Late Manifestations Of Lyme Borreliosis Research Articles

Synovial fluid alpha-defensins in Lyme arthritis-a useful marker.

Lyme arthritis, one of the possible late manifestations of Lyme borreliosis, predominantly affects the supporting joints and in adults most often occurs in the form of monoarthritis of the knee. Early diagnosis is based on clinical findings and serology. PCR detection of Borrelia in synovial fluid has become an integral part of the laboratory testing algorithm. The clinical presentation and inflammatory markers in Lyme arthritis can resemble septic arthritis. Determining the levels of alpha-defensins (human neutrophil peptide (HNP 1-3)) in synovial fluid by liquid chromatography is a highly sensitive method revealing the presence of inflammatory process. Between 2020 and 2022, we examined eleven patients with Lyme arthritis of the knee. We measured levels of HNP 1-3 from synovial fluid by HPLC in patients, and we compared it with the corresponding C-reactive protein (CRP) levels in paired serum samples. In patients diagnosed with Lyme arthritis, HNP 1-3 levels in synovial fluid ranged from 2.5 to 261mg/L, with a median of 46.5mg/L. Average serum CRP was 43mg/L. The results show that elevated HNP 1-3 can be consistent with not only septic arthritis or systemic disease, but also with Lyme arthritis, especially in patients with negative culture and 16S PCR from synovial fluid. Final diagnosis must be verified by examination for anti-Borrelia antibodies from serum and synovial fluid. The aim of this work is to introduce an HPLC method for the determination of alpha-defensins as one of the possible diagnostic markers.

Intraarticular corticosteroids in refractory childhood Lyme arthritis

Lyme arthritis caused by infection with Borrelia burgdorferi is a common late manifestation of Lyme borreliosis. Current treatment recommendations include at least one oral or intravenous antibiotic course, followed by antirheumatic therapy in case of refractory arthritis. We reviewed the course of 31 children with Lyme arthritis who had received antibiotic treatment and assessed outcome and requirement of antirheumatic therapy. Of a total of 31 patients, 23 (74%) showed complete resolution of arthritis after one or two courses of antibiotics, whereas in 8 patients (28%), steroid injections had been performed due to relapsing or remaining symptoms. All of these 8 patients showed immediate resolution of symptoms after intraarticular steroid injections. Four of them (50%) remained asymptomatic so far with a follow-up period between five up to 40 months. In two cases, multiple intraarticular corticosteroid injections were required; three patients received additional or consecutive treatment with systemic antirheumatic treatment. Patients with antibiotic refractory arthritis showed a higher rate of positivity of the IgG p58 and OspC immunoblot bands (p = 0.05) at presentation. Antibodies against OspA, an indicator of later stage infection, occurred more frequently in the refractory group without reaching significant level. No clinical marker as indicator for severe or prolonged course of Lyme arthritis was identifiable. A quarter of childhood Lyme arthritis patients were refractory to antibiotics and required antirheumatic treatment. Intraarticular steroid injections in childhood Lyme arthritis refractory to antibiotics can lead to marked clinical improvement.

Tick-Specific Borrelial Antigens Appear to Be Upregulated in American but Not European Patients With Lyme Arthritis, a Late Manifestation of Lyme Borreliosis

Borrelia burgdorferi (Bb) sensu lato, the etiologic agent of Lyme borreliosis, adapts to distinct environments in the mammalian host and the tick vector by differential gene expression. As a result, infected mice are not exposed to and rarely make antibodies to the set of antigens that are preferentially expressed in the tick, including outer surface protein A (OspA), Borrelia iron and copper-binding protein A (BicA), and OspD. Surprisingly, however, antibodies to OspA and BicA have been noted in American patients with Lyme arthritis. Here, we examined serum samples from 210 American patients and 66 European patients with a range of early or late manifestations of Lyme borreliosis and found that only American patients with Lyme arthritis commonly had antibody responses to OspA, BicA, and OspD. This suggests that infection with American but not European Borrelia strains often leads to concerted upregulation or derepression of tick-specific spirochetal antigens in these patients.

Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans

BackgroundDespite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e.g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome.MethodsA prospective follow-up study of 109 patients with EM was conducted at the Åland Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-γ, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines.FindingsNone of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-γ in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels.ConclusionPatients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.

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.

