Best Brains Exchange Report – Lyme Disease Diagnostics

The Canadian Institutes of Health Research (CIHR)
In collaboration with The Public Health Agency of Canada (PHAC)

CIHR Boardroom
160 Elgin Street
Ottawa, Ontario
Monday, June 29, 2015

Table of Contents

  1. Executive Summary
  2. Setting the Stage: Lyme Diagnostics – The Current State of Affairs
  3. Post-treatment Lyme Disease Syndrome and Chronic Lyme Disease
  4. Plenary Discussion
  5. Development of the Lyme Diagnostic Service in Scotland
  6. The Challenges in Developing a Lyme Disease Diagnostic: Lessons from Oncology
  7. Plenary Discussion
  8. Next Steps
  9. Conclusion

1. Executive Summary

About the Best Brains Exchange

The Best Brains Exchange (BBE) is a one-day, in-camera meeting for policy makers and researchers to: highlight existing and relevant research evidence on the topic; identify where the gaps in evidence lie; bring together both decision maker and researcher expertise on the issue; and, candidly discuss the applicability of the research.

The BBE on Lyme disease diagnostics was hosted by the Canadian Health Institutes of Health Research (CIHR) in collaboration with the Public Health Agency of Canada (the Agency) and provided an opportunity for over 35 key stakeholders from across sectors, jurisdictions and disciplines to respectfully share insight and unique perspectives on the topic of the diagnosis of Lyme disease caused by Borrelia burgdorferi. The focus of this BBE was on facilitating a dialogue of research evidence and identifying areas for further research on Lyme disease diagnostics.

A complete list of participants is provided in Appendix 1 of this report.

Background

Lyme disease is an infectious, vector-borne disease that is forecast to continue to spread in Canada’s most populous regions over the next decade. The number of reported cases of Lyme disease in Canada has increased significantly since it first became nationally notifiable - from 128 in 2009 to 522 in 2014. Based on current trends, Lyme disease cases in Canada are forecast to rise to 15,000 annually in the next decade.

Diagnosing Lyme disease can be difficult. Symptoms can vary from one person to another, and can be similar to a multitude other chronic illnesses and infectious diseases. The earlier a diagnosis is received, the greater the chances of a successful treatment. However, due to the individual nature of the natural process the human body takes to develop antibodies, blood tests may be negative in patients with early Lyme disease. The accuracy of blood tests becomes more reliable as the infection progresses.

While the accuracy of the tests is acceptable in late infection, it is possible that a small proportion of patients with late-stage Lyme disease may also test negative. As well, the differences in severity, types of symptoms suffered and length of illness across a broad span of patients are not clearly understood. More research is necessary to improve diagnostic testing sensitivity and to gain a better understanding of how Lyme disease symptoms present across a wide range of patients in order to better diagnose patients.

Meeting objectives

 The agenda for this meeting was developed with a focus on the following two questions:

  1. How effective are current diagnostic tests in detecting Lyme disease (during early disseminated, late disseminated and post-treatment phases)?
  2. What novel methods show promise in improving patient diagnosis?

Overview of the meeting

Four presentations addressed key topics related to the many challenges of Lyme disease diagnostics and treatment:

  • Todd Hatchette, Chief, Division of Microbiology, Department of Pathology and Laboratory Medicine, Nova Scotia Health Authority & Professor, Department of Pathology, Dalhousie University: Lyme diagnostics – The Current State of Affairs.
  • John Aucott, Director, Lyme disease Clinical Research Center, Division of Rheumatology, Johns Hopkins University: Post-treatment Lyme Disease Syndrome and Chronic Lyme Disease.
  • Sally Mavin, Clinical Scientist, National Lyme Borreliosis Testing Laboratory (Inverness, Scotland): Development of the Lyme Diagnostic Service in Scotland.
  • Mark Duncan, Professor, School of Medicine, Endocrinology, Metabolism and Diabetes, University of Colorado: The Challenges in Developing a Lyme Disease Diagnostic: Lessons from Oncology.

The agenda and speaker biographies are provided in Appendix 2 and 3 of this report.

Key Questions Discussed

The following seven questions formed the basis of the three plenary sessions at the BBE:

  1. What is the science of current diagnostics telling us? Where are the gaps?
  2. Where do we need to focus efforts for improvement in the science of Lyme diagnostics?
  3. Are there lessons learned/best practices from other parts of the world that we can apply?
  4. Are there lessons learned that we could apply from diagnostics in other diseases?
  5. How do we plan for and implement transformation and innovation in Lyme diagnostics?
  6. What are the key research questions and concepts that need to be shared within the academic community?
  7. How do we get more researchers involved in this area?

2. Setting the Stage: Lyme Diagnostics – The Current State of Affairs

Dr. Todd Hatchette, Chief, Division of Microbiology, Department of Pathology and Laboratory Medicine, Dalhousie University truly set the stage for the day.

There are numerous diagnostic challenges. The performance of serology depends on the stage of the infection. The predominant limitation of the current testing is poor sensitivity in identifying early localized infection. A similar challenge is that positive Lyme serology can persist for 10 years or more making diagnosis of re-infection problematic.

No test has 100% sensitivity and specificity. The predicative value of each test directly relates to the pre-test probability that someone has the infection based on presenting symptoms and prevalence of the infection.

Laboratories are unable to detect re-infection using serology because positive serology in treated individuals can persist for a decade or more and no pattern has been identified to differentiate re-infection from previous infections. In addition, there is no test of cure and no diagnostic testing for Post Treatment Lyme Disease Syndrome.

Key elements in defining Lyme diagnostics depend on the stage of the illness. This review focused on the first three stages of Lyme: Early localized Lyme disease (30 days); early disseminated Lyme disease (< 3 months); and late Lyme disease (> 3 months). It does not refer to Post Lyme disease Syndrome.

