Lyme borreliosis: diagnosis and management.

Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear. Persistent active infection in humans has not been identified as a cause of this syndrome, and randomized treatment trials have invariably failed to show any benefit of prolonged antibiotic treatment. For prevention of Lyme borreliosis, post-exposure prophylaxis may be indicated in specific cases, and novel vaccine strategies are under development.

CD4+ cell-derived interleukin-17 in a model of dysregulated, Borrelia-induced arthritis.

Lyme borreliosis, which is caused in the United States by the spirochete Borrelia burgdorferi, may manifest as different arrays of signs, symptoms and severities between infected individuals. Recent studies have indicated that particularly severe forms of Lyme borreliosis in humans are associated with an increased Th17 response. Here, we hypothesized that a murine model combining the dysregulated immune response of an environment lacking interleukin-10 (IL-10) with a robust T-cell-driven inflammatory response would reflect arthritis associated with the production of IL-17 by CD4+ cells. We demonstrate that IL-10 regulates the production of IL-17 by Borrelia-primed CD4+ cells early after interaction with Lyme spirochetes in vitro and that infection of Borrelia-primed mice with B. burgdorferi leads to significant production of IL-17 that contributes to the development of severe arthritis. These results extend our previous findings by demonstrating that a dysregulated adaptive immune response to Lyme spirochetes can contribute to severe, Th17-associated arthritis. These findings may lead to therapeutic measures for individuals with particularly severe symptoms of Lyme borreliosis.

Arthritis is developed in Borrelia-primed and -infected mice deficient of interleukin-17.

Interleukin-17 (IL-17) has been shown to participate in the development of Lyme arthritis in experimental mice. For example, neutralization of IL-17 with antibodies inhibits induction of arthritis in Borrelia-primed and -infected C57BL/6 wild-type mice. We hypothesized that mice lacking IL-17 would fail to develop Borrelia-induced arthritis. IL-17-deficient and wild-type C57BL/6 mice were primed with heat-inactivated Borrelia and then infected with viable spirochetes 3 weeks later. No swelling or major histopathological changes of the hind paws were detected in IL-17-deficient or wild-type mice that were primed with Borrelia or infected with viable spirochetes. By contrast, IL-17-deficient and wild-type mice that were primed and subsequently infected with heterologous Borrelia developed severe swelling and histopathological changes of the hind paws. In addition, Borrelia-primed and -infected IL-17-deficient mice exhibited elevated gamma-interferon (IFN-γ) levels in sera and increased frequencies of IFN-γ-expressing lymphocytes in popliteal lymph nodes compared to Borrelia-primed and -infected wild-type mice. These results demonstrate that IL-17 is not required for development of severe pathology in response to infection with Borrelia burgdorferi, but may contribute to disease through an interaction with IFN-γ.

5-Lipoxygenase-deficient mice infected with Borrelia burgdorferi develop persistent arthritis.

The enzyme 5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid into the leukotrienes, which are critical regulators of inflammation and inflammatory diseases, such as asthma and arthritis. Although leukotrienes are present in the synovial fluid of Lyme disease patients, their role in the development of Lyme arthritis has not been determined. In the current study, we used a murine model of Lyme arthritis to investigate the role 5-LO products might have in the development of this inflammatory disease. After infection of Lyme arthritis-susceptible C3H/HeJ mice with Borrelia burgdorferi, mRNA expression of 5-LO and 5-LO-activating protein was induced in the joints, and the 5-LO product leukotriene B(4) was produced. Using C3H 5-LO-deficient mice, we demonstrated that 5-LO activity was not necessary for the induction of Lyme arthritis, but that its deficiency resulted in earlier joint swelling and an inability to resolve arthritis as demonstrated by sustained arthritis pathology through day 60 postinfection. Although production of anti-Borrelia IgG was decreased in 5-LO-deficient mice, bacterial clearance from the joints was unaffected. Phagocytosis of B. burgdorferi and efferocytosis of apoptotic neutrophils was defective in macrophages from 5-LO-deficient mice, and uptake of opsonized spirochetes by neutrophils was reduced. These results demonstrate that products of the 5-LO metabolic pathway are not required for the development of disease in all models of arthritis and that caution should be used when targeting 5-LO as therapy for inflammatory diseases.

