunoblot. Seroprevalence was estimated controlling for the survey design. Risk factors for seropositivity were analyzed using a generalized linear mixed-effect model. In 2016/2017, the seroprevalence in The Netherlands was 4.4% (95% CI 3.5-5.2). Estimates were higher in men (5.7% [95% CI 4.4-7.2]) than in women (3.1% [95% CI 2.0-4.0]), and increased with age from 2.6% (95% CI 1.4-4.4) in children to 7.7% (95% CI 5.9-7.9) in 60- to 88-year-olds. The seroprevalence for B. burgdorferi s.l. in the general population in The Netherlands was comparable to rates reported in European countries. The main risk factors for seropositivity were increasing age, being male and the tick bite frequency. The dynamics of LB infection are complex and involve variables from various disciplines. This could be further elucidated using infectious disease modelling.

Previous studies have shown that monocytes can be 'trained' or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: Cellular tests for Lyme borreliosis might be able to overcome major shortcomings of serological testing, such as its low sensitivity in early stages of infection. Therefore, we aimed to assess the sensitivity and specificity of three cellular tests., Methods: This was a nationwide, prospective, multiple-gate case-control study done in the Netherlands. Patients with physician-confirmed Lyme borreliosis, either early localised or disseminated, were consecutively included as cases at the start of antibiotic treatment. Controls were those without Lyme borreliosis from the general population (healthy controls) and those with potentially cross-reactive conditions (eg, autoimmune disease). We used three cellular tests for Lyme borreliosis (Spirofind Revised, iSpot Lyme, and LTT-MELISA) as index tests, and standard two-tier serological testing (STTT) as a comparator. Clinical data from Lyme borreliosis patients were collected at baseline and at 12 weeks after inclusion, and blood samples were obtained at baseline, 6 weeks, and 12 weeks. Control participants underwent clinical and laboratory assessments at baseline only., Findings: Cases comprised 271 patients with Lyme borreliosis (of whom 245 had early-localised Lyme borreliosis and 26 had disseminated disease) and controls comprised 228 participants without Lyme borreliosis from the general population and 41 participants with potentially cross-reactive conditions. Recruitment occurred between May 14, 2018, and March 16, 2020. The specificity of STTT in healthy controls (216 of 228 samples [94·7%, 95% CI 91·5-97·7]) was higher than that of the cellular tests: Spirofind (140 of 171 [81·9%, 76·1-87·2]), iSpot Lyme (32 of 103 [31·1%, 21·5-40·3]) and LTT-MELISA (100 of 190 [52·6%, 44·9-60·3]). Cellular tests had varying sensitivities: Spirofind (88 of 204 [43·1%, 36·4-50·4]), iSpot Lyme (51 of 94 [54·3%, 44·5-63·7]), and LTT-MELISA (66 of 218 [30·3%, 23·8-36·7]). The Spirofind and iSpot Lyme outperformed STTT for sensitivity, but were similar to the C6-ELISA (C6-ELISA: 135 of 270 [50·0%, 44·5-55·5]; STTT: 76 of 270 [28·1%, 23·0-33·6])., Interpretation: The cellular tests for Lyme borreliosis used in this study have a low specificity compared with serological tests, which leads to a high number of false-positive test results. We conclude that these cellular tests are unfit for clinical use at this stage., Funding: Netherlands Organization for Health Research and Development, AMC Foundation (Amsterdam UMC), and Ministry of Health of the Netherlands., Competing Interests: Declaration of interests The assays under study were supplied by AID/GenID (Strassberg, Germany), InVitaLab (Neuss, Germany), QIAGEN (Germantown, MD, USA), and Oxford Immunotec (Oxford, UK), either free of charge or at a reduced price; none of the authors have received any direct financial compensation from any of these companies for this project or any other project. MEB and JWH collaborate with Bio-Rad Laboratories, ZEUS Scientific, and Pfizer on unrelated projects on Lyme borreliosis. JWH collaborates with Antigen Discovery on unrelated projects on Lyme borreliosis; JWH has an application for a provisional patent related to Borrelia antigens pending. FRvdS and LABJ collaborate with Hycult Biotech on developing novel diagnostic tests for Lyme borreliosis. B-JK and LABJ are coinventors of the Spirofind, an experimental in-house assay for Lyme borreliosis, which is owned by Radboudumc and was licensed for development to Boulder Diagnostics (Boulder, Colorado, USA) and subsequently Oxford Immunotec (Oxford, UK) until 2018. The other authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: A substantial proportion of individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), report persisting symptoms weeks and months following acute infection. Estimates on prevalence vary due to differences in study designs, populations, heterogeneity of symptoms and the way symptoms are measured. Common symptoms include fatigue, cognitive impairment and dyspnoea. However, knowledge regarding the nature and risk factors for developing persisting symptoms is still limited. Hence, in this study, we aim to determine the prevalence, severity, risk factors and impact on quality of life of persisting symptoms in the first year following acute SARS-CoV-2 infection., Methods and Analysis: The LongCOVID-study is both a prospective and retrospective cohort study being conducted in the Netherlands, with a one year follow-up. Participants aged 5 years and above, with self-reported positive or negative tests for SARS-CoV-2 will be included in the study. The primary outcome is the prevalence and severity of persistent symptoms in participants that tested positive for SARS-CoV-2 compared with controls. Symptom severity will be assessed for fatigue (Checklist Individual Strength (CIS subscale fatigue severity)), pain (Rand-36/SF-36 subscale bodily pain), dyspnoea (Medical Research Council (mMRC)) and cognitive impairment (Cognitive Failure Questionnaire (CFQ)). Secondary outcomes include effect of vaccination prior to infection on persistent symptoms, loss of health-related quality of life (HRQoL) and risk factors for persisting symptoms following infection with SARS-CoV-2., Ethics and Dissemination: The Utrecht Medical Ethics Committee (METC) declared in February 2021 that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (METC protocol number 21-124/C). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: All authors have no conflicts of interests to disclose.

