Annexin A2 antibodies in post-treatment Lyme disease.

Background: Anti-annexin A2 (AA2) antibodies have been described in Lyme arthritis and erythema migrans, although they have not been described in post-treatment Lyme disease (PTLD). Objectives: Determine whether anti-AA2 antibodies are present among patients with PTLD and determine the clinical relevance of these antibodies. Design and methods: Anti-AA2 levels were tested serially in a longitudinal cohort of 44 patients with acute Lyme disease, 22 with a return to health (EM RTH), and 22 with PTLD. Anti-AA2 antibodies were also assessed in a cross-sectional group of 281 patients with PTLD. Results: Anti-AA2 antibodies were highest after antimicrobial therapy in both the EM RTH and PTLD cohorts. By 6 months, there was no difference between EM RTH and healthy controls. Anti-AA2 antibodies were higher in the cross-sectional PTLD group (79.69 versus 48.22 units, p < 0.0001), though with no difference in total symptom burden. Conclusion: Anti-AA2 persists in PTLD, though did not identify a clinical phenotype.

Autoantibodies in post-treatment Lyme disease and association with clinical symptoms.

OBJECTIVES: Autoantibodies have been described in the post-infectious state, specifically after Lyme disease and COVID-19. We aimed to describe the prevalence and potential clinical utility of several commercially available autoantibodies after these infections. METHODS: Euroimmun panels (myositis, scleroderma and ANA5) were assayed using sera from patients with Lyme disease with return to health (RTH) (n=70), post-treatment Lyme disease (n=58), COVID-19 RTH (n=47) and post-acute symptoms of COVID-19 (n=22). The post-Lyme questionnaire of symptoms (PLQS) was used to determine symptom burden after Lyme disease. RESULTS: There was no statistically significant difference in autoantibody prevalence across the four groups (p=0.746). A total of 21 different antibodies were found in the Lyme cohorts and 8 different antibodies in the COVID-19 cohorts. The prevalence of scleroderma-associated antibodies was higher after Lyme disease than COVID-19 (12.5% vs. 2.9%, p=0.026). There was no statistically significant difference in symptom burden based on antibody status. CONCLUSIONS: Several autoantibodies were found after Borrelia burgdorferi and SARS-CoV2 infection, although the prevalence was similar in those with persistent symptoms and those who returned to health. While our data show no difference in autoantibody prevalence across the four post-infectious states, we do not imply that autoantibodies are irrelevant in this setting. Rather, this study highlights the need for novel antibody discovery in larger cohorts of well-defined patient populations.

Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?

Dysautonomia, or dysfunction of the autonomic nervous system (ANS), may occur following an infectious insult and can result in a variety of debilitating, widespread, and often poorly recognized symptoms. Dysautonomia is now widely accepted as a complication of COVID-19 and is an important component of Post-Acute Sequelae of COVID-19 (PASC or long COVID). PASC shares many overlapping clinical features with other infection-associated chronic illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS), suggesting that they may share common underlying mechanisms including autonomic dysfunction. Despite the recognition of this complication of Lyme disease in the care of patients with PTLD, there has been a scarcity of research in this field and dysautonomia has not yet been established as a complication of Lyme disease in the medical literature. In this review, we discuss the evidence implicating Borrelia burgdorferi as a cause of dysautonomia and the related symptoms, propose potential pathogenic mechanisms given our knowledge of Lyme disease and mechanisms of PASC and ME/CFS, and discuss the diagnostic evaluation and treatments of dysautonomia. We also outline gaps in the literature and priorities for future research.

Time to Diagnosis and Treatment of Lyme Disease by Patient Race.

This cross-sectional study compares stages at which Lyme disease was diagnosed by race in a specialty clinic in the US.

Validation of Claims-Based Algorithm for Lyme Disease, Massachusetts, USA.

Compared with notifiable disease surveillance, claims-based algorithms estimate higher Lyme disease incidence, but their accuracy is unknown. We applied a previously developed Lyme disease algorithm (diagnosis code plus antimicrobial drug prescription dispensing within 30 days) to an administrative claims database in Massachusetts, USA, to identify a Lyme disease cohort during July 2000-June 2019. Clinicians reviewed and adjudicated medical charts from a cohort subset by using national surveillance case definitions. We calculated positive predictive values (PPVs). We identified 12,229 Lyme disease episodes in the claims database and reviewed and adjudicated 128 medical charts. The algorithm's PPV for confirmed, probable, or suspected cases was 93.8% (95% CI 88.1%-97.3%); the PPV was 66.4% (95% CI 57.5%-74.5%) for confirmed and probable cases only. In a high incidence setting, a claims-based algorithm identified cases with a high PPV, suggesting it can be used to assess Lyme disease burden and supplement traditional surveillance data.

