Peer Reviewed Evidence of Persistence of Lyme Disease Spirochete Borrelia burgdorferi and Tick-Borne Diseases

 

The following is a list of over 700 peer reviewed articles that support the evidence of persistence of Lyme and other tick-borne diseases. It is organized into different categories—general, psychiatric, dementia, autism and congenital transmission. General: Persistence of Lyme Disease Spirochete Borrelia burgdorferi The following section of references for persistence of Lyme disease (Lyme borreliosis) are listed alphabetically and chronologically: Entire 700 articles HERE

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1. Aalto A, Sjowall J, Davidsson L, Forsberg P, Smedby O. Brain magnetic resonance imaging does not contribute to the diagnosis of chronic neuroborreliosis. Acta Radiol 2007; 48: 755-762. [white matter hyperintensities or basal ganglia lesions].HERE

Abstract

Background: Borrelia infections, especially chronic neuroborreliosis (NB), may cause considerable diagnostic problems. This diagnosis is based on symptoms and findings in the cerebrospinal fluid but is not always conclusive.

Purpose: To evaluate brain magnetic resonance imaging (MRI) in chronic NB, to compare the findings with healthy controls, and to correlate MRI findings with disease duration.

Material and Methods: Sixteen well-characterized patients with chronic NB and 16 matched controls were examined in a 1.5T scanner with a standard head coil. T1- (with and without gadolinium), T2-, and diffusion-weighted imaging plus fluid-attenuated inversion recovery (FLAIR) imaging were used.

Results: White matter lesions and lesions in the basal ganglia were seen in 12 patients and 10 controls (no significant difference). Subependymal lesions were detected in patients down to the age of 25 and in the controls down to the age of 43. The number of lesions was correlated to age both in patients (ρ = 0.83, P<0.01) and in controls (ρ = 0.61, P<0.05), but not to the duration of disease. Most lesions were detected with FLAIR, but many also with T2-weighted imaging.

Conclusion: A number of MRI findings were detected in patients with chronic NB, although the findings were unspecific when compared with matched controls and did not correlate with disease duration. However, subependymal lesions may constitute a potential finding in chronic NB.

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2. Abele DC and Anders KH. The many faces and phases of borreliosis. J Am Acad Dermotol 1990; 23:401-410. [chronic Lyme borreliosis].HERE

Abstract

Lyme disease is increasingly being reported throughout the United States and many parts of the world. Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that, not unlike the treponema of syphilis, can cause a spectrum of disease from the initial skin lesion, through widely varied symptoms and signs, to chronic neurologic and arthritic disability. The borrelial spirochete and Lyme disease are the subject of this review. A subsequent article will review other definite and possible cutaneous manifestations of borreliosis.

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3. Aberer E and Klade H. Cutaneous manifestations of Lyme borreliosis. Infection 1991; 19: 284-286. [chronic Lyme borreliosis].HERE

Summary

The dermatological symptoms of Lyme borreliosis present with a typical clinical pattern and characteristic time of appearance. In contrast to other manifestations of Lyme borreliosis they are easily recognizable in most of the cases. In the first stage, erythema migrans arises at the tick bite site. With this symptom the diagnosis of Lyme borreliosis can be established. During all manifestations of Lyme borreliosis the history of erythema migrans is an important parameter to verify the diagnosis. In the early stage of disease a lymphocytic proliferation can appear at the tick bite site, at the ear lobe, or at the mamilla. Borrelia lymphocytoma can be diagnosed when antibodies againstBorrelia burgdorferi are positive. Years after infection, acrodermatitis chronica atrophicans arises at distal body sites causing livid swelling and gradually skin atrophy. Skin lesions can be accompanied by neuropathies, mostly of the lower legs, which in contrast to the skin lesions, do not respond well to antibiotic therapy. There is evidence that some cases of Shulman syndrome, morphea and lichen sclerosus et atrophicus might be related to a borrelia infection as indicated by cultivation ofB. burgdorferi from skin biopsies of morphea and response to antibiotic treatment in some cases. The classical dermatological symptoms of Lyme borreliosis, erythema migrans, borrelia lymphocytoma and acrodermatitis chronica atrophicans respond to oral antibiotic treatment. In acrodermatitis chronica atrophicans parenteral antibiotic therapy is sometimes necessary.

