Persistent Symptoms After Lyme Disease: Clinical Characteristics, Predictors, and Classification.

Persistent symptoms after an infection have been described for a number of infectious diseases, including Lyme disease. Studies have confirmed a moderate but consistent increase in the prevalence of such symptoms after Lyme disease, though the risk increase varies dependent on study design and the definition of persistent symptoms. Various possible predictors have been proposed, including a dysregulation of the immune system, metabolic changes, increased sensitization to pain signals, cognitive-behavioral factors, or-controversially-the persistence of the causative Borrelia bacteria or remnants thereof. Research on the precise roles of any of these factors is still ongoing. The lack of biological underpinning also makes it difficult to assess with certainty which patients' (generally nonspecific) persistent symptoms are etiologically related to the previous Lyme disease episode and which are not, particularly as these symptoms occur in the general population relatively frequently. The diagnostic criteria for posttreatment Lyme disease syndrome have shown their usefulness in both clinical and research settings but leave out a number of patients whose symptoms may fall just outside said criteria. Though the relationship between these symptoms and the previous Lyme disease episode may be very uncertain, we would argue that a uniform description and classification of these patients will aid in future research and patient management, regardless of the eventual underlying cause. Thus, we argue for an inclusive classification system for all persistent symptoms attributed to Lyme disease in order to promote validation of patient experiences and perspectives, while also maintaining scientific nuance regarding the very uncertain etiology of these patients' symptoms.

Evaluation and 1-year follow-up of patients presenting at a Lyme borreliosis expertise centre: a prospective cohort study with validated questionnaires.

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.

Determinants of persistent symptoms after treatment for Lyme borreliosis: a prospective observational cohort study.

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).

Digital disparities among healthcare workers in typing speed between generations, genders, and medical specialties: cross sectional study.

OBJECTIVE: To investigate the typing skills of healthcare professionals. DESIGN: Cross sectional study. SETTING: Two large tertiary medical centres in Amsterdam, the Netherlands. PARTICIPANTS: 2690 hospital employees working in patient care, research, or medical education. MAIN OUTCOME MEASURES: Participants completed a custom built, web based, Santa themed, typing test in 60 seconds and filled out an associated questionnaire. The primary outcome was corrected typing speed, defined as crude typing speed (words per minute) multiplied by accuracy (correct characters as a percentage of total characters in the final transcribed text). Feelings towards administrative tasks scored on the Visual Analogue Scale to Weigh Respondents' Internalised Typing Enjoyment (VAS-WRITE), in which 0 represents the most negative and 100 the most positive feelings towards administration, were also recorded. RESULTS: Between 18 and 21 May 2021, a representative cohort of 2690 study participants was recruited (1942 (72.2%) were younger than 40 years; 2065 (76.8%) were women). Respondents' mean typing speed was 60.1 corrected words per minute (standard deviation 20.8; range 8.0-136.6) with substantial differences between professions and specialties, in which physicians in internal medicine were the fastest among the medical professionals. Typing speed decreased significantly with every age decade (rho -0.51, P<0.001), and people with a history of completing a typing course were more than 20% faster than those who had not (mean difference 12.1 words (standard error 0.8), (95% confidence interval 10.6 to 13.6), P<0.001). The corrected typing speed did not differ between genders (0.5 (0.9) words, (-1.4 to 2.4), P=0.61). Women were less negative towards administration than were men (mean difference VAS-WRITE score 7.68 (standard error 1.17), (95% confidence interval 5.33 to 10.03), P<0.001). Of all professional groups, medical staff reported the most negative feelings towards administration (mean VAS-WRITE score of 33.5 (standard deviation 22.9)). CONCLUSIONS: Important differences were reported in typing proficiency between age groups, professions, and medical specialties. Specific groups are at a disadvantage in an increasingly digitalised healthcare system, and these data could inform the implementation of training modules and alternative methods of data entry to level the playing field.

Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production.

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.

Knowing the entire story - a focus group study on patient experiences with chronic Lyme-associated symptoms (chronic Lyme disease).

