Chronic Lyme Borreliosis Research Articles

Diagnosis of chronic lyme borreliosis involving the nervous system

Diagnosis of chronic Lyme disease is a challange for a clinician, even if there is modern laboratory and instrumental facilities at the hospital. Borreliosis is known for polysystemic and variable clinical picture. This article describes the clinical feachures and diagnosis of chronic borreliosis with central nervous system involvement. Various clinical variants of the disease and available methods of specific and nonspecific diagnosis are listed. The theoretical part of the work was carried out based on materials from 34 publications devoted to the problem of chronic neuroborreliosis. Also we describe the clinical case that illustrates the difficulties of managing this group of patients.

CLINICAL AND IMMUNOLOGICAL FEATURES OF REACTIVATION OF CHRONIC LYME BORRELIOSIS AFTER A PREVIOUS INFECTION OF COVID-19

A clinical case of reactivation of chronic Lyme borreliosis after a COVID-19 infection has been described. The purpose of the study is to use the example of a clinical case of reactivation of chronic Lyme borreliosis to demonstrate the peculiarities of its course, and modern methods of diagnosis and treatment, as well as to confirm the potential impact of coronavirus disease on the possibility of reactivation of chronic infectious pathology, even with a mild course of the COVID-19 infection. Materials and Methods. A diagnosis of borreliosis polyarthritis and Lyme myocarditis has been established. Since the specific lesions occurred for no apparent reason, and the symptoms appeared in winter, this ruled out the possibility of re-infection with Lyme borreliosis. During the further search for a potential causative agent that led to the detected changes, the patient was tested for the detection of antibodies to Borrelia burgdorferi by immunoenzymatic analysis. Results and discussion. The obtained positive result in the detection of specific antibodies (IgM – 46.64 units/ml, IgG – 87.31 units/ml) indicated the reactivation of Lyme borreliosis. At the same time, the immunological changes were significantly deeper than during the initial episode of infection. Treatment was prescribed: doxycycline 100 mg twice a day for 28 days, anti-inflammatory therapy. After completion of the course of etiotropic therapy, there was clinical remission, as well as negative results of specific IgM after 3, 6, and 12 months. Even 3 months after achieving clinical remission, the patient had residual immunological changes. Conclusion. So, the clinical case shows the difficulties of establishing a diagnosis of reactivation of Lyme borreliosis, and the need for clinical vigilance of practical healthcare specialists regarding similar cases, even with a mild course of the COVID-19 infection, is emphasized.

Invasion of chronic lymphocytic leukemia (cll/sll) bloodstream tumor cells by borrelia spirochetes

A sixty-six-year-old woman with a strong family history of breast cancer noted gradual onset of axillary lymph node enlargement in 2019. Axillary lymph node biopsies disclosed Lymph node involvement by Chronic Lymphocytic Leukemia (CLL/SLL). Immunophenotype analysis of nodal tissue and of bloodstream leukemic cells in immunohistochemistry and flow cytometry and next generation molecular diagnostics confirmed CLL/SLL. Replicate absolute peripheral blood lymphocyte counts in excess of 5.0x10e3/microliter confirmed the numerical threshold for diagnosis of Chronic Lymphocytic Leukemia in the bloodstream. FISH studies disclosed an immunoglobulin “mutation negative” CLL/SLL genotype without a light chain restriction pattern. No translocations or germline mutations were present. Borrelia spirochetes in the bloodstream were detected with simultaneous high spirochetemia of both borrelia miyamotoi and borrelia burgdorferi. FISH hybridization of leukemic lymphocytes disclosed extensive borrelia invasion of the cytoplasm and of the nucleus compartments of CLL/SLL tumor cells. Retrospective studies of the patient’s archival stored blood smears obtained three years prior in 2016 at age 63 disclosed no evidence of CLL/SLL but confirmed asymptomatic bloodstream borrelia miyamotoi and borrelia burgdorferi borrelia infection. Lyme serology had been reported as negative in 2016. Additionally, retrospective FISH DNA hybridizations focused on preleukemic bloodstream Lymphocytes disclosed rare borrelia spirochetal adherence to benign blood lymphocytes in the year 2016 in the preleukemic blood smears. This case report is the very first to describe precursor chronic asymptomatic Lyme borreliosis and Miyamotoi borrelia bloodstream infections three years prior to the diagnosis of Rai Stage 1 Chronic Lymphocytic leukemia.