Laboratory diagnosis of Lyme borreliosis (LB) is mainly based on serology, which has limitations, particularly in the early stages of the disease. In recent years there have been conflicting reports concerning a new diagnostic tool using the cytokine interferon-gamma (IFN-γ). Previous studies have generally found low concentrations of IFN-γ in early LB infection. The goal of this study is to investigate IFN-γ regulation during early LB and provide insights into the host response to B. burgdorferi. We performed in vitro experiments with whole blood assays and peripheral blood mononuclear cells (PBMCs) of LB patients and healthy volunteers exposed to B. burgdorferi and evaluated the IFN-γ response using ELISA and related interindividual variation in IFN-γ production to the presence of single nucleotide polymorphisms. IFN-γ production of B. burgdorferi - exposed PBMCs and whole blood was amplified by the addition of interleukin-12 (IL-12) to the stimulation system. This effect was observed after 24 h of B. burgdorferi stimulation in both healthy individuals and LB patients. The effect was highly variable between individuals, but was significantly higher in LB patients 6 weeks since the start of antibiotic treatment compared to healthy individuals. IL-12 p40 and IL-18 mRNA were upregulated upon exposure to B. burgdorferi, whereas IL-12 p35 and IFN-γ mRNA expression remained relatively unchanged. SNP Rs280520 in the downstream IL-12 pathway, Tyrosine Kinase 2, was associated with increased IFN-γ production. This study shows that IL-12 evokes an IFN-γ response in B. burgdorferi exposed cells, and that LB patients and healthy controls respond differently to this stimulation.

Objectives: We aimed to identify populations at a high risk for SARS-CoV-2 infection but who are less likely to present for testing, by determining which sociodemographic and household factors are associated with a lower propensity to be tested and, if tested, with a higher risk of a positive test result., Design and Setting: Internet-based participatory surveillance data from the general population of the Netherlands., Participants: Weekly survey data collected over a 5-month period (17 November 2020 to 18 April 2021) from a total of 12 026 participants who had contributed at least 2 weekly surveys was analysed., Methods: Multivariable analyses using generalised estimating equations for binomial outcomes were conducted to estimate the adjusted ORs of testing and of test positivity associated with participant and household characteristics., Results: Male sex (adjusted OR for testing (OR t ): 0.92; adjusted OR for positivity (OR p ): 1.30, age groups<20 (OR t : 0.89; OR p : 1.27), 50-64 years (OR t : 0.94; OR p : 1.06) and 65+ years (OR t : 0.78; OR p : 1.24), diabetics (OR t : 0.97; OR p : 1.06) and sales/administrative employees (OR t : 0.93; OR p : 1.90) were distinguished as lower test propensity/higher test positivity factors., Conclusions: The factors identified using this approach can help identify potential target groups for improving communication and encouraging testing among those with symptoms, and thus increase the effectiveness of testing, which is essential for the response to the COVID-19 pandemic and for public health strategies in the longer term., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tick-borne encephalitis virus (TBEV) has only recently been detected in the Netherlands. With still few autochthonous tick-borne encephalitis (TBE) patients, human exposure to TBEV is expected to be very low among the general population. We aimed to assess the exposure to TBEV among persons with an occupationally high risk of tick bites in the Netherlands. In our cross-sectional serological survey, employees and volunteers of nature management organizations provided a single blood sample and completed an online questionnaire in 2017. The sera were screened in the anti-TBEV IgG Enzyme-Linked Immunosorbent Assay (ELISA), after which a TBEV-specific virus neutralization test (VNT) was applied to confirm positive ELISA outcomes. Ten sera tested positive for IgG antibodies in the TBEV ELISA, among 556 participants who did not report vaccination against TBEV. Through confirmation in VNT, TBEV-specific IgG antibodies were detected among 0.5% (3/556, 95%CI 0.1%-1.6%). During the five years prior to the questionnaire, 87% reported tick bites. Half of the participants considered that most of their tick bites (75% to 100%) had been acquired while being at work. A very low seroprevalence of TBEV exposure was observed among these nature management workers, even though they report a six times higher exposure to tick bites, compared to our general population. Nonetheless, the emergence of TBEV in the Netherlands reaffirms the need for education and preventative measures against tick bites and tick-borne diseases., (Copyright © 2021. Published by Elsevier GmbH.)