 

4. Aberer E, Breier F, Stanek G, and Schmidt B. Success and failure in the treatment of acrodermatitis chronica atrophicans skin rash. Infection 1996; 24: 85-87.HERE

Summary

To determine the most effective treatment for acrodermatitis chronica atrophicans, several clinical trials were undertaken in recent years to evaluate whether a 2-week course of ceftriaxone would be superior to oral antibiotics. Of the 46 patients suffering from acrodermatitis chronica atrophicans, 14 were treated with ceftriaxone 2g for 15 days. The remaining patients received either oral penicillin V 1.5 million IU t.i.d. or doxycycline 100 mg b.i.d. for 20 to 30 days. Patients were followed up for at least 1 year. Of the 14 ceftriax-one-treated patients four showed incomplete regression of the inflammatory skin changes after 6 to 12 months. Two out of five patients who were monitored forBorrelia burgdorferi DNA excretion were still positive after 12 months as compared to none of six patients who were treated orally for 20–30 days. Six out of 11 patients treated orally for only 20 days needed retreatment after 6 months because of continuing skin manifestations, neuropathy or arthralgia. A 30-day duration of treatment with oral antibiotics and not the chosen antibiotic is crucial for curing acrodermatitis chronica atrophicans. The duration of treatment with ceftriaxone needed for eradication ofBorrelia in acrodermatitis chronica atrophicans has yet to be determined in future studies.

 

5. Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W. Heterogeneity of Borrelia burgdorferi in the skin. Am J Dermatopathol 1996; 18(6): 571-519.

Summary

To determine the most effective treatment for acrodermatitis chronica atrophicans, several clinical trials were undertaken in recent years to evaluate whether a 2-week course of ceftriaxone would be superior to oral antibiotics. Of the 46 patients suffering from acrodermatitis chronica atrophicans, 14 were treated with ceftriaxone 2g for 15 days. The remaining patients received either oral penicillin V 1.5 million IU t.i.d. or doxycycline 100 mg b.i.d. for 20 to 30 days. Patients were followed up for at least 1 year. Of the 14 ceftriax-one-treated patients four showed incomplete regression of the inflammatory skin changes after 6 to 12 months. Two out of five patients who were monitored forBorrelia burgdorferi DNA excretion were still positive after 12 months as compared to none of six patients who were treated orally for 20–30 days. Six out of 11 patients treated orally for only 20 days needed retreatment after 6 months because of continuing skin manifestations, neuropathy or arthralgia. A 30-day duration of treatment with oral antibiotics and not the chosen antibiotic is crucial for curing acrodermatitis chronica atrophicans. The duration of treatment with ceftriaxone needed for eradication ofBorrelia in acrodermatitis chronica atrophicans has yet to be determined in future studies.

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6. Akin E, McHugh Gl, Flavell RA, Fikrig E, Steere AC. The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged Lyme arthritis and the IgG response to P35 with mild and brief arthritis. Infect Immun 1999; 67: 173-181. HERE

ABSTRACT

In an effort to implicate immune responses to specificBorrelia burgdorferi proteins that may have a role in chronic Lyme arthritis, we studied the natural history of the antibody response to B. burgdorferi in serial serum samples from 25 patients monitored throughout the course of Lyme disease. In these patients, the immunoglobulin G (IgM) and IgG antibody responses to 10 recombinant B. burgdorferi proteins, determined during early infection, early arthritis, and maximal arthritis, were correlated with the severity and duration of maximal arthritis. The earliest responses were usually to outer surface protein C (OspC), P35, P37, and P41; reactivity with OspE, OspF, P39, and P93 often developed weeks later; and months to years later, 64% of patients had responses to OspA and OspB. During early infection and early arthritis, the levels of IgG antibody to P35 correlated inversely with the subsequent severity or duration of maximal arthritis. In contrast, during periods of maximal arthritis, the levels of IgG antibody to OspA and OspB, especially to a C-terminal epitope of OspA, correlated directly with the severity and duration of arthritis. Thus, the higher the IgG antibody response to P35 earlier in the infection, the milder and briefer the subsequent arthritis, whereas during maximal arthritis, the higher the IgG response to OspA and OspB, the more severe and prolonged the arthritis.