Clinical manifestations and diagnosis of lyme borreliosis.

Lyme borrelosis is a multi-systemic disease caused byBorrelia burgdorferisensu lato. A complete presentation of the disease is an extremely unusual oberservation, in which a skin lesion follows a tick bite, the lesion itself is followed by heart and nervous system involvement, and later on by arthritis; late involvement of the eye, nervous system, joints and skin may also occur. Information on the relative frequency of individual clinical manifestations of Lyme borreliosis is limited; however, the skin is most frequently involved and skin manifestations frequently represent clues for the diagnosis. The only sign that enables a reliable clinical diagnoisis of Lyme borreliosis is a typical erythema migrans. Laboratory confirmation of a borrelial infection is needed for all manifestations of Lyme borreliosis, with the exception of typical skin lesions.

Adenoviral delivery of interleukin-10 fails to attenuate experimental Lyme disease.

Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10(-/-) mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10(-/-) mice. However, in contrast to previous in vitro work, infection of C3H IL-10(-/-) mice led to decreased in vivo expression of the cytokines KC, IL-1beta, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

Lyme disease with lymphocytic meningitis, trigeminal palsy and silent thalamic lesion.

We describe a follow-up in a 15-year-old boy with neuroborreliosis diagnosed by clinical symptoms, CSF and serum analysis. MRI revealed a thalamic lesion and an enhancement of the right trigeminal nerve clinically associated with mild hypasthesia in the right maxillary region. Both, clinical symptoms and radiological findings disappeared within 2 months after treatment. Borrelia burgdorferi specific IgM and IgG in CSF and IgG in serum became negative between 6 and 12 months after diagnosis. We show that neuroborreliosis at an early stage may present only with moderate neurological deficits and that at this stage MRI reveals distinct cerebral lesions which might even precede clinical manifestation. Thus, early diagnosis and treatment of neuroborreliosis may prevent persistent neurologic lesions.

Review of treatment options for lyme borreliosis.

Lyme borreliosis (Lyme disease) is the most common tick-borne bacterial infection and the incidence is increasing in parts of Europe and the USA. Prompt antimicrobial therapy using oral agents such as doxycycline or amoxicillin is successful among more than 90% of patients. Inadequate penetration of oral agents into the CNS may result in the development of overt neuroborreliosis. The parenteral agent ceftriaxone is the drug of choice for severe acute and chronic infections, due to good penetration into CSF, convenient single daily dosage regimen and proven high efficacy in clinical trials involving a wide variety of disseminated infections. Regardless of therapeutic agent, there appears to a small minority of patients (<10%) who do not respond; such cases may be due to long-term persistence of borrelial cysts and to misdiagnoses based solely on seropositivity. Several adjunct therapies are available, including hyperbaric oxygen therapy and immune system supplements, but clinical trials have yet to be conducted.

Histopathological studies of experimental lyme disease in the dog.

Experimental borrelia infection was induced in 62 specific--pathogen-free beagle dogs by exposure to Ixodes scapularis ticks harbouring the spirochaete Borrelia burgdorferi. Clinical signs of Lyme disease occurred in 39/62 dogs, the remaining 23 being subclinically infected. Clinical signs consisted of one to six episodes of transitory lameness with joint swelling and pain, most commonly affecting the elbow or shoulder joints. The polymerase chain reaction and culture demonstrated that the dogs remained infected for up to 581 days. At necropsy, gross findings consisted of lymphadenopathy in the area of tick attachment. Microscopical changes consisted of effusive fibrinosuppurative inflammation or nonsuppurative inflammation, or both, affecting synovial membranes, joint capsules and associated tendon sheaths. Plasma cells dominated areas of chronic inflammation, with CD3(+) T cells being present in lesser numbers. Microscopical signs of arthritis were polyarticular and more widespread than indicated by clinical signs, and most of the subclinically affected animals also had synovitis. In areas of tick attachment to the skin, hyperkeratosis and a mixture of suppurative and nonsuppurative dermatitis were encountered. Lymphadenopathy in superficial lymph nodes resulted from follicular and parafollicular hyperplasia. In 14/62 dogs, lymphoplasmacytic periarteritis and perineuritis were noted, resembling lesions found in human Lyme disease and syphilis, in which an underlying microangiopathy has been proposed.