Spätmanifestationen der Lyme-Borreliose

Month to years after an early local or an early disseminated infection some patients develop late manifestations of lyme borreliosis. Most frequently involved organs are the skin (acrodermatitis chronica atrophicans), joints (Lyme arthritis) and the nervous system. A history of exposure and the clinical picture may suggest Lyme borreliosis, however, confirmation by serological and other tests is needed. Antibiotic treatment during early stages normally prevents development of late manifestations. Late stages persist if not treated. By adequate antimicrobial therapy they are treatable and usually show a good prognosis. Recovery may be delayed, some patients suffer from residual difficulties. Currently there is no accepted case definition for a "post lyme syndrome". The term "chronic Lyme disease" suggests (a never proven) persistent infection by viable bacteria. Repeated and prolonged antibiotic treatments are not indicated.

Diagnosis of lyme borreliosis.

A large amount of knowledge has been acquired since the original descriptions of Lyme borreliosis (LB) and of its causative agent, Borrelia burgdorferi sensu stricto. The complexity of the organism and the variations in the clinical manifestations of LB caused by the different B. burgdorferi sensu lato species were not then anticipated. Considerable improvement has been achieved in detection of B. burgdorferi sensu lato by culture, particularly of blood specimens during early stages of disease. Culturing plasma and increasing the volume of material cultured have accomplished this. Further improvements might be obtained if molecular methods are used for detection of growth in culture and if culture methods are automated. Unfortunately, culture is insensitive in extracutaneous manifestations of LB. PCR and culture have high sensitivity on skin samples of patients with EM whose diagnosis is based mostly on clinical recognition of the lesion. PCR on material obtained from extracutaneous sites is in general of low sensitivity, with the exception of synovial fluid. PCR on synovial fluid has shown a sensitivity of up to >90% (when using four different primer sets) in patients with untreated or partially treated Lyme arthritis, making it a helpful confirmatory test in these patients. Currently, the best use of PCR is for confirmation of the clinical diagnosis of suspected Lyme arthritis in patients who are IgG immunoblot positive. PCR should not be used as the sole laboratory modality to support a clinical diagnosis of extracutaneous LB. PCR positivity in seronegative patients suspected of having late manifestations of LB most likely represents a false-positive result. Because of difficulties in direct methods of detection, laboratory tests currently in use are mainly those detecting antibodies to B. burgdorferi sensu lato. Tests used to detect antibodies to B. burgdorferi sensu lato have evolved from the initial formats as more knowledge on the immunodominant antigens has been collected. The recommendation for two-tier testing was an attempt to standardize testing and improve specificity in the United States. First-tier assays using whole-cell sonicates of B. burgdorferi sensu lato need to be standardized in terms of antigen composition and detection threshold of specific immunoglobulin classes. The search for improved serologic tests has stimulated the development of recombinant protein antigens and the synthesis of specific peptides from immunodominant antigens. The use of these materials alone or in combination as the source of antigen in a single-tier immunoassay may someday replace the currently recommended two-tier testing strategy. Evaluation of these assays is currently being done, and there is evidence that certain of these antigens may be broadly cross-reactive with the B. burgdorferi sensu lato species causing LB in Europe.

Diagnosis of lyme borreliosis by polymerase chain reaction

Diagnosis of lyme borreliosis by polymerase chain reaction

Ocular manifestations in children and adolescents with Lyme arthritis

BACKGROUNDLyme arthritis is the most frequent late manifestation of Lyme borreliosis and has been associated with ocular inflammation.METHODSA group of 153 children and adolescents with arthritis, 84 of whom had...

Subacute Multiple-Site Osteomyelitis Caused by Borrelia burgdorferi

In a pediatric case of severe multiple-site osteomyelitis caused by Borrelia burgdorferi, the presence of spirochetes in a bone lesion was documented both by culture and by the polymerase chain reaction (PCR). Positive PCR results were also obtained with culture fluid yielding spirochetal growth and with acute-phase serum. Although the disease evidently was a late manifestation of Lyme borreliosis, antibodies to B. burgdorferi were low in titer and were restricted to the IgM class. The distribution of osteomyelitic lesions in multiple bones and the positive PCR results obtained with serum argue for hematogenous spread of the spirochetes. Before the specific diagnosis was established, the patient received several potent antimicrobial drugs, without a favorable outcome. In contrast, therapy with ceftriaxone led to a rapid cure that persisted thereafter. We conclude that infection due to B. burgdorferi must be considered a possible cause of subacute pediatric osteomyelitis.