Background: Tick-borne pathogens other than Borrelia burgdorferi sensu lato - the causative agent of Lyme borreliosis - are common in Ixodes ricinus ticks. How often these pathogens cause human disease is unknown. In addition, diagnostic tools to identify such diseases are lacking or reserved to research laboratories. To elucidate their prevalence and disease burden, the study 'Ticking on Pandora's Box' has been initiated, a collaborative effort between Amsterdam University Medical Center and the National Institute for Public Health and the Environment., Methods: The study investigates how often the tick-borne pathogens Anaplasma phagocytophilum, Babesia species, Borrelia miyamotoi, Neoehrlichia mikurensis, spotted fever group Rickettsia species and/or tick-borne encephalitis virus cause an acute febrile illness after tick-bite. We aim to determine the impact and severity of these tick-borne diseases in the Netherlands by measuring their prevalence and describing their clinical picture and course of disease. The study is designed as a prospective case-control study. We aim to include 150 cases - individuals clinically suspected of a tick-borne disease - and 3 matched healthy control groups of 200 persons each. The controls consist respectively of a group of individuals with either a tick-bite without complaints, the general population and of healthy blood donors. During a one-year follow-up we will acquire blood, urine and skin biopsy samples and ticks at baseline, 4 and 12 weeks. Additionally, participants answer modified versions of validated questionnaires to assess self-reported symptoms, among which the SF-36, on a 3 monthly basis., Discussion: This article describes the background and design of the study protocol of 'Ticking on Pandora's Box'. With our study we hope to provide insight into the prevalence, clinical presentation and disease burden of the tick-borne diseases anaplasmosis, babesiosis, B. miyamotoi disease, neoehrlichiosis, rickettsiosis and tick-borne encephalitis and to assist in test development as well as provide recommendations for national guidelines., Trial Registration: NL9258 (retrospectively registered at Netherlands Trial Register, trialregister.nl in in February 2021).

Background: Concerns about long-lasting symptoms attributed to Lyme borreliosis (LB) are widespread in the Western world, while such symptoms are highly prevalent in the general population., Methods: In the largest prospective study to date, adults with physician-confirmed LB were included at the start of antibiotic treatment. Primary outcomes, prevalence of persistent symptoms and symptom severity, were assessed using three-monthly standardised questionnaires during one year. Persistent symptoms were defined as impaired scores for fatigue (CIS, subscale fatigue), cognitive impairment (CFQ) or pain (SF-36, subscale bodily pain) ≥6 months, with onset <6 months. Outcomes were compared with a longitudinal general population and a tick-bite cohort without LB as a reference., Findings: Of 1135 LB patients (94•8% erythema migrans, 5•2% disseminated LB), 1084 fulfilled primary analysis criteria, as well as 1942 population and 1887 tick-bite controls. Overall prevalence of persistent symptoms in LB patients was 27•2% (95%CI, 24•7%-29•7%); 6•0% and 3•9% higher than in population (21•2%, 95%CI, 19•3%-23•1%; p < 0•0001) and tick-bite (23•3%, 95%CI 21•3%-25•3%; p  = 0•016) cohorts, respectively. At 12 months, fatigue, cognitive impairment, and pain were significantly more severe in erythema migrans patients than in reference cohorts, while in disseminated LB patients, only pain was more severe., Interpretation: In treated LB patients, persistent symptoms were significantly more prevalent and symptoms were more severe than in individuals without LB, although the background prevalence was substantial. This suggests an association, either direct or indirect, between persistent symptoms and LB in a relatively small subset of patients., Funding: ZonMw; Dutch Ministry of Health, Welfare and Sport., Competing Interests: All authors have completed the ICMJE uniform disclosure form and declare: JWH, LABJ, and CCvdW report grants from the Netherlands Organization for Health Research and Development (ZonMw), and the Dutch Ministry of Health, Welfare and Sport (VWS); LABJ has a patent on Lyme diagnosis issued; JWH was supported by the European Union's regional development fund (INTERREG) as part of the NorthTick project; all other authors have no conflicts to declare., (© 2021 The Authors.)

