Late-stage Lyme Disease Research Articles

Epidemiology and clinical manifestations of reported Lyme disease cases: Data from the Canadian Lyme disease enhanced surveillance system.

Lyme disease cases reported in seven Canadian provinces from 2009 to 2019 through the Lyme Disease Enhanced Surveillance System are described herein by demographic, geography, time and season. The proportion of males was greater than females. Bimodal peaks in incidence were observed in children and older adults (≥60 years of age) for all clinical signs except cardiac manifestations, which were more evenly distributed across age groups. Proportions of disease stages varied between provinces: Atlantic provinces reported mainly early Lyme disease, while Ontario reported equal proportions of early and late-stage Lyme disease. Early Lyme disease cases were mainly reported between May through November, whereas late Lyme disease were reported in December through April. Increased awareness over time may have contributed to a decrease in the proportion of cases reporting late disseminated Lyme disease. These analyses help better describe clinical features of reported Lyme disease cases in Canada.

P11 Acrodermatitis chronica atrophicans: a sign of late lyme disease

Abstract Borrelia infection manifests a variety of signs and symptoms, and its insidiousness and heterogeneity mean that its diagnosis can be delayed. We describe two patients from south-east Scotland who presented with unilateral asymptomatic atrophic areas of skin discoloration. The first was a 71-year-old woman, who presented with a 4-month history of a nonprogressive, mottled, erythematous rash involving her right thigh, buttock and calf. Case 2 was a 56-year-old woman with a 2-year history of an erythematous area of atrophic skin involving the medial aspect of her left thigh and shin. Histology from case 1 showed a normal epidermis with a largely ‘top-heavy’ superficial and deep, predominantly interstitial and focally perivascular, lymphohistiocytic infiltrate, with a predominance of mononuclear histiocytes and with focal extension to deep reticular dermis. Scattered plasma cells were identified, but eosinophils were not a prominent feature. Well-formed granulomas were absent, as were interface dermatitic activity and vasculitic changes. On close questioning, each patient remembered ‘insect’ bites in the vicinity of the cutaneous changes, although neither recalled rashes that could have been consistent with erythema chronicum migrans. In both cases, serology confirmed infection with Borrelia burgdorferi (sensu lato) and diagnoses of acrodermatitis chronica atrophicans (ACA) were made. Both patients responded well to oral treatment with doxycycline. ACA is a cutaneous sign of late-stage Lyme disease and is caused by ongoing active skin infection by tick-borne bacteria of the Lyme disease group of Borrelia species. The tick bite has usually occurred months or years before symptom onset. Typically, there is an early, unilateral inflammatory stage with bluish-red discoloration of the skin and an oedematous appearance. This is followed by an atrophic stage where the skin becomes thin and wrinkled (‘cigarette paper’-like), with the loss of epidermal and dermal structures. Histological features usually include marked atrophy of the epidermis and dermis, loss of adnexal structures and an absence of elastic tissue. A band-like lymphocytic infiltration with plasma cells and mast cells is seen in the dermis, especially in the early stage of disease. Laboratory-confirmed cases of Lyme borreliosis in the UK have risen steadily since reporting began in 1986. ACA is likely to be underdiagnosed and, if there is a clinical suspicion, a detailed history, careful skin examination, Borrelia serology and skin biopsy should be undertaken. Early recognition and treatment reduce the risk of irreversible skin changes and systemic symptoms.

Spontaneous Knee Effusion in an Adolescent Soccer Player

A 13-year-old female recreational soccer player presented with spontaneous left knee effusion approximately 2 weeks after the start of soccer season. Radiographic imaging was negative, and a complete blood count identified an increase in inflammatory markers. Additional two-tier testing confirmed a Lyme disease diagnosis, which was unusual for an athlete residing in the southeast region of the United States. The presentation of knee effusion, and subsequently Lyme arthritis, is a common clinical manifestation of late-stage Lyme disease. Early recognition of this infection and prompt treatment by a variety of specialists reduce the severity or chronicity of symptoms.

