2016 Lyme disease conference breakout session 2: Guidelines and best practices

Conference to develop a federal framework on Lyme disease

May 15-17, 2016, Government of Canada Conference Centre, 111 Sussex Drive, Ottawa, ON

Conference day 2: Monday May 16, 2016, Algonquin Room

Audio Recording

Transcript

Lise: [13:51]

Then, just before we start, I wanted to review the process that we will follow this afternoon. I will be inviting each of our speakers to speak in turn, then we'll be going to a break. Then we'll be having two more speakers, and then we'll have a Q&A with all four speakers. So, just so we understand the process and how we'll be doing things on this afternoon, the idea of leaving the questions until later is you can get the whole picture, and then we can make sure that we have a general equivalent time for all of our speakers. Once we've done the questions and answers, before we leave this afternoon, about a half hour before the end, so I'm assuming around four o'clock, I'll invite you to switch from questions and answers to key messages. So, as you're listening to the speakers this afternoon, jot down questions you might have for each speaker so you are ready with them by the time the Q&A session comes up. And also, if you're noticing some important things, whether it's a link between what a speaker is saying and what you've heard elsewhere today or yesterday, or a reaction, whatever it is, you know, take your own notes as we're going through, and we'll have a bit of a conversation around that at the end of the afternoon.

So this is the only process. I invite you, of course, when it comes to questions and answers, to express yourself in the official language of your choice, and we will proceed now with our first speakers, so our first speaker, Dr. Elizabeth Maloney, will speak about evidence-based, patient-centred guidelines for the diagnosis and treatment of Lyme disease.

Elizabeth: [15:42]

Good afternoon, my thanks to the planners for inviting me to join in this very important discussion. I have no ties to the pharmaceutical device or communication companies; I did co-author the International Lyme and Associated Diseases Society's 2014 treatment guidelines on Lyme disease. I'm President of Partnership for Healing and Health, that provides educational materials on tick-borne diseases to health care professionals and the public. I have not received any funding for this program from any organization.

From my perspective as a family physician, this is the essence of all clinical guidelines. Listening to the comments last night and this morning highlight the need for additional research into diagnostics and treatment, but I'd like to champion research into the underlying pathophysiology, especially how hosts and pathogens interact; I think that information would inform the other topics. Co-infections also apparently need significant research, as many people brought that up in their comments last night. Yet, our challenge today is to generate guidelines in the here and now, not wait for further research. So my comments today are really going to look at the framework of how you develop guidelines. So, guidelines need to assist physicians. Why would physicians need help? Well, the role of taking care of patients has become increasingly complex, and there's more data for them to manage, and even clinical mandates to be mindful of. And so many of them are trying to provide evidence-based care, but it's very difficult to stay on top of the expanding research base. So, from time to time, out of necessity, they turn to treatment guidelines, and they do this trusting that it will cut through the details and get to the chase, so that they can take care of patients. So, physicians doing this also become reliant on guideline developers. They trust that they'll know which questions to ask, and which evidence to consider. Most of all, they trust that the recommendations will improve the lives of their patients. Now, clinicians need help, they don't need more bureaucracy. So, they think of guidelines as tools that their judgement governs. If we develop guidelines that govern physicians, then we really haven't helped them at all.

A good set of guidelines is like a travel advisory; it tells us where to start, where we might run into problems, and how to make a detour if we have to. But treatment recommendations have different levels of directedness, and they should be closely tied to how certain we are about the underlying evidence. So, a recommendation that tells physicians, "Do this and only this," has to have a great deal of certainty. It has to have high-quality evidence, there needs to be a significant treatment effect, and there has to be very little risk to patients. On the other hand, treatment recommendations that say, "Well, you may do this, but you don't have to," are usually issued when the evidence is very uncertain or patient risk-benefit analyses are very individualized. Now, that's the situation we encountered when we were trying to determine how to best help patients who had persistent manifestations of Lyme disease following treatment.

There are several potential causes for persistent disease, and persistent infection is just one of many. Now, the trouble is, you can't look at an individual patient and know whether or not they remain infected. And because we knew that the findings from the retreatment trials in the U.S. were mixed, and that patients had very divergent opinions as to how they view antibiotics, and they're very different in terms of what their ongoing impairments are, we decided that the best course of action was to make a recommendation that supported treatment or retreatment on an individual basis, but not recommended across the board.

So, guidelines that are assistive do not restrict physicians from exercising their clinical judgement, and that's important because it allows them to provide patient-specific care, and to do so with their skill set. So, how one sculpts that log might depend on whether they're more comfortable with a chainsaw or a chisel. Guideline developers may have a tool that they favour, but insisting that all physicians use it isn't necessarily wise. Patients are the final end users of all guidelines, and therefore guidelines should be centred on meeting patients' needs and goals. They need to provide flexibility because patients aren't all the same, and physicians have to accommodate different patient variables.

Five years ago, the Institute of Medicine released eight standards that they thought should be used to identify trustworthy guidelines, and I'm going to touch on three of those: Standard Three addresses panel composition, and so, if guidelines assist front-line physicians and serve patients, then those two groups have to be highly represented, and they should fully participate throughout. You can't just bring them in at the end for rubber-stamping. Patients are best suited to identify treatment priorities, and because they live with the end results of our interventions, they should be the ones to help define what is a success, failure, and reasonable risk. Primary care physicians, on the other hand, are there to identify what questions they need help with. They're also there to identify what are the things within the clinical realities that might get in the way of developing or delivering patient care. And, in the end, they're the ones responsible for making sure that recommendations can work in the real world. Other panelists will probably be needed to round out the expertise of the group, but they really should serve as consultants and not be the driving force behind recommendations.

Standard Number One calls for transparency. Processes for establishing, analyzing, and reading the evidence have to be very transparent, and doing this allows for the recommendations to have high integrity. Vetting of panelists should really look at more than just financial conflicts. When panelists are drawn from a small circle of experts, collegial and institutional alliances can get in the way of the careful analysis of the evidence. To put it another way, it's hard to reject the findings and conclusions from a poorly done study when your friend, the lead author, is sitting across the table. So, we want to make sure that we don't run into those situations. Evidence analysis must be detailed and patient-centred. Most of the Lyme clinical trials used research-centred definitions and end points. These are easily measured but not necessarily what matter most to patients. And that makes it hard to construct patient-centred treatment recommendations. So, end point definitions have a domino effect; they directly impact outcome findings, which in turn impact and influence treatment recommendations. So, if you start with the wrong end point you're likely to get the wrong recommendation. Here's another example from my work: So, the U.S. erythema migraines trials use resolution of the rash as their primary endpoint. But patients are really more concerned about returning to their pre-Lyme baseline and avoiding disease progression. Trial subjects who had persistent symptoms after their rash resolved were still included as successes, which would inflate the outcome findings. By applying a patient-centred definition, we found that the failure rates were actually higher, and that led us to make a different recommendation regarding the duration of therapy.

Now, before you can construct evidence-based recommendations, you really have to have an understanding of what the evidence is. And in Lyme disease, this can be tricky because things aren't always as they appear. So, for instance, the abstract of this paper said that the C6 ELISA was 100 percent sensitive. But the table indicates they're really talking about relative sensitivity. Absolute sensitivity was 83 percent. Terminology in much of the Lyme literature is often inappropriately vague, and I think it leads people to draw false conclusions. For example, review articles typically describe Lyme encephalopathy as mild, but they don't provide a frame of reference. So, here's the original, where mild came into play as a descriptor. So, I would depart from Dr. Dattwyler's definition. If I look at this, I would not consider this to be mild and I think I would have a very difficult time selling that definition to my patients.

Publication in a respected journal doesn't earn a paper a pass. They still need to be analyzed. And randomized control trials aren't always synonymous with high-quality evidence. And Brian touched on the PLEASE study so I don't want to go over that too much in detail, but I think that is a study that's an example of both of those statements. I was especially surprised to find that the entrance criteria were so loose, that subjects who were already a standard deviation-functioning a standard deviation ahead of a base of their peers and general population, were allowed into the study. So, if you're functioning that well, I'm not sure how much better one could get.

In each of the three examples I just mentioned, peer reviewers missed an opportunity to catch and correct the problems, and it's important that the process to develop guidelines not follow that line of-not make that same mistake. So, I think one way to do that is to use a grade model. We found that very useful when we were developing our guidelines because it really made us focus on the individual studies, and then the studies as a group. Providing detailed evidence, assessment tables, is another way to make sure that everyone's done their work. The recommendations that I worked on have often been faulted because they've been based on low-quality evidence, and I think what critics misunderstand is that we were using the same evidence as everyone else, it's just that our examination of the evidence, perhaps, was more rigorous, because we picked up inadequacies that other people missed.

Standard Five has to do with the reasoning behind recommendations. So, developers state how they develop recommendations, not only based on evidence, but also based on opinion, their values, their clinical expertise. So, this is actually quite consistent with evidence-based medicine, which integrates clinical research, clinical expertise, and patient values. Now, the relative importance of these things fluctuates. So, for instance, in the diagram on the left, when the clinical research evidence is quite good, then patient values and clinical expertise are less important. However, when research evidence is not good, then expertise and patient values have increased importance. We'll talk a little bit about diagnostics, but I think many of our speakers covered some of the problems there.

Take a minute and read this quote from Dr. Paul Mead. I'm not going to read it out loud. He's contrasting surveillance and clinical case definitions, and on this portion of it, he comments on their divergent purposes. And here, he's saying how those purposes play out. So, in general, I think diagnostic guidelines should acknowledge that the lack of direct tests of infection have caused a great deal of diagnostic uncertainty. I would encourage developers of guidelines to heed Dr. Mead's comments and generate lab criteria for clinical use that are highly sensitive. Guidelines should not discourage testing when Lyme is a possibility. Pre-test probabilities are very ill-defined and almost impossible to calculate. I know several speakers before me have talked about the importance of positive predictive values, but I'd also say it's important to consider negative predictive values.

In the near term, diagnostic guidelines should inform clinicians about the inadequacies of serology, and we've heard about that. I'd like to point out that most of the tests available in the U.S. were FDA-cleared, not approved. So, they did not have to demonstrate clinical validity, and most importantly, I think that we should have guideline recommendations for diagnosis that reject the current two-tier strategy, which tends to prioritize specificity. Instead, we should adopt lab criteria for clinical cases that are less stringent than those used in a surveillance case definition.

So, one way to do that would be to change the ITG western blot interpretive criteria. I have no problems with the criteria as selected if they're used for the purpose for which they were intended, which was to do a surveillance case definition. But when Dr. Dressler went back to his own patient population and applied the five of ten criteria to his well-characterized patients, only 72 percent of the active neuroborreliosis patients were identified, so he missed 28 percent. Interestingly, only four percent of the Lyme arthritis patients were missed.

Another encephalopathy trial also that strove to make sure they only included Lyme patients had 17 percent of its subjects being seronegative, so I think it's time to put the idea that seronegativity does not exist to bed. It's likely that the inability of two-tier testing to identify neuroborreliosis is suppressing neurologic case numbers, and more importantly, it's keeping people from the treatment they need.

One thing I'd like to say after bashing the two-tier, the one thing I don't want to see is to have it altered such that western blots are totally replaced by the C6, because doing that denies clinicians some important data that they might be able to use, particularly if they're using a different interpretive criteria for the western blot.

Let's see, here. So, I think I've covered this part, because I didn't want to stick too long on the lab portion. Oh, I'm going the wrong way, that's the problem.

Treatment guidelines. And so, primarily, I want to talk about framework issues. I recognize that non-antibiotic therapies have a role to play. Guideline panels process the information and generate recommendations, but physicians have to use them on patients in the flesh, and this lack of scientific certainty leads to a lot of grey zones and close calls. In close calls we weigh risk/benefits, and that needs to be done on an individualized patient basis, and so it really needs to be left to clinicians and their patients.

Now, the American Academy of Pediatrics has a model that they would suggest for developing guideline recommendations when the science is uncertain. And as you can see, when certainty fades, then the strength of a recommendation fades with it. We could encourage shared decision making so that patients are fully informed of their options, and they talk to their doctors about their goals. The physicians still make the choice but the patients get to weigh in, and it informs the ultimate selection of the antibiotic.

First do no harm: we hear it a lot, but I think this simple adage is too simple. It certainly isn't applicable to oncology patients or surgical situations when a choice to not harm is also a choice to not help. We apply it when we don't understand the risk/benefits of a treatment option. Many times, when it's applied, it is also saying that risk is present and you should not do harm, even if it means not helping. Lyme patients would turn that on their head, recognizing that antibiotics are generally safe, and that doing nothing can be harmful. More importantly, that feeling gets in the way of clinical innovation, and I think clinical innovation is very important in Lyme disease, because treatment trials are missing. We need that information, and they don't arise de novo; they start when innovative physicians try something and see how it works out.

Patient-centred treatment guidelines should not be constructed as therapeutic policy statements. Medical recommendations should reflect the current science and serve patient interests. Policies, on the other hand, balance diverse interest in goals of several groups. In a single payer system, I think guideline panels should identify and support the implementation of best practices. If policy makers choose other approaches, the burden of explaining the decision is on them. Consider how this plays out in antibiotic stewardship: antibiotic resistance is growing, and everyone should be mindful. Stewardship policies would put the burden on patients, but recognizing that most antibiotics are used in the food animal industry, and that people are still getting antibiotics for viral infections, it would be important for a guideline panel to put the burden where it belongs.

I know, I'm just-last. Guidelines exist to assist physicians and serve patients. I encourage the health ministry to establish a framework that builds on that foundation. Thank you.

Lise: Thank you, Dr. Maloney, for your good advice on developing guidelines. Our next speaker is Dr. William Bowie, who is Professor of the Division of Infectious Diseases, Faculty of Medicine, University of British Columbia. (Inaudible).

William: [37:11]

Thanks very much. So, I'd like to thank the organizers for putting this on. I'd like to thank the audience for the opportunity for us to collectively hear stories, and I'd like to thank the organizers for the opportunity and the mandate for us to collectively move forward, which I think is a goal of all of us.

So, I've been asked to talk about the treatment of Lyme disease, and quite a bit of what I'm going to say is quite concordant with Dr. Maloney's comments, particularly her last slide, which has not come up in-the content really hasn't come up in the discussion I've heard today. Treatment guidelines, whether they're for pneumonia, whether they're for whatever, are guidelines, and they always have to be interpreted in the light of the patient in front of us. And so, it's been anxiety-provoking to hear a lot of the talk here, where it sounded like they're carved in stone, and clinicians, and patients along with clinicians, have no flexibility. That's just totally wrong, and that's not the intent of guidelines.

How do I move forward? Green arrow. So, did this get changed?

So, I don't think I have any particular conflicts, here. I have research funding for pneumonia from Pfizer, and GSK for influenza studies. I avoid speakers bureaus, I don't do consultation fees, etc., etc. Oh, this didn't get changed. The bottom line is I didn't understand how this conference was funded, but there's no conflict. I do want to acknowledge that I am a member of AMMI Canada, and I am a member of IDSA, and in terms of this subject, I am the AMMI Canada representative to the ongoing process to revise the Lyme treatment guidelines, which are done by the IDSA, but with equal involvement of the American Academy of Neurology, and the American College of (inaudible), so we're really trying to expand the involvement of groups. So, no mitigating biases (inaudible).

So, I'm going to take a somewhat different tack to how we develop guidelines. But first, comments about goals of eradication of-goals of treatment of infection. So, our primary goal is to eradicate infection. And for the vast, vast majority of infections, we actually have regimens, at least for bacterial and fungal infections, that are good at that.

Next goal is to try and get the person affected back to their pre-illness baseline. Here, things are a little more complicated. Improvement in signs and symptoms is usual but not universal, and recovery of signs may be partial. So, if you have endocarditis, you have infection on your heart valve, we can get rid of the infection, but you may remain highly compromised. Or, if you have meningitis, or if you have sceptic arthritis, we get rid of the infection, but the manifestations don't necessarily go away.

