Lyme disease

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This presentation tackles the controversy regarding Lyme disease by reviewing the evidence for immune evasion and persistent infection by the Lyme spiorchete, Borrelia burgdorferi. The evidence shows that physicians called upon to assist patients with this potential diagnosis should be open to the possibility of persistent infection even in patients who have already received antibiotic treatment for their condition. Lacking evidence on how best to treat a chronic infection of this kind, physicians should be allowed to rely on their experience and to exercise their best clinical judgment in managing patients with Lyme disease.

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Lyme disease

  1. 1. Lyme DiseaseA Systems Medicine Approach Keith Berndtson, MD
  2. 2. Lyme Wars, circa 2013 ILADSIs not a persistent infection! vs. Is so a persistent infection!
  3. 3. The 2011 Institute of Medicine ReportUnderpowered studies that purport todemonstrate universal efficacy must beviewed with circumspection.Everyone is studying the early stage of thisinfection; no one is studying the persistentphase of the disease. It is important that 2011those studies occur.All the bitterness of the debate does notserve the science or the patient...[it]drowns out the complexity and nuance ofthe work that needs to be done.
  4. 4. What is the physician’s dutywhen assisting patients with Lyme disease? Know and teach the evidence for immune evasion and persistent infection in Lyme disease. Learn the varied clinical presentations of Lyme disease. Apply evidence-based care strategies within a shared decision-making model that respects patient values. Monitor and document clinical outcomes. Hippocratic Oath on papyrus, 200 AD
  5. 5. 2012 Yale Lyme Risk Map• Map produced by the Yale School of Public Health• Released February, 2012• Includes a high risk “sliver” in Northern Illinois• Most of Northern Illinois considered a transitional area
  6. 6. July 2012 Illinois Tick survey56.4% of over 1,067 ticks collected from 17 sites in Cook, Lake, McHenry, and DuPage counties were deer ticks.
  7. 7. Bloated tick on a Cedar WaxwingDispersal of Borrelia burgdorferiby songbirds can help accountfor the dramatic increase in theincidence of tick-borne diseasesin North America and Europeover the past 16 years.
  8. 8. Research shows a 7 to 10- fold increase in Chicago area Bb-infected deer ticks between 2005 and 2007.In a 2007 tick survey of Lake and Cook Questing Deer tickcounties, 37% of adult deer ticks collectedwere + for Borrelia burgdorferi. (1)A 2006 report by this team found that Borrelia burgdorferionly 3-5% of adult deer ticks in Cook andDuPage counties were + for Bb. (2)(1) Jobe DA, Nelson JA, Adam MD, Martin SA.Lyme disease in urban areas, Chicago. EmergingInfectious Diseases. 2007;13(11):1799-1800.(2) Jobe DA, Lovrich SD, Nelson JA, et al. Borreliaburgoderferi in Ixodes scapularis ticks, Chicagoarea. Emerging Infectious Diseases.2006;12:1039-1041.
  9. 9. Evidence for ImmuneEvasion in Lyme Disease Cross-disciplinary studies
  10. 10. Evidence for Immune Evasion in Lyme Disease A Flexibly Adaptive Genome“Borrelia species may well have the mostunusual genomes on the planet. No otherbacteria have such a large complement ofextra-chromosomal elements. Theyperform an uncommon process known astelomere resolution that can explain thewide-ranging variability in linear plasmidsize, content, and sequence scrambling.” - George Chaconas, the Canadian Society for Microbiology Murray Lecture Canadian Journal Microbiology 2011;58(3):236-48.
  11. 11. Evidence for Immune Evasion in Lyme Disease Bb Commandeers Tick Salivary Protein Tick salivary protein (Salp-15) binds to CD4 on T helper cells and to OspC on Bb, which delays the humoral response to Bb, allowing early dissemination into connective tissue and the central nervous system. Salp-15 and OspC collaborate to enhance the virulence of Bb during the early stages of infection. Hovius J, et. al. Tick-host-pathogen interactions in Lyme borreliosis. Trends in Parasitology 2007;23(9):434-438.Ramamoorthi N, et al. The Lyme disease antigen exploits a tick protein to infect the mammalian host. Nature 2005;436(7050):573-7.
