Recent Lyme & TBD Abstracts  - ARCHIVE


J Bacteriol. 2010 Oct 8. [Epub ahead of print].

Whole Genome Sequences of Thirteen Isolates of Borrelia burgdorferi.
Schutzer SE, Fraser-Liggett CM, Casjens SR, Qiu WG, Dunn JJ, Mongodin EF, Luft BJ.

Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103; Institute for Genome Sciences, University of Maryland, School of Medicine, Department of Microbiology and Immunology, Baltimore, MD 21201; Department of Pathology, Division of Microbiology and Immunology, University of Utah Medical School, Salt Lake City, UT 84112; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10021; Biology Department, Brookhaven National Laboratory, Upton, NY 11793; Department of Medicine, Health Science Center, Stony Brook University, Stony Brook, NY 11794.

Borrelia burgdorferi is a causative agent of Lyme disease in North America and Eurasia. The first complete genome sequence of B. burgdorferi strain 31, available for more than a decade, has assisted research on the pathogenesis of Lyme disease. Because a single genome sequence is not sufficient to understand the relationship between genotypic and geographic variation and disease phenotype, we determined the whole genome sequences of 13 additional B. burgdorferi isolates that span the range of natural variation. These sequences should allow improved understanding of pathogenesis and provide a foundation for novel detection, diagnosis, and prevention strategies.

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J Med Entomol. 2010 Jul;47(4):695-8.

Trial of a minimal-risk botanical compound to control the vector tick of Lyme disease.
Rand PW, Lacombe EH, Elias SP, Lubelczyk CB, St Amand T, Smith RP Jr.

Vector-Borne Disease Laboratory, Maine Medical Center Research Institute, 75 John Roberts Road, Suite 9B, South Portland, ME 04106, USA. randp@mmc.org

We compared the application of IC2, a minimal-risk (25B) botanical compound containing 10% rosemary oil, with bifenthrin, a commonly used synthetic compound, and with water for the control of Ixodes scapularis Say (= Ixodes dammini Spielman, Clifford, Piesman & Corwin), on tick-infested grids in Maine, in an area where Lyme disease is established and other tick-borne diseases are emerging. High-pressure sprays of IC2, bifenthrin, and water were applied during the peak nymphal (July) and adult (October) seasons of the vector tick. No ticks could be dragged on the IC2 grids within 2 wk of the July spray, and few adult ticks were found in October or the following April. Similarly, no adult ticks could be dragged 1.5 wk after the October IC2 spray, and few the following April. No ticks were found on the bifenthrin grids after either spray through the following April, whereas substantial numbers of ticks remained throughout on the grids sprayed with water. Thus, IC2 appears to be an effective, minimum-risk acaricide to control the vector tick of Lyme disease.

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J Infect Dis. 2010 Jun 15;201(12):1849-58.

Recognition of Borrelia burgdorferi by NOD2 is central for the induction of an inflammatory reaction.
Oosting M, Berende A, Sturm P, Ter Hofstede HJ, de Jong DJ, Kanneganti TD, van der Meer JW, Kullberg BJ, Netea MG, Joosten LA.

Department of Medicine, Nijmegen Institute of Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Toll-like receptor 2 (TLR2) plays an important role in the recognition of Borrelia bacteria, the causative agent of Lyme disease, but the existence and importance of additional receptors in this process has been hypothesized. In the present study, we confirmed the role played by TLR2 in the recognition of Borrelia bacteria but also demonstrated a crucial role for the intracellular peptidoglycan receptor NOD2 for sensing the spirochete. Cells from individuals who were homozygous for the loss-of-function mutation 3020insC in the NOD2 gene were defective with respect to cytokine release after stimulation with Borrelia species, and this was confirmed in peritoneal macrophages from mice lacking RICK, the adaptor molecule used by NOD2. In contrast, NOD1 played no major role in the recognition of Borrelia spirochetes. This raises the intriguing possibility that recognition of Borrelia spirochetes is exerted by TLR2 in combination with NOD2 and that both receptors are necessary for an effective induction of cytokines by Borrelia species. The interplay between TLR2 and NOD2 might not only be necessary for the induction of a proper immune response but may also contribute to inflammatory-induced pathology.

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Clin Vaccine Immunol. 2010 Jun;17(6):904-9. Epub 2010 Apr 14.

Rapid, simple, quantitative, and highly sensitive antibody detection for lyme disease.
Burbelo PD, Issa AT, Ching KH, Cohen JI, Iadarola MJ, Marques A.

Neurobiology and Pain Therapeutics Section, 49 Convent Drive, Building 49, Room 1C20, NIDCR, NIH, Bethesda, MD 20892-4410, USA. burbelop@nidcr.nih.gov

There is currently a need for improved serological tests for the diagnosis and monitoring of Lyme disease, an infection caused by Borrelia burgdorferi. In the present study, we evaluated luciferase immunoprecipitation systems (LIPSs) for use for profiling of the antibody responses to a panel of B. burgdorferi proteins for the diagnosis of Lyme disease. Initially, serum samples from a cohort of patients and controls (n = 46) were used for training and were profiled by the use of 15 different B. burgdorferi antigen constructs. For the patient sera, the antibody responses to several B. burgdorferi antigens, including VlsE, flagellin (FlaB), BmpA, DbpA, and DbpB, indicated that the antigens had high levels of immunoreactivity. However, the best diagnostic performance was achieved with a synthetic protein, designated VOVO, consisting of a repeated antigenic peptide sequence, VlsE-OspC-VlsE-OspC, Analysis of an independent set of serum samples (n = 139) used for validation showed that the VOVO LIPS test had 98% sensitivity (95% confidence interval [CI], 93% to 100%; P < 0.0001) and 100% specificity (95% CI, 94% to 100%; P < 0.0001). Similarly, the C6 peptide enzyme-linked immunosorbent assay (ELISA) also had 98% sensitivity (95% CI, 93% to 100%; P < 0.0001) and 98% specificity (95% CI, 90% to 100%; P < 0.0001). Receiver operating characteristic analysis revealed that the rates of detection of Lyme disease by the LIPS test and the C6 ELISA were not statistically different. However, the VOVO LIPS test displayed a wide dynamic range of antibody detection spanning over 10,000-fold without the need for serum dilution. These results suggest that screening by the LIPS test with VOVO and other B. burgdorferi antigens offers an efficient quantitative approach for evaluation of the antibody responses in patients with Lyme disease.

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PLoS One. 2010 Jun 11;5(6):e10980.

Establishing the Proteome of Normal Human Cerebrospinal Fluid.
Schutzer SE, Liu T, Natelson BH, Angel TE, Schepmoes AA, Purvine SO, Hixson KK, Lipton MS, Camp DG, Coyle PK, Smith RD, Bergquist J.

Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA. schutzer@umdnj.edu

BACKGROUND: Knowledge of the entire protein content, the proteome, of normal human cerebrospinal fluid (CSF) would enable insights into neurologic and psychiatric disorders. Until now technologic hurdles and access to true normal samples hindered attaining this goal. METHODS AND PRINCIPAL FINDINGS: We applied immunoaffinity separation and high sensitivity and resolution liquid chromatography-mass spectrometry to examine CSF from healthy normal individuals. 2630 proteins in CSF from normal subjects were identified, of which 56% were CSF-specific, not found in the much larger set of 3654 proteins we have identified in plasma. We also examined CSF from groups of subjects previously examined by others as surrogates for normals where neurologic symptoms warranted a lumbar puncture but where clinical laboratory were reported as normal. We found statistically significant differences between their CSF proteins and our non-neurological normals. We also examined CSF from 10 volunteer subjects who had lumbar punctures at least 4 weeks apart and found that there was little variability in CSF proteins in an individual as compared to subject to subject. CONCLUSIONS: Our results represent the most comprehensive characterization of true normal CSF to date. This normal CSF proteome establishes a comparative standard and basis for investigations into a variety of diseases with neurological and psychiatric features.

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Philos Ethics Humanit Med. 2010 Jun 9;5:9.

The Infectious Diseases Society of America Lyme guidelines: a cautionary tale about the development of clinical practice guidelines.
W Johnson L, Stricker RB.

California Lyme Disease Association, Ukiah, CA, USA.