And then the bottom one, improvement of some symptoms, particularly subjective symptoms, may be slow, and incomplete despite eradication of the infection. This is common to almost all the infections that we treat. Lyme is not unique.

So, what's the hierarchy of evidence that we usually use when we try to develop guidelines? And this is well established and fits well in terms of antibiotic treatment guidelines as you're going to see next, where we can define studies pretty well.

So the top is traditionally randomized control trials, and then cohort studies, case reports, and at the bottom is expert opinion. Clearly, expert opinion is required to interpret all of this, but if it's only expert opinion, that's really not very helpful as we come to looking at antibiotic treatment regimens.

Two comments: first is the plural of anecdotes, especially unevaluated anecdotes, is not data. So, stories are important, but a large number of stories can't really be evaluated, doesn't help a great deal; may identify issues, but it doesn't help in terms of developing guidelines. In terms of expert opinions, it is required to interpret data from all sources. But, as I mentioned earlier, expert opinion that's not systematically acquired and evaluated doesn't constitute data.

I'm just going to skip that in the interest of time.

So, what's the recommended evidence base for when we develop guidelines? So, fortunately, any recommended antimicrobial treatment regimen is amenable to evaluation using standard and well-developed methodologies. This science is pretty good, is pretty clear. Most typical is a randomized control trial, where a regimen is compared with a placebo or an agent of known value, and appropriately designed studies look not only at efficacy using, hopefully, some pre-defined end points, but also look at adverse events, and ultimately have to come up with an assessment of risk versus benefits.

So, Dr. Maloney mentioned the grade methodology, which has become a really well-accepted way of trying to come up with guidelines. It has many advantages. One of the advantages, again, that we just heard about, it does include a special emphasis on outcomes, and an emphasis on patient-centred wishes. All of us support that. However, I'll make the comment that all of the grade methodologies start off with high-quality data, where defined regimens are assessed and compared.

So, how are these questions asked when we develop guidelines? So, we use a framework, a PICO framework. So, a typical study has a clearly defined population. So, we try to articulate the patient population and the question that applies in that patient population. We have an intervention, which is usually a specific regimen under study, with a drug, a defined dose, and a defined duration of the drug, a comparator, which could be another placebo or another drug, and then we have the pre-determined outcomes.

So, coming to Lyme, I don't deal with any other infection where there's such controversy around the issue of treatments. And I would argue that there's a lot of confusion, if not worse, in terms of terminology around Lyme disease. I'm going to break it down subsequently. But the term is used to encompass a range of folk where there's no questionable diagnosis of Lyme disease, all the way to those who have little or no evidence of active infection. And many of the so-called treatments that are recommended have never been subjected to this initial stage of actually demonstrating activity of a specific regimen versus the standard, let alone looking at benefits versus harm.

So, this is a slide I've used now for a decade or more, around lab diagnosis, but it's totally applicable to the treatment. So, on the left, where it says 'Public Health Laboratory' we have the IDSA-type guidelines. On the right we have the ILADS recommendations. Across the top, we have kind of irreconcilable recommendations, but who's caught in the middle? Well there's - thanks very much. So, patients, families, and supporters of patients, there's health care providers, there's public health officials, and the media, stuck right in the middle of this issue that we can't find a way around.

So, how do we move forward? So, we can certainly clarify terminology, and I'm going to argue we should be assessing data and studies according to specific groups. And then, looking further forward, we can try to figure out, "how do we fill these gaps of knowledge?" And I've said here, "Hold accountable those who promote treatments without conclusive baseline-supportive evidence." I don't mean punitive, I mean raising the question, holding all of us to account on how solid is the data on which you make recommendations. Sorry, I wander.

So, what are the categories that are labelled 'Lyme disease'? And David Patrick used this this morning, not surprisingly, since we work in the same group, and we've worked on this issue a long time. So, the first category are people who have Lyme disease and no one's particularly going to dispute that. The second category is what we're hearing about a fair amount here, are people who are given a label such as 'post-treatment Lyme disease', where they had clear evidence of Lyme disease, as in category number one, but they have incomplete resolution of symptoms after standard antimicrobial therapy. The next one is the one that David Patrick was particularly talking about, those who have alternately diagnosed Lyme disease, where folks are diagnosed on clinical grounds but the only positive laboratory testing is when it's done by labs where we question the results. So, I could name IGeneX for an example, which is a recurring theme. And then there's a fourth category of people who are diagnosed purely on clinical grounds, and if any testing is done, they test seronegative for Lyme, at a time beyond the initial stage of Lyme disease where we would expect most of them to have positive tests if they have active Lyme disease.

So, what about the quality of the data supporting treatment recommendations? So for group one, which are essentially the IDSA-type guidelines, these are based by and large on well-designed studies that, in our opinion, provide sufficient evidence to support the guidelines, even though there are always going to be questions. You can't answer all questions in a guideline. None of our recommendations are for treatment beyond four weeks of therapy. And in the vast majority of people treated according to these guidelines, people improve.

What about the quality of the data behind groups two, three, and four? We're going to have some differences of opinion here, but none of the studies, including the study from the Netherlands, in my opinion and the opinion of my colleagues, provide convincing evidence of benefit of longer-course therapies. And for these non-IDSA type treatments, there are no studies demonstrating efficacy of those treatments, let alone studies looking at the assessment of real or potential harm and overall cost of the studies.

So, I'm going to not go through this study that's been mentioned several times, except to make-so, this is a recent Netherlands study, the comparison of ceftriaxone and then longer-course therapy. I don't have a pointer here, but I point out that participants usually were highly symptomatic for at least two years. Most of them had received antibiotics for 30 to 40 days, and most had received two or more course. And the outcome is a bizarre study. I don't think anybody in this room likes this study, and the design of this study. But what it shows is, well, it shows a couple of things. Firstly, 50 at the top is what the general population would be in terms of health status, and the lower the number, the worse the health status. So this is a group of people who are significantly compromised by symptoms, but I interpret this data to say that there's no obvious benefit of giving antibiotics beyond the two week course of ceftriaxone, and that antibiotics were no better than placebo. I'm sure one can do some sub-group analysis and tease out little bits of this, that, and other thing, but those really aren't the traditional way of doing a study. The stupidity of this study, well, there are many stupidities, unfortunately didn't do an evaluation after the two weeks of the ceftriaxone. So, we don't actually know when that apparent improvement between zero weeks and 14 weeks actually occurred. So, makes it difficult to interpret a lot of the benefit, but it makes me feel fairly comfortable, I don't see any added benefit of 12 weeks of antibiotics.

I'm going to talk just really briefly about the ILADS guidelines. So, as we've heard, the data that IDSA used are looked at differently, and there's a belief system that the traditional, shorter courses of therapies aren't adequate. However, the recommendation is based on very low-quality evidence. We should be able to do better than that when it comes to treatment trials with antibiotics. And then, if you look at continuation of therapy, long-course therapy, at least four to six weeks, for which there's no evidence from randomized studies, and then there's this approach that we don't do in any other infection, if there's strong to moderate response we'll give therapy longer, if there's not a very good response, increase the dose or switch to a different drug, and if there's no response, then switch to a combination of first-line agent. There are no data that support that this actually works.

So, there's been a lot of discussion about, what are the potential harms of this? Well, there are lots. You know, desperate and vulnerable folks may be given an incorrect label and subjected to unproven treatment for which there's no valid evidence of benefit, let alone that benefits exceed risk. There's a focus on Lyme to the exclusion of other possibilities. The risks of antimicrobials to oneself, and the risks of antimicrobials to the community at large, the debate or angst that we have between the different groups, severely undermines medicine and public health. We do not develop guidelines for Lyme disease differently from all other diseases. We use the same methodology for hypertension, for diabetes, for all other infections. And so, some of the debate is actually undermining particularly our public health colleagues, and those of us who develop guidelines. So, it undermines all of us. And then I have the new issue. I now treat people with acute Lyme who now fear for their lives. Even though they have a treatable disease, they're now scared stiff that they're going to develop long-term consequences.

So, my comment, which may be taken as inflammatory but I feel it strongly: the ILADS-set recommendations have gone on for a couple of decades. There have been a huge number of people subjected to-exposed to these treatment regimens. There ought to have been an opportunity to actually evaluate those regimens. I think that's a reasonable expectation. And certainly, it constitutes missed opportunities to help provide better, evidence-based care.

So, what could a potential study look like? I'm not driving this study, but in any other infection, we define a population. So, in this case, individuals who meet criteria, for example, alternately diagnosed Lyme disease, and one could define that and level of disability, etc., etc. We have an intervention, which I've said doxycycline 100 mg twice daily for six months, but it could be any regimen. There should be a comparator. I would argue, given the total absence of data, that these regimens actually make a difference. There probably could and should be a placebo-controlled study, and pre-specified outcome measures should be defined; so, the health-related quality of life and related measures, which has become a little bit of a standard for a lot of these studies, and then secondary analysis of adverse events.

So, moving forward, we're all concerned about the profound disabilities people in categories two to four have. People deserve formal evaluations of treatments given to them, as well as better efforts to understand what's going on, and that focusing on their perceived diagnosis of Lyme disease actually has the potential to be highly detrimental.

So, what are recommendations? So, although this focus is this meeting is based around Lyme disease, I and I think most of us would argue that Health Canada could and should use this opportunity to better understand and support individuals with chronic debilitating manifestation, whether or not it has anything to do with Lyme disease.

Then, final two comments: guidelines are always going to be incomplete, particularly with tick-transmitted pathogens, where there are new pathogens, they are spreading geographically, and new knowledge accrues. So, no guideline should ever be carved in stone, and we all must be prepared to revise our understanding of disease and treatments as high-quality new knowledge is acquired or developed, and this ability to change tack with new data is at the core of scientific method. That's it.

Lise: Thank you, Dr. Bowie. So, we are going to take a 15-minute break, now, come back for two more presenters, and then do a Q&A with all four presenters. So, 15 minutes by that clock back there, we'll be back, ready to start at two-thirty. Looking forward to further discussion. Good break.

We'll be starting in just one moment. One more minute and we will start. Could the speakers, come to the front, please. Dr. Hatchette and Dr. Zhang. Problem with my microphone? How's the audio now?

I'll just introduce you briefly. You're Dr. Hatchette?

Todd: I am.

Lise: I'll be sitting-yes, if you can sit over there.

So there's a buzz in the audio system. Is that better? I'm hearing noise. Okay.

Just to comment before we start up, I've been asked if these slide presentations will be shared. The organizers of the conference will not be sharing the slide presentations. They belong to the presenters. So I'm not sure if they have a mechanism to share that, but you won't be getting them from the conference per se, although the recordings, as has been said, will be shared.

So we have two more presenters. So just before the break, we had two contrasting but, I am reassured, potentially compatible views on guidelines, so looking forward to the Q&A on those presentations. Just out of curiosity, how many people have questions for our first two speakers? Just to get a sense in the room. Okay, so we do have some questions coming up.

I'm now going to present the first of our two speakers for after the break, then we'll go to questions and answers.

So remember, the Q&A is not right now. We're doing the other two speakers and then we'll go to questions and answers.

So, the current state of Lyme diagnostics in Canada, by Dr. Hatchette.

Todd: Thanks.

[01:14:04]

So, thanks for the conference organizers for inviting me. It's been actually quite informative. I'm going to go through my presentation, which is going to be a lot of stuff that we had heard about this morning, but hopefully will put you in more of the Canadian context. And at the end, I'm going to read something that I wrote about four o'clock this morning because I think was thinking a lot about the patient stories last night, and tried to frame what I was taking away from what I was hearing. And hopefully I've captured it, and if not, I'm sure you'll let me know.

So I do have some grant support from GSK and Pfizer. I oversee the diagnostic testing for the Serious Outcomes Surveillance Network looking at community-acquired pneumonia and influenza. I did receive an honorarium for talking about latent TB infection and reactivation in biological therapies, but I don't have any consulting fees. Funding for the honorarium that I had had nothing to do with Lyme disease, so really there's no bias from that perspective. I will declare that I am the co-chair of the working group looking at Lyme disease diagnostics for Canada as part of the provincial public health laboratory group.

So I think a lot of people have talked about definitions, and from a laboratory perspective it's very important to clearly define who you're testing because the testing and all of the data that we generate through the tests are based on who we're testing, so the validations we go through need to be on clearly-defined cohorts. So we've already heard about localized Lyme disease, disseminated Lyme disease, the late Lyme disease, the post-Lyme disease syndrome, and then chronic Lyme disease. And within the chronic Lyme disease, we've heard it's been divided into two: there's the ones that have been diagnosed with alternative diagnostic methods, we've heard through IGeneX, and the other one where all the tests are negative but are diagnosed clinically.

So again, this is just a very short summary of some of the manifestations. Clearly, not all-encompassing, but just to divide sort of the framework in terms of early localized is days to weeks, disseminated is weeks to months, and then late is months to years.

And this is just a slide that kind of shows that with time in some of the typical manifestations, so the acute cutaneous disease. You say that over 75% of patients can have them. That was in clinical trials, really that were dedicated at following patients very, very closely as part of vaccine trials, and it may not be that high in routine clinical care. Disseminated disease can be neurologic, as well as carditis, which tends to be less frequent than the neurologic disease. And then, the late disseminated disease, the predominant one that we see in North America, at least that's reported in the literature, is arthritis, with neurologic disease occurring less frequently, but you can see that it can span multiple time points. I know that I don't have to go over any of that given that most of you already realize that.

But the factors about diagnostic testing that people need to remember are, one, is the type of specimen. So, are we dealing with blood? Are we dealing with urine? Are we dealing with CSF? The collection time in respect to the disease state will help define how well the test is in terms of its accuracy. The kinetics of antibody expansion, so how the body responds to the pathogen will influence how accurate the tests are. The methodology. So is it PCR? Is it culture? Is it serology? And then the bacterial strains. We've talked a lot about the strains in North America, but if you travel to Europe those strains are different, those Borrelia strains are different, and our testing may not pick up those particular strains. And then the prevalence of disease, which we heard a lot talked about by Dr. Patrick, will influence the pre-test probability, or the positive and negative predictive values. So those are all the things that we think about when we think about diagnostic testing.

So what we currently do in Canada, we do serology. We do the two-tier algorithm. You guys are all aware of what that is. I will show you exactly what each public health lab in the country is doing later on in the slides. PCR is offered for synovial fluid and for CSF. That's done in a number-in a couple of the public health labs, but mainly done in Robbin Lindsay's lab at the National Microbiology Lab. Culture is not really done in Canada. It tends to be a specialist test. It's not that sensitive, but obviously when you get it it's helpful.

Tests of uncertain performance. So there is the urinary antigen detection, which some people have talked about. There is not a lot of good data to support its use at this point. The CD57 is another that is mentioned, NK cells, and there is not a great correlation there. And then, the ELISpot is gaining some traction. Certainly some of the early ELISpot stuff, the sensitivity was not high, but we heard from Dr. Dattwyler today that he's working on that, and hopefully that may be something that will be used in the future to help us diagnose not only earlier clinical disease but help with treatment and who needs ongoing treatment. But at the moment, it's not part of the mainstream testing.

So, Western blots cannot be used independent of the EIAs, and that's because they have poor specificity. So the IgM Western blots will be false positive if used alone, and Dr. Dattwyler did show some data there, particularly with his two-dimensional gel, how some of the other bacterial antigens, or antibodies that you get to other bacterial antigens, may mimic areas where you would see the same pattern for Lyme-specific stuff. And of course, European species can be falsely negative on the North American Western blots, and we always advocate to physicians, if they have a person who's travelled in Europe, that that clinical history is important for us to know so that we can forward it on for the proper testing.