During the first wave of the severe acute respiratory syndrome-coronavirus-2 epidemic in the Netherlands, notifications consisted mostly of patients with relatively severe disease. To enable real-time monitoring of the incidence of mild coronavirus disease 2019 (COVID-19) - for which medical consultation might not be required - the Infectieradar web-based syndromic surveillance system was launched in mid-March 2020. Our aim was to quantify associations between Infectieradar participant characteristics and the incidence of self-reported COVID-19-like illness. Recruitment for this cohort study was via a web announcement. After registering, participants completed weekly questionnaires, reporting the occurrence of a set of symptoms. The incidence rate of COVID-19-like illness was estimated and multivariable Poisson regression used to estimate the relative risks associated with sociodemographic variables, lifestyle factors and pre-existing medical conditions. Between 17 March and 24 May 2020, 25 663 active participants were identified, who reported 7060 episodes of COVID-19-like illness over 131 404 person-weeks of follow-up. The incidence rate declined over the analysis period, consistent with the decline in notified cases. Male sex, age 65+ years and higher education were associated with a significantly lower COVID-19-like illness incidence rate (adjusted rate ratios (RRs) of 0.80 (95% CI 0.76-0.84), 0.77 (0.70-0.85), 0.84 (0.80-0.88), respectively) and the baseline characteristics ever-smoker, asthma, allergies, diabetes, chronic lung disease, cardiovascular disease and children in the household were associated with a higher incidence (RRs of 1.11 (1.04-1.19) to 1.69 (1.50-1.90)). Web-based syndromic surveillance has proven useful for monitoring the temporal trends in, and risk factors associated with, the incidence of mild disease. Increased relative risks observed for several patient factors could reflect a combination of exposure risk, susceptibility to infection and propensity to report symptoms.

Objectives: A single dose of doxycycline after a tick bite can prevent the development of Lyme borreliosis in North America, but extrapolation to Europe is hampered by differences in Borrelia burgdorferi sensu lato genospecies and tick species. We assessed the efficacy of prophylaxis after a tick bite in Europe., Methods: We conducted an open-label randomized controlled trial, administering a single dose of 200 mg doxycycline within 72 h after removing an attached tick from the skin, compared to no treatment. Potential participants ≥ 8 years of age who reported a recent tick bite online were invited for the study. After informed consent, they were randomly assigned to either the prophylaxis or the no-treatment group. Participants in the prophylaxis group were asked to visit their general practitioner to administer the antibiotics. All participants were followed up by online questionnaires. Our primary outcome was the development of physician-confirmed Lyme borreliosis in a modified-intention-to-treat analysis. This study is registered in the Netherlands Trial Register (NTR3953) and is closed., Results: Between April 11, 2013, and June 10, 2015, 3538 potential participants were randomized, of whom 1689 were included in the modified-intention-to-treat analysis. 10 cases of Lyme borreliosis were reported out of 1041 participants (0.96%) in the prophylaxis group, and 19 cases out of 648 no-treatment participants (2.9%), resulting in a relative risk reduction of 67% (95% CI 31 - 84%), and a number-needed-to-treat of 51 (95% CI 29 - 180). No serious adverse events were reported., Conclusions: This primary care-based trial provides evidence that a single dose of doxycycline can prevent the development of Lyme borreliosis after an Ixodes ricinus tick bite., Competing Interests: Declaration of Competing Interest We declare no competing interests., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: Lyme borreliosis (LB) is a tick-borne disease caused by spirochetes belonging to the Borrelia burgdorferi sensu lato species. Due to a variety of clinical manifestations, diagnosing LB can be challenging, and laboratory work-up is usually required in case of disseminated LB. However, the current standard of diagnostics is serology, which comes with several shortcomings. Antibody formation may be absent in the early phase of the disease, and once IgG-seroconversion has occurred, it can be difficult to distinguish between a past (cured or self-cleared) LB and an active infection. It has been postulated that novel cellular tests for LB may have both higher sensitivity earlier in the course of the disease, and may be able to discriminate between a past and active infection., Methods: VICTORY is a prospective two-gate case-control study. We strive to include 150 patients who meet the European case definitions for either localized or disseminated LB. In addition, we aim to include 225 healthy controls without current LB and 60 controls with potentially cross-reactive conditions. We will perform four different cellular tests in all of these participants, which will allow us to determine sensitivity and specificity. In LB patients, we will repeat cellular tests at 6 weeks and 12 weeks after start of antibiotic treatment to assess the usefulness as 'test-of-cure'. Furthermore, we will investigate the performance of the different cellular tests in a cohort of patients with persistent symptoms attributed to LB., Discussion: This article describes the background and design of the VICTORY study protocol. The findings of our study will help to better appreciate the utility of cellular tests in the diagnosis of Lyme borreliosis., Trial Registration: NL7732 (Netherlands Trial Register, trialregister.nl).

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.