Flawed clinical practice guidelines may compromise patient care. Commercial conflicts of interest on panels that write treatment guidelines are particularly problematic, because panelists may have conflicting agendas that influence guideline recommendations. Historically, there has been no legal remedy for conflicts of interest on guidelines panels. However, in May 2008, the Attorney General of Connecticut concluded a ground-breaking antitrust investigation into the development of Lyme disease treatment guidelines by one of the largest medical societies in the United States, the Infectious Diseases Society of America (IDSA). Although the investigation found significant flaws in the IDSA guidelines development process, the subsequent review of the guidelines mandated by the settlement was compromised by a lack of impartiality at various stages of the IDSA review process. This article will examine the interplay between the recent calls for guidelines reform, the ethical canons of medicine, and due process considerations under antitrust laws as they apply to the formulation of the IDSA Lyme disease treatment guidelines. The article will also discuss pitfalls in the implementation of the IDSA antitrust settlement that should be avoided in the future.

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Mil Med. 2010 May;175(5):367-9.

An unexpected case of Lyme disease in a soldier serving in northern Iraq.
Fisher JB, Curtis CE.

Tropic Lightning TMC, Bldg. 677, Schofield Barracks, HI 96857, USA.

Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. Cases have been reported across the United States, Canada, and Europe. Additional cases have been described in other parts of the world including Japan, Mexico, and Turkey. We report an unexpected case of Lyme disease from Iraq.

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PLoS One. 2010 May 14;5(5):e10650

Genotypic variation and mixtures of Lyme Borrelia in Ixodes ticks from North America and Europe.
Crowder CD, Matthews HE, Schutzer S, Rounds MA, Luft BJ, Nolte O, Campbell SR, Phillipson CA, Li F, Sampath R, Ecker DJ, Eshoo MW.

Ibis Biosciences, Carlsbad, California, United States of America.

BACKGROUND: Lyme disease, caused by various species of Borrelia, is transmitted by Ixodes ticks in North America and Europe. Studies have shown the genotype of Borrelia burgdorferi sensu stricto (s.s.) or the species of B. burgdorferi sensu lato (s.l.) affects the ability of the bacteria to cause local or disseminated infection in humans.

METHODOLOGY/PRINCIPAL FINDINGS: We used a multilocus PCR electrospray mass spectrometry assay to determine the species and genotype Borrelia from ticks collected in New York, Connecticut, Indiana, Southern Germany, and California and characterized isolates from parts of the United States and Europe. These analyses identified 53 distinct genotypes of B. burgdorferi sensu stricto with higher resolution than ospC typing. Genotypes of other members of the B. burgdorferi sensu lato complex were also identified and genotyped including B. afzelii, B. garinii, B. lusitaniae, B. spielmanii, and B. valaisiana. While each site in North America had genotypes unique to that location, we found genotypes shared between individual regions and two genotypes found across the United States. Significant B. burgdorferi s.s. genotypic diversity was observed between North America and Europe: only 6.6% of US genotypes (3 of 45) were found in Europe and 27% of the European genotypes (3 of 11) were observed in the US. Interestingly, 39% of adult Ixodes scapularis ticks from North America were infected with more than one genotype of B. burgdorferi s.s. and 22.2% of Ixodes ricinus ticks from Germany were infected with more than one genotype of B. burgdorferi s.l.

CONCLUSIONS/SIGNIFICANCE: The presence of multiple Borrelia genotypes in ticks increases the probability that a person will be infected with more than one genotype of B. burgdorferi, potentially increasing the risks of disseminated Lyme disease. Our study indicates that the genotypic diversity of Borrelia in ticks in both North America and Europe is higher then previously reported and can have potential clinical consequences.

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J Antimicrob Chemother. 2010 Jun;65(6):1137-44. Epub 2010 Apr 9.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systemic review and meta-analysis.
Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA. stephen@doctorsw.com.

BACKGROUND: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect. METHODS: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews. Trials were selected if their patients were randomly allocated to a treatment or placebo group within 72 h following an Ixodes tick bite and had no clinical evidence of Lyme disease at enrollment. Details of the trial design, patient characteristics, interventions and outcomes were extracted from each article. Study quality was assessed using the Jadad scale. RESULTS: Four placebo-controlled clinical trials were included for review. Among 1082 randomized subjects, the risk of Lyme disease in the placebo group was 2.2% [95% confidence interval (CI), 1.2%-3.9%] compared with 0.2% (95% CI, 0.0%-1.0%) in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo (pooled odds ratio=0.084; 95% CI, 0.0020-0.57; P=0.0037). CONCLUSIONS: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

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Environ Health Perspect. 2010 Jul;118(7):909-14. Epub 2010 Mar 25.

Active and passive surveillance and phylogenetic analysis of Borrelia burgdorferi elucidate the process of Lyme disease risk emergence in Canada.
Ogden NH, Bouchard C, Kurtenbach K, Margos G, Lindsay LR, Trudel L, Nguon S, Milord F.

Centre for Food-Borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada. nicholas_ogden@phac-aspc.gc.ca

BACKGROUND: Northward expansion of the tick Ixodes scapularis is driving Lyme disease (LD) emergence in Canada. Information on mechanisms involved is needed to enhance surveillance and identify where LD risk is emerging.

OBJECTIVES: We used passive and active surveillance and phylogeographic analysis of Borrelia burgdorferi to investigate LD risk emergence in Quebec.

METHODS: In active surveillance, we collected ticks from the environment and from captured rodents. B. burgdorferi transmission was detected by serological analysis of rodents and by polymerase chain reaction assays of ticks. Spatiotemporal trends in passive surveillance data assisted interpretation of active surveillance. Multilocus sequence typing (MLST) of B. burgdorferi in ticks identified likely source locations of B. burgdorferi.

RESULTS: In active surveillance, we found I. scapularis at 55% of sites, and we were more likely to find them at sites with a warmer climate. B. burgdorferi was identified at 13 I. scapularis-positive sites, but infection prevalence in ticks and animal hosts was low. Low infection prevalence in ticks submitted in passive surveillance after 2004-from the tick-positive regions identified in active surveillance-coincided with an exponential increase in tick submissions during this time. MLST analysis suggested recent introduction of B. burgdorferi from the northeastern United States.

CONCLUSIONS: These data are consistent with I. scapularis ticks dispersed from the United States by migratory birds, founding populations where the climate is warmest, and then establishment of B. burgdorferi from the United States several years after I. scapularis have established. These observations provide vital information for public health to minimize the impact of LD in Canada.

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J Rheumatol. 2010 May;37(5):1049-55. Epub 2010 Apr 1.

Outcomes of children treated for Lyme arthritis: results of a large pediatric cohort.
Tory HO, Zurakowski D, Sundel RP.

Department of Pediatrics, Yale-New Haven Children's Hospital, New Haven, CT 06520-8064, USA.  heather.tory@yale.edu

OBJECTIVE: Children often develop arthritis secondary to Lyme disease; however, optimal treatment of Lyme arthritis in pediatric patients remains ill-defined. We sought to characterize the outcomes of a large cohort of children with Lyme arthritis treated using the approach recommended by the American Academy of Pediatrics and the Infectious Diseases Society of America.

METHODS: Medical records of patients with Lyme arthritis seen by rheumatologists at a tertiary care children's hospital from 1997 to 2007 were reviewed. Patients were classified with antibiotic responsive or refractory arthritis based on absence or presence of persisting joint involvement 3 months after antibiotic initiation. Treatment regimens and outcomes in patients with refractory arthritis were analyzed.

RESULTS: Of 99 children with Lyme arthritis, 76 had arthritis that responded fully to antibiotics, while 23 developed refractory arthritis. Most patients with refractory arthritis were successfully treated with nonsteroidal antiinflammatory drugs (6 patients), intraarticular steroid injections (4), or disease-modifying antirheumatic drugs (DMARD) (2). Five were lost to followup. Six patients with refractory arthritis were initially treated elsewhere and received additional antibiotic therapy, with no apparent benefit. Three subsequently required DMARD, while 3 had gradual resolution of arthritis without further therapy. Antibiotic responsiveness could not be predicted from our clinical or laboratory data.

CONCLUSION: Lyme arthritis in children has an excellent prognosis. More than 75% of referred cases resolved with antibiotic therapy. Of patients with antibiotic refractory arthritis, none in whom followup data were available developed chronic arthritis, joint deformities, or recurrence of infection, supporting current treatment guidelines.

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Environ Health Perspect. 2010 Jul;118(7):909-14. Epub 2010 Mar 25.

Active and passive surveillance and phylogenetic analysis of Borrelia burgdorferi elucidate the process of Lyme disease risk emergence in Canada.
Ogden NH, Bouchard C, Kurtenbach K, Margos G, Lindsay LR, Trudel L, Nguon S, Milord F.

Centre for Food-Borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada. nicholas_ogden@phac-aspc.gc.ca

BACKGROUND: Northward expansion of the tick Ixodes scapularis is driving Lyme disease (LD) emergence in Canada. Information on mechanisms involved is needed to enhance surveillance and identify where LD risk is emerging.