CME: Musculoskeletal Manifestations of Lyme Disease

CME: Musculoskeletal Manifestations of Lyme Disease Abstract. Lyme disease is the most common vector-borne illness in Switzerland and Lyme arthritis the most prevalent manifestation of late-stage Lyme disease. It presents as a monoarthitis or oligoarthritis in large joints, often involving the knee. Such a clinical presentation, together with positive Lyme serologies or polymerase chain reactions from synovial fluid/tissue, is considered diagnostic. If there is no tick bite or erythema migrans in the patient's history the diagnosis can be challenging due to the many differential diagnoses. The initial treatment is a prolonged course of oral antibiotics.

CME/Answers: Musculoskeletal Manifestations of Lyme Disease

Lyme disease is the most common vector-borne illness in Switzerland and Lyme arthritis the most prevalent manifestation of late-stage Lyme disease. It presents as a monoarthitis or oligoarthritis in large joints, often involving the knee. Such a clinical presentation, together with positive Lyme serologies or polymerase chain reactions from synovial fluid/tissue, is considered diagnostic. If there is no tick bite or erythema migrans in the patient's history the diagnosis can be challenging due to the many differential diagnoses. The initial treatment is a prolonged course of oral antibiotics.

A Pilot Open-Label Study Assessing the Effects of AHCC Supplementation on Lyme Disease Patients

Background: Lyme disease is the most commonly reported vector-borne illness in the United States. The disease is caused by the bacterium Borrelia burgdorferi and is transmitted to humans through the bite of infected ticks. Typical symptoms include fever, headache, fatigue, a skin rash, and joint pain. If left untreated, infection can spread to the joints, heart, and nervous system, resulting in inflammation and long-term symptoms that include arthritis and/or intermittent pain in joints and muscles, facial palsy, cardiovascular abnormalities and cognitive disturbances. Recent research suggests that late-stage Lyme disease may be a result of malfunctioning immune function. AHCCÒ is a natural immune modulating compound derived from a unique fraction of special cultured medicinal mushroom mycelia. Previous studies have also suggested that AHCCÒ exhibits preventive effect against a wide range of infections caused by MRSA, influenza and West Nile virus. The effect of AHCCÒ supplementation on Lyme disease patients was evaluated in the current study.Methods: In a pilot open-label study, 12 Lyme disease patients were administered 3 grams of AHCCÒ daily for 8 weeks. Before commencement of the administration and after 4 and 8 weeks, the effects of AHCCÒ were evaluated clinically based on symptoms, serum antibodies to pathogens, inflammatory activity and serum immunological parameters. Patients completed questionnaires pertaining to Qualify of Life parameters.Results: After 8 weeks of AHCCÒ administration, AHCCÒ ameliorated flu-like symptoms and manifestations in the eye, joint, muscle, nervous system and cardiovascular system. In addition, erythrocyte sedimentation rate, an index as inflammation and serum interleukin-8 was significantly decreased.Conclusion: This study provides preliminary evidence that AHCCÒ may be effective in treating patients with Lyme disease.

PIN60 LYME DISEASE FIRST-LINE TREATMENT AND PROGRESSION IN FLORIDA AND THE NORTHEASTERN US: A COMPARISON USING REAL-WORLD DATA

To assess the implementation of IDSA- and EUCALB-recommended first-line treatment of early Lyme Disease (LD) and progression to later-stage LD in the Northeastern United States (NE) compared to Florida, utilizing a large real-world dataset. Patients with medical histories consistent with early-stage LD diagnoses were identified within the TriNetX EHR and payer dataset (∼190M patients). Patients were also required to have medical documentation in the 3 to 12 months prior and following LD diagnosis. Proportions of patients who received recommended LD first-line treatment (amoxicillin, doxycycline, or cefuroxime) in the NE and Florida were compared. To demonstrate efficacy of first-line treatment in preventing later-stage LD symptoms within the dataset, a propensity score analysis (1:1 greedy-nearest-neighbor matching) was run. A further cohort of all LD patients was defined and risk ratios of those who experienced symptoms consistent with later-stage LD in the two regions were compared. 135,835 LD patients were identified across Florida and the NE, 92,542 experienced early-stage LD symptoms, and 43,293 experienced late-stage LD symptoms. Of early-stage LD patients, a significantly higher proportion of patients received recommended treatment in the NE (42.2%) than in Florida (21.8%) (p<0.0001). The risk of developing later-stage LD was significantly lower in patients that received recommended treatment (9.4%) compared to patients that did not (11.5%) (p<0.0001). Of all patients diagnosed with LD, patients had a significantly higher risk of being diagnosed with late-stage LD in the NE (30.9%) compared to Florida (46.2%) (p<0.0001). LD is rapidly on the rise in Florida. This research indicates a significant deficit in recommended first-line treatment of LD and an increased proportion of late-stage diagnoses in Florida compared to the NE. These results signify that increased training/communication efforts may be warranted for Florida physicians to diagnose LD patients early in their disease and follow recommended first-line treatment.