  12. 12. Evidence for Immune Evasion in Lyme Disease Antigen Masking Kurtenbach K, et al. Host association of Bb sensu lato - the key role of host complement. Trends in Microbiology. 2002;10(2): 74-9. Bb’s Factor H “hall pass”Bb evades complement-mediated killing by interacting with complement regulators throughdistinct complement regulator-acquiring surface proteins (CRASPs). CRASP-1 is a multifunctionalprotein of Bb that binds to several human extracellular matrix proteins and plasminogen. Theseinteractions contribute to adhesion, bacterial colonization, and organ tropism and assist withdissemination of Bb in the host. Kraiczy P, Stevenson B. Complement regulator-acquiring surface proteins of Bb: structure, function, and regulation of gene expression. Ticks and Tick Borne Diseases. 2013 Feb;4(1-2):26-34.
  13. 13. Evidence for Immune Evasion in Lyme DiseaseBb Usurps the Host’s Plasminogen Activating System The Blood-Brain Barrier Plasmin + MMPs Bb spirochete able to disrupt tight junctions causing a leaky blood-brain barrier and a portal of entry into the brain. Bb’s outer membrane protein, OspC, binds to plasminogen, activating the serine protease, plasmin. Plasmin induces the release of collagenases and MMPs (matrix metallproteinases), which enhance Bb’s ability to pass through tight junctions. Bb thus usurps the fibrinolytic pathways of its host to help it penetrate otherwise impermeable tissue barriers. The result: rapid deep tissue invasion. Hu LT, et al. Binding of human plasminogen to Borrelia burgdorferi. Infection and Immunity. 1995 Sep;63(9):3491-6. Toledo A, et al. The enolase of Borrelia burgdorferi is a plasminogen receptor released in outer membrane vesicles. Infection and Immunity. 2012 Jan;80(1):359-68.
  14. 14. Evidence for Immune Evasion in Lyme DiseaseBb Encodes for “Best in Class” Antigenic Variation 15  silent  vls  casse-es expressed  vlsE  casse-eThe VlsE sequence variants produce different antigen epitopes. Recombination occurs continuously duringmammalian infection and plays a key role in immune evasion and the long-term survival of Bb in humans. Norris SJ. How do Lyme Borrelia organisms cause disease? The quest for virulence determinants. Open Neurology Journal. 2012;6(Suppl 1-M8):119-123.Ongoing antigenic variation frustrates the host’s antibody response to Borrelia burgdorferi. B-cells becomeconfused, causing excess B-cell traffic in lymph nodes and a weak and delayed marrow plasma cell response.Hastey CJ, et al. Delays and diversions mark the development of B cell responsesto Borrelia burgdorferi infections. Journal of Immunology 2012;188(11):5612-22.
  15. 15. Sources of Immune Evasion in Lyme Disease Atypical FormsRolled forms A cystic form. Bb strain ADBI thickened membrane Bb strain B31The results indicate that atypical extra- and intracellular pleomorphic and cystic forms of Borreliaburgdorferi and local neuroinflammation occur in the brain in chronic Lyme neuroborreliosis.The persistence of these more resistant spirochete forms, and their intracellular location inneurons and glial cells, may explain the long latent stage and persistence of Borrelia infection. Mikossly J, et al. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme borreliosis. J Neuroinflammation 2008;5:40.
  16. 16. Sources of Immune Evasion in Lyme Disease Atypical Forms Rolled forms of Bb Cystic forms of Bb. Plasma membrane Cystic forms of Bb. inside cystic structure (i) thinner than extracystic plasma membrane (e).Brorsson O, Brorsson SH. Transformation of cystic forms of Miklossy J, et al. Persisting atypical and cystic forms ofBorrleia burgdorferi to normal, mobile spirochetes. Infection Borrelia burgdorferi and local inflammation in Lyme1997;4:241-46. borreliosis. J Neuroinflammation 2008;5:40.
  17. 17. Sources of Immune Evasion in Lyme Disease Horizontal Gene Transfer Conjugation TransformationGene transfer by bacterial conjugation and by DNA transformation happensefficiently in biofilms, and this process helps stabilize the biofilm structure. Molin S. Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilization of the biofilm structure. Curremt OPinions in Biotechnology. 2003;14:255-261.
  18. 18. Evidence for Immune Evasion in Lyme Disease Advanced Motility Capabilities
  19. 19. Evidence for Immune Evasion in Lyme Disease High Performance Flagellar Motors
  20. 20. Evidence for Immune Evasion in Lyme Disease Elite Flagellar Design
  21. 21. Evidence for Immune Evasion in Lyme Disease Advanced Flagellar Maneuverability
  22. 22. Evidence for Immune Evasion in Lyme DiseaseEvasive Chemotaxis and Niche-Seeking Behavior Moriarty TJ, et al. Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of the living host. PLoS Pathogen 2008;4(6).