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7. Albert S, Schulze J, Riegel H, Brade V. Lyme arthritis in a 12-year-old patient after a latency period of 5 years. Infection 1999; 27(4- 5): 286-288.HERE

Summary

Lyme arthritis (LA) may be confused with other rheumatic diseases, particularly in the absence of a history of erythema migrans (EM). We report the case of a 12-year-old patient who developed a large effusion of the tight knee joint. The titer for antinuclear antibodies was 1:80 and the test for rheumatoid factor was negative. – Investigations for antibody response to Borrelia burgdorferi demonstrated remarkable elevation of IgG antibody and no specific IgM response. These results were confirmed by immunoblotting reactivity with the bands p83/100, p58, p43, p41, p39, OspA, p30, OspC, p21, and p17. We subsequently learned that the child had suffered a tick bite followed by an EM 5 years earlier and had been treated with trimethoprim/sulfamethoxazole at that time. The patient now was given intravenous ceftriaxone, 2 g daily for 14 days. In the absence of clinical improvement 3 weeks later a knee joint aspiration was performed which resulted in a positive polymerase chain reaction (PCR) test for B. burgdorferi DNA (OspA) in the synovial fluid. The patient fully recovered 2 months later without further treatment. The case indicates that the latency period between EM and onset of LA may last up to 5 years. In addition to serologic test methods, analysis of synovial fluid using PCR may be decisive for making the final diagnosis of LA

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8. Al-Robaiy S, Dihazi H, Kacza J, et al. Metamorphosis of Borrelia burgdorferi organisms―RNA, lipid and protein composition in context with the spirochete’s shape. J Basic Microbiol 2010, 50 Suppl 1, S5-17. HERE

Abstract

Borrelia burgdorferi, the agent of Lyme borreliosis, has the ability to undergo morphological transformation from a motile spirochetal to non-motile spherical shape when it encounters unfavorable conditions. However, little information is available on the mechanism that enables the bacterium to change its shape and whether major components of the cells--nucleic acids, proteins, lipids--are possibly modified during the process. Deducing from investigations utilizing electron microscopy, it seems that shape alteration begins with membrane budding followed by folding of the protoplasmatic cylinder inside the outer surface membrane. Scanning electron microscopy confirmed that a deficiency in producing functioning periplasmic flagella did not hinder sphere formation. Further, it was shown that the spirochetes' and spheres' lipid compositions were indistinguishable. Neither phosphatidylcholine nor phosphatidylglycerol were altered by the structural transformation. In addition, no changes in differential protein expression were detected during this process. However, minimal degradation of RNA and a reduced antigen-antibody binding activity were observed with advanced age of the spheres. The results of our comparisons and the failure to generate mutants lacking the ability to convert to spheres suggest that the metamorphosis of B. burgdorferi results in a conditional reconstruction of the outer membrane. The spheres, which appear to be more resistant to unfavorable conditions and exhibit reduced immune reactivity when compared to spirochetes, might allow the B. burgdorferi to escape complete clearance and possibly ensure long-term survival in the host.

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9. Appel MJG, Allan S, Jacobson RH, Lauderdale TL, Chang YF, Shin SJ, Thomford JW, Todhunter RJ, and Summers BA. Experimental Lyme disease in dogs produces arthritis and persistent infection. J Inf Dis 1993; 167: 651-664.HERE

ABSTRACT

In specific-pathogen-free dogs experimentally infected with Borrelia burgdorferi by tick exposure, treatment with high doses of amoxicillin or doxycycline for 30 days diminished but failed to eliminate persistent infection. Although joint disease was prevented or cured in five of five amoxicillin- and five of six doxycycline-treated dogs, skin punch biopsies and multiple tissues from necropsy samples remained PCR positive and B. burgdorferi was isolated from one amoxicillin- and two doxycycline-treated dogs following antibiotic treatment. In contrast, B. burgdorferi was isolated from six of six untreated infected control dogs and joint lesions were found in four of these six dogs. Serum antibody levels to B. burgdorferi in all dogs declined after antibiotic treatment. Negative antibody levels were reached in four of six doxycycline- and four of six amoxicillin-treated dogs. However, in dogs that were kept in isolation for 6 months after antibiotic treatment was discontinued, antibody levels began to rise again, presumably in response to proliferation of the surviving pool of spirochetes. Antibody levels in untreated infected control dogs remained high.