Early localized Lyme disease refers to the early local manifestations suggestive of Borrelia burgdorferi infection including fever, headache and myalgia with the presence of a single, localized skin lesion known as erythema migrans (EM). Early disseminated Lyme disease usually involves multiple EM or cardiac abnormalities or arthralgia or neurologic symptoms such as facial nerve palsies.

Late manifestations refer to those that happen more than 4-6 weeks after infection but less than three months, which are usually arthritis and neuroborelliosis.

The current recommendation is if you assess a patient with signs/symptoms of early localized Lyme disease, you should treat them first and not test them. This recognizes the limitations of serology in diagnosing early localized infection.

Two-tier testing is the testing method recommended by the Center for Disease Control and Prevention in the US and the Canadian Public Health Laboratory Network. In two tier testing, patients with suspect B. burgdorferi infection have serum taken and tested with an ELISA (step/tier one). If the ELISA is negative, the serum is not tested further. If the ELISA is positive (or indeterminate), the specimen is tested by Western Blot (2nd step or tier). There are challenges with the Western Blot method – it does not perform equally well in all stages of infection. The main limitation is during the early stage of infection. There are a number of prospective studies that have evaluated the performance of 2-tier testing suggesting the accuracy in late Lyme infection is high. Attempting to culture B. burgdorferi is difficult and is currently not recommended. However, other methods of testing are being proposed and need to be studied. One of the more interesting to come out is Metabolomics.

The rapidly emerging field of metabolomics combines strategies to identify and quantify cellular metabolites using sophisticated analytical technologies with the application of statistical and multi-variant methods for information extraction and data interpretation. It’s an alternative approach that could hold some promise.

Lyme disease vectors (tick species) and hosts (mice species) are different in the East in comparison to the West coast thus B. burgdorferi infestation rates also differ significantly (low in the West vs. high in the East). In addition, different strains of B. burgdorferi exist in different regions and we need to ask ourselves how do we detect different B. burgdorferi strains (biodiversity, genosequencing) and how does strain diversity affect diagnosis? Biodiversity can affect some serologic tests more than others. Although there are data to suggest the performance of the C6 ELISA is affected by genomic variations in the different strains of B. burgdorferi , the performance of Western blots is clearly affected. The impact of biodiversity and the Canadian strains of B. burgdorferi on serologic testing should be further studied.

Different groups across the country are doing research in Lyme disease. For example, British Columbia is doing a large study on chronic complex diseases including MS and Lupus patients plus metagenomics and proteomics on all individuals suspected of chronic Lyme disease, while Nova Scotia is undertaking a serosurvey for antibodies to zoonotic pathogens including Lyme. New Brunswick is also assessing MS patients for Lyme disease.

It is essential that we have a gold standard to validate collected data and methods used for diagnosis of Lyme disease. Well-defined, well-pedigreed collections of specimens (clear cohorts) for clinical validation are lacking. The challenge and critical importance of a gold standard is addressed repeatedly throughout this BBE.

3. Post-treatment Lyme Disease Syndrome and Chronic Lyme Disease

Dr. John Aucott, Director, Lyme disease Clinical Research Center, Division of Rheumatology, Johns Hopkins University.

Chronic Lyme disease is the most common patient complaint. A patient’s perspective of Lyme disease is one of “living in limbo”, and that a sense of being invisible (fatigue, pain, headaches, memory issues, “you look normal”) is common. Complex relationships (mistrust, feeling abandoned) with physicians and medicine as a whole are common as well.

The natural history of untreated Lyme disease is one of a systemic illness with early and late symptoms. Looking at Post Treatment Lyme Disease Syndrome (PTLDS) specifically, symptoms depend on how early treatment took place. That being said, even when people are treated early, some still report symptoms in the first year after treatment. Adequate treatment of early Lyme disease prevents the majority of later signs of organ system manifestations.

PTLDS risk factors include delayed diagnosis, inadequate treatment and severe initial disease. Severity depends on the stage of infection at time of treatment (mild/self-limited after ideal early diagnosis and treatment; severe after non-ideal or delayed treatment).

PTLDS is often first recognized months to years after the initial treatment of early Lyme disease and so the relationship of the symptoms to prior Lyme disease may be unclear.

Re-infection does not explain recurrent symptoms in a vast majority of patients with PTLDS. Prior Lyme disease doesn’t prevent future new infection. The role of persistent infection in PTLDS remains an area of ongoing controversy and investigation. PTLDS has significant impact on quality of life, morbidity and cost to North American populations. It occurs in approximately 10-15% of individuals after treatment of Lyme disease.

The symptoms of PTLDS overlap with those in the general population and other symptom-based syndromes, but are more pervasive, severe, and have a greater impact on quality of life.

Well-controlled prospective studies suggest that the pathophysiology of PTLDS may involve identifiable immune mechanisms that are triggered by infection with B. burgdorferi.

The presentation was concluded by pointing out that we need a biomarker (like in syphilis) to determine if treatment is working (nucleic acid biomarkers; different platforms; different modalities). We need a biomarker to identify those patients that were not clinically diagnosed with Lyme and therefore did not fall within the PTLDS grouping.

4. Plenary Discussion

What is the science of current diagnostics telling us? Where are the gaps?