Brain herniation death in pediatric cerebral lyme borreliosis followed by kidney organ donation

Fatal pediatric patient outcomes in chronic Lyme borreliosis are rarely identified. One sudden cardiac Lyme death in a seventeen-year-old black adolescent has been autopsy confirmed and reported in 2017 from Westchester, New York four years after his death in 2013. Herein is a case report of a pediatric Lyme disease brain death in a nineteen-month-old South Asian infant whose duration of disease was twelve months after sustaining three ixodid tick bites, to his sudden death from cerebellar tonsil herniation. This infant’s kidneys were transplanted into an unknown recipient.

Chronic Lyme borreliosis associated with minimal change glomerular disease: a case report

BackgroundThere are only few cases of renal pathology induced by Lyme borreliosis in the literature, as this damage is rare and uncommon in humans. This patient is the first case of minimal change glomerular disease associated with chronic Lyme borreliosis.Case presentationA 65-year-old Caucasian woman was admitted for an acute edematous syndrome related to a nephrotic syndrome. Clinical examination revealed violaceous skin lesions of the right calf and the gluteal region that occurred 2 years ago. Serological tests were positive for Lyme borreliosis and skin biopsy revealed lesions of chronic atrophic acrodermatitis. Renal biopsy showed minimal change glomerular disease. The skin lesions and the nephrotic syndrome resolved with a sequential treatment with first ceftriaxone and then corticosteroids.ConclusionWe report here the first case of minimal change disease associated with Lyme borreliosis. The pathogenesis of minimal change disease in the setting of Lyme disease is discussed but the association of Lyme and minimal change disease may imply a synergistic effect of phenotypic and bacterial factors. Regression of proteinuria after a sequential treatment with ceftriaxone and corticosteroids seems to strengthen this conceivable association.

Lyme borreliosis

Lyme borreliosis is a multisystem infectious disease affecting mainly the skin, nervous system, joints and heart. It is caused by spirochetes of the Borrelia burgdorferi sensu lato complex which are transmitted by ticks. The diagnosis of Lyme borreliosis is based primarily on typical clinical symptoms and signs with serological confirmation. Antibiotic therapy is beneficial for all manifestations and treatment refractory cases are rare. The diagnosis "chronic Lyme borreliosis" is increasingly being misused for all conceivable medically unexplained symptoms.

Cerebrospinal Fluid T-Regulatory Cells RecognizeBorrelia BurgdorferiNapa in Chronic Lyme Borreliosis

The NapA protein of B. burgdorferi is essential for the persistence of spirochetes in ticks. One of the most intriguing aspects of NapA is its potential to interfere with the host immune system. Here, we investigated the role of the acquired immune responses induced by NapA in the cerebrospinal fluids (CSF) of patients with chronic Lyme borreliosis. We evaluated the cytokine profile induced in microglia cells and CSF T cells following NapA stimulation. We report here that NapA induced a regulatory T (Treg) response in the CSF of patients with chronic Lyme borreliosis and it is able to expand this suppressive response by promoting the production of TGF-beta and IL-10 by microglia cells. Collectively, these data strongly support a central role of NapA in promoting both Treg response and immune suppression in the CSF of patients with chronic Lyme borreliosis and suggest that NapA and the Treg pathway may represent novel therapeutic targets for the prevention and treatment of the disease.

Borrelia burgdorferi tissue morphologies and imaging methodologies

This manuscript offers an image presentation of diverse forms of Borrelia burgdorferi spirochetes which are not spiral or corkscrew shaped. Explanations are offered to justify the legitimacy of tissue forms of Borrelia which may confuse the inexperienced microscopic examiner and which may lead to the misdiagnosis of non-spiral forms as artifacts. Images from the author's personal collection of Borrelia burgdorferi images and a few select images of Borrelia burgdorferi from the peer-reviewed published literature are presented. A commentary justifying each of the image profiles and a survey of the imaging modalities utilized provides the reader with a frame of reference. Regularly spiraled Borrelia are rarely seen in solid tissues. A variety of straightened, undulating, and clipped-off profiles are demonstrated, and the structural basis for each image is explained. Tissue examination is a diagnostic tool and a quality control for judging the eradication or the persistence of borreliosis following attempts to eradicate the infection with antibiotic therapy. The presence or absence of chronic Lyme borreliosis may be objectively adjudicated by tissue examinations which demonstrate or which fail to show pathogenic microbes in patients who have received a full course of antibiotics.