Outpatient visits before and after Lyme disease diagnosis in a Maryland employer-based health plan.

BACKGROUND: Insurance claims data have been used to inform an understanding of Lyme disease epidemiology and cost of care, however few such studies have incorporated post-treatment symptoms following diagnosis. Using longitudinal data from a private, employer-based health plan in an endemic US state, we compared outpatient care utilization pre- and post-Lyme disease diagnosis. We hypothesized that utilization would be higher in the post-diagnosis period, and that temporal trends would differ by age and gender. METHODS: Members with Lyme disease were required to have both a corresponding ICD-9 code and a fill of an antibiotic indicated for treatment of the infection within 30 days of diagnosis. A 2-year 'pre- diagnosis' period and a 2-year 'post-diagnosis period' were centered around the diagnosis month. Lyme disease-relevant outpatient care visits were defined as specific primary care, specialty care, or urgent care visits. Descriptive statistics examined visits during these pre- and post-diagnosis periods, and the association between these periods and the number of visits was explored using generalized linear mixed effects models adjusting for age, season of the year, and gender. RESULTS: The rate of outpatient visits increased 26% from the pre to the post-Lyme disease diagnosis periods among our 317-member sample (rate ratio = 1.26 [1.18, 1.36], p < 0.001). Descriptively, care utilization increases appeared to persist across months in the post-diagnosis period. Women's care utilization increased by 36% (1.36 [1.24, 1.50], p < 0.001), a significantly higher increase than the 14% increase found among men (1.14 [1.02, 1.27], p = 0.017). This gender difference was mainly driven by adult members. We found a borderline significant 17% increase in visits for children < 18 years, (1.17 [0.99, 1.38], p = 0.068), and a 31% increase for adults ≥ 18 years (1.31 [1.21, 1.42], p < 0.001). CONCLUSIONS: Although modest at the population level, the statistically significant increases in post-Lyme diagnosis outpatient care we observed were persistent and unevenly distributed across demographic and place of service categories. As Lyme disease cases continue to grow, so will the cumulative prevalence of persistent symptoms after treatment. Therefore, it will be important to confirm these findings and understand their significance for care utilization and cost, particularly against the backdrop of other post-acute infectious syndromes.

Initial Presentation and Time to Treatment in Early Lyme Disease.

The erythema migrans (EM) rash is an important initial diagnostic sign of early Lyme disease. We tested the hypothesis that patients who noticed EM first differed from those who noticed viral-like symptoms first. "EM First" participants (167/271, 61.6%) had shorter illness duration before treatment (5.0 versus 6.2 days, P = 0.019), were more likely to have seen or removed a tick (P = 0.048) and to be non-Hispanic White (P = 0.025), and were less likely to present with disseminated lesions at the time of diagnosis (P = 0.003) than "Symptoms First" participants (104/271, 38.4%). In multivariate analyses, EM First participants had a 22% decrease in time to treatment (P = 0.012) compared with Symptoms First participants, suggesting that initial presentation affects time to treatment. In a large minority of patients, EM may not be the initial sign or symptom of early Lyme disease. There is a need for rapid diagnostics and improved physician awareness of the varied manifestations of early Lyme disease.

Disseminated Lyme disease and dilated cardiomyopathy: A systematic review.

Lyme carditis is a well-established manifestation of early disseminated Lyme infection, yet the relationship between late disseminated Lyme disease and the development of dilated cardiomyopathy (DCM) remains unclear. The present systematic review aims to summarize existing literature on the association between late disseminated Lyme disease and DCM. A systematic review was conducted in PubMed, Embase, CENTRAL, and MEDLINE databases, after which a total of 11 observational studies (n = 771) were ultimately included for final data extraction. Although most studies (7/11) identified evidence associating Borrelia-infection with DCM, further research is required to isolate late disseminated Borrelia infection as a causative agent of DCM.

Gene set predictor for post-treatment Lyme disease.