  • Methods are needed to detect early B. burgdorferi infection so patients can be identified and treated early.
  • New technologies are being reported in the literature as alternatives to or complementary to our current testing methods. However, there is not a lot of data regarding these technologies in Canada.
  • Common language is needed to help develop information and algorithms that clinicians can use to diagnose B. burgdorferi infection.
  • Ticks carry other bacterial and viral pathogens and contain pathogens that can be infectious to humans. The spectrum of illness caused by some of these pathogens is not completely understood.
  • There is inability, in some instances, to detect post Lyme disease, and therefore not able to monitor. It would be interesting to learn what proportion of the population (based on a systematic approach) has antibody evidence without symptoms.
  • With EM rashes, a common misperception is that the rash is caused by a spider bite or has to have a zone of central clearing (no ring within a ring) when in reality the rash of early Lyme localized infection can be variable. This can lead to misdiagnosis.
  • Physicians may not look for Lyme disease and may not know what to do if a patient presents with Lyme disease. This may contribute to under reporting as clinicians may be reluctant to report Lyme disease to public health officials because a serologic test is negative, despite symptoms/signs compatible with Lyme disease. The publication of defined endemic areas often lags behind the actual number of regions with infected ticks which makes the use of endemic regions to inform treatment decisions difficult. The definition of an endemic region requires refinement (e.g. 16 ticks found vs. 600 ticks found).

Improvement in the science of Lyme diagnostics

  • The ability to validate current or new methods of diagnostic testing is hampered by the lack of specimens from a well pedigreed cohort of patients with different stages of B. burgdorferi infection. This requires the recruitment and prospective collection of specimens from a well-defined cohort of patients with Lyme disease using consistent sets of clinical definitions and biomarkers.
  • The specificity of new investigational biomarkers and diagnostic tests could be evaluated using a well-defined cohort of individuals with no evidence or suggestion of Lyme disease to evaluate the specificity.
  • The clinical utility of other biomarkers could be investigated. The clinical utility of the EliSpot (Interferon γ-test) to detect infection with B. burgdorferi and various other pathogens in Canada could also be investigated.
  • Research into other possible co-infections, tick related proteins, or how to monitor for PTLDS and the resolution of infections could be undertaken.
  • The genomic diversity of B. burgdorferi in Canada could be further researched to determine the biodiversity as well as its impact on diagnostic testing.
  • Comprehensive, active surveillance of Lyme disease in Canada beyond the enhanced surveillance system currently in place, could address the need for improved tracking of Lyme disease positive ticks and humans. This could include surveillance of human infection, surveillance of ticks and animal hosts in the environment and examination of the genomic diversity of B. burgdorferi and other tick-associated infections in Canada.
  • Stronger education initiatives could be developed to educate clinicians and patients about when to suspect B. burgdorferi infection and how to diagnose Lyme disease.

5. Development of the Lyme Diagnostic Service in Scotland

Sally Mavin, Clinical Scientist, National Lyme Borreliosis Testing Laboratory (Inverness, Scotland)

As of 2010, Lyme disease was no longer notifiable in Scotland. According to anecdotal reports, only 10-20% of patients were referred for testing, with actual incidence figures potentially ten times higher.

In the history of Lyme disease testing in Scotland, from 1988 to 2003 (when the National Lyme Borreliosis Testing Laboratory was established) some four different testing methods were applied.

The presentation focused on three principal issues that had a significant impact on Lyme diagnosis - Sensitivity, Finance & Red Tape, and the Detection of Current Infection:

Sensitivity

It was found that many classic cases of Lyme disease were still seronegative. This raised a number of key questions. Were patients tested too early? Did they receive the proper treatment? Or were they not using the best strain of B. burgdorferi for the preparation of their Western blot? There was concern that they were missing cases of B. afzelii and B. garinii.

A study was carried out (2007-2009) that investigated the use of B.burgdorferi sensu stricto and B. afzelii isolated from local ticks within the in-house Western blot. The study showed that the use of these local isolates and the revision of interpretation criteria increased Western blot sensitivity and improved patient management.

Finance & Red Tape

The National Health Service was facing financial and staffing pressures. The National Lyme borreliosis testing service was part of routine microbiology laboratory testing and not centrally funded.

In-house tests are laborious and difficult to standardize. Changing the accreditation body from the Clinical Pathology Accreditation to the United Kingdom Accreditation Service rendered in-house testing almost impossible.

In 2013 there were studies comparing five IgG commercial Immunoblot kits with the in-house IgG Western blot. Four out of the five line blots detected different species of B. burgdorferi sensu lato with no two kits producing the same results and sensitivity, and specificity varied. The evaluations clearly illustrate the challenges and complexities in Lyme disease diagnosis (and treatment).

Detection of current infection

There is strong evidence that we need to identify markers of current infection. Laboratory diagnosis detects B. burgdorferi antibodies in serum but IgG (and IgM) antibodies can persist for years. Thus, serological testing is limited in that it cannot identify between current or past infection and that could potentially lead to unnecessary antibiotics or delay further investigations.

Based, on lessons learned within Scotland, key recommendations to strengthen Lyme diagnostics for the Scottish scenario, include:

  • Mandatory reporting of all laboratory confirmed and clinically diagnosed Lyme disease cases.
  • Provide centralized funding for a Lyme disease reference laboratory that captures all research, studies of the disease as well as information about the tick populations.
  • Lyme disease diagnostics must undergo a constant, regular review of testing procedures to improve results and to resolve any outstanding questions, limitations. The review should evaluate commercial immunoblots and tests from non-accredited laboratories and promote ongoing research into new assays and technology.
  • Need to work collaboratively and globally to identify markers of current infection.

6. The Challenges in Developing a Lyme Disease Diagnostic: Lessons from Oncology

Dr. Mark Duncan, Professor, School of Medicine, Endocrinology, Metabolism and Diabetes, University of Colorado

Cancer research has made some strides forward in diagnoses compared to areas such as infectious diseases, in large part because of much greater investment and more activity.