Background: Understanding and quantification of the risk of Lyme borreliosis after a tick bite can aid development of prevention strategies against Lyme borreliosis., Methods: We used 3,525 single tick bite reports from three large prospective studies on the transmission risk of tick-borne pathogens to humans, with 50 reports of Lyme borreliosis during the follow-up period, among 1,973 reports with known outcome. A structural equation model was applied to estimate the risk of Lyme borreliosis after a tick bite, and quantify the influence of: developmental stage of the tick, detection of Borrelia burgdorferi s.l. DNA in the tick by PCR, tick engorgement, patient-estimated duration of tick attachment, and patient age., Results: The overall risk of developing Lyme borreliosis after a tick bite was 2.6% (95%CI 1.4-5.1). The risk increased with: - Tick engorgement: 1.4% (95%CI 0.7%-2.3%) for low engorgement to 5.5% (95%CI 2.8%-9.2%) for substantially engorged ticks;- Rising patient-estimated tick attachment duration: 2.0% (95%CI 1.3%-2.8%) after <12 hours, to 5.2% (95%CI 3.0%-8.9%) after ≥4 days;- Detection of Borrelia burgdorferi s.l. DNA in ticks: 6.7% (95%CI 3.6%-13.5%), versus 1.4% (95%CI 0.7%-2.9%) when ticks tested negative.The highest observed risk of Lyme borreliosis was 14.4% (95%CI 6.8%-24.6%) after one tick bite of a substantially engorged tick that tested positive for Borrelia burgdorferi s.l. DNA, which corresponds to one new case of Lyme borreliosis per 7 (95%CI 4-15) of such tick bites., Conclusions: An individual's risk of Lyme borreliosis after a tick bite can be predicted with tick engorgement, patient-estimated duration of tick attachment, and detection of Borrelia burgdorferi s.l. DNA in the tick.

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., (This article is copyright of The Authors, 2017.)

Background: Lyme borreliosis (LB) is the most frequently reported tick-borne infection in Europe and North America. The aim of this study was to estimate the cost-of-illness of LB in the Netherlands. We used available incidence estimates from 2010 for tick bite consultations and three symptomatic LB outcomes: erythema migrans (EM), disseminated LB and Lyme-related persisting symptoms. The cost was estimated using these incidences and the average cost per patient as derived from a patient questionnaire. We estimated the cost from a societal perspective, including healthcare cost, patient cost and production loss, using the friction cost method and a 4% annual discount rate. Tick bites and LB in 2010 led to a societal cost of €19.3 million (95% CI 15.6-23.4; 16.6 million population) for the Netherlands. Healthcare cost and production loss each constituted 48% of the total cost (€9.3 and €9.2 million/year), and patient cost 4% (€0.8 million/year). Of the total cost, 37% was related to disseminated LB, followed by 27% for persisting symptoms, 22% for tick bites and 14% for EM. Per outcome, for an individual case the mean cost of disseminated LB and Lyme-related persisting symptoms was both around €5700; for EM and GP consultations for tick bites this was €122 and €53. As an alternative to the friction cost method, the human capital method resulted in a total cost of €23.5 million/year. LB leads to a substantial societal cost. Further research should therefore focus on additional preventive interventions., (© The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Insights into transmission dynamics of enteropathogens in children attending daycare are limited. Here we aimed at identifying daycare centre (DCC) characteristics associated with time-clustered occurrence of enteropathogens in DCC-attending children. For this purpose, we used the KIzSS network, which comprises 43 DCCs that participated in infectious disease surveillance in The Netherlands during February 2010-February 2013. Space-time scan statistics were used to identify clusters of rotavirus, norovirus, astrovirus, Giardia lamblia and Cryptosporidium spp. in a two-dimensional DCC characteristic space constructed using canonical correlation analysis. Logistic regression models were then used to further identify DCC characteristics associated with increased or decreased odds for clustering of enteropathogens. Factors associated with increased odds for enteropathogen clustering in DCCs were having indoor/outdoor paddling pools or sandpits, owning animals, high numbers of attending children, and reporting outbreaks to local health authorities. Factors associated with decreased odds for enteropathogen clustering in DCCs were cleaning child potties in designated waste disposal stations, cleaning vomit with chlorine-based products, daily cleaning of toys, extra cleaning of toys during a suspected outbreak, and excluding children with gastroenteritis. These factors provide targets for reducing the burden of gastrointestinal morbidity associated with time-clustered occurrence of major enteropathogens in DCC attendees.

Background: Nationwide surveys have shown a threefold increase in general practitioner (GP) consultations for tick bites and early Lyme borreliosis from 1994 to 2009 in the Netherlands. We now report an update on 2014, with identical methods as for the preceding GP surveys., Methods: To all GPs in the Netherlands, a postal questionnaire was sent inquiring about the number of consultations for tick bites and erythema migrans diagnoses (most common manifestation of early Lyme borreliosis) in 2014, and the size of their practice populations., Results: Contrasting to the previously rising incidence of consultations for tick bites between 1994 and 2009, the incidence decreased in 2014 to 488 consultations for tick bites per 100,000 inhabitants, i.e., 82,000 patients nationwide. This survey revealed a first sign of stabilization of the previously rising trend in GP diagnosed erythema migrans, with 140 diagnoses per 100,000 inhabitants of the Netherlands. This equals about 23,500 annual diagnoses of erythema migrans nationwide in 2014., Conclusions: In contrast to the constantly rising incidence of GP consultations for tick bites and erythema migrans diagnoses in the Netherlands between 1994 and 2009, the current survey of 2014 showed a first sign of stabilization of erythema migrans diagnoses and a decreased incidence for tick bite consultations.