This is a very busy slide, but it just goes to reflect the different proteins that are on the Western blot. There are three colours there. The red and the green speak to sensitivity and specificity. The blue is a receiver operating curve, which is a statistical method to see how well it performs in predicting who and who doesn't have Lyme disease. And you can see that the sensitivity and specificity are variable for different things. VlsE tends to have the best performance in terms of sensitivity and specificity, but things like P41, for example, have a lot of false positives. If you have specific questions about this, I'm sure Robbin will be happy to answer them in our question period.

So, the performance of serology really does depend on the stage of the disease. And I'm sure you guys have seen this study before. It's from Allen Steere's group in 2008, where they followed people with culture-confirmed erythema migrans. They have a number of people with late Lyme disease or other illnesses, and they had objective clinical findings and they had positive serology. So you're going to say, "Okay, well, they had positive serology, so obviously the population is biased." But this is what we currently have at our disposal now to validate new assays.

So one of the things you're going to take away from this hopefully is that we really need to have our own, well-defined cohorts in Canada. So if we want to change our recommendations, we need to have our bloods [sic] that we can do our testing on to make sure, to show that that's a reasonable thing to do.

They also had other mimickers of people who have post-Lyme disease syndrome or chronic Lyme disease, as well as controls who were otherwise healthy. And you can see here, this again is not news. We know that this two-tiered system in particular does not perform well in early disease. Less than 50% of people will have positive results. But as the disease progresses, the performance of the test is actually quite good, and for arthritis in particular it's very good. Now, disseminated neurologic infection, if you look at that 85%, a couple of those patients had more early neurologic symptoms, so they had things like Bell's palsy rather than the more later disseminated.

Just as important as sensitivity is specificity. And you can see here that the specificity of the two-tier algorithm is high. You didn't get a lot of false positives in any of the healthy states, whereas if you just used C6 alone, you would. So we've heard pleas for not abandoning the C6, or moving to a single assay and not abandoning C6, because it has some importance.

So this is a more recent study. Those were a well-characterized group. This is the CDC panel that they have. So they're realized that the validation of Lyme diagnostics is very difficult because we don't have well-defined cohorts. This is their attempt to do that by collecting sera from different categories of patients, so people with acute disease, convalescent serum, people with arthritis, and then people with other, more late-disseminated manifestations.

In addition, just like any other validation that we would do, it's important to look at the specificity, so they had similar-like diseases as well as healthy controls. And you can see here, based on this panel, and they used-you'll see the whole cell lysate, as well as the two-tiered system and the standard interpretation, again, acute disease doesn't work very well. Less than 50% of people were identified, whereas things like Lyme arthritis, it works quite well. Lyme Borreliosis in this one was 90% sensitive. So again, it depends on the stage of the disease. And again, it depends on where you're collecting your specimens from.

But a lot of the earlier stuff, particularly showing that there was a lot of false positives and poor sensitivity, was on older assays that were more heterogeneous in their antigenic composition. So, their proteins were the whole cell lysate, so you grow the Borrelia. We heard from Dr. Dattwyler that when you grow the bug, you may not necessarily have the same proteins that it is when it's in your body. So they have looked at the various proteins and tried to figure out which ones are more accurate in the diagnostics. C6 was the first one. We saw that. There is recombinant VlsE itself, and then there is a new one called C10, peptide C10, which is a portion of the outer surface protein C. And I'll show you some data that suggests that if you use combinations of these things, that the performance is actually a little bit better. There's also some other lipoproteins that are being looked at. Again, one of the things that Dr. Dattwyler talked about was looking at combinations rather than our current status, and I think that that's probably where going to end up going.

So this is from a review that was just published in the Journal of Clinical Microbiology, and you can see this kind of gives you the evolution of diagnostics within Lyme disease, going from the whole cell lysate to the two-tier system to the C6 ELISA, to the C6 ELISA used in a two-tier, to the VlsE, the C-peptide, and the VlsE and C-peptide combined. So the C-peptide tends to come up early in disease. It tends to be IgM-focused, where the VlsE tends to be more IgG. But if you use both of those in combination, you can see that the sensitivity for early detection is actually higher than many of the other ones. It's at 67%, which is pretty good, and it increases as it goes across. And just as importantly, the specificity in healthy people is about the same as the current two-tier system. So there is some data that's coming out to suggest that things are going to evolve, but we can't make those recommendations without having the serum to really challenge them.

What about alternative algorithms to the two-tier? Well, this study is a little bit old now, it's from 2011, but it looked at using the whole cell lysate and then the C6 as a confirmatory method. That showed better sensitivity and equal specificity on a small subset of specimens. Again, this VlsE IgG and the peptide C10 IgM done in a multiplex assay looks like it has very good performance characteristics. Again, small subsets. Needs larger in order for it to be validated from an FDA perspective.

So this is the summary table that I'm sure you're all waiting for. The is what the various labs across the country are using for Lyme disease testing. So you can see that all of the labs except for Prince Edward Island and Newfoundland will do their initial screen in-house. P.E.I. sends their stuff to us, Nova Scotia. Newfoundland sends it directly to the National Micro Lab. Quebec has various ELISAs, including C6 and some of the newer ones like the VlsE. You can see that many of them use C6 in their algorithms. We use the combination of a whole cell plus C6. Of course, the theme with this is that it is-they follow the two-tier recommendations, and any positive or equivocal specimens, any reactive specimens, are sent to the National Lab for Western blot testing.

I don't think I need to spend too much time on this. This is Brian Fallon's paper, which highlighted the fact that if you use alternative criteria for grading Western blots, you can lead to significantly spurious results. And again, 57% of healthy individuals had some indication that they would have said it was Lyme disease here, so it's a problem.

This is just some other new data just to remind people that just because a new test is out there doesn't mean that it should be used without proper validation. And as laboratory scientists, we're very, very careful about our validation because we have accreditation requirements that require us to make sure that the accuracy of the tests are true.

This is a light microscopy method that was used to diagnose Borrelia in blood in Sweden, I think it was, and they found that 25 out of 41 healthy controls had positive microscopy, again speaking to the false positive potential of these assays. And when they tried to confirm some of them with PCR, there was concerns that there was cross-contamination, so molecular methods haven't been the panacea that they have been for other infections. We rely on molecular methods a lot now. But as Dr. Dattwyler said, the bacterial load in late infections tends to be lower, so the sensitivity for PCR tends to be less.

You've already seen this: specificity is important.

One of the neat approaches that I think is going to take hold is this whole "-omics" thing, so transcriptomics; this is metabolomics, so it's looking at metabolic signatures in a person's serum or a person's urine, and you can use mass spec to get basically a fingerprint, if you like, of what someone with Lyme disease would have. And you can see that when they use this metabolomics approach, it actually performed very well and it's on the end of that table there. You can see that the sensitivity in early Lyme in this small study was 99%. The specificity was very high as well. And then as they went further down, you can see that the healthy controls are not-the specificity is still not great. It's 95 and 94%.

So although it holds promise, it's still not ready for prime time because they haven't been able to tweak the system enough. So you look at the signature, you clean up what the background is, and you look for what is unique to people with the various stages that they're presenting with their Lyme disease. And hopefully, at some point, we may get to the point where that genetic signature or that metabolic signature will allow us to definitively diagnose that.

We heard about reinfection. It's a huge challenge. In Nova Scotia, we've had Lyme disease since well before 2002. First case was diagnosed in 2002, but certainly the ticks have been around for a while. We have the highest incidence of Lyme disease in the country. In Lunenburg County we have an incidence of over 200 per 100,000. So, reinfection is a real problem for us because we can't tell who is re-infected. Right now, you have to sort of pick out extra EM that is not in the original EM, and we know that EM is not always there. So developing a test that will be able to differentiate reinfection from previous infection is going to be very important, and maybe some of the research that Dr. Dattwyler and Dr. Fallon's doing that's looking at these overall characterized signatures will be able to do that.

Biodiversity. I'm just going to quickly go through some of this. This has always been raised as a question of how does biodiversity affect our diagnostics? There's no question that there is a biodiverse population of Borrelia, and from an evolutionary perspective I'm not the expert. There's actually other experts within this conference. You can talk to Janet Sperling, who will tell you about the biodiversity of Borrelia in ticks in Canada. And there are unique signatures in different areas, so the question is if they vary genetically, how much antigenic variation is there and does that influence testing?

Well, there is at least a little bit of data out there from Wormser's group in 2008-there's not a whole lot of data otherwise-that shows that the C6 was pretty good at detecting the same amount of people with acute Lyme disease of different RST types, or different genetic variation, if you will. Whereas the two-tier system we know doesn't work, and that may be because the Western blot can be influenced because of these proteins. But the C6 should pick it up, so you should be getting a positive C6 as your initial screen.

So I'm going to summarize quickly. I've got two minutes left. Poor performance of serology in early infection is well-known. We know that it's a limitation. In fact, when I give education talks to physicians in Nova Scotia, I remind them that when someone presents with erythema migrans, that treatment is what is required and not testing. There is no test of cure. Seroconversion can influence the ability of us to pick up serology. So if you treat early, then seroconversion may not actually occur because you've aborted the immune response. Serology can persist for a decade, again making it difficult to diagnose reinfection. The influence of diversity really needs to be further explored. Some preliminary data says that it will influence the two-tier system, for sure, but the C6 should pick it up. There's no current diagnostic testing for post-Lyme disease syndrome, and I think that the group at Johns Hopkins is doing some great work looking at, again, these metabolomics signatures and some of these transcriptomes to try and predict who that has Lyme disease and gets treated is going to be at risk for getting post-Lyme disease syndrome.

So for me, what we need is current-is well-characterized specimens. Convenient samples, as I said, are used for determining sensitivity and specificity in our testing. It's difficult to compare the new tests if the reference method is based on the two-tier system to begin with. So, my plea is that we need to really have cohorts where we can follow and get the appropriate specimens so that we can actually do some analysis of the newer methods that are coming down the pipe. We need to have these better-defined cohorts, and again, just to come back to the ones that I mentioned first, these are the cohorts that I think we need to focus on. Some of them are more easily definable than others.

So with that, I'm just going to end you [sic], and I wrote it down just because I don't know if I was thinking clear in the morning at four o'clock, but I did really find it profound to listen to people's suffering yesterday. It's clear that many people have suffered, some for years, with chronic, debilitating symptoms. I'm a father, a husband, and a son, and I cannot begin to imagine how this has affected your lives.

What I've also heard was stories which had a lot of similar features, but also reflected a heterogeneous nature to those that are suffering. There are those that tested positive for Lyme in Canada that could not get testing or acknowledgement by physicians. This is clearly unacceptable. It requires ongoing education of medical professionals. There is no reason for anyone in this room who has been diagnosed in Canada to not have access to treatment.

There are those that have tested negative by Canadian laboratories but tested positive by the IGeneX lab, or other labs; I suppose I don't know if it's all IGeneX, but from where we come from, that's usually the lab that does the testing. There are those of you that are negative by all tests but diagnosed by clinical symptoms alone.

To me, I believe that the last two groups of patients are where the primary problems lie. And the problem is that is it an issue that the tests are not being able to detect the Lyme? Is it they're not detecting another co-infection? Or is it that there is another disease that's being missed? And if it wasn't for people recognizing clusters of arthritis in kids, they wouldn't have found Lyme in the first place. So I wouldn't want to have blinders on to make us not think of the possibility that there is something else causing some of these symptoms. And when I listened to everybody's stories, there were similarities but there was distinctions. Some people had more cognitive issues. Some people had more neurologic issues. This is a very heterogeneous group, and I think to better define exactly how to move forward, we need to look at the cohorts very closely.

We heard a lot of moving stories last night. Some questioned why a cancer patient could access treatment when those suffering with Lyme cannot. One of the answers is that because these treatments have been proven in clinical trials, and those that have no proof are not used by oncologists. While many would see the researchers and doctors who discovered these new treatments as heroes, I would suggest that it is the patients who volunteer to be in clinical trials to test hypotheses on what the best approach is to treatment are the true heroes. Without them, without you, we will not find the answers we need.

So is testing perfect? No. There are clear data that states that tests are accurate in detecting Lyme disease based on the serologic stuff that we have shown you. We know that it does not perform well in early disease and can miss up to 50% of the cases, but there is hope in that the newer diagnostic technologies out there will help us develop newer diagnostic tests. But to do that, what I would like to see is support for well-designed studies that examine all the categories of Lyme disease, that we can collect the samples necessary to assess the new diagnostic methods, and in doing so we can leverage the same infrastructure to learn more about why people are suffering, the pathophysiology of disease. Is it Lyme going undetected? Is it co-infections that are being missed? Or is it something that we have yet to adequately describe? Is it the pathogen, the host, or both? These are questions that need to be explored in well-designed studies, and to me, that's what we should be advocating for.

Lise: [01:37:42]

Thank you. My brain is already almost ready to explode. I don't envy our fourth speaker, but you get to give us our fourth presentation. Dr. Zhang, "Challenges of post-treatment Lyme disease syndrome: will persister drugs help to cure PTLDS?"

Ying: [01:38:02]

Well, thank you very much. Good afternoon. It's really nice to be here. First of all, I'd like to thank the meeting organizers for the opportunity to present the work. So, I'm really going to talk about the challenges of post-treatment Lyme disease syndrome, as well as our recent work that may impact the treatment of this disease condition. So how do I do this? Okay. Here.

Alright, first, I don't really-I don't think I have a conflict of interest. I receive research grant supports from, you know, various Lyme disease foundations. And then, I don't believe I have any conflict of interest to declare, and I don't think I have any potential bias in my presentation, so let me move on.

So Lyme disease, we all know, is the most common vector-borne disease in the U.S., as well as in Europe, and it's really a fascinating disease because it's caused by the Spirochete organism, Borrelia burgdorferi, and related organisms. The disease, the organism is actually very distinct from common bacterial infections. So you have Staph or urinary tract infection organisms; these, when they relapse, when they have persistent, you know, chronic, persistent infection, when they relapse you can see the organism. But with Borrelia infections, the Lyme disease, when the patient relapses you can't see it. It can't be cultured. The organism cannot be cultured. I think this is really a unique property of the organism that creates a lot of confusion. It's a unique feature of the disease. I think it's important as a microbiologist: I need to bring this up.

The other thing is that the organism actually, as it grows in different phases, as it changes the form, changes morphology, from the spirochetal form to round body form, and also to microcolony aggregates, like a biofilm type of structure, okay? So as well, under stress conditions, they change morphology as well, into round bodies, into cyst forms, into biofilm-like structures. These are much more resistant to antibiotics or different stresses, so I'm going to come back to this.

So because the organism is very strange, very peculiar, it has these morphological changes, it actually can-oops, how do I go back? Alright. So, I don't have a pointer. Ah! Alright. That's okay. So because the organism changes morphology, each time it changes morphology, it changes antigen, protein antigen expression. That actually confuses the immune system, and you get various antigen changes each time the morphology changes. So that creates a problem for diagnosis, for treatment as well, and also it has a very diverse, heterogeneous disease expression. I think this is also related to the very unique feature of the organism; that is, it tends to change its shape, change its morphology.

So at every stage and term of the disease, if you look at them, it's never straightforward, okay? It always goes up and down. Never linear, okay? So this is a very distinct organism in this sense. That is, we are really dealing with something very complex we're not quite used to, not like a common bacteria, okay? So I think in this sense, it is important to remain open-minded, okay? There are still lots of things we don't know about this organism, okay?

If you look at the Lyme disease, the disease has various stages. The early stage is a localized EM rash stage, then moving on to early disseminated form, as in the case of Bell's palsy or carditis, late stage of the disease, arthritis, and the PTLDS. So it's a continuing spectrum, okay? So at the early stage of the disease, it's relatively easy to cure, okay? So the current IDSA guideline is two to four weeks of antibiotics treatment with doxycycline, a single drug, doxycycline or amoxicillin or cefuroxime. So if it doesn't quite respond, then the late stage of the arthritis sometimes people use UV ceftriaxone, okay? Because it's a stronger antibiotic. But then when it's reached the stage of PTLDS stage, the current treatment doesn't work very well, okay? So I'll come back to that as to why.