‘Gold standard’ in diagnostics is the pregnancy test that offers a clear “Yes/No” diagnostic without the complexities and concerns of numerous confounders. It is also affordable and easy to use as a point of care (POC) test.

Dr. Duncan stressed that moving forward with Lyme diagnostics will present numerous challenges, indicating that we have to do our research. We must be very clear: What are our specific goals and what exactly would be an acceptable test? Developing a test is primarily the task of laboratory scientists, but defining the need and acceptable performance parameters (e.g., sensitivity) are decisions that practicing clinicians must make. Biomarker development should be an intensely collaborative venture.

Getting researchers involved in Lyme disease diagnostics is crucial. Making it interesting to them, and giving them training/career incentives to enter and stay in this important field will broaden expertise in this area.

It is essential that investigators/researchers are accountable and that they do what they said they would do. Biomarker development is a difficult process with several stages (e.g., discovery, validation, large-scale testing) and it is hard work, without any guarantee of success. Nevertheless, the process is extremely important. You need to “check in” on what’s being done, monitor progress, and ensure that we constantly advocate for the patients. This can’t be viewed as a research exercise – work must translate to tests with clinical utility.

Developing a diagnostic test/tool for Lyme disease is a global “product” and not just a “Canada-specific” exercise; this is an international problem which requires a collaborative strategy moving forward. Biomarker development must be collaborative, and needs the involvement of industry, government, and end-user groups. It is critical that all stakeholders be involved and that diverse needs and limitations (barriers) be understood to ensure successful and comprehensive diagnostic tests and tools to address Lyme disease diagnostics.

It’s important to have funding and continuation contingent on all participants remaining committed. If there is no ongoing dialogue with health care providers (provinces/ territories) there will be a problem moving forward.

If commercial companies are not interested and government is not committed, can we take testing to a national level? Smaller companies and entrepreneurs could be encouraged to engage in this area.

The funding agency/organization has to be very innovative and need to hold academic organizations that receive funding accountable to goals, budgets and deadlines. Funding agencies are no longer Ivory Towers providing a “bottom up” funding research approach; they are vulnerable “thin glass buildings”.

Given current realities, one diagnostic test for Lyme disease is unrealistic. Choose what you want to support and fund (test for early Lyme? Test for PLDTS? Other?), but be mindful of what has been done already and how it links to what you are trying to achieve. And remember, the true costs have to be matched with the available funds.

7. Plenary Discussion

Are there lessons learned/best practices from other parts of the world that we can apply?

  • Some participants indicated that a new test is not needed but rather existing private, for–fee laboratory tests could be considered for validation in Canada. The question is: What will have the most impact?
  • Physicians at the table indicated they would be prepared to assist with the collection of patient oriented data though funding to compensate for time spent on such activities would need to be considered.
  • It was acknowledged that coming up with a cohesive approach is difficult in terms of building consensus.
  • In Canada, a centralized process for research versus a local geographic approach could provide better end results. Centralization can work when no one else wants to get involved or be responsible to initiate projects in a given area. That being said, centralized testing models could mean delays in Canada due to its large geographic area and diversity across the nation. Finding the right balance will be key to any success in this area.

Are there lessons learned that we could apply from diagnostics in other diseases?

  • It would be useful to look beyond serological testing: e.g., use existing serologic tests as much as possible for now, while investigating the potential for new diagnostics such as the identification of biomarkers.
  • Getting back to basic research in Lyme disease may prove useful in determining a better way forward. No one test will do everything that is needed (identify Lyme in each stage; determine reinfection etc.). Potentially there will need to be several tests to meet the varying needs and we have to narrow the focus before a ’standard’ test can be identified. Transparency in the process will be necessary to engage experts and improve outcomes.

How do we plan for and implement transformation and innovation in Lyme diagnostics?

  • In the diagnosis for Lyme disease, there are many, very complex confounders that limit the ability to identify and implement new and innovative testing methods. There have been tests developed rapidly for other infectious diseases (e.g. Ebola, syphilis, SARS) but the complexities of doing so with Lyme disease needs to be recognized by all stakeholders. Questions continue such as: What is it about the pathology/biology of Lyme that make it difficult to develop a test?
  • It was suggested that thinking needs to shift towards ‘outside the box’ thinking. There is a recognized need to begin thinking about different, innovative ways to attack this problem and approach it from a different direction.
  • In the call for innovation, hypothesis generating will be an important by-product. Lessons from abroad and innovation in other areas of diagnostics will be helpful. As well, approaching Lyme disease by looking at each of the stages of the disease and how to diagnose them is needed to further the work.
  • There is no suggestion to discard the last 40 years of work in the area of Lyme disease diagnostics; rather there is an understanding that the current approach can be enhanced or redeveloped.
  • Overall, there is recognition that a strategy is needed to push this work forward. Questions are: Who would be involved? What is best approach? How do stakeholders move forward within a federal government action plan?

How do we get more researchers involved in this area?

  • Exploration across the various organizations and institutes who conduct, support or fund infection, immunity, public health or policy research will be needed.
  • To date, samples are not being collected to develop a database or cohort study. Incentives must be provided to young researchers- funding, resources, nurturing/mentoring and helpful guidance with their research and academic career paths.
  • Engagement with clinicians and creation of a meaningful and sustainable dialogue between clinicians and academics could be one way to push this work forward. With the understanding that if clinicians are involved in providing information or services that there must be some way to compensate them for time taken away from their practice.