Borrelia burgdorferi and localized scleroderma

L yme borreliosis is a multisystemic disorder caused by the spirochete Borrelia burgdorferi and transmitted by the Ixodes tick. The initial manifestations of the disease are the characteristic skin lesion, erythema migrans, and symptoms of general malaise (stage I). This may be followed weeks to months later by acute articular, cardiac, and neurologic manifestations (stage II). Months to years later intermittent or continuous attacks of mono/oligoarthritis may occur (stage III). Cutaneous manifestations occur in all three stages of the disease; erythema migrans in stage I and lymphadenosis benigna cutis in stage II. Stage III is associated with acrodermatitis chronica atrophicans (ACA);lb4 although many other scleroatrophic skin conditions have been reported as possible late manifestations of Lyme borreliosis. These include lichen sclerosus et atrophicus,5*6 morphea,z*3,6-12 linear scleroderma,g disseminated localized scleroderma,13 generalized scleroderma,14 morphea profunda,15 atrophoderma Pasini Pierini,16~17 eosinophilic fasciitis (or Shulman’s syndrome),ls,lg erythema chronicum migrans et atrophicans,20 progressive facial hemiatrophy of Parry-Romberg,21 and porphyria cutanea tarda with sclerodermic alterations.22 In contrast to acrodermatitis chronica atrophicans, however, the relationship of these conditions to Borrelia burgdorferi infection is uncertain. In 1985 Aberer et al.’ suggested for the first time that morphea may be a late manifestation of Lyme borreliosis; however, since then there have been numerous conflicting reports.

Tick-borne Borreliosis in the Archipelage of Southern Sweden

Sera from 480 individuals living on an island at the Baltic coast in southern Sweden were tested by ELISA for detection of antibodies against Borrelia burgdorferi. The area was found to be highly endemic for Lyme borreliosis with elevated IgG antibody levels in 90/480 individuals (19%). Of 149 ticks collected on the island 16 nymphs (17%) and 15 adults (26%) were infected by B. burgdorferi. The occurrence of antibodies to B. burgdorferi increased with age and time spent in the endemic area. Infection without manifest disease seemed to dominate since only 18/480 (4%), or 6/90 (7%) with positive serology, had been treated for Lyme borreliosis. However, the prevalence of symptoms associated with late manifestations of Lyme borreliosis e.g. arthralgia, chronic skin efflorescences or neurologic disorders was significantly higher among seropositive compared to seronegative individuals.

Tick-borne Borreliosis in the Archipelage of Southern Sweden

Sera from 480 individuals living on an island at the Baltic coast in southern Sweden were tested by ELISA for detection of antibodies against Borrelia burgdorferi. The area was found to be highly endemic for Lyme borreliosis with elevated IgG antibody levels in 90/480 individuals (19%). Of 149 ticks collected on the island 16 nymphs (17%) and 15 adults (26%) were infested by B. burgdorferi. The occurrence of antibodies to B. burgdorferi increased with age and time spent in the endemic area. Infection without manifest disease seemed to dominate since only 18/480 (4%), or 6/90 (7%) with positive serology, had been treated for Lyme borreliosis. However, the prevalence of symptoms associated with late manifestations of Lyme borreliosis e.g. arthralgia, chronic skin efflorescence or neurologic disorders was significantly higher among seropositive compared to seronegative individuals.

Advances in investigations of Lyme borreliosis in the territory of the former USSR.

Whereas late manifestations of Lyme borreliosis were described in Russia more than 100 years ago, early manifestations were described as different disease entities such as tick-borne erythema, etc. In 1985 Lyme borreliosis was first verified serologically and the agent was first identified in 1986. By the beginning of 1992 Lyme borreliosis was serologically confirmed in patients from the Baltics to the Far East. Their geographical patterns in Russia are closely related to areas of the hard ticks Ixodes persulcatus and Ixodes ricinus which are also the main vectors of tick-borne encephalitis virus. As in the case of this infection, in the west of Russia there are "ricinus" natural foci of Lyme borreliosis, and to the east there are similar "persulcatus" foci; through large territories in the East Europe there are common foci for both species. Many Borrelia burgdorferi strains of tick origin have been isolated from various regions of Russia and neighbouring republics. Adult tick infection rates vary from several per cent to 30% in I. ricinus and up to 50-60% in I. persulcatus. Double infections of Lyme borreliosis spirochetes and tick-borne encephalitis virus have been recorded for ticks as well as for humans. Lyme borreliosis morbidity and its importance for the Russia territory are discussed.