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10. Åsbrink E, Hovmark A. Successful cultivation of spirochetes from skin lesions of patients with erythema chronicum migrans, Afzelius and acrodermatis chronica atrophicans. Acta Pathol Microbiol Immunol Sect B 1985; 93: 161-163.HERE

Abstract

C3H/HeJ mice were inoculated intraperitoneally with 10(7) uncloned Borrelia burgdorferi at 4 weeks of age and examined on days 30, 90, 180, and 360. Spirochetes were isolated from multiple tissues at all intervals. Joint and heart disease were present in all mice at 30 days and resolved after 90 days. At 180 and 360 days, some mice had mild recurrent joint and heart disease, and most had peripheral segmental periarteritis. The protein electrophoretic migration of 360-day isolates differed from the original inoculum. The experiment was repeated with C3H/HeN and BALB/cByJ mice inoculated intradermally with 10(4) cloned B. burgdorferi. Characterization of infection and disease at 180 and 360 days were similar to those of the first experiment, but spirochetal proteins of isolates from both intervals displayed no protein variation in electrophoretic mobilities. Spirochetes isolated at 360 days were fully pathogenic in naive mice. Sera from infected mice showed an initial immunoglobulin M response, followed by a sustained immunoglobulin G response, involving IgG1, IgG2a, IgG2b and IgG3, with expanding reactivity against multiple antigens over time. These results indicate that immunocompetent mice sustain persistent infections and develop early acute joint and heart lesions that resolve and then recur intermittently.

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11. Åsbrink E, Hovmark A, and Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakteriol Mikrobiol Hyg A 1986; 26: 253-261. [chronic Lyme borreliosis].HERE

Abstract

A study was made of 50 consecutive patients with untreated acrodermatitis chronica atrophicans (ACA). In all patients elevated anti-spirochetal antibody titers were found at indirect immunofluorescence and enzyme-linked immunosorbent assays, and histologically biopsies exhibited a dermal lymphocytic infiltrate with a moderate to rich admixture of plasma cells and telangiectases. Nine patients had a history consistent with spontaneously healing erythema chronicum migrans Afzelius (ECMA) on the extremity on which, after 0.5-8 years, ACA lesions developed. Eight patients had a history indicating previous cranial nerve involvement and nine had had periods of severe pains in the cervical or lumbar region. Two patients had developed ECMA, facial palsy and ACA in chronological order. In 15 patients radiographic abnormalities of joints and/or bone tissue were found. Besides ACA lesions, lichen sclerosus et atrophicus- or scleroderma-like lesions were found in six patients. The inflammatory ACA lesions were sometimes discrete and had been overlooked. Joint deformities, sclerotic lesions, diffuse edema or pain were the cardinal symptoms in some patients. The findings indicate that clinical recognition of ACA may be difficult and that a combination of clinical, histopathologic and serologic findings may be necessary to establish the diagnosis. The results are consistent with the concept that ACA is a late manifestation of infection by the same spirochete as causes ECMA and Bannwarth's syndrome.

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12. Asch ES, Bujak DI, Weiss M, Peterson MGE, and Weinstein A. Lyme Disease: an infectious and postinfectious syndrome. J Rheumatol 1994; 21 (3): 451-461.HERE

Abstract

OBJECTIVE:

To determine chronic morbidity and the variables that influence recovery in patients who had been treated for Lyme disease.

METHODS:

Retrospective evaluation of 215 patients from Westchester County, NY, who fulfilled Centers for Disease Control case definition for Lyme disease, were anti-Borrelia antibody positive and were diagnosed and treated at least one year before our examination.

RESULTS:

Erythema migrans had occurred in 70% of patients, neurological involvement in 29%, objective cardiac problems in 6%, arthralgia in 78% and arthritis in 41%. Patients were seen at a mean of 3.2 years after initial treatment. A history of relapse with major organ involvement had occurred in 28% and a history of reinfection in 18%. Anti-Borrelia antibodies, initially present in all patients, were still positive in 32%. At followup, 82 (38%) patients were asymptomatic and clinically active Lyme disease was found in 19 (9%). Persistent symptoms of arthralgia, arthritis, cardiac or neurologic involvement with or without fatigue were present in 114 (53%) patients. Persistent symptoms correlated with a history of major organ involvement or relapse but not the continued presence of anti-Borrelial antibodies. Thirty-five of the 114 (31%) patients with persistent symptoms had predominantly arthralgia and fatigue. Antibiotic treatment within 4 weeks of disease onset was more likely to result in complete recovery. Children did not significantly differ from adults in disease manifestations or in the frequency of relapse, reinfection or complete recovery.