Background: Lyme borreliosis (LB) is the most commonly reported tick-borne infection in Europe and North America. In the last 15 years a 3-fold increase was observed in general practitioner consultations for LB in the Netherlands. To support prioritization of prevention and control efforts for LB, we estimated its burden expressed in Disability-Adjusted Life Years (DALYs)., Methods: We used available incidence estimates for three LB outcomes: (i) erythema migrans (EM), (ii) disseminated LB and (iii) Lyme-related persisting symptoms. To generate DALYs, disability weights and duration per outcome were derived using a patient questionnaire including health-related quality of life as measured by the EQ-5D., Results: We estimated the total LB burden for the Netherlands in 2010 at 10.55 DALYs per 100,000 population (95% CI: 8.80-12.43); i.e. 0.60 DALYs for EM, 0.86 DALYs for disseminated LB and 9.09 DALYs for Lyme-related persisting symptoms. Per patient this was 0.005 DALYs for EM, 0.113 for disseminated LB and 1.661 DALYs for a patient with Lyme-related persisting symptoms. In a sensitivity analysis the total LB burden ranged from 7.58 to 16.93 DALYs per 100,000 population., Conclusions: LB causes a substantial disease burden in the Netherlands. The vast majority of this burden is caused by patients with Lyme-related persisting symptoms. EM and disseminated Lyme have a more modest impact. Further research should focus on the mechanisms that trigger development of these persisting symptoms that patients and their physicians attribute to LB., (© The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Lyme borreliosis is the most common vector-borne disease in Europe and North America. The objective of this study is to estimate the incidence of tick bites and Lyme borreliosis, representative of our entire country, including erythema migrans, disseminated Lyme borreliosis and persisting symptoms attributed to Lyme borreliosis., Methods: A questionnaire on clinical diagnoses of Lyme borreliosis was sent to all GPs, company physicians, and medical specialists. To adjust for possible misclassification and telescoping bias, we sent additional questionnaires to categorize reported cases according to likelihood of the diagnosis and to exclude cases diagnosed outside the target period., Results: Adjusted annual incidence rate for disseminated Lyme borreliosis was 7.7 GP reports per 100,000 inhabitants, and for persisting symptoms attributed to Lyme borreliosis was 5.5 GP reports per 100,000 inhabitants, i.e. approximately 1,300 and 900 cases respectively. GP consultations for tick bites and erythema migrans diagnoses were 495 and 132 per 100,000 inhabitants, respectively, i.e. 82,000 and 22,000 cases in 2010., Conclusions: This is the first reported nationwide physician survey on the incidence of tick bites and the whole range of manifestations of Lyme borreliosis, including persisting symptoms attributed to Lyme borreliosis. This is crucial for complete assessment of the public health impact of Lyme borreliosis.

Objectives: Severe influenza can lead to Intensive Care Unit (ICU) admission. We explored whether ICU data reflect influenza like illness (ILI) activity in the general population, and whether ICU respiratory infections can predict influenza epidemics., Methods: We calculated the time lag and correlation between ILI incidence (from ILI sentinel surveillance, based on general practitioners (GP) consultations) and percentages of ICU admissions with a respiratory infection (from the Dutch National Intensive Care Registry) over the years 2003-2011. In addition, ICU data of the first three years was used to build three regression models to predict the start and end of influenza epidemics in the years thereafter, one to three weeks ahead. The predicted start and end of influenza epidemics were compared with observed start and end of such epidemics according to the incidence of ILI., Results: Peaks in respiratory ICU admissions lasted longer than peaks in ILI incidence rates. Increases in ICU admissions occurred on average two days earlier compared to ILI. Predicting influenza epidemics one, two, or three weeks ahead yielded positive predictive values ranging from 0.52 to 0.78, and sensitivities from 0.34 to 0.51., Conclusions: ICU data was associated with ILI activity, with increases in ICU data often occurring earlier and for a longer time period. However, in the Netherlands, predicting influenza epidemics in the general population using ICU data was imprecise, with low positive predictive values and sensitivities.

Background: A commercially available self-test for the detection of Borrelia burgdorferi sensu lato in ticks was evaluated for its ability to predict erythema migrans formation., Findings: The self-test was performed on 127 Ixodes ricinus from 122 humans that reported tick bites at enrolment and occurrence of symptoms during follow-up. The self-test gave negative results on all the 122 individuals, 14 of whom reported erythema migrans (EM) at follow-up of which 10 were confirmed by their GP. The estimated sensitivity of the self-test for prediction of EM formation is 0% (95% CI: 0%-28%)., Conclusions: This self-test is not suitable for reducing the number needed to treat in a post-exposure prophylaxis setting as it already missed all the obvious early Lyme borreliosis cases.