OBJECTIVES: We used passive and active surveillance and phylogeographic analysis of Borrelia burgdorferi to investigate LD risk emergence in Quebec.

METHODS: In active surveillance, we collected ticks from the environment and from captured rodents. B. burgdorferi transmission was detected by serological analysis of rodents and by polymerase chain reaction assays of ticks. Spatiotemporal trends in passive surveillance data assisted interpretation of active surveillance. Multilocus sequence typing (MLST) of B. burgdorferi in ticks identified likely source locations of B. burgdorferi.

RESULTS: In active surveillance, we found I. scapularis at 55% of sites, and we were more likely to find them at sites with a warmer climate. B. burgdorferi was identified at 13 I. scapularis-positive sites, but infection prevalence in ticks and animal hosts was low. Low infection prevalence in ticks submitted in passive surveillance after 2004-from the tick-positive regions identified in active surveillance-coincided with an exponential increase in tick submissions during this time. MLST analysis suggested recent introduction of B. burgdorferi from the northeastern United States.

CONCLUSIONS: These data are consistent with I. scapularis ticks dispersed from the United States by migratory birds, founding populations where the climate is warmest, and then establishment of B. burgdorferi from the United States several years after I. scapularis have established. These observations provide vital information for public health to minimize the impact of LD in Canada.

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Brain Behav Immun. 2010 Mar 17. [Epub ahead of print]

Anti-neural antibody reactivity in patients with a history of Lyme Borreliosis and persistent symptoms.
Chandra A, Wormser GP, Klempner MS, Trevino RP, Crow MK, Latov N, Alaedini A.

Department of Neurology and Neuroscience, Cornell University, New York, NY, USA.

Some Lyme disease patients report debilitating chronic symptoms of pain, fatigue, and cognitive deficits despite recommended courses of antibiotic treatment. The mechanisms responsible for these symptoms, collectively referred to as post-Lyme disease syndrome (PLS) or chronic Lyme disease, remain unclear. We investigated the presence of immune system abnormalities in PLS by assessing the levels of antibodies to neural proteins in patients and controls. Serum samples from PLS patients, post-Lyme disease healthy individuals, patients with systemic lupus erythematosus, and normal healthy individuals were analyzed for anti-neural antibodies by immunoblotting and immunohistochemistry. Anti-neural antibody reactivity was found to be significantly higher in the PLS group than in the post-Lyme healthy (p<0.01) and normal healthy (p<0.01) groups. The observed heightened antibody reactivity in PLS patients could not be attributed solely to the presence of cross-reactive anti-borrelia antibodies, as the borrelial seronegative patients also exhibited elevated anti-neural antibody levels. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The results provide evidence for the existence of a differential immune system response in PLS, offering new clues about the etiopathogenesis of the disease that may prove useful in devising more effective treatment strategies.

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J Neurobiol Dis. 2010 Mar;37(3):534-41. Epub 2009 Nov 26.

Inflammation and central nervous system Lyme disease.
Fallon BA, Levin ES, Schweitzer PJ, Hardesty D.

Department of Psychiatry, Columbia University, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.

Lyme disease, caused by the bacterium Borrelia burgdorferi, can cause multi-systemic signs and symptoms, including peripheral and central nervous system disease. This review examines the evidence for and mechanisms of inflammation in neurologic Lyme disease, with a specific focus on the central nervous system, drawing upon human studies and controlled research with experimentally infected rhesus monkeys. Directions for future human research are suggested that may help to clarify the role of inflammation as a mediator of the chronic persistent symptoms experienced by some patients despite antibiotic treatment for neurologic Lyme disease.

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Clin Infect Dis. 2010 Feb 15;50(4):512-20.

Antibiotic Treatment Duration and Long-Term Outcomes of Patients with Early Lyme Disease from a Lyme Disease-Hyperendemic Area.
Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA.

Section of Infectious Disease and Departments of Medical Education, Gundersen Lutheran Medical Foundation, La Crosse, WI 54601. USA. TJKowals@gundluth.org.

BACKGROUND: The length of antibiotic therapy and long-term outcomes in patients with early Lyme disease are incompletely described. We report the long-term clinical outcomes of patients with early localized and early disseminated Lyme disease based on the duration of antibiotic therapy prescribed. METHODS: A retrospective cohort study and follow-up survey of patients diagnosed as having early localized and early disseminated Lyme disease from 1 January 2000 through 31 December 2004 was conducted in a Lyme disease-hyperendemic area. RESULTS: Six hundred seven patients met the study inclusion criteria. Most patients (93%) were treated with doxycycline for treatment durations of 10 days, 11-15 days, or 16 days in 17%, 33%, and 47% of doxycycline-treated patients, respectively. Treatment failure criteria, defined before performing the study, were met in only 6 patients (1%). Although these 6 patients met a priori treatment failure criteria, 4 of these patients' clinical details suggested reinfection, 1 was treated with an inappropriate antibiotic, and 1 developed facial palsy early in therapy. Reinfection developed in 4% of patients. The 2-year treatment failure-free survival rates of patients treated with antibiotics for 10 days, 11-15 days, or 16 days were 99.0%, 98.9%, and 99.2%, respectively. Patients treated with antibiotics for 16 days had lower 36-item Short-Form Health Survey social functioning scores on the follow-up survey. No other differences were found in follow-up clinical status or 36-item Short-Form Health Survey scores by duration of antibiotic treatment. CONCLUSIONS: Patients treated for 10 days with antibiotic therapy for early Lyme disease have long-term outcomes similar to those of patients treated with longer courses. Treatment failure after appropriately targeted short-course therapy, if it occurs, is exceedingly rare.

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Minerva Med. 2010 Feb;101(1):1-7.

Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease.
Stricker RB, Green CL, Savely VR, Chamallas SN, Johnson L.

Union Square Medical Associates, San Francisco, CA, USA. rstricker@usmamed.com.

AIM: Although intravenous antibiotic therapy is recommended for neurologic Lyme disease, safety concerns have been raised about treatment beyond 30 days in patients with persistent neurologic symptoms. The goal of our study was to evaluate the safety of extended intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. METHODS: We enrolled 200 consecutive patients with significant neurologic symptoms and positive testing for Borrelia burgdorferi. Patients were treated with intravenous antibiotics using various intravascular devices (IVDs). Standard IVD care was administered to all patients, and monitoring for medication reactions and IVD complications was performed on a weekly basis. RESULTS: The mean length of intravenous antibiotic treatment was 118 days (range, 7-750 days) representing 23,654 IVD-days. Seven patients (3.5%) experienced allergic reactions to the antibiotic medication, and two patients (1.0%) had gallbladder toxicity. IVD complications occurred in 15 patients (7.5%) representing an incidence of 0.63 per 1,000 IVD-days. The IVD problems occurred an average of 81 days after initiation of treatment (range, 7-240 days). There were six suspected line infections for an incidence of 0.25 per 1,000 IVD-days. Only one of the IVD infections was confirmed, and no resistant organisms were cultured from any patient. None of the IVD complications were fatal. CONCLUSION: Prolonged intravenous antibiotic therapy is associated with low morbidity and no IVD-related mortality in patients referred for treatment of neurologic Lyme disease. With proper IVD care, the risk of extended antibiotic therapy in these patients appears to be low.

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Clin Infect Dis. 2010 Jan 1;50(1):20-6.

2-Tiered Antibody Testing for Early and Late Lyme Disease Using Only an Immunoglobulin G Blot with the Addition of a VlsE Band as the Second-Tier Test.
Branda JA, Aguero-Rosenfeld ME, Ferraro MJ, Johnson BJ, Wormser GP, Steere AC.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. branda.john@mgh.harvard.edu.

BACKGROUND: Standard 2-tiered immunoglobulin G (IgG) testing has performed well in late Lyme disease (LD), but IgM testing early in the illness has been problematic. IgG VlsE antibody testing, by itself, improves early sensitivity, but may lower specificity. We studied whether elements of the 2 approaches could be combined to produce a second-tier IgG blot that performs well throughout the infection. METHODS: Separate serum sets from LD patients and control subjects were tested independently at 2 medical centers using whole-cell enzyme immunoassays and IgM and IgG immunoblots, with recombinant VlsE added to the IgG blots. The results from both centers were combined, and a new second-tier IgG algorithm was developed. RESULTS: With standard 2-tiered IgM and IgG testing, 31% of patients with active erythema migrans (stage 1), 63% of those with acute neuroborreliosis or carditis (stage 2), and 100% of those with arthritis or late neurologic involvement (stage 3) had positive results. Using new IgG criteria, in which only the VlsE band was scored as a second-tier test among patients with early LD (stage 1 or 2) and 5 of 11 IgG bands were required in those with stage 3 LD, 34% of patients with stage 1, 96% of those with stage 2, and 100% of those with stage 3 infection had positive responses. Both new and standard testing achieved 100% specificity. CONCLUSIONS: Compared with standard IgM and IgG testing, the new IgG algorithm (with VlsE band) eliminates the need for IgM testing; it provides comparable or better sensitivity, and it maintains high specificity.