The Early Dissemination Defect Attributed to Disruption of Decorin-Binding Proteins Is Abolished in Chronic Murine Lyme Borreliosis

The laboratory mouse model of Lyme disease has revealed that Borrelia burgdorferi differentially expresses numerous outer surface proteins that influence different stages of infection (tick-borne transmission, tissue colonization, dissemination, persistence, and tick acquisition). Deletion of two such outer surface proteins, decorin-binding proteins A and B (DbpA/B), has been documented to decrease infectivity, impede early dissemination, and, possibly, prevent persistence. In this study, DbpA/B-deficient spirochetes were confirmed to exhibit an early dissemination defect in immunocompetent, but not immunodeficient, mice, and the defect was found to resolve with chronicity. Development of disease (arthritis and carditis) was attenuated only in the early stage of infection with DbpA/B-deficient spirochetes in both types of mice. Persistence of the DbpA/B-deficient spirochetes occurred in both immunocompetent and immunodeficient mice in a manner indistinguishable from that of wild-type spirochetes. Dissemination through the lymphatic system was evaluated as an underlying mechanism for the early dissemination defect. At 12 h, 3 days, 7 days, and 14 days postinoculation, DbpA/B-deficient spirochetes were significantly less prevalent and in lower numbers in lymph nodes than wild-type spirochetes. However, in immunodeficient mice, deficiency of DbpA/B did not significantly decrease the prevalence or spirochete numbers in lymph nodes. Complementation of DbpA/B restored a wild-type phenotype. Thus, the results indicated that deficiency of DbpA/B allows the acquired immune response to restrict early dissemination of spirochetes, which appears to be at least partially mediated through the lymphatic system.

Reversibility of dilated cardiomyopathy by low-dose oral roxithromycin in a patient with chronic lyme-borreliosis

It has been shown earlier that dilated cardiomyopathy can be associated withBorrelia burgdorferi infection.

Propensity to excessive proinflammatory response in chronic Lyme borreliosis

The clinical course of Lyme borreliosis is extremely variable. However, all the clinical manifestations, acute or chronic, are characterized by strong inflammation. Borrelia burgdorferi can induce the production of several proinflammatory and anti-inflammatory cytokines. The aim of our study was to find out whether the balance between inflammatory and regulatory mechanisms is important in determining the course of Lyme borreliosis. 13 patients with early Lyme borreliosis, 8 patients with chronic Lyme disease with neurological or joint manifestations, and 15 age- and sex-matched healthy controls were studied. Chronic forms of Lyme borreliosis were characterized by stronger TNF-alpha response by monocytes to lipopolysaccharide as well as to borrelia antigen compared to early Lyme borreliosis and the healthy state. The percentage of IL-10-secreting monocytes in response to borrelia lysate was lower in the Lyme borreliosis patients than in healthy controls. The percentage of CD4(+) CTLA-4(+) regulatory T cells showed the highest values in early Lyme borreliosis. We conclude that chronic forms of Lyme borreliosis can evolve due to an aberrant innate proinflammatory response.

Decreased up-regulation of the interleukin-12Rβ2-chain and interferon-γ secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomaticBorrelia-exposed individuals

Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rbeta2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rbeta2 and FoxP3 mRNA expression was analysed with real-time reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of IL-12Rbeta2 on CD3(+), CD4(+), CD8(+) and CD56(+) cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-gamma, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rbeta2 on CD8(+) cells and also a lower number of Borrelia-specific IFN-gamma-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.