  23. 23. Evidence for Immune Evasion in Lyme Disease Movement through Vascular Walls Moriarty TJ, et al. Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of the living host. PLoS Pathogen 2008;4(6).
  24. 24. Evidence for Immune Evasion in Lyme Disease Rapid Escape from Vascular Compartment into the Extracellular MatrixSpirochetes would transmigrate through the venule wall, typically at the endothelialcell junctions, and escape into the surrounding extracellular matrix in a process thataveraged 10.8 minutes. The speed of the final escape yielded images in whichspirochetes appeared to burst away from the vessel. The matrix is like a sanctuaryfrom immune traffic, and Bb escapes to it in a hurry. Moriarty TJ, et al. Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of the living host. PLoS Pathogen 2008;4(6).
  25. 25. Evidence for Immune Evasion in Lyme Disease Bb Quorum Sensing and Biofilm-Like Behavior Sapi E, et al. Characterization of biofilm formation by Borrelia burgdorferi In Vitro. PLoS ONE;7(10):e48277. Bb respond to AI-2 by expressing factor H-binding protein to enhance immune evasion. Babb K, et al. Synthesis of autoinducer-2 by the Lyme disease spirochete. Journal of Bacteriology 2005;187:3079-87.Stevenson B, et al. LuxS-mediated quorum sensing in the Lyme disease spirochete. Infection and Immunity 2002;70:4099-4105.
  26. 26. Evidence for Immune Evasion in Lyme Disease Biofilm-Like AggregationsBb-induced effects included multilevel arrangements of alginates, calcium, andextracellular DNA, highly consistent with biofilm. Bb grown on agarose-coated micadiscs. Imaged by atomic force microscopy, measurements made with Nanorule software. Sapi E, et al. Characterization of biofilm formation by Borrelia burgdorferi In Vitro. PLoS ONE;7(10):e48277.
  27. 27. Evidence for PersistentInfection in Lyme Disease Definitive studies
  28. 28. Evidence for Persistent Infection in Lyme Disease Barthold, 2010 Forms of proof given for post-antibiotic persistence of viable and infective Bb in this study: Allograft -transmissible Bb Xenodiagnosis -Bb acquisition by ticks -Bb transmission by ticks -Bb survival through tick life cycle .. .. RNA transcripts .. .. .. - showing metabolically .. .. .. active, viable Bb ..
  29. 29. Evidence for Persistent Infection in Lyme Disease Yrjanainen, 2010 Forms of proof given for post-antibiotic persistence of viable Bb in this study: .. Culture .. from tissue samples .. of mice treated with anti-TNFa 4 weeks post antibiotic treatment .. ....
  30. 30. Evidence for Persistent Infection in Lyme Disease Embers, 2012 Forms of proof given for post-antibiotic persistence of viable and infective Bb in this study: Xenodiagnosis acquisition transmission Culture Immunofluorescence PCR C6 antibody .. Bb antigen .. .. .. .. RNA transcripts
  31. 31. Conclusions1. Bb has an unusually adaptive combined genome that encodes for a powerful set of immune evasion capabilities.2. Bb exploits tick and host proteins, antigen masking and variation, elite motility skills, strategic niche-seeking, horizontal gene transfer, atypical forms, biofilm-like behavior, and antibiotic tolerance to help it persist within mammalian hosts.3. In mice and primates, Bb subsets are proven to remain viable and infective despite culture negativity following antibiotic challenge.4. Immune suppressed mice are more susceptible to the reactivation of viable Bb that persist despite antibiotic challenge.5. Solid evidence supports the existence of persistent Lyme disease. Health care policy needs to accommodate efforts to prevent, detect, and treat it.
  32. 32. Added Sources ofComplexity in Lyme Disease Clinical Considerations
  33. 33. Sources of Added Complexity in Lyme Disease Co-infectionsAnaplasmosis Babesiosis Bartonella EhrlichiosisGranulocytes Red blood cells Red blood cells Monocytes WBCs, RBCs, platelets Fever, chills, sweats Endothelial cells Fever, chills, body achesElevated liver enzymes Headache, fatigue Fever, rash, headache Confusion, GIFever, chills, aches Ring forms, Maltese cross Fatigue, brain fog disturbanceHeadache, diarrhea Howell-Jolly bodies Endocarditis, sore soles Headache Morula (colony) formsBorreliaburgdorferi (124 strains), afzellii, garinii (European forms)50+ symptoms reported, invasion of most tissues documented, primarily connective tissue, synovium, liver,testes, pelvic organs, central, peripheral, and autonomic nervous system cells, heart cells, and immune cells. A new breed of polymicrobial, polyphasic infection?