So I think most controversies surrounding Lyme disease are because of this disease condition, PTLDS, okay? So it's defined I think, as alluded to by previous speakers, that it is actually a disease condition, despite standard antibiotic treatment of Lyme disease, these patients continue to have symptoms six months after the treatment. And Brian Fallon actually mentioned some of these clinical studies or these clinical trials, treatment trials of these, so I'm not going to go to specifics, except to say that some studies demonstrate activity of the antibiotics, whereas others did not. So, but it's really quite interesting. So this actually suggests something that has to do with persistent infection because otherwise how come antibiotics would have any effect, right? If the organism is not there or it's not a persistent infection, antibiotics would have no effect, right?

Well, they have placebo control there, but it also says, especially the Dutch study, the Dutch PLEASE study, it actually says only two things. One is that the current antibiotics do not work very well, okay? It does not say-well, because the current Lyme antibiotics, as I will show you, have limited activity against the persister form of the organism.

So, the PTLDS is like, you know, the elephant in the room because, you know, even though some people recognize it, they try to ignore it because there's not much one can do about it because it's not in the guideline. How you treat such patients is really a challenge.

So what causes PTLDS? There are different theories, different possibilities. One is that it's actually immune response to antigenic debris, the other is autoimmune disease, and then the other has to do with co-infections, and in some cases it's due to secondary, maybe opportunistic infections, even due to prolonged antibiotic use somehow related to that. And then it's, you know, residual damage to tissues. The last possibility is the antibiotic resistance or persistence due to the organism not responsive [sic] to current antibiotics.

And there is no FDA-approved protocol for PTLDS treatment. As a consequence, you know, patients try all sorts of things that don't work very well, and these patients suffer and it's really a huge cost-you know, incur very large health costs, about $1.3 billion, and yet they don't work very well.

So here, I'm going to share with you some evidence for persistent infection, okay? Where, you know, it's being demonstrated in different animal models, in mice, in dogs, and in monkeys, where after standard treatment with Lyme antibiotics, you have these persisting organisms in the sense of a molecular test, by DNA test, but not culturable. The organism cannot be cultured. This has been a very unique feature of the disease. That's why I think some more conservative physicians would not really recognize this. So they would say, "Show me. Show me where the organism is," right?

As I said, it's a different organism. But then, you can't culture it, so it's in a state of a viable but nonculturable form, okay? Science on that is still meager. We don't quite know very well what is the molecular basis for viable but nonculturable, dormant form of the bacteria in any organism. In fact, it's a type of persister bacteria, okay?

So there's been recent interest from the U.S. CDC as well on the persistence issue as they increasingly recognize this as a problem. And as well, you know, human studies at NIH by Adriana Marques showed that xenodiagnosis, which is based on the tick bite of the patient after antibiotic treatment, can pick up Borrelia DNA, but again, it's not culturable. But the DNA, you might say, "Well, it's DNA. It's not the organism. It's not viable, right?" But if you put DNA, dead DNA from dead organisms, into the tissue, they degraded very quickly, within a week. But these persist months and months after antibiotic treatment in the case of animals, so it's really suggesting it's something. It's actually there. The DNA is there, persisting. It's very likely a sign of persisting infection, but you can't culture it.

But the very intriguing study is done by Stephen Barthold's group that's showing the sense of resurgence phenomenon. I think this is really very interesting, but deserves a lot more attention. That is, this is a mouse experiment. So they treated Borrelia-infected mice with 30 days of ceftriaxone. So then, they monitored the treated mice, stopped the treatment, monitored two months, four months, eight months, and twelve months. So within the first eight months, you don't see anything if you survey the infected organs, different tissues. You don't see anything by molecular test. However, at the end of twelve months, okay? Sorry. You started to see these molecular tests turning positive. This is really a late resurgence phenomenon, where again it's in the form of increased DNA detection, DNA content; that really suggests that the organism actually replicated in a state yet not culturable. So this is really a very interesting phenomenon that really suggests that something analogous may happen in vivo, but we just can't culture it.

So it turns out not only in vivo, current Lyme antibiotics cannot quite eliminate the Borrelia organism, but in vitro as well. We and many other groups have actually demonstrated that current Lyme antibiotics have good activity against the growing forms like, you know, this log phase culture, but have very poor activity against this stationary phase culture, which has been reached in persister forms, okay?

Then the concept of the bacterial persisters. So persister is nothing new. It's been shown before, since 1940s. So when penicillin became available, they showed that always there's a small percentage of bacteria not killed by penicillin. So these are actually not due to genetic resistance, but due to phenotypic resistance. That is, the organism in a dormant state, when you remove the antibiotic, they come back, and when they start growing still remain susceptible to the same antibiotic. So it's a phenotypic, more subtle resistance in persisters, okay? So in fact, this persister form is actually underlying different bacterial persistent infections like tuberculosis, urinary tract infections, and I believe in the case of Lyme as well.

So you might wonder: why are persisters important, right? I'm going to show you this cartoon where this current Lyme antibiotics or antibiotics are like this mower: you chop off the top part. I know when people see this, they always laugh because it's such a, you know, very good way to demonstrate the problem. So the mower is the current antibiotics that kill the growing form of the bacteria. The root is still there, remaining intact. When you remove the antibiotic, they grow back, okay? Even though you can't quite see it, often times in the case of Lyme. So what you need is drugs like this, like a shovel to dig out the root, okay? Then the whole thing dies.

In the case of tuberculosis, I'm going to give you this very important drug called pyrazinamide, okay? It's a persister drug like the shovel to dig out the root, then can shorten the TB therapy. In the field of tuberculosis, where I originally came from, we know the importance of pyrazinamide, PZA, because it's a persister drug, inclusion of which is critical for shortening the therapy, without which the therapy is longer. That's why, in the TB field, we know the importance of persister drugs. I think the same principle applies for Lyme treatment.

So this is actually in the form of a yin/yang model. So here, in the case of tuberculosis treatment, we use three drugs. Pyrazinamide, that kills this yin/yang. Yang means growing form of the bacteria. Yin means non-growing form. So we have a TB drug like isoniazid that kills only the growing form, and rifampin kills both growing and non-growing forms, then pyrazinamide exclusively kills the non-growing persister form. So you need the three drugs in combination in the case of TB to more effectively cure TB because a single antibiotic like isoniazid, in the case of TB, people did in the '50s; it took 18 months to cure TB, okay? But with a drug combination, treat TB in six months.

This is exactly because of the heterogeneity of the organism in vivo such that a single antibiotic does not always take care of all different bacterial populations. So that's why we need a drug combination, but it's not any drug combination because if you only use a drug combination to kill only the growing forms, different antibiotics to kill the growing forms, it's not as effective. You need to take care of this persister population.

So, unfortunately when we started, we don't have this type of antibiotic in the case of Lyme disease, so we had to really develop a high-throughput, SYBR Green viability assay that allows us to screen FDA-approved drugs against Borrelia persisters. And we were able to identify a range of FDA-approved drugs that have high activity, better activity, than the current Lyme antibiotics against Borrelia persisters. So these include daptomycin, used to treat MRSA, as well as clofazimine, used to treat leprosy as well as MDR-TB. By the way, clofazimine was recently endorsed by the WHO for treating MDR-tuberculosis, being able to shorten the TB treatment from 18 months to 9 months. It's actually analogous here: clofazimine, we found, also had good activity killing the persister form of Borrelia. So, then along with some other cephalosporin antibiotics. So these studies were recently published in the past year or two in different journals, so I'm not going to go over in detail.

So while we evaluate these drug candidates, we found, in fact, among the current Lyme antibiotics, the most effective one that actually can be assessed by our SYBR Green PI viability assay are the cephalosporin antibiotics like ceftriaxone, which is very interesting. It correlates very well. That actually turned out to have better, the best activity, against Borrelia persisters. In addition, close to that is cefuroxime, which is the third Lyme antibiotic, which is not very commonly used. Very peculiar. But this really turned out to have very good activity against Borrelia persisters. It may be interesting to evaluate the third antibiotic, cefuroxime, also called Ceftin, in a clinical setting because it shows pretty good activity against persisters.

With this assay, so we were able to rank the relative activity of the current Lyme antibiotics as well as the new drug candidates we identified. But of course, the new drug candidates we identified are much more active than the current Lyme antibiotics. So even that, we found that there is a hierarchy of Borrelia persisters. Starting from the spirochetal form, which is actually more easily killed, in spirochetal form. Even though it's a persister, non-growing form, it's more easily killed by the drug candidates we identified. Then, followed by round bodies. The most resistant form is an aggregated microcolony of biofilm-like structures, which a single persister drug like daptomycin, clofazimine, are not able to kill entirely, so you would need a drug combination, okay? A similar sort of story as I alluded to earlier, you need drug combinations to take care of all three different bacterial populations in order to achieve this more eradicative cure. Well, this is all done in vitro, of course.

So as you can see here, unfortunately I don't have a pointer, but anyway, so as you can see here in the middle panel, this aggregated structure in green means live cells, so this is stained under microscopy by SYBR Green PI assay. The SYBR Green stains the live cells green, dead cells red, so the red is stained by PI, propidium iodide. So with this very visual assay, we're able to quickly determine the relative activity of antibiotics against the persister form. You can see the current drugs like doxycycline hardly had any activity against the aggregated form. It's still green. That means still viable after treatment, whereas daptomycin, the very right-hand corner one, is actually a lot of cells turned red, but still some green cells, okay? That means on its own it had limited activity.

So when daptomycin is used in combination with a second drug, it's actually better. You can see more red cells. But to achieve complete eradication, you need three-drug combinations, so doxycycline, cefoperazone, as well as daptomycin. The three drugs in combination are able to completely eradicate it so that we don't get any growth during the subculture studies.

So this is a subculture study shown by actually the very bottom one, bottom right-hand one, is one that's the best drug combination, where in subculture studies, nothing grew back. No spirochetes, okay? Whereas any other single drug, or two-drug combinations, they all have spirochetes growing back, so that means they're not as good.

So more recently, we did all this, evaluated the different persister drugs, including daptomycin, mitomycin C, as well as daunomycin, an anthracycline antibiotic. It's actually quite interesting because in another study, some study claimed mitomycin C had better activity than daptomycin, but it turned out not to be true because when you use a younger culture, then you can see mitomycin C more active than daptomycin. But for older cultures, primarily consisting of persisters, in fact it's the other way around: daptomycin is more active than mitomycin C. So we showed that in drug combinations as well as in subculture studies, these are able to completely eradicate, these triple drugs. Again, it's a triple-drug combination being important, okay? Two-drug combination is not good, so it'll have things grow back.

So I'm going to skip that.

So finally, I think I'll move to this unified yin/yang model. So this is really quite amazing to see the polarization in the field where, you know, the IDSA guidelines seem to be actually more geared towards this relatively early stage to this late Lyme arthritis stage of the disease. Beyond that, these two to four weeks of antibiotics do not work very well. Whereas ILADS, seems to sort of more taking care of the physicians-sorry, taking care of the patients that are not taken care of by IDSA Lyme physicians, okay? So this-but you know, both groups are important. There's sort of a continuing spectrum of the disease, I believe. So in order to actually more effectively cure this Lyme disease, I think more studies are needed to evaluate these drug combinations.

So my question then for the future would be whether the drug combinations that eradicated this microcolony, biofilm-like structures, are active in vivo, in animal models as well as in patients, okay? And what are the causes for PTLDS, okay? And the role of this persisting infection. I think now it's possible to address that. And also, when we address that, it's important to recognize the heterogeneity of the patient group, PTLDS, so that actually they may have more than one condition. They are not mutually exclusive. They may have more than one condition in that particular case.

So then, what would be the biomarkers that predict treatment response as well as cure? And also, what is really the basis for this viable but non-culturable form of Borrelia persisters? And whether we'll be able to design drugs that better kill such forms; see whether they can improve clinical treatment of the persistent form of the disease.

Yeah. So I think finally I'm going to end this with two quotes. One is from William Osler. I think this is very important. We really need to remain open-minded. And I'm really pleased to see this sort of flexibility coming from the IDSA line of physicians that's beginning to recognize the issue of persistent Lyme and recognize that we don't know everything. And there are still many things we don't know. It's important. That approach is important, because otherwise if we claim we know everything, that is dangerous, okay? We tend to shut ourselves out and we're not really going to be very helpful and we're only going to make the problem worse.

So I think, you know, to end I want to really quote William Osler, who was at Johns Hopkins but, by the way, is from Canada. Probably many of you don't know that. So, "The greater the ignorance the greater the dogmatism." As well as from Willy Burgdorfer, who discovered Borrelia. In the context of persistence, he made this comment: "It is there, but you can't see it."

So I'm going to stop, and (inaudible). Thank you. Thank you for your attention.

Lise: [02:02:52]

Thank you for your words of wisdom, Dr. Zhang. I'd invite our other presenters to come forward and sit at the front to be ready to answer questions. I'm going to as has been done previously and invite people who have questions to come to microphones, and I'll simply alternate between the left-hand and the right-hand. First come, first serve for questions. At some point, about three or four questions in, I will look to see if there is anybody who has questions but cannot get up and go to the microphone and I'll ask you to flag me, so I'll also take a few from those people. And I have some microphone runners in the room; hopefully they will help me with that management.

So as you come up to the microphone, please identify yourself and then ask your question. I would invite you, given the number of questions that I'm sensing in the room, that you please keep your question short and to the point, and we'll move through as many as possible. Remember, this afternoon we're building the foundation for our discussions tomorrow on where do we go from here. So we're looking for better understanding through these questions, and I'll leave it at that. Over to you, sir.

Male: [02:04:03]

Yes, this … This question would be directed at Dr. Bowie. In part of your presentation, you indicated that the current debate that's going on over the disease is standing in the way of medicine. Our position on that is science requires debate, and if it's not debated then it's not science, it's politics. So what's your view on that?

William: [02:04:40]

So, I would be the last person you will ever meet who will disagree with the idea of debate. I would argue with the debate, though, one should have-one should be able to marshal one's arguments that are reasonably compelling. And so, there's debate where there's good data to support differences of opinion, and then I would argue there's debate where there's less good evidence to support differences of opinion. We can move forward if we can reach a common ground on agreeing, "Okay, what do we agree on? What don't we agree on?" But I-anyway, I'll stop.

Lise: Okay, so it sounds like-oh, okay, I'll be using the podium microphone. So it sounds like you're violently agreeing. I like that. Over to you, sir.

Ted: [02:05:33]

My name is Ted Cormode. I'm a retired pediatrician. I was a general practitioner for three years and I did my pediatrics here at UBC. And I have a conflict of interest that I must declare, and that is that three years ago, I knew absolutely nothing about Lyme disease. When my daughter called me from her car and said she had numbness in her face, she was bit by a tick ten days earlier, she had tingling in her feet, she had severe photophobia, severe headache, and hyperacusis, I told her to see a neurologist and get a brain scan, and she told her story last night.

Since then, I've read. I've spent hundreds of hours in the last three years, because I'm retired and I can do this sort of thing. And the more I read, the less I knew. And no doctor could spend the amount of time that I did in reading about this. So what I would do is I would get a guide-I'd go to a guideline and we talked about the guidelines earlier-and even though you try to not make them, "You got to do it this way," if I'm in general practice and I don't have much time to review these things, and you tell me that 80% of people have bull's-eyes, that's the truth. And if less than 36 hours is no problem, you don't have a problem.

Lise: …question in there somewhere?