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Med Microbiol Immunol. 2010 Jan 6. [Epub ahead of print]

Presence of Borrelia burgdorferi in endomyocardial biopsies in patients with new-onset unexplained dilated cardiomyopathy.
Palecek T, Kuchynka P, Hulinska D, Schramlova J, Hrbackova H, Vitkova I, Simek S, Horak J, Louch WE, Linhart A.

1st Medical Faculty, 2nd Medical Department - Clinical Department of Cardiology and Angiology, Charles University of Prague, Prague, Czech Republic. tpalec@lf1.cuni.cz.

Dilated cardiomyopathy (DCM) represents the third most common cause of heart failure and the most frequent cause of heart transplantation. Infectious, mostly viral, and autoimmune mechanisms, together with genetic abnormalities, have been reported as three major causes of DCM. We hypothesized that Lyme disease (LD), caused by spirochete Borrelia burgdorferi (Bb), might be an important cause of new-onset unexplained DCM in patients living in a highly endemic area for LD such as the Czech Republic. We performed endomyocardial biopsy (EMB) in 39 consecutive patients presenting with symptomatic unexplained left ventricular (LV) systolic dysfunction lasting no more than 12 months. In eight subjects (21%), Bb was detected in the EMB sample by polymerase chain reaction or by electron microscopy. None of these patients exhibited any form of atrioventricular block or other extracardiac manifestation of Bb infection. Serological testing identified IgG antibodies against Bb in only two cases and IgM antibodies in none. All affected patients were treated with intravenous ceftriaxone for 3 weeks. At 6 months follow-up, LV morphology and function as well as functional status of these patients significantly improved. In conclusion, Bb infection may represent an important cause of new-onset unexplained DCM in patients living in endemic regions such as the Czech Republic. Because the antibiotic treatment appears to be markedly effective and serological examination does not provide a tool for diagnosing the disease, EMB focused on the detection of Bb should be performed in all patients from endemic areas with new-onset unexplained DCM not responding to conventional therapy.

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Cent Eur J Public Health. 2009 Dec;17(4):179-82.

Direct detection of Borrelia burgdorferi spirochetes in patients with early disseminated Lyme borreliosis.
Schwarzová K, Kost'anová Z, Holecková K, Spitalská E, Boldis V.

Institute of Virology, Slovak Academy of Sciences, Bratislava. virukats@savba.sk

The detection of spirochetes in 15 patients with clinically documented early disseminated LB has been analysed when using cultivation method of the plasma or the cerebrospinal fluid, electron microscopy, commercial Western blot and detecting the DNA of the pathogen in vitro cultures by PCR-RFLP. Spirochetes were isolated in eight blood and one cerebrospinal fluid culture samples. In seven cases (47%), previous serodiagnostic laboratory tests were negative. Borrelial DNA was detected by PCR in 67% patients (9 blood samples and 1 CSF sample). Using Msel restriction fragments of PCR products of the amplified rrf-rrl region, we identified Borrelia garinii (80%), one B. afzelii isolate and one B. burgdorferi s.s.

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J Econ Entomol. 2009 Dec; 102 (6):2316-24.

Ability of two natural products, nootkatone and carvacrol, to suppress Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae) in a Lyme disease endemic area of New Jersey.
Dolan MC, Jordan RA, Schulze TL, Schulze CJ, Manning MC, Ruffolo D, Schmidt JP, Piesman J, Karchesy JJ.

Division of Vector-Borne Infectious Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80521, USA. mat.pound@ars.usda.gov

We evaluated the ability of the natural, plant-derived acaricides nootkatone and carvacrol to suppress Ixodes scapularis Say and Amblyomma americanum (L.) (Acari: Ixodidae). Aqueous formulations of 1 and 5% nootkatone applied by backpack sprayer to the forest litter layer completely suppressed I. scapularis nymphs through 2 d. Thereafter, the level of reduction gradually declined to < or =50% at 28 d postapplication. Against A. americanum nymphs, 1% nootkatone was less effective, but at a 5% concentration, the level of control was similar or greater to that observed with I. scapularis through 21 d postapplication. Initial applications of 0.05% carvacrol were ineffective, but a 5% carvacrol formulation completely suppressed nymphs of both species through 2 d and resulted in significant reduction in I. scapularis and A. americanum nymphs through 28 and 14 d postapplication, respectively. Backpack sprayer applications of 5% nootkatone to the shrub and litter layers resulted in 100% control of I. scapularis adults through 6 d, but the level of reduction declined to 71.5% at 28 d postapplication. By contrast, high-pressure applications of 2% nootkatone to the litter layer resulted in 96.2-100% suppression of both I. scapularis and A. americanum nymphs through 42 d, whereas much lower control was obtained from the same formulation applied by backpack sprayer. Backpack sprayer application of a 3.1% nootkatone nanoemulsion resulted in 97.5-98.9 and 99.3-100% reduction in I. scapularis and A. americanum nymphs, respectively, at 1 d postapplication. Between 7 d and 35 d postapplication, the level of control varied between 57.1% and 92.5% for I. scapularis and between 78.5 and 97.1% for A. americanum nymphs. The ability of natural products to quickly suppress and maintain significant control of populations of these medically important ticks at relatively low concentrations may represent a future alternative to the use of conventional synthetic acaricides.

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Arthritis Rheum. 2009 Dec;60(12):3831-40.

HLA-DR alleles determine responsiveness to Borrelia burgdorferi antigens in a mouse model of self-perpetuating arthritis.

Iliopoulou BP, Guerau-de-Arellano M, Huber BT.

Tufts University, Boston, Massachusetts 02111, USA.

OBJECTIVE: Arthritis is a prominent manifestation of Lyme disease, which is caused by infection with Borrelia burgdorferi (Bb). Chronic Lyme arthritis persisting even after antibiotic treatment is linked to HLA-DRB1*0401 (DR4) and related alleles. In contrast, patients whose Lyme arthritis resolves within 3 months postinfection show an increased frequency of HLA-DRB1*1101 (DR11). The aim of this study was to analyze the underlying mechanism by which HLA-DR alleles confer genetic susceptibility or resistance to antibiotic-refractory Lyme arthritis. METHODS: We generated DR11-transgenic (DR11-Tg) mice on a murine MHCII-/- background and compared their immune response to Bb antigens with the response of DR4-Tg mice after immunization with Bb outer surface protein A (OspA) or infection with live Bb. RESULTS: T cells from OspA-immunized and Bb-infected DR11-Tg mice had defective production of interferon-gamma as compared with those from DR4-Tg mice. In contrast, DR11-Tg mice developed higher titers of anti-OspA and anti-Bb antibodies, respectively, than did DR4-Tg mice. Consistent with this observation, we found that the Bb-infected DR11-Tg mice had a decreased spirochetal burden as compared with the DR4-Tg mice, as measured by quantitative polymerase chain reaction. CONCLUSION: This study provides direct evidence that in the presence of HLA-DR11, the immune response against Bb antigens is directed toward a protective antibody response. In contrast, an inflammatory Th1 response is induced in the presence of DR4. These observations offer an explanation for the differential genetic susceptibility of DR4+ and DR11+ individuals to the development of chronic Lyme arthritis and, eventually, the progression to antibiotic-refractory Lyme arthritis.

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Proc Biol Sci. 2009 Nov 22;276(1675):3911-9. Epub 2009 Aug 19.

Hosts as ecological traps for the vector of Lyme disease.
Keesing F, Brunner J, Duerr S, Killilea M, Logiudice K, Schmidt K, Vuong H, Ostfeld RS.

Department of Biology, Bard College, Annandale, NY 12504, USA. keesing@bard.edu.