BACKGROUND: Healthcare providers frequently struggle to provide effective care to patients with chronic Lyme-associated symptoms (chronic Lyme disease, CLD), potentially causing these patients to feel misunderstood or neglected by the healthcare system. This study is the first to use a combined medical and communication science approach, and aims to assess patients' experiences with CLD & CLD-related care, identify themes and repertories in these patients' narrations, and provide potential ways to improve communication with them. METHODS: Informed by the principles of 'clean language', we conducted focus groups with self-identified CLD patients (N = 15). We asked participants about their experiences with CLD and CLD-related healthcare. We performed thematic analyses using a bottom-up approach based in discourse analysis. We also sought to identify specific types of verbalizations (repertoires) across themes. RESULTS: Participants thematised a heterogeneous set of CLD-associated symptoms, which they frequently labelled as 'invisible' to others. Their illness significantly affected their daily lives, impacting their work, social activities, relationships with loved ones, hobbies and other means of participating in society. Negative experiences with healthcare providers were near-universal, also in patients with short-lived CLD-associated symptoms. Verbalizations were notable for frequent use of communicative modes that implicitly create common ground between participants and that give a certain validity to personal experiences (impersonal 'you' and other forms of presupposition). CONCLUSION: Central themes found in CLD patients' communication are 1. the experience of significant symptoms, 2. for which adequate relief is only rarely found from conventional medical practitioners, and 3. that are largely invisible to the outside world. Verbalizing these themes, patients use various repertoires for their shared experiences, such as a feeling of abandonment or not being heard by the medical system, feelings of loss with respect to their previous health, and the idea that they might have been better off had they been diagnosed sooner. Working with these repertoires will enable healthcare providers to establish a shared perspective with their CLD patients, thus engaging in more fruitful doctor-patient communication. We hypothesize that these findings are not unique to CLD, but may also be applicable to other conditions with an uncertain aetiology, such as Long COVID.

Diagnostic parameters of cellular tests for Lyme borreliosis in Europe (VICTORY study): a case-control study.

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.

Diagnostic performance of the ZEUS Borrelia VlsE1/pepC10 assay in European LB patients: a case-control study.

This retrospective case-control study assesses the sensitivity, specificity, and area under the curve of the ZEUS Borrelia VlsE1/pepC10 assay in comparison with the C6-ELISA in European patients with Lyme borreliosis, healthy blood donors, and potentially cross-reactive controls. We included a convenience series of 161 sera from patients with physician-confirmed early localized or disseminated Lyme borreliosis (n = 143), 400 sera from healthy blood donors and 44 sera with potentially cross-reactive antibodies, on which we performed the aforementioned serological assays and the recomLine immunoblot. Diagnostic parameters were compared in various single-tier and two-tier algorithms. The specificities of the C6-ELISA and the ZEUS Borrelia VlsE1/pepC10 were comparable in healthy blood donors (e.g., single-tier permissive: C6: 362/400, 90.5% [87.2-93.2]; VlsE1/pepC10: 361/400, 90.3% [86.9-93.0]). The C6-ELISA had an apparently higher sensitivity in EM sera (e.g., both time points combined: C6: 61/76, 80.3% [69.5-88.5]; VlsE1/pepC10: 54/76, 71.1% [59.5-80.9]), but these differences were all not-significant. Interestingly, the VlsE1/pepC10 assay had a significantly higher specificity in sera with potentially cross-reactive antibodies (e.g., single-tier permissive: C6: 34/44, 77.3% [62.2-88.5]; VlsE1/pepC10: 40/44, 90.9% [78.3-97.5]; p = 0.031). While the areas under the curve for both assays were excellent, that of the C6-ELISA exceeded that of the VlsE1/pepC10 (C6: AUC = 0.925; VlsE1/pepC10: AUC = 0.878; p = 0.003). The novel ZEUS Borrelia VlsE1/pepC10 assay has generally comparable diagnostic parameters to the C6-ELISA with potentially improved specificity in cross-reactive sera. Thus, it is a useful tool for the serodiagnosis of Lyme borreliosis in Europe.

Diagnostic Performance of the Novel BioPlex Lyme Serological Assays in European Patients with Lyme Disease.