Ted: And so, that's perhaps you. And the other question is to Dr. Bowie. With interest, I watched your testimony at the Senate review of Bill C-442, and in it you said, "Individuals who present with Lyme disease who are diagnosed and managed by recognized and evidence-based approaches are almost always cured of their acute infection. Infectious disease clinicians see relatively few of these individuals, mainly because they are adequately managed in the community." Could you elaborate on the comment that these people are adequately managed and how you know that?

William: [02:07:41]

So, my experience, so I'm in B.C. I'm in a low prevalence area, but I almost never see someone with an acute erythema migrans. I'm called by the ED doc who's treated this person or I'm called by the family physician who's initiated treatment. So my experience, as seems to be the collective experience of other colleagues, is that the vast majority of people do not need and should not wait for specialist involvement to get the acute treatment. You know, again, we are trying to get the clinicians to initiate treatment when someone presents with a reasonable, reasonably-supported treatment-or, sorry, presentation, a reasonable history of tick exposure, plus or minus bull's-eye rash or maybe Bell's palsy. That's enough to initiate treatment, and it should be done right then. You know, and that's-I mean, that's part of what I was trying to get at in terms of guidelines. Guidelines absolutely need to be looked at in the context of the person in front of you.

Ted: In the testimonies last night, over and over and over again, I heard people say that I was not treated with the initial presentation, so I would suggest that another reason that you don't possibly see these in your office is because most of them are missed and you don't see them until they have obvious-until they move into this more chronic state. And certainly, that's what conclusion I would come to from what I heard before, and I think we need to really inform people about early diagnosis.

William: [02:09:26]

So I can't agree with you more. You know, I think that Bonnie Henry did a nice study in B.C., you know, trying to systemically look at clinicians' knowledge, and I was pleasantly surprised that it was better than I thought it would be. Does that mean people don't fall through the cracks? Absolutely not. I mean, that's part of the travesty, because it shouldn't be happening if collectively we're doing our job right.

Lise: And remember that there's another group that's doing education and awareness, so we're going to hope that they pick up on this significantly. Over to you, sir.

Ben: [02:09:59]

Thank you. Hi, I'm Dr. Ben Boucher, and I have a question for each of the panel members, if possible. Over seven years, I treated 200 patients for possible vector-transmitted infections. The most common, from clinical presentations, were Bartonella, Borrelia, and Babesia. So it's not just Lyme and it's not just ticks. Several insects have been shown to carry and transmit these vector-transmitted infections, and Bartonella seemed to be the most prevalent. Yet this organism, with just as devastating effects as Lyme, was barely mentioned today. There certainly seems to be a lot of confusion regarding tests and their validity. So far, I've heard that we need better testing and more trials. Meanwhile, there are a lot of apparently infected people not recognized, nor treated, with devastating results, as we heard last night. So why not base the possible diagnosis of a vector-transmitted infection on possible exposure, constellation of symptoms and findings, in a previous healthy person, that are in keeping with a specific vector-transmitted infection, then do a trial treatment with herbals or antibiotics specific to the suspected infection, to see if this creates a Herx reaction - and almost all of the 200 patients had one. So, serology and brain MRIs may help diagnose, but is not a clinical diagnosis what we need now?

Lise: [02:11:48]

Okay, so I'm hearing a recommendation there rather than a question. You want them to react to your recommendation? Is that …?

Ben: Well, the question is why don't we base our diagnosis on clinical presentations while we have such unreliable testing?

Lise: Anybody think we should not do that? Or who wants to tackle the question?

William: Sure.

Lise: Can we have one of the other panelists who've … Okay.

William: Gladly.

Todd: [02:12:20]

So I'll speak to that. Again, I don't think that clinical symptoms alone are going to define exactly what's going on, and you're at risk of missing something. So by saying that they've got 30 or 40 symptoms that means they've got Bartonella, I see no evidence to suggest that that's the case. And my concern is that we are missing something that we should be looking for. We should be looking more closely to see why these people have similar stories. And we've stories about family members; maybe there's something with their own genetics that makes them predisposed to something within an arthropod bite or other sort of bite. I don't think that it's specific enough to say, "You've got 30 or 40 symptoms, I'm going to put you on four years of antibiotics." I think that that does a disservice to people because they haven't really been told what they have.

Lise: Responses from other panelists?

Ben: [02:13:20]

But the clinical presentation does indicate they have such an infection and the treatment results in the Herx reaction and then improvement. So, what, just tell them, "Goodbye"?

Lise: Okay, Dr. Maloney?

Elizabeth: [02:13:36]

Well, I'd like to address the idea of a clinical diagnosis, because a clinical diagnosis not only looks and evaluates people for things that are consistent with Lyme disease, or whatever disease you're interested in, but a good clinical evaluation would also investigate, via questioning and exam, other potential diagnoses that might look similar. So it is actually a combination of doing both that one arrives at a clinical diagnosis. I think it would be great if clinical diagnoses were supported by laboratory values, but we have lots of other medical conditions which are clinical diagnoses made without lab support.

And I think the other piece of that is that when one does make a clinical diagnosis and begins treatment, regardless of what condition you're treating, you have to carefully observe the outcome of that empiric treatment. And if you're not getting the expected response, you need to come back and revisit your clinical diagnosis, but if everything seems to be rolling along as you would have anticipated, then I think you're on the right path, and I think that therefore kind of goes back and justifies the original diagnosis.

Lise: Okay, Dr. Zhang?

Ying: I'd like to (inaudible)? Hello?

Lise: Yeah.

Ying: [02:14:56]

Yeah. So I'd like to respond to this question about Bartonella co-infection. In fact, the organism is not easily detected by current diagnostic tests. It cannot be cultured. And I talk to Ed Breitschwerdt at UNC, North Carolina. He has his company, you know, his company is about the only place I can do this sort of test. But on the other hand, it's really-based on this clinical response with drugs that's being used to treat Bartonella or Babesia, but then it does not necessarily mean that they necessarily have-I'm not really denying they may have. They may well do, but it's just the current diagnostic tests are not sufficient.

And then, the drugs used to treat such co-infections happen to have activity against Borrelia persisters. So, atovaquone, along with Levaquin along with some other drugs, rifampin and, you know, along with some others, turned out to have activity-artemisinin-used for treating these co-infections. Anti-fungals turned out to have activity against Borrelia persisters as well. So in a way, we don't, quote, know. I think this is an area that more research definitely is needed to know what kind of co-infection it is there, or whether, when the patient doesn't quite respond to current Lyme antibiotics, then that's not really necessarily due to co-infection. So that, we have to be sure as well, because it's really a complicated issue here. So I'm not really completely ruling out the problem of co-infection, I'm just saying we have to be cautious. More, better tests are needed in order to address this better. Treatment strategy is also needed.

Lise: [02:16:49]

Okay, and Dr. Bowie, I didn't mean to shut you down. Did you want to add anything?

William: No, (inaudible).

Lise: Okay. I'll go the gentleman on my right here. Thank you, sir.

Male: [02:16:55]

So my question, my question is for Dr. Hatchette. In your presentation, Dr. Hatchette, you alluded to something that I've seen in print as well, and that's that we should not rely on the Western blot studies in isolation from the EIAs. Could you reconcile that with the CDC permitting or allowing or defining as one of the categories for the case surveillance diagnosis single-tier IgG Western blot as being one of the criteria that can be met? Because that doesn't seem to reconcile with the CDC's case definition.

Todd: [02:17:38]

I don't know what the CDC case definitions are. I'm only familiar with the Canadian ones.

Male: [02:17:45]

Okay, so that's interesting. So we're going to be recommending treatment according to the IDSA guidelines, the American guidelines, but you're not familiar with the CDC case definitions? I'm just curious about that fact.

Todd: [02:18:07]

No, I can't tell you what the CDC case definitions are. I'm sorry.

Male: [02:18:11]

Okay, fair enough. Dr. Bowie, are you familiar with the CDC case definitions?

William: [02:18:17]

I don't actually know that criterion, which is my ignorance. I don't know if-so one of the things we have talked about a little bit, but really haven't discussed very much, is this distinction between clinical management and surveyance, you know, counting for cases. You know, we discussed Canadian laboratory diagnosis in great detail a few years ago. This didn't come up as something that we would propose, but I can only expect that it's the CDC is talking about that surveyance reason rather than clinical management.

Male: [02:19:05]

So I struggle as a clinician when I have a patient who meets the CDC's defined criteria for an IgG Western blot but does not have the preliminary study. They meet a case definition diagnosis or definition for Lyme disease, and I struggle with what to do and how to report that because they don't meet the criteria for reporting in Canada. As a member of the IDSA Guidelines Committee, I would hope to get perhaps some guidance from you.

William: [02:19:37]

So I am not a laboratory diagnostician. We've been working, though, on the IDSA guideline for about two years. There are an incredible number of-so I use the term PICOs, you know, trying to identify specific populations, specific issues. A huge number of things we're looking at, you know, are diagnostic strategies, diagnostic tests. If that's in the current guidelines or the current CDC thing, then I presume it will be, you know, will be looked at. You know, I would like, though, still to know the context in which the IgG is being looked at. You know, we've talked repeatedly that presence of an IgG, you know, you have mumps IgG, you don't have mumps right now, and so it's the same kind of issue with Borrelia burgdorferi. I don't know the context in which you're trying to apply it.

Todd: [02:20:31]

So from a diagnostic perspective, the IgG Western blot has better performance than the IgM Western blot, and that was clear in Fallon's study: most of the false positives were actually due to IgM Western blots, so …

Male: Yeah, that's not a criteria, though, of the CDC. The CDC criteria is specifically set for the IgG Western blot.

Todd: Okay.

Lise: So it sounds like there's an opportunity to make a connection there. I would suggest that we move on to the next question.

Male: Sure, absolutely.

Lise: Unless there's … Okay. Now, I did say that I would go to people who cannot physically move to microphones at this stage. Is there anybody who would like a microphone carried to them anywhere on the left-hand side of the room? No? Okay. On the right-hand side, is there anybody? Alright, go ahead, sir.

Male: [02:21:14]

Sorry. Thanks to all the presenters. A quick question for Dr. Zhang. When you looked at treating persisters with multiple antibiotics in vitro, what sort of timeframe are you seeing 100% kill at. And that's my first question. I actually have two questions, so …

Ying: [02:21:31]

Yeah, Yeah, so these are depending on how old the culture is. So that's why previous studies done by the other groups are saying that persisters are very easy to cure, kill, even by ceftriaxone. We found that not to be true. We used older cultures with microcolonies, with aggregated forms of the structure, of the persisters. In fact, we found we need drug combinations in order to do that, to kill these forms. So these are actually-sorry, yeah, let me be more specific.

So, the other group used, like, a late log phase, maybe like a three to four days, where we used cultures much older, which is actually seven days or sometimes ten days, so these tend to have more aggregated forms of the persisters, which are more difficult to be killed by-any single antibiotic cannot do that, so we need drug combinations. Not any drug combination, it has to be persister-active antibiotics like daptomycin, plus two other drugs, like doxycycline then plus Ceftin or cefuroxime, in order to achieve that.

Male: [02:22:49]

Sorry, my question was how long did it take to achieve that? You said (inaudible).

Ying: How long? Yeah, these would take about five days to seven days.

Male: Five to seven days …

Ying: Yeah.

Male: … to totally eradicate the persisters in vitro?

Ying: In vitro, yeah.

Male: In vitro. So I think one of the things we're looking for is sort of new trials to look at …

Lise: I'm not sure your microphone is on. Is it? And … Okay.

Male: (Inaudible). So, that's great. Thank you very much for that because we're really looking at trials and how we can (inaudible).

Ying: Okay, great. Yeah, we can talk more if you're interested. Yeah, thank you.

Lise: Okay, thank you.

Male: Five days? To kill everything?

Ying: Yeah, about seven days, yeah.

Lise: About seven days, he says.

Male: Seven? Seven days?

Ying: I said seven, yeah.

Lise: Over here?

Female: [02:23:25]

Hi, there. I was tested for Lyme disease six weeks after hiking in an endemic area in Canada, and I tested positive in Canada, and I received my test back eight weeks later after having a lot of symptoms, neurological symptoms of Lyme disease. I was treated initially and my treatment was very effective, and effective enough to make me able to go back to work. When my treatment was finished, I quickly deteriorated and was unable to work. When I went back to see my infectious disease doctor, I was flatly refused any further treatment based on the current guidelines. That forced me to go see a naturopath and a doctor in the United States to receive some sort of treatment, and I ended up getting some treatment there but I found a doctor here that was willing to treat me outside the guidelines, conservatively, and after 18 months of long-term antibiotics in Canada I am recovered from Lyme disease.

I know that our infectious diseases doctors, Dr. Bowie, rely upon your association for guidance as to how they treat Lyme disease. And my question to you is what will you be doing to help our infectious diseases doctors and all of our physicians across the country to feel more comfortable to treat Lyme disease outside the guidelines and also outside the current testing criteria?

William: [02:25:03]

So a couple comments. I'm glad you're feeling better.

Female: Thank you.

William: You're in many ways reinforcing some of the concern that I raised in my talk. We don't know. You know, part of the problem is we have not got data to know how to best evaluate you, best manage someone who has symptoms beyond standard treatment. We don't know that you have ongoing infection. I don't want to go through the stories of, you know, through all your history in detail. You know, whether antibiotics made a difference or not, I don't know. So how do I …

Female: They did. They did.

William: Well, you got better.

Female: I did.

William: You got better.

Female: Yeah.

William: That doesn't prove …

Female: Yes, I tried to wean and stop the antibiotics several times in that 18 months and my symptoms returned.

William: Yeah, yeah. So …

Female: Until the final time when they didn't return.

William: [02:25:57]

So the point I really want to make and try and reinforce is until we actually try to formally evaluate folks who are in your situation, I can't stand-you know, it is hard for me, hard for anyone, to come up and say, "Boy, you screwed up. You should have given more antibiotics." Same token, I'm not going to jump up and down and say one absolutely should not have given you more antibiotics at the end of four weeks. It's (inaudible)…

Female: My doctor did.

William: Yeah, no, I understand that. Remember, doctors …

Female: True guidance.

William: Docs are in a hard place. We're under a great deal of pressure to justify what we do. I wear an antimicrobial stewardship hat. We jump all over people in terms of, you know, inappropriate use of antibiotics. So there are all these conflicts for which we don't have the data to make an informed decision.

Female: [02:26:53]

Yeah. My question then would be to you: do you go to all of the dermatology conferences and ask those doctors to stop prescribing the same antibiotic that I received that was life-changing because of all the risks due to that antibiotic?

William: [02:27:11]

So we raise those issues. Do I personally go? No.

Female: There are thousands of people that receive that same antibiotic for …

William: Yeah, so you're probably talking about doxycycline or minocycline.

Female: I am.

William: So part of the issue, again, which is raised and why we need studies, the antibiotic may have made a huge difference but there are all these anti-inflammatory effects and immune-modulatory effects that may also be causing those effects.

Female: I won't deny that. I won't deny that.

Lise: [02:27:39]

Okay, so I'm going to step in here.

William: Yeah, yeah.

Lise: Because I recognize that this can be an opportunity for you to try to nudge and push people to where you want them to go, but I'm going to ask you this afternoon to try to keep your questions to questions of understanding of what the status quo is because your important task going forward is going to be to make recommendations. So please don't use the question and answer period to make the recommendations. You will have that opportunity. Because otherwise, we might be missing some important facts for moving forward, okay?

Female: [02:28:13]

Okay, so I did have a question, and my question is what would you be doing in the future to encourage doctors to treat with a risk versus benefit, versus strictly to the guidelines?

William: [02:28:27]

So I'm going to do what I said in, you know, my talk. I'm going to argue to Health Canada and every one of us in this room who gives "treatments" that we either formally evaluate them in formal double-blind studies, or if I'm going to give you or somebody else long-term doxycycline, or Drug X, that we come up with some kind of a strategy whereby we can collectively learn from what happens in you. Which really means, you know, we need to try and document and evaluate so that we're not sitting here talking-you know, you're raising a question, you've had a horrible course, but I'm not one step further ahead knowing how to interpret that, and that's wrong. I mean, that's a failure of all of us. We've had this opportunity and we haven't done it. We need to do it. And that is a place where we can move forward, I hope.