Brainstem response audiometry in chronic Lyme borreliosis.

Auditory brainstem responses (ABR) were investigated in 26 patients with acrodermatitis chronic atrophicans, which is a late manifestation of Lyme borreliosis. Nine of the patients showed pathological ABR, four of them unilaterally and five bilaterally. The main pathological findings were: 1) Poor reproducibility of waves IV-V or of wave V; 2) Increased latency of wave V. After antibiotic treatment, ABR was improved in eight of the nine patients, and in three of them it was normal. In the five patients who did not completely recover, the improvement consisted in better reproducibility and a tendency towards normal wave V latencies. The results of this study indicate that the central nervous system may become involved in patients with acrodermatitis chronica atrophicans.

Brainstem Response Audiometry in Chronic Lyme Borreliosis

Auditory brainstem responses (ABR) were investigated in 26 patients with acrodermatitis chronic atrophicans, which is a late manifestation of Lyme borreliosis. Nine of the patients showed pathological ABR, four of them unilaterally and five bilaterally. The main pathological findings were: 1) Poor reproducibility of waves IV-V or of wave V: 2) Increased latency of wave V. After antibiotic treatment, ABR was improved in eight of the nine patients, and in three of them it was normal. In the five patients who did not completely recover, the improvement consisted in better reproducibility and a tendency towards normal wave V latencies. The results of this study indicate that the central nervous system may become involved in patients with acrodermatitis chronica atrophicans.

Immunochemische analyse der immunantwort bei spätmanifestationen der Lyme Borreliose: Immunochemical analysis of the immune response in late manifestations of Lyme Borreliosis

Compared to American strains, European Borrelia burgdorferi strains revealed considerable heterogeneity of major proteins. Four strains isolated from ticks, human skin and human CSF were selected from our 23 Borrelia burgdorferi isolates. These strains and the American type strain B31 were characterized by SDS-PAGE (Coomassie Blue staining) and Western blots (using rabbit immune sera against two of the strains and two monoclonal antibodies (H5323 and H3TS) against a major outer surface protein (OspA)). The strains showed considerable differences in SDS-PAGE pattern. Corroborating the results of a previous study, we could demonstrate that the OspA (31/32K) can change from a minor to a major protein and in reverse the pC (21/22K) from a major to a minor protein during subculturing. Moreover, European strains can antigenically differ in OspA, pC and also in a further low molecular weight protein of 17/18K. To examine whether the antigenic heterogeneity of European isolates is reflected in the immune response of European patients we examined sera from patients with late manifestations of Lyme Borreliosis by Western blot using the five strains as antigens. Sera from seven patients with acrodermatitis chronica atrophicans (ACA) showed a surprisingly strong reactivity with the skin isolate. All sera had antibodies against the 17/18K protein of the skin isolate, but none was reactive with the analogous 17/18K of the other strains. On the other hand a comparable predominance of one strain was not found testing sera from patients with Lyme arthritis. One patient even had antibodies against OspA and OspB proteins of strain B31. Contrary to findings in American Lyme Disease antibodies against the OspA were rarely observed in the sera of our patients (only one patient had such antibodies) although we tested the patients sera with five different strains. Only two patients had stronger reactions with the skin isolate. These findings suggest that ACA is caused by antigenically closely related Borreliae. This could explain the finding that ACA is rarely observed in the US (US strains are antigenically closely related to strain B31). Our findings in patients with Lyme Arthritis — on the other hand — suggest that “different serotypes” can cause Lyme Arthritis. This does not exclude the possibility that Borrelia proteins are an important factor in the pathogenesis of Lyme arthritis. Finally the differences in reactivity of sera with different strains in the Western blot led us to examine whether such differences are also found in serodiagnostic tests using different strains as antigens. Except in two ACA sera (which reacted stronger with the skin isolate) no significant differences were found using the five strains as antigens in the IgG immunofluorescent assay (we tested four sera from ACA patients, four sera from patients with neurological manifestations, four sera from Lyme arthritis patients and five sera from control persons without Lyme Borreliosis). These findings suggest that the IgG IFT can be performed by using only one strain as antigen. But in some cases antigen-dependent differences have been observed and we do not know whether different results occur using different antigens in other serodiagnostic tests (i.e. ELISA, IgM IFT).