Lyme Arthritis: An Update for Clinical Practice.

Lyme disease is the most common vector-borne illness in North America, with the majority of cases occurring in the Northeast and upper Midwest. Lyme arthritis is the most prevalent manifestation of late-stage Lyme disease. Lyme arthritis typically presents as a monoarthritis or oligoarthritis in large joints such as the knee. Accompanying positive 2-tier Lyme serologies or polymerase chain reaction from synovial fluid/tissue is considered diagnostic for patients from an endemic area. The mainstay of initial treatment is a prolonged course of oral antibiotics.

Symptom Resolution in Pediatric Patients With Lyme Disease.

We performed a retrospective study to determine the time frame for symptom resolution in 78 pediatric patients hospitalized with laboratory-confirmed early-disseminated or late-stage Lyme disease. The vast majority of the patients improved promptly after receiving appropriate antibiotics. Patients with a longer duration of arthritis before the institution of therapy experienced a longer time to recovery.

Recognising the signs and symptoms of Lyme disease

Lyme disease, which is a tick-borne bacterial infection, is becoming increasingly common and early recognition depends on awareness of the risk factors and early symptoms. Prompt effective tick removal is key to primary prevention, and early antibiotic treatment is essential for improving treatment outcomes. Late-stage Lyme disease in the UK generally causes neurological problems, with relapsing remitting pain and fatigue, and may be associated with a significant degree of disability for both adults and children. Increased awareness, research to clarify the scale of the problem in the UK, and improved diagnostics and treatment are urgently needed. Borreliosis is a bacterial zoonitic infection that is found mainly in the northern hemisphere. Its incidence is increasing, but it can be difficult to spot. Sandra Pearson advises on how to identify the early signs to ensure prompt treatment and avoid potential neurological problems

Update to: Application of Bayesian decision-making to laboratory testing for Lyme disease and comparison with testing for HIV.

In this study, Bayes' theorem was used to determine the probability of a patient having Lyme disease (LD), given a positive test result obtained using commercial test kits in clinically diagnosed patients. In addition, an algorithm was developed to extend the theorem to the two-tier test methodology. Using a disease prevalence of 5%-75% in samples sent for testing by clinicians, evaluated with a C6 peptide enzyme-linked immunosorbent assay (ELISA), the probability of infection given a positive test ranged from 26.4% when the disease was present in 5% of referrals to 95.3% when disease was present in 75%. When applied in the case of a C6 ELISA followed by a Western blot, the algorithm developed for the two-tier test demonstrated an improvement with the probability of disease given a positive test ranging between 67.2% and 96.6%. Using an algorithm to determine false-positive results, the C6 ELISA generated 73.6% false positives with 5% prevalence and 4.7% false positives with 75% prevalence. Corresponding data for a group of test kits used to diagnose HIV generated false-positive rates from 5.4% down to 0.1% indicating that the LD tests produce up to 46 times more false positives. False-negative test results can also influence patient treatment and outcomes. The probability of a false-negative test for LD with a single test for early-stage disease was high at 66.8%, increasing to 74.9% for two-tier testing. With the least sensitive HIV test used in the two-stage test, the false-negative rate was 1.3%, indicating that the LD test generates ~60 times as many false-negative results. For late-stage LD, the two-tier test generated 16.7% false negatives compared with 0.095% false negatives generated by a two-step HIV test, which is over a 170-fold difference. Using clinically representative LD test sensitivities, the two-tier test generated over 500 times more false-negative results than two-stage HIV testing.

Application of Bayesian decision-making to laboratory testing for Lyme disease and comparison with testing for HIV.