Lise: Okay. Do you want to add something, Dr. Maloney?

Elizabeth: [02:29:28]

Well actually, I wanted to agree that I think we have people that are clinical innovators out in the communities and we've kind of marginalized them. It sounds like that many Canadian physicians actually fear for their license. And the difficulty then is they're operating in the shadows and they aren't sharing information. So if someone has realized that this therapy is a dead end, it would be great if they could tell everyone. So I think maybe going forward, one solution to how do we address this huge gap in our evidence is to look at forming collaborative research where people can have an observational model that people agree to, and then they can pool data. And I think that might be one way to get at answers, because otherwise we're going to be having to do tons and tons of, you know, randomized controlled trials, and we'll run out of time. So I think pooling observational data is important, but it has to be very carefully collected, so someone will need to set up a good model for doing that.

Lise: Okay. Anything from the other panelists? No? Thank you. Over to you, sir.

Male: [02:30:37]

My main question is for Dr. Zhang. I was wondering about-it's fascinating, your results from your tests, or your studies, but I was wondering: in the body, there's obviously regions where there's more antibiotics and less antibiotics that go. In your studies, what happens when you have not quite enough antibiotic? Do you find-does it create, like, a dormant phase, like the cystic phase that then can't be killed and it just ends up being dormant, similar to what doxycycline has been shown in other studies to do? Or is the combination always able to kill off the persistent bacteria?

Ying: [02:31:14]

Yeah, so this is in vitro study. This is done in test tubes and, you know, we found that it has to be this three-drug combination that's going to be able to completely eradicate so that they don't quite grow back in subculture studies. So that's not being achieved by any other two-drug combination or the current Lyme antibiotic combination. So we found that this has to be the persister-active, so not all of them, but in fact only certainly very active ones like daptomycin, in combination with some others. But we're working on some other drug combinations as well, trying to find an oral regimen, in fact, that's able to be used by patients more easily. But of course, this is the stage of in vitro testing. The next stage would be in vivo testing, animal models, which is right now ongoing. So …

Male: [02:32:12]

What about the level, though? What if there are-have you studied lower doses to see? Does it kill bacteria over a longer time?

Ying: [02:32:18]

Well, yeah, so, right. So this, in fact, this dynamic there, this is actually lower. Even though you use depending-this has to do with dosing. How often do you dose? Whether or not the drug levels can go lower than being active. But I think this needs more study to find out. I'm sure in vivo situations, there are times that blood drug concentration is lower than the effective concentration, but that may not matter. But of course, this needs to be tested, you know, clinically.

Male: Yeah.

Ying: Or in vivo studies, yeah.

Male: [02:32:56]

I know some of the theories that I've read are that some regions of the body, like in the bones or some regions, there's very low blood flow and the antibiotics don't get in there very well. And a person who's had, you know, a disease for a long time, there may be sequestered bacteria hiding in various areas.

Lise: [02:33:13]

So it sounds like you don't yet have the answer to that question from the testing that you've conducted, Dr. Zhang.

Ying: No, no.

Lise: Is that …?

Ying: Yeah, no.

Lise: Okay.

Ying: Right.

Lise: Thank you. Over to you, sir.

Male: [02:33:23]

My question is for Dr. Zhang. Actually, you kind of already spoke a little bit about it, but could you speak about the prospect of animal and human trials of the drug combinations your team found most effective?

Ying: [02:33:39]

Yeah, that's a great question. So there's different thoughts, schools of thought, about that. One group would like to try these drug combinations directly in patients. The other would be more conservative-type; that is, to do the animal studies first, and if that's positive then move on to the animal [sic] studies. So I see this thing-I mean, I think depending on which way you approach it, I think in terms of helping patients, I know, I mean, some patients are desperate. They want to try that. I'm not entirely against that, but it's only a sort of anecdotal basis, but it may help some individual patients, but in the end it may not really change the guidelines. So to change the guidelines, you need proper clinical trials to do, to set up. But then, to achieve proper clinical trials, often you need government support, but government support tends to be based on more conservative criteria like animal data. So it's like depending on how you view it, it's a complex issue.

But I hear you: this is actually exactly the direction. I mean, we're moving to the next stage, which is in vivo testing. Whether or not-I mean, right now, as I said, we already started the animal testing. It's ongoing. We don't know the results yet, but you know, I think there are some other physicians who wanted to try it in patients because these are FDA-approved drugs. So in terms of safety, it's not really (inaudible). It's just a repurpose of the drugs, used for a different indication. I think that's possible. I mean, depending on specific situations. So I don't know whether I answered your question or not.

Male: Thank you.

Lise: Thank you. I have two other speakers who would like to answer that, Dr. Bowie and then Dr. Maloney.

William: [02:35:33]

So if you were to recommend using these directly in humans, I would have a fit because the literature is absolutely filled, as Dr. Zhang I'm sure knows, of things that look like they're active in the laboratory, in the test tube, that don't pan out in animal studies, let alone human studies. So that would be an incredible leap that I would argue is absolutely unethical and unjustified.

If someone was going to do that, then I start having fits wearing my antimicrobial stewardship hat. Daptomycin is an injectable antibiotic. It's one of our last line antibiotics for MRSA. So to start to promote use of it in the absence of any supportive animal, let alone human, data would be totally wrong. It makes-it just doesn't sound defendable to me at this stage. It may even reach a stage where if it works, then we're going to have to start raising the issue of, you know, where is it appropriate an antibiotic like daptomycin and where is it not, but there are many steps before we get to there.

Lise: [02:36:58]

Well, and if I understood correctly, animal trials have started, right?

Ying: Yes.

Lise: Okay.

Ying: Yes, that's true. Yes. So, yeah, I mean …

Lise: Dr. Maloney?

Elizabeth: [02:37:12]

Well, get ready to have a fit, because I think Dr. Richard Horowitz, but he's published, and it was I believe a series of 100. I have not read the paper in detail, so I can't break it down for you. But I think that's an example of he did take the bench research and he also went through a very detailed, informed consent with patients, and I think that's very important as well, that if we're going to do things like this, that we have to make patients aware and have their participation be completely informed. I think that these medications do have risks to them and I think that we have to be mindful of that, but we also have to keep it in the context of how sick some of these people were. But so, someone has tried it, and I think maybe we should all read the paper and see what we think.

William: Is it published?

Elizabeth: Yeah, it's published.

William: So I should have a retroactive fit.

Lise: [02:38:20]

Okay, so he'll have a retroactive fit, and meanwhile I'll have a fit because I owe a big apology to our WebEx participants. It's my understanding that we have some questions lined up on WebEx, so I'm going to take a couple there before I come back to the in-room microphones. I might not have time to take a lot from the in-room microphones because we do want to get to the stage where we're actually making meaning of everything together, and we will need a bit of time for that. So our first question on the WebEx, to the Operator, please.

Operator: Thank you. The first question is from Kerri Currier. Please go ahead.

Kerri: [02:38:55]

Hi, thank you. Thank you, Dr. Zhang, for acknowledging a cyst and biofilm forms and for Dr. Hatchette for acknowledging co-infections. I feel that these two areas are where considerable, ongoing new research needs to be done. One of my questions will be what is Canada's role in continuing with that type of research? Because it defines the concept of intracellular versus kind of persister cells, kind of treatment modalities that we might undertake.

I am a bit concerned, Dr. Bowie, with one of your comments, constantly looking for kind of rationale on data, and I mean, the data doesn't exist where there's no interest in looking for it. So back to cyst and biofilm form, I would like to think that we're going to continue with investigating that, because lack of a study to justify something isn't proof of anything.

We can agree that flawed clinical practice guidelines can compromise patient care, or lack of guidelines in general. Dr. Maloney, can you comment please on the National Guideline Clearinghouse, the database delisting the IDSA guidelines, and some of the feelings perhaps maybe from a patient standpoint that there's a lack of trust in the IDSA initiative to kind of include patient stakeholders in their development?

Lise: So we'll start with your second question first and then I think you had a first question around Canada's role on furthering the research. Dr. Maloney?

Elizabeth: [02:40:20]

Well, I would not presume to speak about the IDSA process in terms of whether it's right or wrong, although I would like to hope that they've included patients and primary care doctors, because I said I think that those people need to be highly represented on panels and really should be there at the start, especially for question formation.

With regards to the IDSA guidelines coming off the National Guideline Clearinghouse, that's not a surprise. That's simply that their data is five years old. So the guidelines I wrote will come off in '19 if I don't get sharpening the pencil soon, so I don't think that you can deduce anything else from the guidelines coming off.

Lise: Okay, who would be answering the first question?

Elizabeth: Is that fair?

William: Yeah. No, I (inaudible).

Lise: Go ahead, Mr. Hatchette.

Todd: [02:41:11]

So I think that the issue of what's causing people's symptoms is an important one. Co-infections could be possible, or this other, not yet detected entity, disease, process, whatever. The co-infection question is an important one. I think it starts with some surveillance to find out what's actually in the environment so that we can better identify what's in the ticks. Because if we don't know what's in the ticks, then we can't look for them in humans. And I think that, again, the best way to approach this is by targeting areas where we identify these pathogens in the environment and look at individuals who live in those areas and follow them in well-defined cohorts to really see how they present and try to tease things out better. Because as Dr. Fallon said, you know, one of the keys to any trial we do is having a well-defined patient group, because then you can't-if the patient group is too heterogeneous you're not going to be able to tease out the significant results. So I think it really goes back to trying to find out what's going on, and you have to go back to a combination of surveillance and cohort studies.

Kerri: [02:42:34]

But Dr. Hatchette, how can I get surveillance then for Bartonella? I tested positive through North Carolina University and I live in British Columbia, where it's non-reportable and it's seen not to exist, and the testing here is only for two strains. So what does my doctor do with me? Like, where does he-how do I get included in some kind of surveillance of anything when I'm told right away it doesn't exist and it's not here?

Todd: [02:42:56]

So I think we have to acknowledge that there is stuff that's happened in the past that's in the past, that we can't change it. But moving forward in the future, we need to look at-so, surveillance is something that needs to be funded from a programmatic perspective so that you have a systematic review of what's out there in the ticks. That can be passive, it can be active, but it has to be done in a way that's systematic so that you truly know the denominator and you can get an idea of exactly what's out there.

So I can't speak to, you know, when you were infected and what's happening in B.C., but I think that, moving forward, if we really wanted to find these things, then trying to collectively approach this from all aspects - environment, host, and pathogen - is really the best way that we can do it.

Lise: [02:43:43]

Okay, thank you for that. I'm going to take another question on WebEx, and I will try to get through as many people in the room as possible. If we're going to do that, I need for everybody to be very short-winded. So please remember to keep your questions short, and to the speakers, please remember to keep your answers short, please. WebEx, next question, please.

Operator: Thank you. The next question is from Caroline Lennox. Please go ahead.

Caroline: Hi, can you hear me okay?

Lise: Yes, go ahead.

Caroline: [02:44:13]

Okay. Thank you. Thank you to everybody who's showed up today. I just had to write my question down because of my memory problems, so please bear with me, I wasn't expecting to come on. Okay, here we go.

Dr. Zhang, start with you and then maybe others want to join in. I'm really happy to hear you talk about the antigen-variant nature of the Borrelia serotypes and that it's being recognized. In your view, what is the role, and what is the outer surface protein A in the role of the failure of previous vaccines, current research, and what's its relationship with Lyme disease? People who end up with immune (inaudible) systems, they get viruses reactivated as (inaudible) Epstein-Barr and a couple of others, and then they respond to treatment with antivirals. So I mean, what is your view of all of that? And it's not being included in the research.

Ying: [02:45:09]

Wow, that seems to be a lot of questions, so I don't know how to answer you. So OspA, I think, you know, we don't see OspA expression in the persistent bacteria. I didn't have time to talk about that. So we did have a persister study looking at the gene expression profiling in Borrelia persisters. We found actually very poor expression of OspA. In fact, OspC is over-expressed, along with some other genes involved in DNA repair, involved in, you know, antigen expression like, you know, other possibilities, transporters, as well as down regulation of some proteins like the lipoproteins. In fact, many outer membrane proteins are down regulated in persisters, as well as the activity of the ribosomes.

So I mean, this is a complex issue. We don't quite know very well how this gene is expressed in persisters, but we're actually in the process of identifying this persister-related expression in terms of whether it'll be important for improving the sensitivity of diagnostics. So…

Lise: [02:46:31]

Thank you. I will go to microphone on my left, then my right, then to WebEx, and I will roll through for another ten minutes, and then we really do need to move to key messages for tomorrow, otherwise we'll start on the wrong foot tomorrow. Go ahead, please.

Female: [02:46:43]

My question touches on co-infections and standardized Canadian laboratories. Why is it that there are two different styles of reporting Canadian test results for Anaplasmosis, which is a tick-borne infection? If your Anaplasmosis test result is negative, it is clearly noted and the patient is identified on the report form. But if the Anaplasmosis test result is positive in a Canadian lab, the patient's name is removed and the space where the patient's name is normally expected to appear, it is replaced by the sender's name with a laboratory and the patient is identified only by the health card number and birth date. And since clinics don't file patients' medical records by health card number or birth date, it's easy to lose, and then there's nothing on the test report that helps to alert the doctor that this is actually a positive result. The value and interpretation are shown blurred and hard to read, and the test result gets misplaced and you don't find out until years later. And meanwhile, the ID specialist refuses to retest for Anaplasmosis despite doctor-verified bull's-eye rash.

And so, why is there hocus pocus reporting of Canadian laboratory test results?

Lise: Does anybody know why that happens or willing to tackle it? Go ahead.

Todd: [02:48:17]

So I honestly can't really answer your question because the laboratories, certainly I can speak for my laboratory. Every requisition that comes in, the patient is sent to the National Lab. It's where the Anaplasma testing occurs for my lab. I can't speak for the others. They'll send me a report back. That report is entered into our lab information system, and that report is sent back to the physician. The physician is then responsible for calling the patient. But all of that information, at least in Nova Scotia, is on the lab information system, so I can't really answer your question. I'm sorry.

Lise: Okay. So unfortunately, the answer isn't clear. Go ahead, the microphone …

Todd: Oh, Dr. Lindsay may have clarification.

Lise: Oh, Dr. Lindsay? You'd have to get to a microphone so everybody can hear what you have to say, please, sir.

Todd: It's Dr. Robbin Lindsay. He's the head of the National Microbiology Lab.

Robbin: [02:49:15]

It's simply a privacy issue. We're not allowed to transmit through faxes the patient's name. So probably from Ontario or is that the jurisdiction where you've come from? The lady sat down; I can't see her anymore.

Lise: So it's a privacy measure, is what I'm hearing, because you can't transmit. Okay.

Robbin: Yeah, that's strictly-and it doesn't apply in every jurisdiction. Some jurisdictions, we can provide the name, others we do not, so it's strictly a requirement within the public health jurisdiction that you're in for privacy.

Lise: Okay. But it sounds like there are processes that make the information then easier to lose because of that. Okay.

Female: I just wanted to add.

Lise: Very, very briefly.

Female: [02:49:52]

Yeah, very quickly. Well, if it's a privacy issue, why can't the test result itself, the numbers, be clear so it will be easy to read so that it doesn't get missed out? Because if there is no doctor protection legislation in place, you don't get treatment.

Lise: Okay, so I will let that question stand and go to the next question in line, please.

Female: [02:50:14]

It took me 21 years to figure out how to get better. All of these things, I had to figure out on my own. I needed … Everything helped, but I didn't have real improvement … Oh, sorry.

Lise: That's alright. Take your time.