Background: The disease burden of the 2009 influenza pandemic has been debated but reliable estimates are lacking. To guide future policy and control, these estimates are necessary. This study uses burden of disease measurements to assess the contribution of the pandemic influenza A(H1N1) virus to the overall burden of disease in the Netherlands., Methods: The burden of disease caused by 2009 pandemic influenza was estimated by calculating Disability Adjusted Life Years (DALY), a composite measure that combines incidence, sequelae and mortality associated with a disease, taking duration and severity into account. Available influenza surveillance data sources (primary care sentinel surveillance, notification data on hospitalizations and deaths and death registries) were used. Besides a baseline scenario, five alternative scenarios were used to assess effects of changing values of input parameters., Results: The baseline scenario showed a loss of 5800 DALY for the Netherlands (35 DALY per 100 000 population). This corresponds to 0.13% of the estimated annual disease burden in the Netherlands and is comparable to the estimated disease burden of seasonal influenza, despite a different age distribution in incidence and mortality of the pandemic compared to seasonal influenza., Conclusions: This disease burden estimate confirmed that, although there was a higher mortality observed among young people, the 2009 pandemic was overall a mild influenza epidemic. The disease burden of this pandemic was comparable to the burden of seasonal influenza in the Netherlands.

In the last decade, syndromic surveillance has increasingly been used worldwide for detecting increases or outbreaks of infectious diseases that might be missed by surveillance based on laboratory diagnoses and notifications by clinicians alone. There is, however, an ongoing debate about the feasibility of syndromic surveillance and its potential added value. Here we present our perspective on syndromic surveillance, based on the results of a retrospective analysis of syndromic data from six Dutch healthcare registries, covering 1999–2009 or part of this period. These registries had been designed for other purposes, but were evaluated for their potential use in signalling infectious disease dynamics and outbreaks. Our results show that syndromic surveillance clearly has added value in revealing the blind spots of traditional surveillance, in particular by detecting unusual, local outbreaks independently of diagnoses of specific pathogens, and by monitoring disease burden and virulence shifts of common pathogens. Therefore we recommend the use of syndromic surveillance for these applications.

Large Q-fever outbreaks were reported in The Netherlands from May 2007 to 2009, with dairy-goat farms as the putative source. Since Q-fever outbreaks at such farms were first reported in 2005, we explored whether there was evidence of human outbreaks before May 2007. Space-time scan statistics were used to look for clusters of lower-respiratory infections (LRIs), hepatitis, and/or endocarditis in hospitalizations, 2005-2007. We assessed whether these were plausibly caused by Q fever, using patients' age, discharge diagnoses, indications for other causes, and overlap with reported Q fever in goats/humans. For seven detected LRI clusters and one hepatitis cluster, we considered Q fever a plausible cause. One of these clusters reflected the recognized May 2007 outbreak. Real-time syndromic surveillance would have detected four of the other clusters in 2007, one in 2006 and two in 2005, which might have resulted in detection of Q-fever outbreaks up to 2 years earlier.

Objectives: We explored whether excesses in influenza severity can be detected by combining respiratory syndromic hospital and mortality data with data on influenza-like illness (ILI) cases obtained from general practitioners., Methods: To identify excesses in the severity of influenza infections in the population of the Netherlands between 1999 and 2005, we looked for increases in influenza-associated hospitalizations and mortality that were disproportionate to the number of ILI cases reported by general practitioners. We used generalized estimating equation regression models to associate syndromic hospital and mortality data with ILI surveillance data obtained from general practitioners. Virus isolation and antigenic characterization data were used to interpret the results., Results: Disproportionate increases in hospitalizations and mortality (relative to ILI cases reported by general practitioners) were identified in 2003/04 during the A/Fujian/411/02(H3N2) drift variant epidemic., Conclusions: Combined surveillance of respiratory hospitalizations and mortality and ILI data obtained from general practitioners can capture increases in severe influenza-associated illness that are disproportionate to influenza incidence rates. Therefore, this novel approach should complement traditional seasonal and pandemic influenza surveillance in efforts to detect increases in influenza case fatality rates and percentages of patients hospitalized.