In this study, Bayes’ theorem was used to determine the probability of a patient having Lyme disease (LD), given a positive test result obtained using commercial test kits in clinically diagnosed patients. In addition, an algorithm was developed to extend the theorem to the two-tier test methodology. Using a disease prevalence of 5%–75% in samples sent for testing by clinicians, evaluated with a C6 peptide enzyme-linked immunosorbent assay (ELISA), the probability of infection given a positive test ranged from 26.4% when the disease was present in 5% of referrals to 95.3% when disease was present in 75%. When applied in the case of a C6 ELISA followed by a Western blot, the algorithm developed for the two-tier test demonstrated an improvement with the probability of disease given a positive test ranging between 67.2% and 96.6%. Using an algorithm to determine false-positive results, the C6 ELISA generated 73.6% false positives with 5% prevalence and 4.7% false positives with 75% prevalence. Corresponding data for a group of test kits used to diagnose HIV generated false-positive rates from 5.4% down to 0.1% indicating that the LD tests produce up to 46 times more false positives. False-negative test results can also influence patient treatment and outcomes. The probability of a false-negative test for LD with a single test for early-stage disease was high at 66.8%, increasing to 74.9% for two-tier testing. With the least sensitive HIV test used in the two-stage test, the false-negative rate was 1.3%, indicating that the LD test generates ~60 times as many false-negative results. For late-stage LD, the two-tier test generated 16.7% false negatives compared with 0.095% false negatives generated by a two-step HIV test, which is over a 170-fold difference. Using clinically representative LD test sensitivities, the two-tier test generated over 500 times more false-negative results than two-stage HIV testing.

Not So Common? Late Neuroborreliosis in a Referred Population

BackgroundThe nervous system is known to be the third most commonly (12–15%) affected site in Lyme disease (LD) in the U.S. Though previous studies reported peripheral neuropathy, encephalopathy, and encephalitis with some frequency in later stage LD, limited contemporary data exist on the frequency, presentation, and outcomes of these entities.MethodsRetrospective review of 1261 patients referred (2000–2013, single center) for presumptive LD was performed for neuroborreliosis. Symptoms less than 3 months were designated early LD. Patients with remote history of treated neuroborreliosis (> 2 years) were excluded. The diagnosis of LD followed CDC criteria. Response to antibiotics was assessed at the last clinical visit.ResultsOf 185 diagnosed with LD, 19% (35/185) had neuroborreliosis, including 29 early LD (ELD) and 6 late LD (LLD). The mean age was 44 yrs (±20) in ELD and 61(±11) in LLD. The median symptom duration was 14d (1–69) in ELD and 182d (140–2570) in LLD. Facial nerve palsy was most common, 54% (19/29 in ELD vs. 0/6 in LLD), followed by meningitis 20% (4/29 vs. 3/6), radiculopathy 20% (6/29 vs. 1/6), encephalopathy 3% (0/29 vs. 1/6), and peripheral neuropathy 3% (0/29 vs. 1/6) (P = 0.001). No encephalitis was identified. The median treatment duration (days) was 30 (10–135) in ELD and 56 (28–230) in LLD. All 35 patients were treated with doxycycline and/or ceftriaxone (16, 46% IV). Of the 32 followed patients, 28/32 (88%) responded to antibiotics, whereas 4/32 (12%) remained symptomatic with median follow-up duration of 72 days. Four non-responsive cases included 1 ELD (radiculopathy) and 3 LLDs (meningitis, encephalopathy, and peripheral neuropathy). The rate of non-response to antibiotics was higher in late LD (4% of ELD vs. 60% of LLD; P = 0.008). There was no statistically significant difference between outcome groups when comparing age, treatment duration, history of anxiety/depression, and route of treatment (p > 0.05, respectively).ConclusionEncephalopathy, encephalitis, and peripheral neuropathy ascribed to LD were uncommon in this population and poorly responsive to antibiotics. This raises the question whether LD truly was causal or if irreversible damage occurs by late stage LD. Future studies are needed in this regard.Disclosures All authors: No reported disclosures.

The eye and tick-borne disease in the United States.