[Physical factors in rehabilitation treatment of patients with Ixodes tick-borne borreliosis with primary lesions of the joints]. / Fizicheskie faktory v vosstanovitel'nom lechenii bol'nykh iksodovym kleshchevym borreliozom s preimushchestvennym porazheniem sustavov.

The studies made in 96 patients suffering from chronic ixode tick borreliosis with a prevalent joint lesion justified two-stage treatment with physiotherapy at the second stage. The proposed therapy is well tolerated, produced a good improvement in 82.4% patients, the response persisting for 8.8 +/- 0.2 months vs 5.6 +/- 1.0 months in the control group on pharmacotherapy alone.

Protection against tick-transmitted Lyme disease in dogs vaccinated with a multiantigenic vaccine.

In an effort to develop a safe and effective vaccine for the prevention of Lyme borreliosis that addresses concerns raised over currently available vaccines, dogs were vaccinated twice with a multiantigenic preparation of Borrelia burgdorferi, strain N40, on days 0 and 20 of the experiment. About 70 and 154 days after the first immunization, dogs were challenged by exposing them to field-collected Ixodes scapularis ticks harboring B. burgdorferi. Vaccinated dogs were completely protected from infection by all criteria utilized to assess infection, developed high-titer anti-B. burgdorferi serum antibodies and growth inhibitory activity which persisted for over 200 days, and did not demonstrate any untoward consequence of vaccination. Serum absorption experiments revealed that borreliacidal and most likely protective antibodies in dogs receiving the multiantigenic preparation were not only elicited against the OspA antigen, but were also produced against additional yet to be determined targets on B. burgdorferi organisms. These data demonstrate that a multiantigenic vaccine is effective in preventing Lyme disease transmitted via the natural vector.

Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease.

A spectrum of disease severity has been observed in patients with Lyme disease, with approximately 60% of untreated individuals developing arthritis. The murine model of Lyme disease has provided strong evidence that the genetic composition of the host influences the severity of arthritis following infection with Borrelia burgdorferi: infected C3H mice develop severe arthritis while infected C57BL/6N mice develop mild arthritis. Regions of the mouse genome controlling arthritis severity and humoral responses during B. burgdorferi infection were identified in the F2 intercross generation of C3H/HeNCr and C57BL/6NCr mice. Rear ankle swelling measurements identified quantitative trait loci (QTL) on chromosomes 4 and 5, while histopathological scoring identified QTL on a unique region of chromosome 5 and on chromosome 11. The identification of QTL unique for ankle swelling or histopathological severity suggests that processes under distinct genetic control are responsible for these two manifestations of Lyme arthritis. Additional QTL that control the levels of circulating Igs induced by B. burgdorferi infection were identified on chromosomes 6, 9, 11, 12, and 17. Interestingly, the magnitude of the humoral response was not correlated with the severity of arthritis in infected F2 mice. This work defines several genetic loci that regulate either the severity of arthritis or the magnitude of humoral responses to B. burgdorferi infection in mice, with implications toward understanding the host-pathogen interactions involved in disease development.

Prehistoric juvenile rheumatoid arthritis in a precontact Louisiana native population reconsidered.