Vectors of infectious diseases are generally thought to be regulated by abiotic conditions such as climate or the availability of specific hosts or habitats. In this study we tested whether blacklegged ticks, the vectors of Lyme disease, granulocytic anaplasmosis and babesiosis can be regulated by the species of vertebrate hosts on which they obligately feed. By subjecting field-caught hosts to parasitism by larval blacklegged ticks, we found that some host species (e.g. opossums, squirrels) that are abundantly parasitized in nature kill 83-96% of the ticks that attempt to attach and feed, while other species are more permissive of tick feeding. Given natural tick burdens we document on these hosts, we show that some hosts can kill thousands of ticks per hectare. These results indicate that the abundance of tick vectors can be regulated by the identity of the hosts upon which these vectors feed. By simulating the removal of hosts from intact communities using empirical models, we show that the loss of biodiversity may exacerbate disease risk by increasing both vector numbers and vector infection rates with a zoonotic pathogen.

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Cell Host Microbe. 2009 Nov 19;6(5):482-92.

Antibodies against a Tick Protein, Salp15, Protect Mice from the Lyme Disease Agent.
Dai J, Wang P, Adusumilli S, Booth CJ, Narasimhan S, Anguita J, Fikrig E.

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Traditionally, vaccines directly target a pathogen or microbial toxin. Lyme disease, caused by Borrelia burgdorferi, is a tick-borne illness for which a human vaccine is not currently available. B. burgdorferi binds a tick salivary protein, Salp15, during transmission from the vector, and this interaction facilitates infection of mice. We now show that Salp15 antiserum significantly protected mice from B. burgdorferi infection. Salp15 antiserum also markedly enhanced the protective capacity of antibodies against B. burgdorferi antigens, such as OspA or OspC. Mice actively immunized with Salp15 were also significantly protected from tick-borne Borrelia. In vitro assays showed that Salp15 antiserum increased the clearance of Salp15-coated B. burgdorferi by phagocytes, suggesting a mechanism of action. Vaccination with a vector molecule that a microbe requires for infection of the mammalian host suggests a new strategy for the prevention of Lyme disease, and this paradigm may be applicable to numerous arthropod-borne pathogens of medical importance.

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MMWR Morb Mortal Wkly Rep. 2009 Sep 25;58(37):1033-6.

Anaplasmosis and ehrlichiosis - Maine, 2008.
Centers for Disease Control and Prevention (CDC).

Anaplasmosis and ehrlichiosis are rickettsial tickborne diseases that have had at least a twofold increase in prevalence in the United States since 2000. Despite similar clinical presentations, the causative organisms are carried by different ticks with distinct geographic and ecologic associations. Surveillance efforts are complicated by ambiguous terminology and serologic testing with antibody cross-reactivity. Although anaplasmosis historically has been reported in Maine, ehrlichiosis has been reported infrequently. During 2007-2008, the number of physician-reported anaplasmosis cases nearly doubled in Maine, and ehrlichiosis cases increased more than fourfold. To examine this increase, the Maine Department of Health and Human Services (MDHHS) analyzed available data on tick burden and physician-reported cases of anaplasmosis and ehrlichiosis during 2000-2008. This report describes the results of that analysis, which indicated that Ixodes scapularis (the tick vector for Anaplasma phagocytophilum) was broadly distributed in Maine, whereas Amblyomma americanum (the tick vector for Erhlichia chaffeenisis) was scarce. Moreover, 95% of physician-reported ehrlichiosis cases lacked a concurrent serologic assessment to exclude anaplasmosis, suggesting that antibody cross-reactivity might have resulted in misclassification. In 2008, Maine modified case classification to enhance specificity; ehrlichiosis cases that lack a concurrent test for anaplasmosis are now classified as suspect rather than probable and therefore are not included in national surveillance summaries. The accuracy of case classification and surveillance can be improved by educating health-care providers regarding 1) the expected geographic distribution of tick vectors and 2) recommendations for confirmatory testing to distinguish between the causative organisms of anaplasmosis and ehrlichiosis.

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Pediatr Dermatol. 2009 Sep-Oct;26(5):635-6.

Lyme Disease as a Cause of Acropapular Dermatitis of Childhood.
Kennedy CE, Azfar RS, Honig PJ.

Department of Medicine, University of California, San Diego, USA.

Acropapular dermatitis of childhood is a symmetric self-limited papulovesicular exanthem that classically occurs on the cheeks, extensor extremities, and buttocks in young children. The eruption of acropapular dermatitis of childhood represents a reaction to a variety of infections usually of viral origin. We present a child with typical findings of acropapular dermatitis of childhood whose serologic workup revealed an acute Lyme infection.

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J Med Entomol.2009 May; 46(3):557-65.

Isolation of Entomopathogenic Fungi From Soils and Ixodes scapolaris (Acari: Ixodidae) Ticks: Prevalence and Methods.
Tuininga AR, Miller JL, Morath SU, Daniels TJ, Falco RC, Marchese M, Sahabi S, Rosa D, Stafford KC 3rd.

Fordham University, Louis Calder Center and Department of Biological Sciences, Armonk, NY 10504, USA. tuininga@fordham.edu

Entomopathogenic fungi are commonly found in forested soils that provide tick habitat, and many species are pathogenic to Ixodes scapularis Say, the blacklegged tick. As a first step to developing effective biocontrol strategies, the objective of this study was to determine the best methods to isolate entomopathogenic fungal species from field-collected samples of soils and ticks from an Eastern deciduous forest where I. scapularis is common. Several methods were assessed: (1) soils, leaf litter, and ticks were plated on two types of media; (2) soils were assayed for entomopathogenic fungi using the Galleria bait method; (3) DNA from internal transcribed spacer (ITS) regions of the nuclear ribosomal repeat was extracted from pure cultures obtained from soils, Galleria, and ticks and was amplified and sequenced; and (4) DNA was extracted directly from ticks, amplified, and sequenced. We conclude that (1) ticks encounter potentially entomopathogenic fungi more often in soil than in leaf litter, (2) many species of potentially entomopathogenic fungi found in the soil can readily be cultured, (3) the Galleria bait method is a sufficiently efficient method for isolation of these fungi from soils, and (4) although DNA extraction from ticks was not possible in this study because of small sample size, DNA extraction from fungi isolated from soils and from ticks was successful and provided clean sequences in 100 and 73% of samples, respectively. A combination of the above methods is clearly necessary for optimal characterization of entomopathogenic fungi associated with ticks in the environment.

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N Engl J Med. 2009 May 14;360(20):2099-107.

Fatal case of deer tick virus encephalitis.
Tavakoli NP, Wang H, Dupuis M, Hull R, Ebel GD, Gilmore EJ, Faust PL.

C Wadsworth Center, New York State Department of Health and the Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York, USA. norma.tavakoli@wadsworth.org

Deer tick virus is related to Powassan virus, a tickborne encephalitis virus. A 62-year-old man presented with a meningoencephalitis syndrome and eventually died. Analyses of tissue samples obtained during surgery and at autopsy revealed a widespread necrotizing meningoencephalitis. Nucleic acid was extracted from formalin-fixed tissue, and the presence of deer tick virus was verified on a flavivirus-specific polymerase-chain-reaction (PCR) assay, followed by sequence confirmation. Immunohistochemical analysis with antisera specific for deer tick virus identified numerous immunoreactive neurons, with prominent involvement of large neurons in the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord. This case demonstrates that deer tick virus can be a cause of fatal encephalitis. 2009 Massachusetts Medical Society

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Vector Borne Zoonotic Dis. 2009 Sep 2. (Epub ahead of print).

Assessment of Polymicrobial Infections in Ticks in New York State.
Tokarz R, Jain K, Bennett A, Briese T, Ian Lipkin W.

Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY.

Ixodes scapularis ticks are clinically important hematophagous vectors. A single tick bite can lead to a polymicrobial infection. We determined the prevalence of polymicrobial infection with Borrelia burgdorferi, Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and Powassan virus in 286 adult ticks from the two counties in New York State where Lyme disease is endemic, utilizing a MassTag multiplex polymerase chain reaction assay. Seventy-one percent of the ticks harbored at least one organism; 30% had a polymicrobial infection. Infections with three microbes were detected in 5% of the ticks. One tick was infected with four organisms. Our results show that coinfection is a frequent occurrence in ticks in the two counties surveyed.

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Vector Borne Zoonotic Dis. 2009 Aug;9(4):439-48.

The United States Department of Agriculture's Northeast Area-wide Tick Control Project: summary and conclusions.
Pound JM, Miller JA, George JE, Fish D, Carroll JF, Schulze TL, Daniels TJ, Falco RC, Stafford KC, Mather TN.