Tick-borne diseases are increasing in incidence and geographic distribution. Several diseases endemic to the United States have ophthalmic manifestations, including the most common tick-borne disease, Lyme borreliosis. As ocular complaints may lead a patient to seek medical evaluation, it is important to be aware of the systemic and ophthalmic manifestations of tick-borne diseases in order to make the correct diagnosis. Vision-threatening ophthalmic manifestations are relatively common in Lyme disease and Rocky Mountain spotted fever. Ocular involvement is rare in babesiosis, tick-borne relapsing fever, Powassan encephalitis, ehrlichiosis, anaplasmosis, and Colorado tick fever.There are clear guidelines for diagnosis and treatment of Lyme disease; however, confusion and misinformation among the general public as well as controversy about chronic or late-stage Lyme disease can impact the evaluation of ophthalmic disease. Furthermore, there are many gaps in our knowledge regarding the pathophysiology of ocular borreliosis although it seems likely that Lyme uveitis is rare in the United States. Knowledge of systemic and ophthalmic manifestations combined with an understanding of the epidemiology of disease vectors is crucial for the diagnosis of tick-borne diseases.

Differential Diagnosis and the Suspension of Judgment

In this paper I argue that ethics and evidence are intricately intertwined within the clinical practice of differential diagnosis. Too often, when a disease is difficult to diagnose, a physician will dismiss it as being "not real" or "all in the patient's head." This is both an ethical and an evidential problem. In the paper my aim is two-fold. First, via the examination of two case studies (late-stage Lyme disease and Addison's disease), I try to elucidate why this kind of dismissal takes place. Then, I propose a potential solution to the problem. I argue that instead of dismissing a patient's illness as "not real," physicians ought to exercise a compassionate suspension of judgment when a diagnosis cannot be immediately made. I argue that suspending judgment has methodological, epistemic, and ethical virtues and therefore should always be preferred to patient dismissal in the clinical setting.

The HtrA protease of Borrelia burgdorferi degrades outer membrane protein BmpD and chemotaxis phosphatase CheX

Borrelia burgdorferi, the spirochaetal agent of Lyme disease, codes for a single HtrA protein, HtrABb (BB0104) that is homologous to DegP of Escherichia coli (41% amino acid identity). HtrABb shows physical and biochemical similarities to DegP in that it has the trimer as its fundamental unit and can degrade casein via its catalytic serine. Recombinant HtrABb exhibits proteolytic activity in vitro, while a mutant (HtrABbS198A) does not. However, HtrABb and DegP have some important differences as well. Native HtrABb occurs in both membrane-bound and soluble forms. Despite its homology to DegP, HtrABb could not complement an E. coli DegP deletion mutant. Late stage Lyme disease patients, as well as infected mice and rabbits developed a robust antibody response to HtrABb, indicating that it is a B-cell antigen. In co-immunoprecipitation studies, a number of potential binding partners for HtrABb were identified, as well as two specific proteolytic substrates, basic membrane protein D (BmpD/BB0385) and chemotaxis signal transduction phosphatase CheX (BB0671). HtrABb may function in regulating outer membrane lipoproteins and in modulating the chemotactic response of B. burgdorferi.

Lyme disease antiscience

Paul Auwaerter and colleagues1 are among the handful of individuals who have controlled the Lyme disease research agenda for decades and ultimately which data have been reported. Why is it that, in my experience, many people in New Hampshire have been severely debilitated by Lyme disease or know someone who has, whereas Auwaerter and co-workers claim that the disease is easily diagnosed and treated with a short course of antibiotics? Seven states have now passed legislation to protect clinicians who treat late-stage Lyme disease with long-term antibiotics (CT, MA, MN, NY, NH, RI, and TX) and support groups exist in nearly every state, with 19 in Pennsylvania alone.