Background: Although syndromic surveillance is increasingly used to detect unusual illness, there is a debate whether it is useful for detecting local outbreaks. We evaluated whether syndromic surveillance detects local outbreaks of lower-respiratory infections (LRIs) without swamping true signals by false alarms., Methods and Findings: Using retrospective hospitalization data, we simulated prospective surveillance for LRI-elevations. Between 1999-2006, a total of 290762 LRIs were included by date of hospitalization and patients place of residence (>80% coverage, 16 million population). Two large outbreaks of Legionnaires disease in the Netherlands were used as positive controls to test whether these outbreaks could have been detected as local LRI elevations. We used a space-time permutation scan statistic to detect LRI clusters. We evaluated how many LRI-clusters were detected in 1999-2006 and assessed likely causes for the cluster-signals by looking for significantly higher proportions of specific hospital discharge diagnoses (e.g. Legionnaires disease) and overlap with regional influenza elevations. We also evaluated whether the number of space-time signals can be reduced by restricting the scan statistic in space or time. In 1999-2006 the scan-statistic detected 35 local LRI clusters, representing on average 5 clusters per year. The known Legionnaires' disease outbreaks in 1999 and 2006 were detected as LRI-clusters, since cluster-signals were generated with an increased proportion of Legionnaires disease patients (p:<0.0001). 21 other clusters coincided with local influenza and/or respiratory syncytial virus activity, and 1 cluster appeared to be a data artifact. For 11 clusters no likely cause was defined, some possibly representing as yet undetected LRI-outbreaks. With restrictions on time and spatial windows the scan statistic still detected the Legionnaires' disease outbreaks, without loss of timeliness and with less signals generated in time (up to 42% decline)., Conclusions: To our knowledge this is the first study that systematically evaluates the performance of space-time syndromic surveillance with nationwide high coverage data over a longer period. The results show that syndromic surveillance can detect local LRI-outbreaks in a timely manner, independent of laboratory-based outbreak detection. Furthermore, since comparatively few new clusters per year were observed that would prompt investigation, syndromic hospital-surveillance could be a valuable tool for detection of local LRI-outbreaks.

We analysed and reported on a weekly basis clinical and epidemiological characteristics of patients hospitalised in the Netherlands for the 2009 pandemic influenza A(H1N1) using information from the national mandatory notification system. The notification criteria changed on 15 August 2009 from all possible, probable and confirmed cases to only laboratory-confirmed pandemic influenza hospitalisations and deaths. In the period of comprehensive case-based surveillance (until 15 August), 2% (35/1,622) of the patients with pandemic influenza were hospitalised. From 5 June to 31 December 2009, a total of 2,181 patients were hospitalised. Of these, 10% (219/2,181) were admitted to an intensive care unit (ICU) and 53 died. Among non-ICU hospitalised patients, 56% (961/1,722) had an underlying medical condition compared with 70% (147/211) of the patients in ICU and 46 of the 51 fatal cases for whom this information was reported. Most common complications were dehydration among non-ICU hospitalised patients and acute respiratory distress syndrome among patients in ICU and patients who died. Children under the age of five years had the highest age-specific hospitalisation rate (62.7/100,000), but relatively few were admitted to an ICU (1.7/100,000). Characteristics and admission rates of hospitalised patients were comparable with reports from other countries and previous influenza seasons. The national notification system was well suited to provide weekly updates of relevant monitoring information on the severity of the pandemic for professionals, decision makers, the media and the public, and could be rapidly adapted to changing information requirements.

Background: Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe., Methods and Findings: In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel., Conclusions: In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.

Aim: To evaluate to what extent antiviral drugs have been prescribed to patients other than confirmed cases and their contacts since the emergence of New Influenza A (H1N1)., Design: Descriptive., Methods: We inspected monthly and annual counts of oseltamivir (Tamiflu) and zanamivir (Relenza) prescriptions dispensed by public pharmacies in the Netherlands from 2005 until 30 June 2009. We compared these figures with counts of antiviral cures supplied by the Netherlands Vaccine Institute (NVI) to Municipal Health Services (GGDs) for the treatment of confirmed cases and contacts up until 1 July 2009., Results: Counts of oseltamivir prescriptions dispensed by public pharmacies started to increase in April 2009. Although this increase might seem limited compared to increases in 2005/2006 triggered by avian influenza in Turkey, up to 1 July 2009 oseltamivir was dispensed 9069 times, which is 9 times more often than in 2007 and 15 times more often than in 2008. This total was also approximately 10 times more than that dispensed by Municipal Health Services to confirmed cases of H1N1 infection and their contacts. General practitioners prescribed 78% of the prescriptions dispensed. Counts of zanamivir prescriptions dispensed hardly increased., Conclusion: The counts of oseltamivir prescriptions dispensed by Dutch public pharmacies has increased, even though patients with a confirmed H1N1 infection and their contacts had already been treated by the Municipal Health Services. Therefore it cannot be excluded that this increase is due to prescription on a precautionary basis. To avoid unnecessary risks for the spread of resistant strains and a shortage of antivirals later in the epidemic, physicians should refrain from prescribing antiviral drugs if patients do not match the nationally advised medical grounds for treatment.

Syndromic surveillance has been developed in order to detect outbreaks of unusual infectious diseases such as severe acute respiratory syndrome (SARS) or anthrax at an early stage. Whereas the usual surveillance systems are based on established diagnoses and emergency department discharge data, syndromic surveillance uses preliminary outcomes and derived data such as absenteeism, prescription medication and requests for laboratory tests. Investigations abroad have indicated the potential ofsyndromic surveillance. In the Netherlands, the National Institute of Public Health and Environment (RIVM) is examining the feasibility of implementing syndromic surveillance.