Descriptions of skeletal pathological conditions evident in the prehistoric Tchefuncte adolescent 16ST1-14883b are clarified. The basis is reaffirmed for assigning to the described pathological conditions a diagnostic perspective of juvenile rheumatoid arthritis or juvenile Lyme disease--a disease that mimics juvenile rheumatoid arthritis in its arthritic presentation--rather than of assigning them as representative of juvenile onset ankylosing spondylitis or other juvenile spondyloarthropathies. A hypothesis (Lewis [1994] Am. J. Phys. Anthropol. 93:455-475) is restated that 1) the spirochete Borrelia burgdorferi was the infectious agent responsible for prevalence of adult rheumatoid arthritis in prehistoric southeastern Native American populations, 2) that B. burgdorferi is a possible cause of the arthritis evident in individual 16ST1-14883b, and 3) that antibodies to B. burgdorferi provided partial immunity to the related spirochete Treponema pallidum for the 16ST1 precontact Tchefuncte population from Louisiana, protecting them from severe treponemal response. Given the probable widespread existence of Ixodid tick vectors for B. burgdorferi in prehistoric North America, coupled with the existence of treponematosis, it follows that the transition of Native American hunting-gathering economies to more sedentary economies would predictably be linked to an increased incidence of treponematosis due to the loss of benefits of the above-stated partial immunity. In other words, as prehistoric Native American exposure to tick vectors for B. burgdorferi decreased, susceptibility to treponematosis increased. Inferences regarding biological controls interacting with and influencing prehistoric Native American migration patterns are suggested from the link of B. burgdorferi to an Ixodid tick common to northeast Asia.

Infectivity and arthritis induction of Borrelia japonica on SCID mice and immune competent mice: possible role of galactosylceramide binding activity on initiation of infection.

We investigated the relationship between the binding activity to galactosylceramide (GalCer) and the arthritis induction activity of Borrelia japonica. The B. japonica strains maintained the ability to induce arthritis in inbred C3H/HeN and immunodeficient SCID mice, but the ability was lower than that of Borrelia burgdorferi sensu stricto virulent strain 297. Histopathological changes were restricted to the joints, and a marked effusion of polymorphonuclear neutrophils into the joint space was found. The binding activity of B. japonica strains to GalCer was lower than that of the virulent strain 297 but higher than that of the high-passage strain 297. The lower infectivity and virulence of B. japonica may explain its lower binding ability to GalCer.

Treponematosis and Lyme borreliosis connections: explanation for Tchefuncte disease syndromes?

A convergence of evidence from macroscopic, radiographic and histologic examination indicates that treponemal infection was present in the 16ST1 Tchefuncte Indian burial population, dated 500 B.C. to 300 A.D. Pattern and nature of lesions suggests that chronic infection induced by variants of the spirochete Treponema pallidum, causing endemic syphilis and/or yaws, resulted in third-stage osseous response. It is suggested that Tchefuncte Indians acquired partial immunity to treponemal infection by exposure to a variant of the related spirochete, Borrelia burgdorferi, the causative agent of Lyme disease. Partial immunity would help explain the relatively mild expression of the treponemal disease process in the 16ST1 skeletal population and the apparent absence of venereal syphilis. Presence of the Borrelia burgdorferi spirochete might be linked to a single incidence of juvenile rheumatoid arthritis.

[Nodular panniculitis: a manifestation of Lyme borreliosis?]. / Noduläre Pannikulitis: eine Verlaufsform der Lyme-Borreliose?

Infection with Borrelia burgdorferi can induce various skin manifestations. The type of skin manifestation and the histopathological picture depend on the stage of infection and vary from local inflammatory infiltrates to chronic atrophic skin disease. Involvement of subcutaneous tissue has been observed only very rarely. We report on two patients suffering from nodular panniculitis (Pfeifer-Weber-Christian) and present evidence that the disease was caused by Borrelia burgdorferi. In one of the cases Borrelia burgdorferi was repeatedly isolated from skin and subcutaneous tissue biopsies in spite of repeated high-dose therapy with ceftriaxone, Doxycycline and cefotaxime.