  34. 34. Sources of Added Complexity in Lyme Disease Deer Tick Co-infection Rates Among 286 Ixodes scapularis ticks collected in this study: Borrelia + Borrelia + Borrelia + Borrelia Anaplasma Babesia Anaplasma+ Anaplasma Babesia Babesia% positive 182 (64%) 56 (20%) 58 (20%) 45 (16%) 48 (17%) 14 (5%) ticks Assessment of polymicrobial infections in ticks in New York State. Vector Borne Zoonotic Diseases. 2010 Apr;10(3):217-221.
  35. 35. Sources of Added Complexity in Chronic Lyme Disease Co-morbid Conditions in the Host Autoimmune Disease Chronic Allergic Toxicity Sensitivities Psychosocial Degenerative Stresses Lyme Disease Mood or Metabolic Cognitive Disease Disorders Co-infections
  36. 36. Sources of Added Complexity in Chronic Lyme Disease Host Genetic VariationsThe influence of tumor necrosis factor alpha (TNFa) in Bb infection is well documented.There seems to be a polarity in host reactions, perhaps related to gene polymorphisms inTNFa or in promoter genes for the pro-inflammatory cytokines. This results in weaker orstronger cell-mediated immune responses. In pathology studies of neurological Lyme disease, the following polarity is seen: Infiltrative Atrophic cerebral vasculitis frontotemporal atrophy multi-infarct dementia white matter lesions hypoperfusion inflammation apoptosisMiklossy J. Biology and neuropathology of dementia in syphilis and Lyme disease. In Handbook of ClinicalNeurology, vol. 89, 2008, Elsevier: New York.
  37. 37. Sources of Added Complexity in Chronic Lyme Disease The Limits of Diagnostic Testing ILADS• Prefers higher sensitivity on Western Blot • Prefers higher specificity on Western Blot• Tolerates a higher false positive rate • Tolerates a higher false negative rate The search is on for biomarkers with better abilities to rule in (ILADS) and rule out (IDSA) cases of persistent Lyme and associated diseases.
  38. 38. Sources of Added Complexity in Chronic Lyme Disease The Limits of Therapy There is to date no known therapy for the post-Lyme residual autoimmune condition postulated by IDSA-aligned researchers. NIH-sponsored clinical trials were underpowered and likely ILADS underestimate the benefits of antibiotic therapy in chronic Lyme patients. There is no surefire way of proving total eradication of viable Lyme spirochetes. Guidelines for selecting therapies for patients with chronic Lyme continues to rest on a weak evidence base. For this reason, physicians should be allowed to select therapies based on pathophysiologic rationales supported by clinical experience and judgment, with decisions that reflect patient values and preferences.
  39. 39. Sources of Added Complexity in Chronic Lyme Disease Patients Caught in the Crossfire Given the lack of reliable biomarkers for use in monitoring responses to therapy for chronic Lyme disease, outcomes evaluation must rely on methods for assessing the subjective dimensions of the patient’s experience with therapy. Who will help me? OverallThe Rationalists Function The Empiricists Physical Symptoms ? ? Mental Outlook Social ILADSFinding reasons Finding reasons not to treat to treat
  40. 40. Dimensional Outcomes AssessmentsDimensional assessment tools usedin NIH-funded chronic Lymetreatment studies:*• Quality of Life Score (SF-36)• Fibromyalgia Impact Questionnaire (FIQ)• Fatigue Severity Scale (FSS)• Neurocognitive Dysfunction Index (NDI)• McGill Pain Questionnaire (MPQ)• Medical Outcome Scale (MOS)* Klempner, Krupp, and FallonVisual analog scale for practice-basedoutcomes monitoring• Review of Systems Scale (ROSS)
  41. 41. We Need a More Integrative Medical Model• Evidence-based medicine 2.0• Built to handle complexity• Patient values respected• Shared decision-making• Clinical experience valued• Empirical trials encouraged• Dimensional outcome tracking• Biopsychosocial awareness• Systems theory and practice A Systems Medicine Model
  42. 42. Repairing the Broken Bridge All the bitterness of the debate does not serve the science or the patient...all theshouting drowns out the complexity and nuance of the work that needs to be done. - Institute of Medicine Lyme Report, 2011Physicians must be allowed to use current evidence, experience, and clinical judgment to address the complexity of patients with tick-borne illness. - Keith Berndtson, MD
  43. 43. Patient-centered systems medicine. 15 N. Prospect Park Ridge, IL 60068 847-232-9800www.parkridgemultimed.com

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