Female: I agree with Dr. Maloney that there has to be an integral medicine part to treatment. I had to figure out, and many sufferers have to figure out on their own all of the deficiencies, nutrients, vitamins, minerals, amino acids, hormones, dealing with cellular issues, getting IV to get the immune system working. Everyone would love some help here to pay for these things.

Dr. Horowitz, like you said, he was an internal medicine doctor for 28 years, and his 16-point differential diagnosis has been adopted in hospitals to treat those with chronic illness, all chronic illness. He says there are three main things that are present in all illnesses. One is infection, then two is immune system is involved, and three, there's inflammation. This is why we need a Lyme-literate doctor or naturopath so we can actually treat this illness.

Every single Lyme patient is different. People respond completely different to treatment. Everyone needs something different. There needs to be a very open-ended way to treat this based on a person because some people can't take antibiotics, some people can, some people need more, some people need less. So …

Lise: So your question?

Female: Please allow real Lyme doctors, the ones that truly treat people according to patients, as we're the only ones that truly knows what works for us. And I think everyone knows that there's more than just Lyme disease. We have to get to the root of the problem: untreated Lyme disease and everything that goes with it. Like, the co-infections are a huge part of the battle.

Lise: I'm sorry, I'm not hearing a question.

Female: Okay, okay. There is no treatment for post-Lyme syndrome because the definition of it is untreated Lyme. So when will this name change? And the question to the bacteriologist will be when will all forms of Borrelia be acknowledged in treatment that patients actually accept? Because only patients know if it's working.

Lise: Okay, so you're asking when?

Female: And why is there no recognition or seriousness of tick-borne illness? And the statement that William Bowie made, expanding involvement in groups, does not sound very promising. How will the politics change so doctors will be able to treat people? These are the people that do not acknowledge that Lyme exists.

Lise: Okay, I'm sorry, I have to cut you off here. A response to any of that from one of our panelists?

William: [02:53:38]

I think (inaudible), you know, we hear your concerns, I hear your concerns. We need data, and we are given this opportunity here, I think, to try and figure out strategies to start to acquire that data, in cooperation with folks like yourself, to actually know what it is we're doing. I, as an individual, and this applies to any sort of treatment, if someone is given Drug X and something happens, it is unevaluable in terms of knowing, you know, if a response has anything to do with the antibiotic. All of these studies that we looked at longer-term therapies, you know, about a third of people seem to have significant improvement on placebo. Is that placebo effect? Is that some other effect of the antibiotic on your microbiome, on your immune system? Until we actually understand those, I cannot come up with specific recommendations that I can say do more good than harm.

So I hear a story like yourself of needing multiple treatments over many years. That's actually not the way infections normally behave. Normally we can cure an infection pretty quickly. So from an investigative perspective, it's a red flag actually, if someone needs multiple, you know, multiple courses of medication. Does that mean that the antibiotics aren't helping? I can't say that.

Lise: [02:55:16]

I'll step in here.

William: Yeah.

Lise: I'm hearing some points repeated that have been made earlier, so I'm going to throw the question back to the group for discussion in just a few moments. What do you recommend be done going into the future? That's our whole discussion tomorrow.

So I'm going to take one last question from each microphone, two final questions from WebEx. I know I'm going to make us late with this but I really need your help because I don't want to dismiss anybody who's been waiting in line for a very long time. So, WebEx first, then left microphone, right microphone, WebEx, and then we shut down the question and answer, and I'm going to move you to discussion around: what are the key messages from today that you want to share with the people who were not in this room that can inform discussion tomorrow on guidelines and best practices?

WebEx Operator, please, next question.

Operator: Thank you. The next question is from Katherine Leanne Morgan. Please go ahead.

Katherine: [02:56:13]

Yes, hello. Hello. I'd like to thank all of the speakers on the panel today. And my question or my thought on what I've heard is that we need to look at an optimal environment in the host that's infected, the person that's infected. How do we provide an optimal environment so that optimal drugs-and I think Dr. Zhang is right on in his talk. The drugs that we're using now, are they optimal? Maybe we need to look at some other ones. That's my personal experience at this point in my-in curing what I have. That's how I feel. But what can be done by looking at the body, my body, and each person's body, how much biofilm is in them, looking at supplements that they need to offset deficiencies in their body caused by the illness, DNA mutations, to decrease heavy metal burdens that the body takes on when sick, looking at natural supplementation therapies? Are we going to be looking at these things with naturopaths? They're using ozone. They're using laser therapies.

Lise: Okay, I …

Katherine: Perhaps these alternative therapies may also help provide the host with the strength or the means to further kill off the persistent bugs. Thank you.

Lise: Okay, I'm going to interrupt here. Anything that can be done to prepare the body, the host, better for these antibiotics? Any response from the panel? Go ahead, Dr. Zhang.

Ying: [02:58:00]

Well, I think, you know, these drug combinations need to be evaluated. I think, you know, depending on the order, I think I heard some concern as to whether this can be done, but I want to make this comment that's my view, which I said, is to start with the animal studies and then follow on to the humans. That's my general way of thinking. On the other hand, I'm not really entirely against, you know, some individual use of this. But having said that, I'm going to say that, in fact, for the current doxycycline treatment, the guideline is not even based on these stringent criteria. I think it's straight into the clinical studies. So why didn't we have a concern there, right? So I don't think the doxycycline treatment was started with the animal study and then moved on to clinical studies. So I don't think so. This is the sort of issue we can discuss, but I think it's important not to really be too rigid about certain things.

Lise: Okay.

Ying: About, you know, so on the other hand, I'm not saying that we don't pay attention to this cautionary side of things, you know, potential side effects of antibiotics.

Lise: Okay, thank you. Over to you. Yeah, your microphone is on, I think. Yeah, go ahead.

Female: [02:59:24]

Okay. I guess this question is more directed towards Dr. Bowie as he's with the CDC. I'm a registered nurse with my bachelor's degree and I always had really good assessment skills, and I'm on disability due to Lyme disease and Babesiosis. And basically, in 2004, I had a classic expanding bull's-eye rash, flu-like symptoms, and my GP with a magnifying glass noted that I had a very distinctive spider or bug bite, insect bite, in the centre of the bull's-eye; attributed this expanding bull's-eye rash and flu-like symptoms to being a very strange reaction to some sort of spider or insect bite and sent me on my way without treatment. Three years later, I ended up off work, and within eight years after the bite I finally got tested in Canada and it was negative. Yet, I know several people who have been tested …

Lise: I'm sorry, where's the question, please?

Female: … and they're told from the CDC it's a positive test, a false positive test, and recommends further testing. Now, doctors can't often just read the results. They don't read down about further testing. Those doctors that do don't see the-like, who do retest, they keep being sent this form letter to retest. So then, until they finally get a negative, and then they're told it's negative, so they're denied treatment for decades.

So my question is why does the CDC make it so difficult to get reported for Lyme disease and to get treated for Lyme disease? To retest someone, delaying treatment causes you go into third-stage Lyme disease, which cannot be cured with three weeks of doxycycline, like, eight, ten, however many years later. So that's my question.

Lise: Okay.

William: [03:01:44]

So what's the question, quickly?

Lise: So I'm hearing in your question an assumption that the CDC is purposefully delaying diagnosis of Lyme disease.

Female: You either get a false positive or you get a negative.

Lise: Okay.

Female: They don't do very clear positives. I … To the doctor in B.C., the doctor reports.

William: [03:02:08]

So you're talking about British Columbia, is that where?

Female: British Columbia.

William: So again, I can't comment on your, you know, the specifics. What I will comment on, though, is that in BCCDC, so in BC, Dr. Morshed and the lab are usually willing to bend over backwards to try and help figure out serology, you know, when a physician talks directly to him.

Female: Then …

William: So I don't know-you know, I can't comment on anything, you know, further about, you know, what you're saying.

Female: Okay, because I've seen documentation from Morshed saying, "We believe this is a false positive," and yet it's totally positive on the test.

Lise: Okay, so the point is made. Dr. Maloney, you wanted to add something very briefly?

Elizabeth: [03:03:00]

I did want to add something briefly about the timing of serology, because everyone focuses on false negatives when you're testing too early, but I think that there's also a possibility of false negatives when you test too late in disease. And Monica Embers' trial in the monkeys demonstrated that the untreated monkeys, over time their C6 went to normal again, and so clearly the antibodies waned, and that is a problem.

Lise: Okay, thank you.

William: [03:03:30]

Again, sorry, can I just make one other comment? I'm sorry, I know you're trying to push. Again, I'm anxious in hearing your story if total weight is put on a serologic test. Remember, a serologic test is ancillary, and so there's potentially room in the right setting to say, "Okay, you know, you deserve treatment." I would rather-you know, my bias, and it may well be the bias of many of my colleagues, is I'm quite willing to over treat rather than undertreat as long as I can have some justification in my mind for what I'm doing.

Lise: Okay.

William: I can't speak for everybody.

Lise: Alright. Thank you. Go ahead.

Joanne: [03:04:14]

(Inaudible), my name is Joanne McCarthy. I'm Onondaga Nation, Beaver Clan, from the Six Nations of the Grand River Territory, and I got my tick in my backyard. I was so severe that I actually had to have a VP shunt surgery to alleviate the hydrocephalus before we discovered that it was Lyme disease that was causing that.

I want to add a quote to the quote board. "Absence of evidence is not evidence of absence." And I wonder why: why does it seem that the ignorance about Lyme disease seem to negate, marginalize, and obstruct my right to health care? And I hope that the Framework addresses that.

My question is data always seems to be collected based on a biomedical reductionist understanding of health and illness. My experience, my understanding, my cultural understanding is holistic. I'm hoping that you guys will include that in the Framework to be culturally safe and culturally appropriate to other populations.

I've experienced and recovered from Lyme and I do believe that that makes me an expert and not you guys an expert.

I am wondering, I'm wondering how the revered scientific method, testing for the one right, patentable answer, captures the value of collaborative holistic treatments, or culturally appropriate and holistic care.

Lise: Thank you.

Todd: [03:05:49]

So I couldn't agree with you more. I think we need to take a holistic approach to this, but again, in a well-defined, prospective study so that we can figure out exactly what's going on from all different aspects.

Joanne: [03:06:00]

So I have another of my favourite quotes from Albert Einstein. He said that "The definition of stupidity is trying to do the same thing over and over again the same way."

William: So-yeah, so …

Lise: And I think the rest of it is "expecting different results," right?

Joanne: Thank you.

Lise: Thank you.

Joanne: So we need to try a new way, so we need to start trying these new things now.

William: So … Okay.

Lise: We've moved right out of question and answer into recommendations here. So I appreciate what you're saying, I want it to be captured, and the way it's happening now it's not going to be captured efficiently for our conversation tomorrow.

Joanne: [03:06:38]

My question is how they are incorporating holistic care into the new framework.

Lise: And I guess what we're doing here is we don't know the answer to that question. You are actually putting proposals in and that's going to happen later. So I would say …

Joanne: So nobody's thought about that despite all of the stories that people shared yesterday about how holistic care has helped them?

Lise: [03:07:00]

What I'm suggesting is that instead of asking the question, I would like this group to make the recommendation. That's what we're inviting you to do here, okay?

Joanne: Okay, but I have to do that tomorrow?

Lise: Absolutely. Absolutely.

Joanne: I have to fly back to Toronto tomorrow.

Lise: Okay, so everybody heard that.

William: But-she won't let me …

Lise: Let's make sure that makes it into the recommendations, okay? Now, I did promise that I would take one last question on WebEx. I'm afraid to do it but I'm going to trust you to keep it short. Please, one final question on WebEx.

Operator: Thank you. The next question is from Alannah Farrell. Please go ahead.

Alannah: [03:07:37]

Hi there. I'm from Ontario. I'm a veterinarian. Been listening very intently to this, and I have chronic Lyme disease and my son has congenital Lyme disease, so it's, you know, of great importance to me personally as well. Being a veterinarian, we are…such-run things very differently. We're not afraid to try new things and things that may be out of the box as long as we have investigated them very closely. We've talked to a lot of professionals that have perhaps, you know, investigated these things or tried them in the past, and we're comfortable making those decisions as long as we have talked to the client very closely about, you know, perhaps being off-label or, you know, what the concerns are with it, and you know, that it isn't tested completely to our, you know, desire, but it may have great benefits as well.

So I guess my question would be at what point do we give the patient some say in what direction, you know, that… it's going to go or trial treatment is going to go? We've heard a little bit about this previously. But I mean, again, my specific examples-and I know we're really short on time, but my son having congenital Lyme, I mean, he had a symptomatic diagnosis of migraine and he's had, like, all these neurological issues, and again (inaudible).

Lise: Okay, I'm going to have to interrupt.

Alannah: Okay.

Lise: So the question was at what point do we give say to the patient?

Alannah: Yes, because again, in his case, he improved. He is almost-he is 90% better, and you know, if I didn't treat him and he didn't-he actually did have (inaudible) at one point, but we, you know, took a break and then persisted. So it wasn't fun but he made it through, and now he's on the other side and he's so much better. So, yes.

William: [03:09:45]

So the last lady who spoke and your comments, I hope all of us are hearing that we're given an opportunity here to come up and develop a strategy. We're hearing from people who are highly affected. We're hearing that none of us really know what we're doing. And so, I think the challenge to us is how we collectively meld the traditional science, but meld it with input from folks who are affected so that we can come up with strategies to actually learn where we're going so we can learn how to best move forward. And for me personally, I'm thankful we're given this opportunity because of this bill.

Lise: [03:10:32]

So our next task here is to try to summarize some key messages. What have you learned today about guidelines and best practices that you will need to consider as tomorrow we envision a better future and some possible strategies to get there? That's the question we're talking about now. In an ideal world, I would have had you working in small groups to discuss it and coming up with one or two points at each table or in each small group. It is 4:25; I'm not going to do that. I'm going to ask my microphone handlers, please, to each grab one of the microphones and I'm going to look to the room.

So I've got two key messages already captured. One, the importance of a holistic approach, and in the past the approach has been too fragmented. And the other one, which I just heard from Dr. Bowie, which is none of us really know what we're doing. What are some other, pithy key points that you would like to make sure are captured? I will be reporting these back into plenary tomorrow and will use those as a launch pad for further discussion on this topic.

So we're talking about guidelines and best practices specifically. Remember, there are two other groups working on surveillance and education/awareness. I have a hand up here at the middle of the room, please, and then next we'll go to the back.

Female: [03:12:01]

Yeah. I would like to see that the concept that Borrelia is a typical infection be tossed out, according to a lot of research on the persistence of Borrelia. And secondly …

Lise: So Borrelia as …?

Female: Kind of tossed out as a typical infection.

Lise: A typical infection.

Female: Yeah, being looped into that category, because of the evidence of the persistence of Borrelia.

Lise: Okay. So in the past it has not been, and in the future we're going to need to see it …

Female: Yes.

Lise: … as a typical infection?

Female: Yes.

Lise: Okay.

Audience: No.

Female: No, not a typical.

Lise: Okay, not a typical.

Female: No, not a typical.

Lise: An atypical infection.

Female: Atypical with persisters, as documented by Dr. Zhang.

Lise: Perfect, thank you.

Female: [03:12:37]

And then, kind of Dr. Zhang brought up the point that the morphology of the bacteria creates different protein antigen expression, and Dr. Hatchette also kind of brought up different protein antigens, I believe, in laboratory research, so I would really like to see a collaborative approach to this between the two.

Lise: Okay. So Borrelia is an atypical infection, and the morphology evolves and there are different antigen reactions, and that needs to be taken into consideration as you think about moving forward. At the back of the room, the burgundy sweater, please?

Female: [03:13:12]

Yes, my recommendation is, well, first of all, that we …

Lise: Sorry, just to clarify, we're not doing recommendations now. We're simply summarizing what we know today.

Female: Key messages.

Lise: Okay.

Female: Key message is just to expand the holistic therapies, one.

Lise: Mm-hm.