Comparison of immunofluorescence assay (IFA) and LIAISON® in patients with different clinical manifestations of Lyme borreliosis

Serological tests for detection of borrelial antibodies are frequently used in laboratory diagnostics of Lyme borreliosis. Unfortunately these tests are not standardized and the results obtained with different assays may not be concordant. The aim of the present study was to compare two different serological tests, IFA and LIAISON, for detection of Borrelia burgdorferi sensu lato IgM and IgG antibody. We analyzed the serological immune response in 383 patients with different clinical manifestations of Lyme borreliosis and in 49 healthy blood donors. LIAISON detected IgM and IgG antibodies more often than IFA in all groups of patients except those with chronic Lyme borreliosis. The differences were significant for IgM and IgG antibodies in patients with solitary erythema migrans and in those with early disseminated Lyme borreliosis. There was no significant difference in the specificity of the two tests.

Anti-β2-Glycoprotein I Antibodies in Lyme Borreliosis: Differences in Disease Stage and Immunoglobulin Class Distribution

Spirochetes are gram-negative bacteria, which include the Treponema, Borrelia and Leptospira and cause different diseases such as syphilis, Lyme borreliosis and leptospirosis, respectively. Antiphospholipid antibodies as a consequence of the infection with Treponema pallidum subsp. pallidum have been extensively studied. There have also been a few reports of antiphospholipid antibodies in leptospirosis. On the other hand, there are very few data on the presence of antiphospholipid antibodies in Lyme borreliosis and to our knowledge, there is no information about antibodies against β2-glycoprotein I. In this study, we report the frequency of anticardiolipin antibodies and for the first time, the frequency of antibodies against β2-glycoprotein I in patients with acute and chronic Lyme borreliosis. The frequency of anticardiolipin antibodies and IgG antibodies against β2-glycoprotein I was similar in both groups, but antibodies against β2- glycoprotein I of the IgM isotype were surprisingly higher in the late stage of the disease. The frequency of IgM class antibodies against β2-glycoprotein I was 10% in chronic Lyme borreliosis versus none in acute Lyme borreliosis.

Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis

Therapeutic guidelines for treatment of late manifestations of Lyme borreliosis have not yet become well established. Patients with symptoms suggesting central nervous system involvement are often treated with courses of intravenous ceftriaxone. This is an expensive treatment approach with potentially severe side effects. We compared the efficacy, side effects and costs of doxycycline and ceftriaxone in the treatment of such patients. Adult patients qualified for the study if they had nonspecific symptoms suggesting central nervous system involvement for more than six months (but without overt clinical signs of the involvement), had positive serum borrelial antibody titers and/or erythema migrans prior to the onset of symptoms, had not been previously treated with antibiotics and did not have pleocytosis in the cerebrospinal fluid. Patients were given either 100 mg of oral doxycycline twice daily for 4 weeks (23 patients) or 2 g of intravenous ceftriaxone daily for 2 weeks followed by 100 mg of doxycycline twice daily for another 2 weeks (23 patients). Clinical outcome was assessed during a 12-month follow-up period. Improvement in the frequency and/or the intensity of symptoms was reported by more than two-thirds of the 46 patients enrolled in the study. The two treatment regimens were found to be correspondingly effective. Photosensitivity reactions and gastrointestinal symptoms were noted more often among patients receiving doxycycline than in those receiving ceftriaxone. Treatment with doxycycline proved to be much cheaper than with ceftriaxone. In patients with previously untreated chronic Lyme borreliosis with symptoms suggesting central nervous system involvement but without overt clinical signs of it, and without pleocytosis in the cerebrospinal fluid, treatment with doxycycline is as effective as with ceftriaxone. Treatment with doxycycline is cheap and relatively safe, but gastrointestinal symptoms and photosensitivity reactions can be expected more often than with ceftriaxone.

Disseminated and chronic Lyme borreliosis in Norway, 1995 - 2004.