Knipling-Bushland U.S. Livestock Insects Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Kerrville, Texas 78028-9184, USA.  mat.pound@ars.usda.gov

From 1997 to 2002, the U.S. Department of Agriculture's Northeast Area-wide Tick Control Project used acaricide-treated 4-Poster Deer Treatment Bait Stations in five eastern states to control ticks feeding on white-tailed deer. The objectives of this host-targeted technology were to reduce free-living blacklegged (Ixodes scapularis Say) and lone star (Amblyomma americanum [L.]) tick populations and thereby to reduce the risk of tick-borne disease. During 2002 to 2004, treatments were suspended, and tick population recovery rates were assayed. Subsequently, the major factors that influenced variations in efficacy were extrapolated to better understand and improve this technology. Treatments resulted in significant reductions in free-living populations of nymphal blacklegged ticks at six of the seven sites, and lone star ticks were significantly reduced at all three sites where they were present. During the study, maximal significant (p < or = 0.05) efficacies against nymphal blacklegged and lone star ticks at individual sites ranged from 60.0 to 81.7 and 90.9 to 99.5%, respectively. The major environmental factor that reduced efficacy was the occurrence of heavy acorn masts, which provided an alternative food resource for deer. Although the 4-Poster technology requires 1 or more years to show efficacy, this host-targeted intervention was demonstrated to be an efficacious, economical, safe, and environment-friendly alternative to area-wide spraying of acaricide to control free-living populations of these tick species.

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Vector Borne Zoonotic Dis. 2009 Aug;9(4):423-30.

Evaluation of the United States Department of Agriculture Northeast Area-wide Tick Control Project by meta-analysis.
Brei B, Brownstein JS, George JE, Pound JM, Miller JA, Daniels TJ, Falco RC, Stafford KC 3rd, Schulze TL, Mather TN, Carroll JF, Fish D.

Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, Connecticut, USA.

As part of the Northeast Area-wide Tick Control Project (NEATCP), meta-analyses were performed using pooled data on the extent of tick-vector control achieved through seven concurrent studies, conducted within five states, using U.S. Department of Agriculture "4-Poster" devices to deliver targeted-acaricide to white-tailed deer. Although reductions in the abundance of all life-stages of Ixodes scapularis were the measured outcomes, this study focused on metrics associated with I. scapularis nymphal tick densities as this measure has consistently proven to directly correlate with human risk of acquiring Lyme disease. Since independent tick sampling schemes were undertaken at each of the five environmentally distinct study locations, a meta-analytic approach permitted estimation of a single true control-effect size for each treatment year of the NEATCP. The control-effect is expressed as the annual percent I. scapularis nymphal control most consistent with meta-analysis data for each treatment year. Our meta-analyses indicate that by the sixth treatment year, the NEATCP effectively reduced the relative density of I. scapularis nymphs by 71% on the 5.14 km(2) treatment sites, corresponding to a 71% lower relative entomologic risk index for acquiring Lyme disease.

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J Neuroinflammation.  2009 Aug 25;6:23.  

Possible role of glial cells in the onset and progression of Lyme neuroborreliosis.
Ramesh G, Borda JT, Gill A, Ribka EP, Morici LA, Mottram P, Martin DS, Jacobs MB, Didier PJ, Philipp MT.

Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA, USA. gramesh@tulane.edu

BACKGROUND: Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis. METHODS: We inoculated live B. burgdorferi into the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG). RESULTS: ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferi C6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive for B. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detected B. burgdorferi antigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis. CONCLUSION: Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

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Pediatrics. 2009 May;123(5):e835-41.

Lyme carditis in children: presentation, predictive factors, and clinical course.
Costello JM, Alexander ME, Greco KM, Perez-Atayde AR, Laussen PC.

Harvard Medical School, Division of Cardiac Intensive Care, Department of Cardiology, Children's Hospital Boston, 300 Longwood Ave, Bader 600, Boston, MA 02115, USA. john.costello@cardio.chboston.org

OBJECTIVES: We sought to identify predictive factors for Lyme carditis in children and to characterize the clinical course of these patients. METHODS: We reviewed all cases of early disseminated Lyme disease presenting to our institution from January 1994 through July 2008, and summarized the presentation and course of those patients with carditis. A case-control study was used to identify predictive factors for carditis. Controls were patients with early disseminated Lyme disease without carditis. RESULTS: Of 207 children with early disseminated Lyme disease, 33 (16%) had carditis, 14 (42%) of whom had advanced heart block, including 9 (27%) with complete heart block. The median time to recovery of sinus rhythm in these 14 patients was 3 days (range: 1-7 days), and none required a permanent pacemaker. Four (12%) of 33 patients with carditis had depressed ventricular systolic function, 3 (9%) of whom required mechanical ventilation, temporary pacing, and inotropic support. Complete resolution of rhythm disturbances and myocardial dysfunction occurred in 24 (89%) of 27 patients for whom follow-up data were available. Most patients with carditis also had other systemic Lyme involvement. By using multivariate logistic regression analysis, we found that children >10 years of age, those with arthralgias, and those with cardiopulmonary symptoms were more likely to have carditis. CONCLUSIONS: The spectrum of presentation for children with Lyme carditis is broad, ranging from asymptomatic, first-degree heart block to fulminant myocarditis. Variable degrees of heart block are the most common manifestation and occasionally require temporary pacing. Transient myocardial dysfunction, although less common, can be life-threatening. Advanced heart block resolves within 1 week in most cases. In children with early disseminated Lyme disease, older age, arthralgias, and cardiopulmonary symptoms independently predict the presence of carditis.

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Pediatrics. 2009 May;123(5):e829-34.

Prospective validation of a clinical prediction model for Lyme meningitis in children.
Garro AC, Rutman M, Simonsen K, Jaeger JL, Chapin K, Lockhart G.

Rhode Island Hospital, Pediatric Emergency Medicine, Claverick Building, 2nd Floor, Providence, RI 02906, USA. agarro@lifespan.org

OBJECTIVE: Lyme meningitis is difficult to differentiate from other causes of aseptic meningitis in Lyme disease-endemic regions. Parenteral antibiotics are indicated for Lyme meningitis but not viral causes of aseptic meningitis. A clinical prediction model was developed to distinguish Lyme meningitis from other causes of aseptic meningitis. Our objective was to prospectively validate this model. METHODS: Children between 2 and 18 years of age presenting to Hasbro Children's Hospital from April through October of 2006 and 2007 were enrolled if a lumbar puncture for meningitis showed a cerebrospinal fluid white blood cell count of >8 cells per microL. Cerebrospinal fluid was sent for Lyme antibody testing. The probability of Lyme meningitis was calculated by using the percentage of cerebrospinal fluid mononuclear cells, duration of headache, and presence of cranial neuropathy by using the prediction model. Definite Lyme meningitis cases were defined as cerebrospinal fluid pleocytosis with (1) positive Lyme serology confirmed by immunoblot or (2) erythema migrans rash. Possible Lyme meningitis cases were defined as cerebrospinal fluid pleocytosis with positive cerebrospinal fluid Lyme antibody. Sensitivity, specificity, and likelihood ratios for definite and possible Lyme meningitis were determined by using 10% increments of calculated probability of Lyme meningitis. RESULTS: Fifty children were enrolled, including 14 children with definite Lyme meningitis, 6 with possible Lyme meningitis, and 30 with aseptic meningitis. A calculated probability of <10% for Lyme meningitis had a negative likelihood ratio of 0.006 for definite and possible Lyme meningitis cases. A calculated probability of >50% for Lyme meningitis had a positive likelihood ratio of 100 using these definitions. CONCLUSIONS: A clinical prediction model using the percentage of cerebrospinal fluid mononuclear cells, headache duration, and presence of cranial neuropathy can differentiate children with Lyme meningitis from children with aseptic meningitis. Our findings suggest categories of low (<10%), indeterminate (10%-50%), and high (>50%) probability of Lyme meningitis.

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Arch Gen Psychiatry. 2009;66(5):554-563.

Regional Cerebral Blood Flow and Metabolic Rate in Persistent Lyme Encephalopathy.
Fallon BA, Lipkin RB, Corbera KM, Yu S, Nobler MS, Keilp JG, Petkova E, Lisanby SH, Moeller JR, Slavov I, Van Heertum R, Mensh BD, Sackeim, HA.

Columbia University, 1051 Riverside Drive, Unit 69, New York, NY 10032, USA. baf1@columbia.edu

Context  There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease.   Objectives  To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR).

Design  Case-controlled study.  Setting  A university medical center.  Participants  A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment.  Main Outcome Measures  Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia). Results  Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (< .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements. Conclusions  Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

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J Infect Dis. 2009 May 1;199(9):1379-88.

The Antibiotics Doxycycline and Minocycline Inhibit the Inflammatory Responses to the Lyme Disease Spirochete Borrelia burgdorferi.
Bernardino AL, Kaushal D, Philipp MT.

Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana.

Tetracyclines moderate inflammatory responses of various etiologies. We hypothesized that tetracyclines, in addition to their antimicrobial function, could exert control over the inflammation elicited by Borrelia burgdorferi. To model systemic effects, we used the human monocytic cell line THP-1; to model effects in the central nervous system, we used rhesus monkey brain astrocytes and microglia. Cells were stimulated with live or sonicated B. burgdorferi or with the lipoprotein outer surface protein A in the presence of increasing concentrations of doxycycline or minocycline. Both antibiotics significantly reduced the production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 in a dose-dependent manner in all cell types. Microarray analyses of the effect of doxycycline on gene transcription in spirochete-stimulated monocytes revealed that the NFKB and CHUK (alias, IKKA) genes were down-regulated. Functionally, phosphorylation of IkappaBalpha and binding of NF-kappaB to target DNA were both reduced in these cells. Our results suggest that tetracyclines may have a dual therapeutic effect in Lyme disease.

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Arthritis Rheum. 2009 Apr;60(4):1179-86.

HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination.
Ball R, Shadomy SV, Meyer A, Huber BT, Leffell MS, Zachary A, Belotto M, Hilton E, Bryant-Genevier M, Schriefer ME, Miller FW, Braun MM.

Center for Biologics Evaluation and Research, FDA, Rockville, Maryland, USA. Robert.Ball@fda.hhs.gov

OBJECTIVE: To investigate whether persons with treatment-resistant Lyme arthritis-associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. METHODS: Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA-DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. RESULTS: Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5-4.4), and 1.75 (95% CI 0.6-5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5-5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2-2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1-0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). CONCLUSION: Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases.

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Pediatrics. 2009 Mar;123(3):959-65.

Acute pediatric monoarticular arthritis: distinguishing lyme arthritis from other etiologies.
Thompson A, Mannix R, Bachur R.

Children's Hospital Boston, Division of Emergency Medicine, 300 Longwood Ave, Boston, MA 02115, USA. amy.thompson@childrens.harvard.edu

OBJECTIVE: Identify clinical predictors of Lyme arthritis among patients with acute monoarticular arthritis. METHODS: A medical chart review was conducted of children </=18 years of age with monoarticular arthritis who underwent arthrocentesis in a pediatric emergency department located in the northeast United States. Patients were classified into 3 categories of arthritis: septic, Lyme, or nonseptic non-Lyme arthritis. Historical, clinical, and laboratory data were compared to identify distinguishing features of Lyme arthritis. RESULTS: One hundred seventy-nine patients were studied: 46 (26%) patients with septic arthritis, 55 (31%) patients with Lyme arthritis, and 78 (43%) patients with nonseptic non-Lyme arthritis. Compared with those with septic arthritis, patients with Lyme disease were more likely to have a tick-bite history, knee involvement, and less likely to have a history of fever or elevated temperature at triage. Erythrocyte sedimentation rate, C-reactive protein, joint white blood cell count, and joint neutrophil percentage were also statistically lower. In comparison to nonseptic non-Lyme arthritis, knee involvement and tick-bite history were predictors of Lyme. Erythrocyte sedimentation rate, joint white blood cell count, and joint neutrophil percentage were also statistically different. Multivariate analysis comparing Lyme to septic arthritis demonstrated fever history and elevated C-reactive protein level to be negative predictors of Lyme arthritis and knee involvement to be a positive predictor (model sensitivity: 88%; specificity: 82%). CONCLUSIONS: Lyme arthritis shares features with both septic and nonseptic non-Lyme arthritis. This overlap prevents the creation of a clinically useful predictive model for Lyme arthritis. In endemic areas, Lyme testing should be performed on all patients presenting with acute monoarticular arthritis.

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Scand J Immunol. 2009 Jan;69(1):64-9.

Complement split products c3a and c4a in chronic lyme disease.
Stricker RB, Savely VR, Motanya NC, Giclas PC.

International Lyme and Associated Diseases Society, Bethesda, MD, USA. rstricker@usmamed.com

Complement split products C3a and C4a are reportedly elevated in patients with acute Lyme disease. We have now examined these immunologic markers in patients with chronic Lyme disease compared to appropriate disease controls. The study population consisted of 29 healthy controls, 445 patients with chronic Lyme disease, 11 patients with systemic lupus erythematosus (SLE) and six patients with AIDS. The Lyme disease patients were divided according to predominant musculoskeletal symptoms (324 patients) or predominant neurologic symptoms (121 patients). C3a and C4a levels were measured by radioimmunoassay. All patients with chronic Lyme disease and AIDS had normal C3a levels compared to controls, whereas patients with SLE had significantly increased levels of this marker. Patients with predominant musculoskeletal symptoms of Lyme disease and AIDS patients had significantly increased levels of C4a compared to either controls, patients with predominant neurologic symptoms of Lyme disease or SLE patients. Response to antibiotic therapy in chronic Lyme disease was associated with a significant decrease in the C4a level, whereas lack of response was associated with a significant increase in this marker. In contrast, AIDS patients had persistently increased C4a levels despite antiretroviral therapy. Lyme patients with positive single-photon emission computed tomographic (SPECT) scans had significantly lower C4a levels compared to Lyme patients with normal SPECT scan results. Patients with predominant musculoskeletal symptoms of Lyme disease have normal C3a and increased C4a levels. This pattern differs from the increase in both markers seen in acute Lyme disease, and C4a changes correlate with the response to therapy in chronic Lyme disease. C4a appears to be a valuable immunologic marker in patients with persistent symptoms of Lyme disease.

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J Med Entomol. 2009 Jan;46(1):131-8.

Detection of Borrelia burgdorferi and Borrelia lonestari in birds in Tennessee.
Jordan BE, Onks KR, Hamilton SW, Hayslette SE, Wright SM.

University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Lyme disease in the United States is caused by the bacterial spirochete Borrelia burgdorferi s.s. (Johnson, Schmid, Hyde, Steigerwalt, and Brenner), which is transmitted by tick vectors Ixodes scapularis (Say) and I. pacificus (Cooley and Kohls). Borrelia lonestari, transmitted by the tick Amblyomma americanum L., may be associated with a related syndrome, southern tick-associated rash illness (STARI). Borrelia lonestari sequences, reported primarily in the southeastern states, have also been detected in ticks in northern states. It has been suggested that migratory birds may have a role in the spread of Lyme disease spirochetes. This study evaluated both migratory waterfowl and nonmigratory wild turkeys (Meleagris gallopavo silvestris, Eastern wild turkey) for B. burgdorferi and B. lonestari DNA sequences. A total of 389 avian blood samples (163 migratory birds representing six species, 125 wild turkeys harvested in habitats shared with migratory birds, 101 wild turkeys residing more distant from migratory flyways) were extracted, amplified, and probed to determine Borrelia presence and species identity. Ninety-one samples were positive for Borrelia spp. Among migratory birds and turkeys collected near migration routes, B. burgdorferi predominated. Among turkeys residing further away from flyways, detection of B. lonestari was more common. All A. americanum ticks collected from these areas were negative for Borrelia DNA; no I. scapularis were found. To our knowledge, this represents the first documentation of B. lonestari among any birds.

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Pediatr Infect Dis J. 2008 Dec;27(12):1089-94.

Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome.

Skogman BH, Croner S, Nordwall M, Eknefelt M, Ernerudh J, Forsberg P.

Pediatric Clinic at the University Hospital, Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. hedinskogman@ltdalarna.se

BACKGROUND: Evaluation of children with clinically suspected neuroborreliosis (NB) is difficult. With a prospective study design we wanted to characterize children with signs and symptoms indicative for NB, investigate clinical outcome and, if possible, identify factors of importance for recovery. MATERIAL/METHODS: Children being evaluated for NB (n = 177) in southeast Sweden were categorized into 3 groups: "confirmed neuroborreliosis" (41%) with Borrelia antibodies in the cerebrospinal fluid, "possible neuroborreliosis" (26%) with pleocytosis but no Borrelia antibodies in the cerebrospinal fluid, and "not determined" (33%) with no pleocytosis and no Borrelia antibodies in the cerebrospinal fluid. Antibiotic treatment was given to 69% of children. Patients were followed during 6 months and compared with a matched control group (n = 174). RESULTS: Clinical recovery at the 6-month follow-up (n = 177) was generally good and no patient was found to have recurrent or progressive neurologic symptoms. However, persistent facial nerve palsy caused dysfunctional and cosmetic problems in 11% of patients. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. Influence on daily life was reported to the same extent in patients and controls. Consequently, persistent headache and fatigue at follow-up should not be considered as attributable to NB. No prognostic factors could be identified. CONCLUSIONS: Clinical recovery was satisfactory in children being evaluated for NB although persistent symptoms from facial nerve palsy occurred. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls.