Serodiagnosis of Lyme borreliosis (LB) comes with several drawbacks, among which is limited sensitivity in early disease. This study assesses the sensitivity and specificity of the novel BioPlex 2200 Lyme IgG and Lyme IgM assays. It also assesses potential improvements to the assays through receiver-operating characteristic (ROC) analysis. The BioPlex assays were performed on sera of 158 Dutch patients with physician-confirmed LB (both early localized and disseminated), 800 healthy blood donors from the Netherlands, and 90 cross-reactive controls. The BioPlex (Biopl) assays were compared with two commercial enzyme immunoassays (Euroimmun [Eur]/C6-ELISA) and one immunoblot (recomLine). The highest sensitivity in early LB was achieved with the BioPlex assays, which outperformed the Euroimmun and C6-ELISA (Biopl: 81/88, 92.1%; Eur: 64/88, 72.7%; C6: 72/88, 81.8%). Sensitivity of all assays was comparable in patients with disseminated LB. The BioPlex assays were outperformed in terms of specificity (all healthy blood donors, Biopl: 571/800, 71.4%; Eur: 711/800, 88.9%; C6: 727/800, 90.9%), but further analyses showed promising avenues following cutoff optimization. ROC analysis showed that 2/6 antigens of the combined BioPlex IgG and IgM assays had significantly higher areas under the curve (AUCs) than those of the other analyses. Potential modified versions of the assays based on these antigens largely outperformed the Euroimmun and C6-ELISA in EM patients (Biopl: 81/80, 92.1%) while maintaining a comparable or even higher specificity (Biopl: 714/800, 89.3%). The BioPlex 2200 Lyme IgG and Lyme IgM assays are promising tools for the serodiagnosis of early LB, with the potential to be used as a standalone test. Further research is necessary to validate the findings of this discovery cohort.

Diagnostic parameters of modified two-tier testing in European patients with early Lyme disease.

Modified two-tier testing (MTTT) for Lyme borreliosis (i.e. confirmation with an EIA instead of an immunoblot) has been shown to have improved sensitivity compared with standard two-tier testing (STTT) in samples from American patients, without losing specificity. The current study assesses the sensitivity and specificity of various algorithms of MTTT in European patients with erythema migrans (EM) as a model disease for early Lyme borreliosis, and in appropriate controls. Four different immunoassays were used in the first tier, followed by either an immunoblot or the C6-EIA, or were used as standalone single-tier test. These tests were performed on consecutively collected sera of 228 Dutch patients with physician-diagnosed EM in the setting of general practice, 231 controls from the general population, and 50 controls with potentially cross-reactive antibodies. All the variants of MTTT that were studied had significantly higher sensitivity compared with their equivalent STTT, while retaining comparable specificity. Within the MTTT algorithms, classifying equivocal results as positive yielded better diagnostic parameters than classifying equivocal results as negative. The best diagnostic parameters were found using the Enzygnost-2 assay in the first tier, followed by a C6-ELISA in the second tier (sensitivity 77.6%, 95% CI 71.7-82.9; specificity 96.1%, 95% CI 92.7-98.2). This algorithm performed significantly better than the equivalent STTT algorithm in terms of sensitivity (p < 0.001), while maintaining comparable specificity (population controls p = 0.617). Our results show that MTTT can be a useful tool for the serodiagnosis of European patients with early Lyme borreliosis.

[Second-degree atrioventricular block caused by Lyme disease]. / Tweedegraads atrioventriculair blok door lymeziekte.

BACKGROUND: Tick-borne diseases, including Lyme disease, are becoming increasingly common in Europe. Lyme disease has a wide variety of clinical manifestations, as a result of which physicians of diverse disciplines are coming into contact with such patients. CASE DESCRIPTION: A 58-year-old man was seen at the emergency room with a symptomatic Wenckebach-type second-degree atrioventricular (AV) block and periods of 2:1 AV block. Four weeks previously the patient had noticed a red skin lesion on his left lower leg. Under the working diagnosis of early disseminated Lyme disease with cardiac involvement, treatment with ceftriaxone was started. This diagnosis was supported by a positive Borrelia PCR and culture of a skin biopsy and positive Borreliaserology. The AV conduction disorders resolved completely after 2 weeks of treatment with antibiotics and it was not necessary to implant a pacemaker. CONCLUSION: A Borrelia infection is a reversible but rare cause of AV conduction disorders. In the event of sudden onset of symptoms or a severe or progressive AV conduction disorder, Lyme carditis should be considered, especially if the medical history or physical examination provides clues for Lyme disease.

Validation of cellular tests for Lyme borreliosis (VICTORY) study.

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).