Borrelia species induce inflammasome activation and IL‐17 production through a caspase‐1‐dependent mechanism

Borrelia burgdorferi spirochetes cause Lyme disease, which can result in severe clinical symptoms such as multiple joint inflammation and neurological disorders. IFN-γ and IL-17 have been suggested to play an important role in the host defense against Borrelia, and in the immunopathology of Lyme disease. The caspase-1-dependent cytokine IL-1β has been linked to the generation of IL-17-producing T cells, whereas caspase-1-mediated IL-18 is crucial for IFN-γ production. In this study, we show by using knockout mice the role of inflammasome-activated caspase-1 in the regulation of cytokine responses by B. burgdorferi. Caspase-1-deficient cells showed significantly less IFN-γ and IL-17 production after Borrelia stimulation. A lack of IL-1β was responsible for the defective IL-17 production, whereas IL-18 was crucial for the IFN-γ production. Caspase-1-dependent IL-33 played no role in the Borrelia-induced production of IL-1β, IFN-γ or IL-17. In conclusion, we describe for the first time the role of the inflammasome-dependent caspase-1 activation of cytokines in the regulation of IL-17 production induced by Borrelia spp. As IL-17 has been implicated in the pathogenesis of chronic Lyme disease, these data suggest that caspase-1 targeting may represent a new immunomodulatory strategy for the treatment of complications of late stage Lyme disease.

Chemoenzymatic Synthesis of a Glycolipid Library and Elucidation of the Antigenic Epitope for Construction of a Vaccine Against Lyme Disease

Lyme disease (LD) is the most common tick-borne disease in Europe, North America, and Asia. The etiologic agents of LD are spirochetes of the group Borrelia burgdorferi sensu lato, which possess a lipid content of 25-30% of the dry weight. The major glycolipid cholesteryl 6-O-acyl-beta-D-galactopyranoside (ACGal), present in B. burgdorferi sensu stricto, B. afzelii, and B. garinii, is a specific and highly prevalent antigen frequently recognized by antibodies in late-stage LD. Here we report a convenient route for the chemical synthesis of ACGal by employing a combination of chemical synthesis steps with enzymatic transformations. This synthesized molecule was compared with bacterial extracts by immunoblots with patient sera, confirming the preserved antigenicity. Next, a glycolipid library derived from the native molecules with variations in the fatty acyl moiety and derivatives in which the cholesterol has been replaced was designed and synthesized. The chemical structures were confirmed by 1D and 2D NMR spectroscopy and mass spectrometry. The native and synthetic glycolipids were utilized in immunoblots to determine the epitope recognized by antibodies in patient sera. By this method we could demonstrate that galactose, cholesterol, and a fatty acid with a minimal chain length of four carbon atoms comprises the essential structure for recognition by antibodies. Finally, this finding allowed the synthesis of a functionalized ACGal with an omega-mercapto group at the fatty acid and a facile protection and deprotection strategy. This antigenic hapten can be conjugated to a carrier protein to effect immunization against Lyme disease.

Role of aggrecanase 1 in Lyme arthritis

Arthritis is one of the hallmarks of late-stage Lyme disease. Previous studies have shown that infection with Borrelia burgdorferi, the causative agent of Lyme disease, results in degradation of proteoglycans and collagen in cartilage. B burgdorferi do not appear to produce any exported proteases capable of digesting proteoglycans and collagen, but instead, induce and activate host proteases, such as matrix metalloproteinases (MMPs), which results in cartilage degradation. The role of aggrecanases in Lyme arthritis has not yet been determined. We therefore sought to delineate the contribution of aggrecanases to joint destruction in Lyme arthritis. We examined the expression patterns of aggrecanases 1 and 2 (ADAMTS 4 and 5, respectively) in B burgdorferi-infected primary human chondrocyte cell cultures, in synovial fluid samples from patients with active Lyme arthritis, and in the joints of mice by real-time quantitative reverse transcription-polymerase chain reaction and immunoblotting techniques. Bovine cartilage explants were used to determine the role of aggrecanases in B burgdorferi-induced cartilage degradation. ADAMTS-4, but not ADAMTS-5, was induced in human chondrocytes infected with B burgdorferi. The active forms of ADAMTS-4 were increased in synovial fluid samples from patients with active Lyme arthritis and were elevated in the joints of mice infected with B burgdorferi. Using cartilage explant models of Lyme arthritis, it appeared that the cleavage of aggrecan was predominantly mediated by "aggrecanases" rather than MMPs. The induction of ADAMTS-4 by B burgdorferi results in the cleavage of aggrecan, which may be an important first step that leads to permanent degradation of cartilage.