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Arthritis Rheum. 2008 Dec 15;59(12):1742-9.

Role of psychiatric comorbidity in chronic Lyme disease.

Hassett AL, Radvanski DC, Buyske S, Savage SV, Gara M, Escobar JI, Sigal LH.

University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903-0019, USA. a.hassett@umdnj.edu

OBJECTIVE: To evaluate the prevalence and role of psychiatric comorbidity and other psychological factors in patients with chronic Lyme disease (CLD). METHODS: We assessed 159 patients drawn from a cohort of 240 patients evaluated at an academic Lyme disease referral center. Patients were screened for common axis I psychiatric disorders (e.g., depressive and anxiety disorders); structured clinical interviews confirmed diagnoses. Axis II personality disorders, functional status, and traits like negative and positive affect and pain catastrophizing were also evaluated. A physician blind to psychiatric assessment results performed a medical evaluation. Two groups of CLD patients (those with post-Lyme disease syndrome and those with medically unexplained symptoms attributed to Lyme disease but without Borrelia burgdorferi infection) were compared with 2 groups of patients without CLD (patients recovered from Lyme disease and those with an identifiable medical condition explaining symptoms attributed to Lyme disease). RESULTS: After adjusting for age and sex, axis I psychiatric disorders were more common in CLD patients than in comparison patients (P = 0.02, odds ratio 2.64, 95% confidence interval 1.30-5.35), but personality disorders were not. Patients with CLD had higher negative affect, lower positive affect, and a greater tendency to catastrophize pain (P < 0.001) than comparison patients. All psychological factors except personality disorders were related to level of functioning. A predictive model based on these psychological variables was confirmed. Fibromyalgia was diagnosed in 46.8% of CLD patients. CONCLUSION: Psychiatric comorbidity and other psychological factors distinguished CLD patients from other patients commonly seen in Lyme disease referral centers, and were related to poor functional outcomes.

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Arthritis Rheum. 2008 Dec;58(12):3892-901.

Persistent arthritis in Borrelia burgdorferi-infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment.

Iliopoulou BP, Alroy J, Huber BT.

Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

OBJECTIVE: The immunologic events that lead to persistent joint inflammation in certain patients with Lyme arthritis post-antibiotic treatment have been elusive so far. The prevalence of this condition is highest in individuals with rheumatoid arthritis-associated HLA-DR alleles. This study was undertaken to generate a murine model with persistent arthritis post-antibiotic treatment. METHODS: We have previously shown that CD28(-/-) mice develop intermittent monarticular Lyme arthritis that is responsive to antibiotics. Since there seems to be a link in humans between persistent arthritic manifestations post-antibiotic treatment and the HLA-DR4 allele, we generated DR4+/+CD28(-/-)MHCII(-/-) mice, infected them with Borrelia burgdorferi, and subsequently treated them with antibiotics. RESULTS: Thirty-eight percent of the B burgdorferi-infected DR4+/+CD28(-/-)MHCII(-/-) mice, but none of the B burgdorferi-infected CD28(-/-)MHCII(-/-) mice, remained arthritic post-antibiotic treatment. A significant fraction (36%) of these mice, but none of the mice in which arthritis resolved, had serum antibodies to outer surface protein A of B burgdorferi. After abrogation of active B burgdorferi infection, the inflammatory reaction in mice with persistent joint inflammation was restricted to the joints, since their draining lymph nodes were no longer enlarged. Increased CD20 and interferon-gamma messenger RNA expression in the inflamed joints of these mice suggested a possible role of B cells and inflammatory cytokines in the pathogenesis of persistent arthritis post-antibiotic treatment. CONCLUSION: The establishment of this murine model allows, for the first time, the elucidation of the immunologic events that lead to persistent Lyme arthritis post-antibiotic therapy in genetically susceptible individuals.

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Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19863-8. Epub 2008 Dec 5.

NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.

Tupin E, Benhnia MR, Kinjo Y, Patsey R, Lena CJ, Haller MC, Caimano MJ, Imamura M, Wong CH, Crotty S, Radolf JD, Sellati TJ, Kronenberg M.

Divisions of Developmental Immunology and Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037, USA.

Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR alpha chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Valpha14i NKT cell-deficient (Jalpha18(-/-)) BALB/c mice. On tick inoculation with B. burgdorferi, Jalpha18(-/-) mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Valpha14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Valpha14i NKT cells. Valpha14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNgamma in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Valpha14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.

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Am J Pathol. 2008 Nov;173(5):1415-27. Epub 2008 Oct 2.

Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis.

Ramesh G, Borda JT, Dufour J, Kaushal D, Ramamoorthy R, Lackner AA, Philipp MT.

Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.

Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi, often manifests by causing neurocognitive deficits. As a possible mechanism for Lyme neuroborreliosis, we hypothesized that B. burgdorferi induces the production of inflammatory mediators in the central nervous system with concomitant neuronal and/or glial apoptosis. To test our hypothesis, we constructed an ex vivo model that consisted of freshly collected slices from brain cortex of a rhesus macaque and allowed live B. burgdorferi to penetrate the tissue. Numerous transcripts of genes that regulate inflammation as well as oligodendrocyte and neuronal apoptosis were significantly altered as assessed by DNA microarray analysis. Transcription level increases of 7.43-fold (P = 0.005) for the cytokine tumor necrosis factor-alpha and 2.31-fold (P = 0.016) for the chemokine interleukin (IL)-8 were also detected by real-time-polymerase chain reaction array analysis. The immune mediators IL-6, IL-8, IL-1beta, COX-2, and CXCL13 were visualized in glial cells in situ by immunofluorescence staining and confocal microscopy. Concomitantly, significant proportions of both oligodendrocytes and neurons undergoing apoptosis were present in spirochete-stimulated tissues. IL-6 production by astrocytes in addition to oligodendrocyte apoptosis were also detected, albeit at lower levels, in rhesus macaques that had received in vivo intraparenchymal stereotaxic inoculations of live B. burgdorferi. These results provide proof of concept for our hypothesis that B. burgdorferi produces inflammatory mediators in the central nervous system, accompanied by glial and neuronal apoptosis.

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eurology. 2008 Mar 25;70(13):992-1003. Epub 2007 Oct 10.

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, Nelson DR, Sackeim HA.

Columbia University, 1051 Riverside Drive, Unit 69, New York, NY 10032, USA. baf1@columbia.edu

BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

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Appl Neuropsychol. 2008;15(3):208-19.

Memory and executive functions in adolescents with posttreatment Lyme disease.

McAuliffe P, Brassard MR, Fallon B.

Teacher's College, Columbia University New York, New York 10027, USA. drmcauliffe@gmail.com

Although adults with late stage posttreatment Lyme disease often experience difficulties in memory, little is known about the relationship between cognition and Lyme disease in children and adolescents. Twenty-five adolescents with late stage posttreatment Lyme disease (symptoms > 6 months) and 25 participants without Lyme disease (matched on gender, IQ, age, socioeconomic status) were assessed for neuropsychological functioning, depression, school functioning, and predisease academic achievement. The Lyme group had significant deficits in cognition (short-term visual memory, short-term and delayed verbal memory, all forms of recognition memory), as well as worse attendance, grades, and subjective reports of memory problems, without differing in predisease achievement or depression. Deficits in visual memory exceeded deficits in verbal memory-a striking difference from what is reported in adults. These results reveal that adolescents with a history of treated Lyme disease are at risk for long-term problems in cognition and school functioning.

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Microbes Infect. 2006; Nov-Dec;8(14-15):2832-40. Epub 2006 Sep 22.

Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.

Livengood JA, Gilmore RD Jr.

Centers for Disease Control and Prevention, Division of Vector-borne Infectious Diseases, 3150 Rampart Road, CSU Foothills Campus, Fort Collins, CO 80522, USA.

Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems. To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A non-infectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS.

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J Infect Dis. 2004; May 15;189(10):1881-91. Epub 2004 Apr 26.

Borrelia-specific interferon-gamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome.
Widhe M
, Jarefors S, Ekerfelt C, Vrethem M, Bergstrom S, Forsberg P, Ernerudh J.

Divisions of Clinical Immunology and Infectious Diseases, Department of Molecular and Clinical Medicine, Linkoping University, Linkoping, Sweden. mona.widhe@imk.liu.se

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.








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Lyme and Tick-Borne Research Center - images