Lyme disease (LD) is tick-borne disease whose post-treatment sequelae are not well understood. For this study, we enrolled 152 individuals with symptoms of post-treatment LD (PTLD) to profile their peripheral blood mononuclear cells (PBMCs) with RNA sequencing (RNA-seq). Combined with RNA-seq data from 72 individuals with acute LD and 44 uninfected controls, we investigated differences in differential gene expression. We observe that most individuals with PTLD have an inflammatory signature that is distinguished from the acute LD group. By distilling gene sets from this study with gene sets from other sources, we identify a subset of genes that are highly expressed in the cohorts but are not already established as biomarkers for inflammatory response or other viral or bacterial infections. We further reduce this gene set by feature importance to establish an mRNA biomarker set capable of distinguishing healthy individuals from those with acute LD or PTLD as a candidate for translation into an LD diagnostic.

A multimodal neuroimaging study of brain abnormalities and clinical correlates in post treatment Lyme disease.

Lyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10-20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD. This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings. On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process.

A diagnostic classifier for gene expression-based identification of early Lyme disease.

Background: Lyme disease is a tick-borne illness that causes an estimated 476,000 infections annually in the United States. New diagnostic tests are urgently needed, as existing antibody-based assays lack sufficient sensitivity and specificity. Methods: Here we perform transcriptome profiling by RNA sequencing (RNA-Seq), targeted RNA-Seq, and/or machine learning-based classification of 263 peripheral blood mononuclear cell samples from 218 subjects, including 94 early Lyme disease patients, 48 uninfected control subjects, and 57 patients with other infections (influenza, bacteremia, or tuberculosis). Differentially expressed genes among the 25,278 in the reference database are selected based on ≥1.5-fold change, ≤0.05 p value, and ≤0.001 false-discovery rate cutoffs. After gene selection using a k-nearest neighbor algorithm, the comparative performance of ten different classifier models is evaluated using machine learning. Results: We identify a 31-gene Lyme disease classifier (LDC) panel that can discriminate between early Lyme patients and controls, with 23 genes (74.2%) that have previously been described in association with clinical investigations of Lyme disease patients or in vitro cell culture and rodent studies of Borrelia burgdorferi infection. Evaluation of the LDC using an independent test set of samples from 63 subjects yields an overall sensitivity of 90.0%, specificity of 100%, and accuracy of 95.2%. The LDC test is positive in 85.7% of seronegative patients and found to persist for ≥3 weeks in 9 of 12 (75%) patients. Conclusions: These results highlight the potential clinical utility of a gene expression classifier for diagnosis of early Lyme disease, including in patients negative by conventional serologic testing.

Peptidylarginine Deiminase 2 Autoantibodies Are Linked to Less Severe Disease in Multiple Sclerosis and Post-treatment Lyme Disease.

Background: Peptidylarginine deiminase 2 (PAD2) mediates the post-translational conversion of arginine residues in proteins to citrullines and is highly expressed in the central nervous system (CNS). Dysregulated PAD2 activity has been implicated in the pathogenesis of several neurologic diseases, including multiple sclerosis (MS). In this study, we sought to define the cellular and regional expression of the gene encoding for PAD2 (i.e. PADI2) in the human CNS using publicly available datasets and evaluate whether anti-PAD2 antibodies were present in patients with various neurologic diseases. Methods: A total of 491 study participants were included in this study: 91 people with MS, 32 people with neuromyelitis optica (NMO), 281 people with post-treatment Lyme disease (PTLD), and 87 healthy controls. To measure PADI2 expression in the CNS from healthy individuals, publicly available tissue and single cell RNA sequencing data was analyzed. Anti-PAD2 antibodies were measured in the serum of study participants using anti-PAD2 ELISA. Clinical and demographic variables were compared according to anti-PAD2 antibody positivity for the MS and PTLD groups and correlations between anti-PAD2 levels and disease severity were examined. Results: PADI2 expression was highest in oligodendrocytes (mean ± SD; 6.4 ± 2.2), followed closely by astrocytes (5.5 ± 2.6), microglia/macrophages (4.5 ± 3.5), and oligodendrocyte precursor cells (3.2 ± 3.3). There was an increased proportion of anti-PAD2 positivity in the MS (19.8%; p = 0.007) and PTLD groups (13.9%; p = 0.057) relative to the healthy controls (5.7%), and these antibodies were not detected in NMO patients. There was a modest inverse correlation between anti-PAD2 levels and disease severity in people with MS (τ = -0.145, p = 0.02), with levels being the highest in those with relapsing-remitting disease. Similarly, there was a modest inverse correlation between anti-PAD2 levels and neurocognitive score (τ = -0.10, p = 0.027) in people with PTLD, with difficulty focusing, memory changes, fatigue, and difficulty finding words contributing most strongly to the effect. Conclusion: PADI2 expression was observed in diverse regions and cells of the CNS, and anti-PAD2 autoantibodies were associated with less severe symptoms in subsets of patients with MS and PTLD. These data suggest that anti-PAD2 antibodies may attenuate inflammation in diseases of different etiologies, which are united by high PADI2 expression in the target tissue.