8. Next Steps

Throughout the discussion periods, participants agreed on the complexity of Lyme disease and the clear need for an enhanced ability to detect Lyme in all stages of the disease. Key themes that came out of the day were:

  1. Need for innovation: Lessons learned from other fields (i.e. oncology) could be considered within the Canadian context.
  2. Biodiversity needs to be explored: The biodiversity of B. burgdorferi strains and it influence on diagnostic testing as well as the current limits in knowledge of the physiology of ticks are areas which could be targets for further research.
  3. An integrated approach to Lyme disease diagnostics must be pursued. Success will rely upon the ability of varying stakeholders to work together, including policy/decision makers, researchers, clinicians and advocates. There needs to be a better exchange of information between academics and clinicians.
  4. It is essential that there be political will to continue to move forward. Moving into the political arena is a positive development. Given financial limitations and barriers within Canada, it is critical that any confounding factors be transparent to all fields so that work can be pursued.
  5. There is a need for more comprehensive “active surveillance”. Given the deficit of ticks available for study, continuing solely with a passive surveillance system will limit the ability to determine tick species and the infections they may carry.

All participants agreed that more research is required across the spectrum of Lyme disease diagnostics and funding should be available for the next generation of investigators to pursue a career in this research field. There was also agreement that clinicians should be educated further on Lyme disease to enhance their expertise in this field and improve patient diagnosis.

A collaborative approach could be taken to address the current limitations with Lyme disease diagnostics whereby researchers, clinicians, policy makers, and funders, work together to advance knowledge in this area to improve patients’ health outcomes.

The BBE was an important first step in moving this issue forward in a collaborative, productive and transparent manner.

9. Conclusion

The day allowed for the opportunity to, bring policy makers, researchers and key stakeholders together to consider leading research evidence and the current Canadian context, and foster an open, transparent dialogue which will help lay the foundation for a Lyme disease research agenda.

It was recognized that through the BBE, policy makers, researchers and key stakeholders have begun a collaborative process to consider new ideas, concepts and identify knowledge gaps for further exploration among the academic, scientific and clinical communities to advance our understanding and response to Lyme disease diagnostics.

Appendix 1: Participants

Presenters:

  • John Aucott, Director, Lyme disease Clinical Research Center, Division of Rheumatology, Johns Hopkins University
  • Mark Duncan, Professor, School of Medicine, Endocrinology, Metabolism and Diabetes, University of Colorado
  • Todd Hatchette, Chief, Division of Microbiology, Department of Pathology and Laboratory Medicine Nova Scotia Health Authority & Professor, Department of Pathology, Dalhousie University
  • Sally Mavin, Clinical Scientist, National Lyme Borreliosis Testing Laboratory (Inverness, Scotland)

Facilitator:

  • Marc Ouellette, Scientific Director, Institute of Infection and Immunity, Canadian Institutes of Health Research

Participants:

  • William Bowie, Professor, Division of Infectious Diseases, University of British Columbia
  • Alison Bested, Clinical Associate Professor, Faculty of Medicine, University of British Columbia
  • Erika Bontovics, ‎Manager, Infectious Diseases Policy and Programs, Ontario Ministry of Health and Long-Term Care
  • Daniel Cameron, Medical Director, Dr. Daniel Cameron & Associates; Attending Physician, Northern Westchester Hospital
  • George Chaconas, Canada Research Chair in the Molecular Biology of Lyme Borreliosis, Department of Biochemistry & Molecular Biology and Department of Microbiology, Immunology & Infectious Diseases
    The University of Calgary
  • Ted Cormode, Physician (retired)
  • Matthew Gilmour, Scientific Director General, National Microbiology Laboratory, Public Health Agency of Canada
  • Daniel Gregson, Associate Professor of Medicine, Medical Microbiology and Infectious Disease, University of Calgary
  • Radhey Gupta, Professor of Biochemistry, McMaster University
  • Ralph Hawkins, Clinical Associate Professor of Medicine and SHC Site Lead for
    Division of General Internal Medicine, University of Calgary
  • Kamran Kadkhoda, Assistant professor, Department of Medical Microbiology & Infectious Diseases, University of Manitoba; Clinical Microbiologist, Cadham Provincial Public Health Laboratory
  • Reuben Kaufmann, Professor Emeritus of Zoology, University of Alberta
  • Kathleen Kerr, Lecturer, Department of Family & Community Medicine, Women’s College, University of Toronto
  • Joel Kettner, Scientific Director, National Collaborating Centre for Infectious Diseases; Medical Director, International Centre for Infectious Diseases; Associate Professor, College of Medicine, Faculty of Health Sciences, University of Manitoba
  • Robbin Lindsay, Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada
  • Vett Lloyd, Professor, Department of Biology, Mount Allison University
  • Pascal Michel, Director, Infectious Diseases Prevention and Control Branch, Public Health Agency of Canada
  • Tara Moriarty , Assistant Professor, Matrix Dynamics Group, Faculty of Dentistry, Faculty of Medicine, Department of Laboratory Medicine & Pathobiology, University of Toronto
  • Muhammad Morshed, Program Head, Zoonotic Diseases & Emerging Pathogens, BCCDC Public Health Microbiology and Reference Laboratory, Provincial Health Services Authority; Clinical Professor, Department of Pathology & Laboratory Medicine, University of British Columbia
  • Dylan Pillai, Associate Professor, Department of Pathology and Laboratory Medicine, University of Calgary
  • Felix Sperling, Professor, Department of Biological Sciences, University of Alberta; Curator, Strickland Museum of Entomology
  • Janet Sperling, Entomologist; Visiting PhD student, University of Alberta
  • Steven Sternthal, Director General, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Infectious Disease Prevention and Control Branch, Public Health Agency of Canada
  • Elizabeth Zubeck, Family Physician, Shepherd’s Hill Medical Clinic

Planning Committee:

  • Meghan Baker, Senior Advisor, Knowledge Translation Strategy, Canadian Institutes of Health Research
  • Marian Harryman , Executive Director, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases (CFEZID), Public Health Agency of Canada
  • Marc-Étienne Joseph, Associate, Institute of Infection and Immunity, Canadian Institutes of Health Research
  • Jessica Pautz, A/Manager, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada
  • Nick Previsich, Senior Advisor, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada
  • Jennifer Raven, Assistant Director, Institute of Infection and Immunity, Canadian Institutes of Health Research
  • Angelica Stewart, Senior Program Officer, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada

Report Writer:

  • John Banys, Contractor, PENinc Communications Ltd.