CONCLUSION:

Despite recognition and treatment, Lyme disease is associated with significant infectious and postinfectious sequelae

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13. Bankhead T and Chaconas G. The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens. Molecular Microbiology 2007; 65: 1547-1558.HERE

Summary

The linear plasmid, lp28-1, is required for persistent infection by the Lyme disease spirochete, Borrelia burgdorferi. This plasmid contains the vls antigenic variation locus, which has long been thought to be important for immune evasion. However, the role of the vls locus as a virulence factor during mammalian infection has not been clearly defined. We report the successful removal of the vls locus through telomere resolvase-mediated targeted deletion, and demonstrate the absolute requirement of this lp28-1 component for persistence in the mouse host. Moreover, successful infection of C3H/HeN mice with an lp28-1 plasmid in which the left portion was deleted excludes participation of other lp28-1 non-vls genes in spirochete virulence, persistence and the process of recombinational switching at vlsE. Data are also presented that cast doubt on an immune evasion mechanism whereby VlsE directly masks other surface antigens similar to what has been observed for several other pathogens that undergo recombinational antigenic variation.

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14. Barthold SW, Persing DH, Armstrong AL, and Peeples RA. Kinetics of Borrelia burgdorferi dissemination and evolution of disease following intradermal inoculation of mice. Am J Pathol 1991; 139: 263-273. [in mice]HERE

Abstract

Borrelia burgdorferi dissemination to selected target organs was examined on days 1, 2, 3, 4, 7, 10, 15, 21, and 30 after intradermal inoculation of 4-week-old C3H mice. Infection was determined by culture (blood, spleen, kidney, ear punch); polymerase chain reaction (PCR) for outer surface protein A (OSP A) DNA (ear punch); histology and spirochete histochemistry (spleen, kidney, skin, heart, joints); and OSP A DNA in situ hybridization (joints, heart). Blood or spleen of most mice were culture positive by day 3 and ear punch by day 10. Polymerase chain reaction performed on ear punches was also positive by day 10. Inflammation of joints and tendons began on days 4 through 7 and heart on days 7 through 10, which coincided with colonization of tissues with spirochetes. Spirochetes were multifocal in distribution, with a predilection for collagenous connective tissue of joints, heart, arteries, nerves, muscle, skin, and other tissues. Relative numbers of spirochetes peaked at 15 days, then decreased by 21 days. Gamma M immunoglobulin (IgM) antibody was detectable on immunoblots as early as day 4, with subsequent declining reactivity, and IgG antibody was detectable by day 7, with expanding reactivity to multiple antigens through day 30.

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15. Barthold SW, deSouza MS, Janotka JL, Smith AL, and Persing DH. Chronic Lyme borreliosis in laboratory mouse. Am J Pathol 1993; 143: 951-971. [in mice]HERE

Abstract

C3H/HeJ mice were inoculated intraperitoneally with 10(7) uncloned Borrelia burgdorferi at 4 weeks of age and examined on days 30, 90, 180, and 360. Spirochetes were isolated from multiple tissues at all intervals. Joint and heart disease were present in all mice at 30 days and resolved after 90 days. At 180 and 360 days, some mice had mild recurrent joint and heart disease, and most had peripheral segmental periarteritis. The protein electrophoretic migration of 360-day isolates differed from the original inoculum. The experiment was repeated with C3H/HeN and BALB/cByJ mice inoculated intradermally with 10(4) cloned B. burgdorferi. Characterization of infection and disease at 180 and 360 days were similar to those of the first experiment, but spirochetal proteins of isolates from both intervals displayed no protein variation in electrophoretic mobilities. Spirochetes isolated at 360 days were fully pathogenic in naive mice. Sera from infected mice showed an initial immunoglobulin M response, followed by a sustained immunoglobulin G response, involving IgG1, IgG2a, IgG2b and IgG3, with expanding reactivity against multiple antigens over time. These results indicate that immunocompetent mice sustain persistent infections and develop early acute joint and heart lesions that resolve and then recur intermittently.

 

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