Scleritis in Lyme Disease.

PURPOSE: To estimate the incidence of scleritis in Lyme disease and report clinical features. DESIGN: Incidence rate estimate and case series. METHODS: Data were collected from an electronic medical record on patients with scleritis presenting to the Wilmer Eye Institute between January 1, 2012 and December 31, 2020. A diagnosis of Lyme disease was made using the Infectious Diseases Society of America, American Academy of Neurology, and the American College of Rheumatology 2020 joint criteria plus a response to antibiotic therapy. After identifying all new-onset cases of scleritis in the database, the proportion of new-onset scleritis with Lyme disease was calculated. The proportion of Lyme disease cases with scleritis was estimated using the number of cases with Lyme disease from the Baltimore metropolitan area reported to the Centers for Disease Control and Prevention. After querying other major eye centers in the area for any cases of Lyme disease scleritis, none were identified, and the incidence of Lyme disease scleritis was estimated using published U.S. Census data for the greater Baltimore metropolitan area. RESULTS: Six cases of Lyme disease scleritis were identified in the 8-year time frame; 1 additional case was identified in the following year. Lyme disease scleritis accounted for 0.6% of all cases of scleritis, and 0.052% of patients with Lyme disease had scleritis. The estimated incidence of Lyme scleritis was 0.2 per 1,000,000 population per year (95% confidence interval 0-0.4), whereas the estimated incidence of Lyme disease in the area was 3 per 10,000 population per year (95% confidence interval 2.9-3.1). All scleritis cases were anterior, unilateral, without necrosis, and resolved with antibiotic use without relapse in a median of 39.5 days (range 29-57 days). Other features of Lyme disease were present in 4 of 7 patients, including a history of erythema migrans in 2 of 7 patients. CONCLUSIONS: Lyme disease is an uncommon cause of scleritis in endemic areas.

Risk of post-treatment Lyme disease in patients with ideally-treated early Lyme disease: A prospective cohort study.

PURPOSE: Post-treatment Lyme disease (PTLD) is characterized by patient-reported symptoms after treatment for Borrelia burgdorferi infection. The primary aim of this study was to assess whether participants with a history of Lyme disease (LD) would be more likely to meet criteria for PTLD than those without a history of LD. METHODS: We conducted a longitudinal, prospective study among 234 participants with and 49 participants without prior LD. All completed survey metrics for fatigue, pain, sleep, depression, and quality of life. An operationalized PTLD definition was applied to both cohorts, and the distributions of clinical outcomes and symptoms were examined. RESULTS: In total, 13·7% of participants with a history of prior LD met criteria for PTLD compared with 4·1% of those without a history of prior LD. Participants with prior LD were approximately 5·28 times as likely to meet PTLD criteria compared with those without prior LD (p = 0·042) and had 8-15 times as high odds of reporting moderate or severe fatigue and muscle pain (p = 0·002, 0·047, respectively). Risk of meeting PTLD criteria was also independently increased among females and those with higher exposure to previous traumatic life events. CONCLUSION: Participants ideally diagnosed and treated for prior LD reported more symptoms on standardized surveys and were more likely to meet criteria for PTLD than those without prior LD.

The Value of Musculoskeletal Ultrasound for Evaluation of Postinfectious Lyme Arthritis.