Lyme borreliosis is the most common tickborne infection in Norway. All clinical manifestations of Lyme borreliosis other than erythema migrans are notifiable to Folkehelseinstituttet, the Norwegian Institute of Public Health. During the period 1995-2004 a total of 1506 cases of disseminated and chronic Lyme borreliosis were reported. Serological tests were the basis for laboratory diagnosis in almost all cases. The annual numbers of cases showed no clear trend over the period, but varied each year between 120 and 253 cases, with the highest number of cases reported in 2004. Seventy five per cent of cases with information on time of onset were in patients who fell ill during the months of June to October. There was marked geographical variation in reported incidence rates, with the highest rates reported from coastal counties in southern and central Norway. Fifty six per cent of the cases were in males and 44% in females. The highest incidence rate was found in children aged between 5 and 9 years. Neuroborreliosis was the most common clinical manifestation (71%), followed by arthritis/arthralgia (22%) and acrodermatitis chronica atrophicans (5%). Forty six per cent of patients were admitted to hospital. Prevention of borreliosis in Norway relies on measures to prevent tick bites, such as use of protective clothing and insect repellents, and early detection and removal of ticks. Antibiotics are generally not recommended for prophylaxis after tick bites in Norway.

Chronic Lyme borreliosis at the root of multiple sclerosis – is a cure with antibiotics attainable?

Apart from its devastating impact on individuals and their families, multiple sclerosis (MS) creates a huge economic burden for society by mainly afflicting young adults in their most productive years. Although effective strategies for symptom management and disease modifying therapies have evolved, there exists no curative treatment yet. Worldwide, MS prevalence parallels the distribution of the Lyme disease pathogen Borrelia (B.) burgdorferi, and in America and Europe, the birth excesses of those individuals who later in life develop MS exactly mirror the seasonal distributions of Borrelia transmitting Ixodes ticks. In addition to known acute infections, no other disease exhibits equally marked epidemiological clusters by season and locality, nurturing the hope that prevention might ultimately be attainable. As minocycline, tinidazole and hydroxychloroquine are reportedly capable of destroying both the spirochaetal and cystic L-form of B. burgdorferi found in MS brains, there emerges also new hope for those already afflicted. The immunomodulating anti-inflammatory potential of minocycline and hydroxychloroquine may furthermore reduce the Jarisch Herxheimer reaction triggered by decaying Borrelia at treatment initiation. Even in those cases unrelated to B. burgdorferi, minocycline is known for its beneficial effect on several factors considered to be detrimental in MS. Patients receiving a combination of these pharmaceuticals are thus expected to be cured or to have a longer period of remission compared to untreated controls. Although the goal of this rational, cost-effective and potentially curative treatment seems simple enough, the importance of a scientifically sound approach cannot be overemphasised. A randomised, prospective, double blinded trial is necessary in patients from B. burgdorferi endemic areas with established MS and/or Borrelia L-forms in their cerebrospinal fluid, and to yield reasonable significance within due time, the groups must be large enough and preferably taken together in a multi-centre study.

Borrelia-specific interferon-gamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome.

The Borrelia-specific interferon (IFN)- gamma and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN- gamma (P<.05) and subsequent up-regulation of IL-4 (P<.05) were detected in the CSF cells of patients with nonchronic NB. In contrast, persistent Borrelia-specific IFN- gamma responses were observed in the CSF cells of patients with chronic NB (P<.05). In patients with erythema migrans, increased IFN- gamma (P<.001) was observed in blood samples obtained early during the course of disease, whereas increased IL-4 (P<.05) was observed after clearance. On the contrary, patients with acrodermatitis chronica atrophicans had Borrelia-specific IFN- gamma (P<.001), but not IL-4, detected in blood samples. The present data suggest that an initial IFN- gamma response, followed by up-regulation of IL-4, is associated with nonchronic manifestations, whereas a persistent IFN- gamma response may lead to chronic Lyme borreliosis.

Disappearance of specific immune response after successful therapy of chronic Lyme borreliosis

512 consecutive patients suffering from chronic Lyme borreliosis have been treated according to a standardized therapy regimen which was developed using the results of a controlled trial (Hassler et al., 1990; Hassler, 1992). Follow up was performed for at least 6 (maximum 16) years. In the first two years after initial therapy clinical and serological data were collected every six months including Western blot testing, later once a year.

Physical factors for medical rehabilitation of patients with Lyme-borreliosis

Investigations made on 96 patients with chronic Lyme-borreliosis accompanied with predominant joint affection have allowed to ground scientifically an advisability of two-stages treatment, with administration of physical factor complex at the second stage. A treatment technology has been developed that allowed to improve significantly the state of 82,4% of patients with good tolerance.