Appendix 2: Best Brains Exchange: Agenda

Agenda
Time Item Speaker
09:30 – 09:40

Welcome, Opening Remarks

Marc Ouellette, Scientific Director, Institute of Infection and Immunity, Canadian Institutes of Health Research

Steven Sternthal, Director General, Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Infectious Disease Prevention and Control Branch, Public Health Agency of Canada

09:40 – 09:50

Roundtable of Introductions

Facilitated by Marc Ouellette

09:50 – 10:10

Review of Objectives and Overview of the Day

Marc Ouellette

10:10 – 11:30

Presentation #1 –Setting the Stage Lyme diagnostics – The Current State of Affairs

Presentation #2 – Post-treatment Lyme Disease Syndrome and Chronic Lyme Disease

*Two 15-20 min presentations, followed by Q&A

Todd Hatchette, Chief, Division of Microbiology, Department of Pathology and Laboratory Medicine Nova Scotia Health Authority & Professor, Department of Pathology, Dalhousie University

John Aucott, Director, Lyme disease Clinical Research Center, Division of Rheumatology, Johns Hopkins University

11:30 – 12:00

Plenary – Discussion period that considers the “what

  • What is the science of current diagnostics telling us?
  • Where do we need to focus our efforts for improvement in the science of Lyme diagnostics?

Facilitated by Marc Ouellette

12:00 – 13:00

Networking Lunch

13:00 – 13:45

Presentation #3 – Development of the Lyme Diagnostic Service in Scotland

*15-20 min presentation, followed by Q&A

Sally Mavin, Clinical Scientist, National Lyme Borreliosis Testing Laboratory (Inverness, Scotland)

13:45 – 14:30

Presentation #4 – The Challenges in Developing a Lyme Disease Diagnostic: Lessons from Oncology

*15-20 min presentation, followed by Q&A

Mark Duncan, Professor, School of Medicine, Endocrinology, Metabolism and Diabetes, University of Colorado

14:30 – 15:15

Plenary – Discussion period that considers the “how:

  • Are there lessons learned which we could apply from other parts of the world?
  • Are there lessons learned which we could apply from diagnostics in other diseases?
  • How do we plan for and implement transformation and innovation in Lyme diagnostics?

Facilitated by Marc Ouellette

15:15 – 15:30

Health Break

15:30 – 16:15

Plenary – Next Steps

  • What are the key research questions and concepts that need to be shared within the academic community?
  • How do we get more researchers involved in this area?

Facilitated by Marc Ouellette

16:15 – 16:30

Closing remarks & Evaluation

Marc Ouellette & Steven Sternthal

Appendix 3: Speaker Biographies

Dr. Todd Hatchette

Chief, Division of Microbiology, Department of Pathology and Laboratory Medicine
Nova Scotia Health Authority &
Professor, Dept of Pathology, Dalhousie University

Dr. Hatchette earned his MD from Memorial University of Newfoundland in 1995. Following Internal Medicine training at Memorial University and a Fellowship in Infectious Diseases and Medical Microbiology at Dalhousie University, Dr. Hatchette completed post-doctoral research training in virology at St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr. Hatchette is currently the Chief of Service for the Division of Microbiology, QEII Health Sciences Center and the Director of the Virology and Immunology laboratory where they test for Lyme disease in Nova Scotia. He is a Professor in the Department of Pathology, Dalhousie University with cross-appointments in the Departments of Immunology and Microbiology and Medicine where he is a consultant in Infectious Diseases.

As the Province’s only medical virologist, Dr. Hatchette has expertise in the clinical and laboratory diagnosis of viral infections and has given continuing medical education (CME) lectures to various health care professionals and serves as an advisor on a number of local and provincial committees. He is the provincial co-chair of the Lyme disease Diagnostic Working Group of the Canadian Public Health Laboratory Network.

Dr. John Aucott

Director, Lyme disease Clinical Research Center, Division of Rheumatology
Johns Hopkins University

Dr. Aucott is a graduate of the University of California at Berkeley and Johns Hopkins University School of Medicine, and is a diplomat of the American Board of Internal Medicine with sub-specialty training in Infectious Disease at University Hospitals of Cleveland.

Dr. Aucott joined the Faculty of Medicine at Johns Hopkins School of Medicine in 1996 where his focus has been on clinical translation research in Lyme disease and Post-treatment Lyme Disease Syndrome. He is currently the Principal Investigator for the prospective cohort study, SLICE, (Study of Lyme Disease Immunology and Clinical Events). This multiyear study examines patients with untreated acute Lyme and erythema migrans who are characterized before initial antibiotic therapy and then in follow up for two years after therapy. To date the study has enrolled over 170 Lyme patients and matched controls and have samples from over 1,000 different patient visits.

The extensive biorepository of samples from the SLICE study has formed numerous collaborators from around the United States. These collaborations have resulted in 15 peer reviewed publication that focus on understanding the microbiology, immune pathophysiology of Lyme disease and the long term health outcomes related to exposure to Borrelia burgdorferi infection.