BACKGROUND: Inflammatory arthritis is the most common late manifestation of untreated Lyme disease in the United States. While antimicrobial therapy is effective in resolving swelling and pain for 90% of patients, many patients have persistent inflammation, termed postinfectious Lyme arthritis (PILA). Current outcome measures for Lyme arthritis have several limitations, as improvement is considered a dichotomous outcome based solely on physical examination. There is growing interest in the use of ultrasonography to better define outcomes in inflammatory arthritis, and this is particularly relevant for conditions such as late Lyme arthritis and PILA, which are monoarticular or oligoarticular. We describe results from a series of 5 patients who underwent ultrasound evaluations leading to a diagnosis of PILA. METHODS: This is a case series describing 5 patients with PILA who were referred for evaluation and treatment of symptomatic joints. RESULTS: Musculoskeletal ultrasound showed significant joint pathology, even in cases with minimal clinical findings. Synovitis, effusions, enthesitis/tendinopathy, and bone erosions were seen and helped confirm the presence of ongoing inflammatory arthritis. CONCLUSIONS: Marked inflammatory change-with synovitis, enthesitis and erosions-can be seen in selected patients with PILA. Systematic sonographic evaluation of patients with PILA is needed to further evaluate pathology and treatment response.

The Lyme and Tickborne Disease Dashboard: A map-based resource to promote public health awareness and research collaboration.

With the incidence of Lyme and other tickborne diseases on the rise in the US and globally, there is a critical need for data-driven tools that communicate the magnitude of this problem and help guide public health responses. We present the Johns Hopkins Lyme and Tickborne Disease Dashboard (https://www.hopkinslymetracker.org/), a new tool that harnesses the power of geography to raise awareness and fuel research and scientific collaboration. The dashboard is unique in applying a geographic lens to tickborne diseases, aiming not only to become a global tracker of tickborne diseases but also to contextualize their complicated geography with a comprehensive set of maps and spatial data sets representing a One Health approach. We share our experience designing and implementing the dashboard, describe the main features, and discuss current limitations and future directions.

Recent Progress in Lyme Disease and Remaining Challenges.

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

Relations of peri-residential temperature and humidity in tick-life-cycle-relevant time periods with human Lyme disease risk in Pennsylvania, USA.

How weather affects tick development and behavior and human Lyme disease remains poorly understood. We evaluated relations of temperature and humidity during critical periods for the tick lifecycle with human Lyme disease. We used electronic health records from 479,344 primary care patients in 38 Pennsylvania counties in 2006-2014. Lyme disease cases (n = 9657) were frequency-matched (5:1) by year, age, and sex. Using daily weather data at ~4 km2 resolution, we created cumulative metrics hypothesized to promote (warm and humid) or inhibit (hot and dry) tick development or host-seeking during nymph development (March 1-May 31), nymph activity (May 1-July 30), and prior year larva activity (Aug 1-Sept 30). We estimated odds ratios (ORs) of Lyme disease by quartiles of each weather variable, adjusting for demographic, clinical, and other weather variables. Exposure-response patterns were observed for higher cumulative same-year temperature, humidity, and hot and dry days (nymph-relevant), and prior year hot and dry days (larva-relevant), with same-year hot and dry days showing the strongest association (4th vs. 1st quartile OR = 0.40; 95% confidence interval [CI] = 0.36, 0.43). Changing temperature and humidity could increase or decrease human Lyme disease risk.

Contrast Sensitivity Loss in Patients With Posttreatment Lyme Disease.

Purpose: Posttreatment Lyme disease (PTLD) is marked by neurologic symptoms, cognitive impairment, and significant symptom burden, including fatigue and ocular complaints. The purpose of this study was to determine whether contrast sensitivity (CS) is altered in patients with PTLD compared with healthy controls and, second, whether CS is associated with cognitive and/or neurologic deficits. Methods: CS was measured using a Pelli-Robson chart with forced-choice procedures, and the total number of letters read was recorded for each eye. CS impairment was defined for age <60 years as logCS of 1.80 (36 letters or fewer) and for those age ≥60 years as logCS of 1.65 (33 letters or fewer). Participants self-administered a questionnaire to assess presence of ocular symptoms and underwent a neurologic exam and battery of neurocognitive tests. Results: CS impairment was associated with an increased odds of being in the PTLD group that was 2.6 times as high as those without CS impairment (odds ratio, 2.6; 95% confidence interval, 1.3-5.2). Neither cases nor controls had significant distance acuity impairment. CS impairment was not associated with any of the ocular complaints in cases but was borderline associated with neurologic abnormalities and cognitive impairment. Conclusions: CS impairment in patients with PTLD is linked to signs of cognitive and neurologic impairment and may be a marker of illness severity. Translational Relevance: Further investigation into the value of testing CS impairment in PTLD cases is warranted, especially if it is an indicator of cognitive or neurologic manifestations.