In April 1, 2015 Dr. Aucott was appointed the Director of the Lyme disease Clinical Research Center in the Division of Rheumatology at Johns Hopkins University. This state of the art translational research center maintains community based clinical research sites in addition to 2,000 square feet of research space at the Johns Hopkins Bayview campus where the SLICE biorepository, immune phenotyping studies and flow-cytometry core facilities are located.

Ms. Sally Mavin

Clinical Scientist
National Lyme Borreliosis Testing Laboratory (Inverness, Scotland)

After receiving an undergraduate degree in Biomedical Science in 1996 from the University of Aberdeen Sally trained and worked as a Biomedical Scientist in the Virology department at the University Hospital of Wales in Cardiff, where she also gained a Masters degree in Biomedical Science. Sally then relocated to Raigmore Hospital in Inverness to undertake the 3-year Clinical Scientist training programme in Microbiology and another Masters degree (Medical Molecular Microbiology) with the University of Nottingham.

Sally has worked in the National Lyme Borreliosis Testing Laboratory in Inverness as a Clinical Scientist since it was established in May 2003. During this time she has worked hard both to improve the service, utilizing in-house and commercial tests, and to collate epidemiological information on Lyme borreliosis in Scotland. She has spent the past 4 years working on a part-time PhD, focusing on the development of a Western blot assay that can differentiate patients with current infection from those with evidence of past infection with B. burgdorferi in Scottish patients, in collaboration with the University of Aberdeen. Sally is also a member of ESGBOR, the ESCMID (European Society of Clinical Microbiology and Infectious Diseases) study group for Lyme borreliosis.

Dr. Mark Duncan

Professor, School of Medicine, Endocrinology, Metabolism and Diabetes
University of Colorado

Mark Duncan was born and raised in Sydney, Australia. He completed his undergraduate training at the University of New South Wales, with a major in organic chemistry. His Ph.D. degree was undertaken at the Garvan Institute, Sydney. Following graduation he moved to Bethesda, Maryland, to complete postdoctoral training in neuroscience as a Fogerty fellow at the National Institutes of Health. After almost 4 years in the USA he returned to Sydney to take up a faculty appointment in the School of Medicine. In 1999 he moved again, this time to Colorado, to serve as professor and founding director of the proteomics shared resource at the University of Colorado. He is currently Professor of Medicine, in the Division of Endocrinology, Metabolism & Diabetes, UC Denver Anschutz Medical Campus and director, academic collaborations, for Biodesix Inc., a Colorado‐based clinical diagnostics company. Dr Duncan is also a visiting Professor at King Saud University, Saudi Arabia.

Dr Duncan’s research interests are broad. His publications cover the areas of applied mass spectrometry, organic chemistry, biochemistry and several areas of clinical medicine including chemical pathology, endocrinology, neurology and oncology. Together with colleagues at Vanderbilt University, University of Colorado and Biodesix Inc., he developed Veristrat®, a commercially available, mass spectrometry‐based blood test for assessing a patient’s responsiveness to specific cancer therapies. He has served on or chaired over 30 NIH review panels. He is Associate Editor (Genomics, Proteomics and Bioinformatics) of the Journal of Experimental Biology & Medicine, and a member of the editorial boards of Journal of Biomarkers, The Protein Journal and Practical Proteomics. He is a member of the University of Colorado Cancer Center, the Human Medical Genetics Program and the Molecular Structure Program, and an active member of the American Society of Clinical Oncology (ASCO) and the American Society for Mass Spectrometry.

Dr Duncan has authored or co‐authored over 100 peer‐reviewed scientific articles in leading journals including the New England Journal of Medicine, Lancet, Proceedings of the National Academy of Sciences, Science Magazine, PloSOne and Nature Biotechnology. He holds numerous patents, consults for several biotechnology and diagnostic companies, and has been invited to speak at major conferences in more than 15 countries.

In 1990 he joined the Centre de Recherche en Infectiologie, of Laval University as an Assistant professor and is now full professor. Dr. Ouellette's research is focused on antimicrobial resistance where he has made seminal discoveries on resistance mechanism in protozoan parasites. More recently he has implemented proteomic and DNA microarray strategies to study antimicrobial resistance in the parasite Leishmania and the bacteria Streptococcus pneumoniae.

Dr. Marc Ouellette

Scientific Director
Institute of Infection and Immunity
Canadian Institutes of Health Research

Dr. Ouellette obtained his Bachelor of Science (Honours) in Biochemistry at Ottawa University and received his PhD at Laval University on antibiotic resistance in bacteria. His postdoctoral studies were done under the mentorship of Pr. Piet Borst of the Netherlands Cancer Institute in Amsterdam, where he further developed his expertise in antimicrobial resistance studying protozoan parasites.

Dr. Ouellette has received numerous awards for his work including a New Investigator Award in Molecular Parasitology from the Burroughs Wellcome Fund, a MRC Scientist Award, a Scholar Award in Molecular Parasitology of the Burroughs Wellcome Fund, and a Tier 1 Canada Research Chair in Antimicrobial Resistance. He is a Fellow of the Royal Society of Canada and of the Canadian Academy of Health Sciences. He has served on numerous panels of national and international granting agencies and is a strong supporter of scientific exchanges with developing countries.

Appendix 4: Evaluation Form Summary

21 responses
1. Which sector do you represent?
Federal gov't dept/ agency 4
Prov/ Ter. Min/ dept of health 0
Other prov/ ter. Min/ dept (non-health) 0
Regional/ district health auth 0
Prov/ ter. Health research foundation/ org 0
Nat'l health ass/ council/ found 1
University 13
Other 3
2. Are you an…
Invited guest 16
Invited speaker 2
Collaborating Host 2
Other 1
3. How would you rate the following?
Workshop overall 4.571428571
Expert presentations 4.761904762
Afternoon plenary discussions 4.523809524
4. How would you rate the presentations and facilitation?
T. Hatchette 4.666666667
J. Aucott 4.857142857
S. Mavin 4.6
M. Duncan 4.45
M. Ouellette 4.714285714
5. Were the background readings helpful?
  • yes-18
  • n/a-1
  • No-2
6. Did the presentations help to inform the afternoon discussions?
  • yes-19
  • n/a-1
  • No-1
7. Would you be interested in attending future events of this sort?
  • yes-19
  • n/a-2
  • No-0
8. How well were objectives achieved
Objective 1 4
Anticipated Outcome 1 3.736842105
Anticipated Outcome 2 4.157894737
Anticipated Outcome 3 4.157894737
9. What did you like most about this workshop? See appendix
10. What do you think could be improved upon for future engagement workshops? See appendix
11a. Did you gain new knowledge by attending the Exchange?
  • yes-18
  • n/a- 2
  • No-1
11b. What new information did you learn by attending the Exchange? See appendix
12. Should CIHR facilitate follow up?
  • yes-17
  • n/a-4
  • No-0
13. Additional Comments? See appendix

Appendix:

9. What did you like most about this workshop?

  • Free exchange 
  • Interchange of ideas 
  • Plenary sessions 
  • Meeting colleagues
  • Diversity of attendees
  • Interaction with multiple stakeholders.
  • Collaboration 
  • The fact that we actually talked/discussed some volatile issues in a collegial manner.
  • Discussion about ways to move forward Stimulating; thought provoking 
  • Honesty and openness 
  • Format- "in camera"
  • Excellent presentations and discussions
  • Meeting others with like interests and hearing of great amount of evidence
  • Good mixture of people
  • Generally, very respectful dialogue

10. What do you think could be improved upon for future engagement workshops?

  • Earlier distribution of reading material, agenda, etc.
  • More specific goals & outcomes 
  • More time for discussion            
  • Better pre-reading selection
  • More notice ahead of time for many participants (several were last minute) and funding support. 
  • More notice ahead of meeting and contacting researchers, French researcher and other Europeans
  • Next step: workshops- focused on more specific topics
  • Position de l'ASPC; direction manquante
  • Actual changes being described Specific action points
  • Not much!

11b. What new information did you learn by attending the Exchange?

  • Much better understanding of PTLDS
  • Information on PTLDS
  • Better appreciation of the research constraints that some labs feel they are working under.
  • Complexity of problem - meeting people; defining questions to work on
  • >10 pages of notes
  • Limite des testes diagnostic
  • Gained better understanding of clinicians contribution
  • Better definition of gaps and need a different approach to diagnosis
  • New research contacts
  • I learned more about the burning issues and how difficult those are to deal with unambiguously

13. Additional comments.

  • Little discussion re: clinical situation re what to do pending improved testing - but this was not the mandate of this meeting (ie: testing- not clinical implications).
  • This has been an open, transparent meeting. I hope there is an immediate press release that says something like "researchers, clinicians, PHAC, CIHR, etc interested in Lyme disease were at the Best Brains Exchange. After much discussion we recognized that better diagnostic tests and treatment for LD and this is the first step. This will validate the patients experience and help to calm the waters."
  • It is a shame that IDSA guidelines authors were not in attendance.
  • Impressed with the collegial discussions of this very controversial topic.
  • Give us an opportunity to each share if we wish an idea or commentary or article prior to the meeting so others can review it prior if they wish and be informed on the topic.
  • Especially appreciated the lead up and opportunity to suggest participants.
  • Very good moderating. Excellent facilitator
  • Contact me @ Matthew.Gilmour@phac-aspc.gc.ca 
  • Thanks!
  • A very impressive meeting that was organized so impressively. Reuben Kaufman

Appendix 5: Reading List

The following background readings provide context to the presentations and discussions that took place at this Best Brains Exchange on Monday, June 29, 2015. These articles, recommended by the presenters, may prove to be a helpful resource now or in the future.

List of References:

  1. J Alcott, Post treatment Lyme disease syndrome. Infectious Disease Clinics of North America (2015), 29, 309‑323.
  2. M E Aguero-Rosenfeld & G P Wormser, Lyme disease: diagnostic issues and controversies. Expert Review Molecular Diagnostics (2015), 15(1), 1‑4.
  3. J A Branda, K Linskey, Y A Kim et al, Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide enzyme immunoassay. Clinical Infectious Diseases (2011), 53(6), 541‑547.
  4. R L DeBiasi, A concise critical analysis of serologic testing for the diagnosis of Lyme disease. Current Infectious Disease Reports (2014), 16:450.
  5. R Evans, S Mavin, S Holden et al, Lack of accurate information on the prevalence of Lyme disease in the UK. British Medical Journal (2014), 348:g2037.
  6. B A Fallon, M Pavlicova, A comparison of Lyme disease serologic test results from 4 laboratories in patients with persistent symptoms after antibiotic treatment. Clinical Infectious Diseases (2014), 59(12), 1705‑10.
  7. A Rizzoli, H C Hauffe et al, Lyme borreliosis in Europe. Euro Surveillance (2011), 16(27): pii=19906. *Available online: Lyme Borreliosis in Europe
  8. A C Steere, G McHugh et al, Prospective Study of Serologic Tests for Lyme Disease. Clinical Infectious Diseases (2008), 47:188‑95
  9. G P Wormser, D Liveris et al, Effect of Borrelia burgdorferi genotype on the sensitivity of C6 and 2-tier testing in North American patients with culture-confirmed Lyme disease. Clinical Infectious Diseases (2008), 47, 910‑4.
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