Female: That is what I was standing up there to say, but I will just say it in a very pithy way, that we make sure that we include all of the holistic, including diet, lifestyle amendments, all that sort of thing, and those people are also on the final decision-makers of the strategy. It's awesome to have medical doctors, but we need to also include the naturopathic doctors, the functional medicine, etc. Homeopathics [sic], herbalists, and so on.

Lise: Okay, thank you. Here at the front?

Female: [03:13:59]

Hi, just a comment that most of us here I think would be willing to give ourselves to test. Like you were talking about having the cohorts. I think that's the name you used. So you have so many of us in a room and on WebEx that would be so willing to give our blood or whatever you need for research to find out if you're claiming that it's not Lyme disease, because we're all obviously very sick and here for a reason, then we'd be so willing-we just want answers. If that's what the claim is, we'd be-maybe we could even at the end of the day tomorrow just, I don't know-or, even you have our email addresses, somehow get a hold of us and we'd be willing to do that. I'm sure I know I would and all of us at the table would as well.

Lise: Okay. So we've heard a lot today about the importance of clinical trials and I'm hearing, "Yes," and, "We're willing to participate." Over here, please.

Male: [03:14:55]

Diagnosis should not-or guidelines should not supersede clinical diagnosis.

Lise: Thank you. So there are issues with the clinical guidelines. Okay, go ahead.

Female: [03:15:09]

I was just going to say it's quite clear that the diagnostics are not 100%. There is a leeway, and just because you may have a very rare illness, if it remains rare, it doesn't mean that you should be neglected and not treated. And therefore, as it's not, there is a gap where people can be misdiagnosed. Like, not diagnosed with Lyme even though they have it.

Lise: Yes.

Female: And therefore, their doctor should be able to make that clinical judgment, and it should be able to be reported to Public Health under surveillance so that they're recorded in the numbers.

Lise: Mm-hm, so there are gaps in the diagnosis, there are gaps in the surveillance, and those need to be addressed. What else? I've got back here. Okay, and then we'll go to the back of the room in the corner, okay?

Female: [03:16:04]

I just have two quick ones. One that I heard from the panel is that research as much as possible shouldn't be done in silos, so the communication across disciplines.

Lise: Mm-hm.

Female: [03:16:14]

The second piece was just around respecting the importance of quantitative data versus qualitative data, and I think you received quite a bit of qualitative data last night with the 106 people who shared their stories. That cannot go-that is data in and of itself.

Lise: Okay, thank you. I'll come here to the left and then I'll go to WebEx to see if there's anybody who wants to add something there. I've got a couple of hands on the right and a hand on the left, so I'll keep them going as long as I can. Go ahead, please.

Female: [03:16:42]

Yeah, I think in the guidelines part of it, and best practices, as far as allowing the doctors to be able to treat invisible diseases, including Lyme disease.

Lise: Okay.

Female: Without being … Without losing their license.

Lise: [03:16:57]

So in the guidelines, there's a whole slew of issues around being forced to stick to them too tightly, being afraid of going outside of them for fear of losing your license, so we've got a lot there that's wrong with how the guidelines are being applied today, in addition to having issues with the guidelines themselves. Is that a fair statement? Yes?

On WebEx, do we have anything?

Operator: Thank you. Please press *1 at this time if you have a comment.

Lise: Okay, it sounds like there's nobody queued up on WebEx, so we'll let you go for now, come back to the room, and I'll check back with you later. Go ahead, please.

Female: [03:17:37]

Okay. This may be off-topic, but please, before we break up, could you please ask people tomorrow to make it possible for me to participate, and people like me, to ask people to please refrain from using perfumes and scents because there's something very powerful in here and it's wrecking me. So it may be the building or it may be people in here, but this can be very important and make a huge difference. I'm already compromised, so-you know?

Lise: Thank you very much for that statement.

Lise: So, noted for everybody, please refrain from using scents tomorrow. Was there a second hand up in that corner already? Yes? Go ahead. And then I'll come to the back and then I'll go over to the left. Go ahead.

Female: [03:18:20]

Yeah, we heard today that one of the goals, or the goal, of the guidelines was eradication of infection, and yet we also heard today that our current testing is ineffective in proving eradication of the infection, so perhaps a different goal for the guidelines would be better, like functional improvement.

Lise: Okay, thank you. Back of the room?

Female: [03:18:49]

Hi, I'd just like to reiterate what Elizabeth Maloney was saying about the IOM guidelines.

Lise: Please put the microphone close to you. Thank you.

Female: Oh, sorry. I'd like to reiterate what Elizabeth Maloney was saying about the IOM guidelines and that the Canadian guidelines should reflect a trustworthy system that stakeholders are involved with physicians, researchers; that we need to be included in the final decisions and the reporting.

Lise: [03:19:13]

Okay. And I would categorize that in the recommendations piece, so we won't lose it, but we need to repeat it tomorrow. Facts of the situation that you will use to make recommendations tomorrow. What else do you know about the situation in the past that is important to put in this summary? Over on the right here.

Female: [03:19:34]

I think a key message that I heard loud and clear today was that patients and families want to be heard and that doctors want to do good, and I appreciate what the lady said earlier, just about qualitative and quantitative research, and is there a way of marrying those things so that they're happening concurrently, not exclusively?

Lise: Thank you, and that ties in with the other message on no silos as well, so very good. Back here?

Male: [03:20:03]

Thank you. Going back to Todd Hatchette's presentation, I think you laid out a very nice spectrum of we have acute, localized Lyme disease, all the way down to chronic Lyme disease, and I think if we look across that spectrum, the needs are very different. Early on, I think the guidelines seem to be relatively good. The problem may be that people don't know the guidelines and aren't applying them well. In those later stages, I think that's where, first, we don't really know enough, and the testing may not be working as well. And second, we need to have some sort of guidance on what to do for those patients beyond saying, "This does not fit with our current knowledge of Lyme disease," but having some action that we can actually give them.

Lise: Okay, so the biggest issue is later stages. The early stages seem to be reasonably addressed. Somebody-now, I'll check in again with our WebEx participants. Has anybody come on saying they want to add something?

Operator: Thank you. Please go ahead, Ms. Catherine Copp.

Catherine: Hello?

Lise: Yes?

Catherine: [03:21:03]

I'd like to just share my observations of what I've seen today, and what really stands out to me is how the human element just really seems to be missing from the members of the panel. This is affecting our lives, and time and time again, when the panelists are answering the information, they're quoting statistics and saying we need more research. That's all great, but you know, here we are, and there's people that this is affecting, and you have to look at that part. That's a big part of it. Instead of putting your head down and quoting statistics and saying that we need more, you know, research and studies.

Lise: Okay.

Catherine: What is going to be done now?

Lise: And that ties in well, I think, with some other observations that have been made, which is that the qualitative and the quantitative have not been speaking to each other and the patients have not been heard, and that needs to be addressed in the future Framework.

I'll go over to the right. Was there somebody else or did I miss? Okay, and then I'll come here. Go ahead.

Female: [03:22:14]

Hi. Speaking also to the sort of human aspect, I kind of wandered about a bit and went to one of the other workshops. But interestingly, although it supposedly wasn't about this creation of guidelines, I found it more relevant. There was an actual doctor presenting, and she went through a very clear description, clinical description, of all these different Lyme and, you know, 'gang of friends of Lyme' infections, and also very clear descriptions of available tests in Canada which she has effectively used. So I would really recommend that in looking at creating these guidelines, that all available tools be identified, including these clinical descriptions, which do exist, and also the different tests, their effective tests, and their limitations.

Lise: [03:23:10]

Okay, so there are clinical descriptions, and even if we didn't get all that information in here today, we'll be getting reports from the other sessions as well in the recommendation to look at all information.

Before we go further, I just want to do a quick logistical point here. The first shuttle bus back to the Sheraton leaves at 4:45. There will be a second run at 5:15. I'm going to keep going as long as I have hands up or until 5:00, whichever comes first. So I had a hand up here on the left. I'm not sure where my microphone is. Oh, over there against the wall, and then we'll come back into the room. Okay, go ahead.

Male: [03:23:45]

Thank you. Our ID community obviously needs science, our chronically ill patients need treatment, and I just want to know how we will bridge the gap with our Framework.

Lise: Okay, so there are differing needs in these two communities and that's been a source of conflict and friction in the past, and they need to be reconciled somehow so that patients get treatment but the science also advances. Thank you.

Here? Go ahead, and then I'll come to the back.

Female: [03:24:13]

I guess my point kind of tag-teams the woman who was volunteering her blood, okay? In that there are many of us here who have been fighting this disease for a long time, myself included. During that time, I was encouraged to write a journal and to document my journey through this disease. And when we're looking through data, I've been fighting this disease for eleven years; I have eleven years of data. I have notebooks, I have files, I have whatever you need. So I don't know if it can be used, but I would love for there to be a purpose out of what I've done, and I'm sure I'm not alone. So I guess what I'm saying is when you're talking about needing help and research and all of that, is there some way we can think outside the box and take all our collective experiences and use all that documentation that we all have to help you guys out?

Lise: And again, it's not only about the blood, it's about the human element, and there is information out there.

Go ahead.

Female: [03:25:11]

I'll just add to that. Actually, most of my Lyme patients are the most intelligent people I've ever met, and in fact I learn something from each and every one of them. I think we need to stop having barriers to this kind of access to infectious disease specialists. I think other doctors need to be given permission to practice medicine. That's been completely taken away from them, and I think that's an absolute shame.

Lise: Okay, thank you. I'll go to WebEx.

Lise: Sorry, yeah.

Operator: Thank you. The next comment is from Caroline Stengl. Please go ahead.

Caroline: [03:25:43]

Hi. I think I'm reiterating something that's already been said in a few different ways, but I think it's just very important that we acknowledge the urgency in the room and in the Lyme community. All these patients, including myself, who have been suffering intensely over many years, some of us, and that urgency needs to be acknowledged, similarly to what happened with the AIDS crisis a few decades back; that all the testing and the research and development in treatment and all these things need to be accelerated in a way that still keeps it safe but takes care of the urgent need of patients to get some relief.

Lise: Okay, thank you. Back to my left here. Go ahead.

Male: My turn?

Lise: Yes.

Joel: [03:26:36]

Hi. I'm Joel Kettner. I'm feeling uncomfortable about a comment that was made three or four comments back that, if I understood it right, characterized the presentations of our panelists as lacking a human element. That was certainly not my observation or sense. I think that I heard from all of them, from their professional perspectives, a great effort to address the issues at hand, and I heard a lot of comments about caring about people who are ill regardless of what we know about the cause or what we know about the treatment.

Lise: Thank you.

Lise: Okay. I will amend that. We do have other comments around the differing needs of science and patients, and I'll pick up on the patients and families wanting to be heard and doctors and researchers wanting to do good. Back over here?

Female: [03:27:39]

We need Lyme-literate doctors, ones that are able to treat all forms of tick illnesses, and to be able to address all forms of the Lyme bacteria, including the biofilms, and things need to be acknowledged that they can travel, so it's not always in the blood and, you know, that our test's not great. And so, we need to rely on a clinical diagnosis, and so how do we get through the politics of that and how do we make that happen? My thought is that, you know, it would be good to have some kind of system that allows doctors access to a Lyme-literate doctor online or on the phone or however, online, however it is. And a real Lyme-literate doctor can allow the doctor to treat it properly.

Lise: Okay, thank you. Over here. Where's the microphone? Okay. Go ahead.

Female: [03:28:50]

Hi. Just a note. We've also touched a bit on Babesiosis, Anaplasmosis, and Bartonella and stuff, and so just along with Lyme disease, ticks do carry other infections, so I don't think we should forget about that.

Lise: Okay.

Female: And we should also look at other infections that could have been transmitted through ticks as well.

Lise: That's right. We've talked a lot about co-infection today in different areas. Okay. What else is a new theme we haven't captured yet? Over here. Go ahead?

Female: [03:29:30]

Yes. Hi. I would just like to say I was also impressed by the humanity of everybody here on the panel and in the audience, and I very much appreciate everybody's input. I just wanted to make sure that Dr. Zhang's work is mentioned in the final report. I find it totally fascinating and very promising-sounding, so thank you very much, in particular.

Lise: So the complexity or the organism that was illustrated in his presentation. And obviously, my remarks tomorrow are going to be a very small summary of all of that.

Who else did we have? You here at the front. Were you next? Okay.

Female: [03:30:08]

I don't know if it's appropriate for now, and it's okay if you stop me, but you've talked a lot about the tick-borne illness, but there are other ways that it's transmitted, and we didn't discuss sexually-transmitted. I don't remember a tick and I had-there's a history. I won't give you the whole history but I wish that had have been talked about in today's conversation.

Lise: Okay. So it's not so much that it was a major theme today, but it is something that came up, I remember, in the stories yesterday.

Female: Yeah.

Lise: So just as there are multiple illnesses potentially being tick-borne, Lyme doesn't only come through ticks.

Female: Right. We-there's two of us at the table that, well, her …

Lise: Okay.

Female: Yeah, without giving the full history, it's …

Lise: That's alright.

Female: Yeah.

Lise: Thank you. Other key messages? At the back here.

Male: [03:30:57]

Hi, I stepped out for a moment so I don't know if this was already mentioned, but I think it's important to highlight what Dr. Zhang mentioned today in his talk, that like Lyme-literate doctors, Dr. Zhang's study found that combinations-just one antibiotic or two antibiotics are not resolving the infection.

Lise: Yeah.

Male: That's something that we should really highlight and remember.

Lise: Okay, thank you. Over there. Yes?

Male: [03:31:38]

Hi. The conversation earlier went to talking about science being debated, and that if it's not debated than it's not science. And I want to elaborate on that and say that Dr. Bowie agreed that science is to be evidence-based if the discussion is to be had, but that discussion has to be had by everybody to evaluate what we're going to consider evidence. So that was the point of my asking that question, is the patient and their experts have not been able to participate in that evaluation of the quality of the evidence. And I think from this point forward, I think that has to be a critical part of where policy development, right from the design stage, right from the planning stage, goes. And I just wanted to make that point that if it isn't robustly debated and evaluated, then it isn't science and it becomes dogma, and that's where we don't want to go from here.

Lise: [03:32:52]

Okay, and I also heard pretty clearly …

Yes, in the room, that the nature of the evidence that has been considered in the past feels too narrow to the people in this room, and that there's this whole slew, and we've talked about holistic and we've talked about qualitative, and that's been ignored a little bit too much in the past. In future, we'll need to consider that more.

Okay, what else am I missing? Just before I go to the room again, I realize I've been ignoring WebEx a little bit, so let's go back to WebEx first. Is there anybody else on WebEx who would like to say something?

Operator: Thank you. Please go ahead, Ms. Caroline Stengel.

Caroline: [03:33:28]

Hi, I just wanted to add to the point about urgency. It's very important that we acknowledge that right now the burden of cost for treatment is squarely on the shoulders of Lyme patients, and people like me and my friends who have Lyme have had to sell their homes and fundraise online and rely on charity from other people in order to get access to privately-paid-for treatment. That is unjust. Health care in Canada is supposed to be universal, and Lyme patients are what I could call medically disenfranchised. Thank you.

Lise: Thank you. Next over here?

Okay, I'll go to you afterwards. I'll come here first. Go ahead.

Male: [03:34:14]

I'd like to just make sure that one of Dr. Maloney's proposals doesn't slip through the cracks, which was about some kind of a standardized reporting scheme for treatments, and also not being attacked for them, but some way of getting that information back.

Lise: Right, so there's all kinds of stuff happening in the treatment field that's not being captured and documented properly, so it gets dismissed as evidence, and that needs to be fixed as well. Good, thank you. At the back here?

Female: [03:34:49]

Thank you. The point I wanted to make was to make sure we have the key message on our blackboard of what Dr. Maloney said earlier, and I don't know how many people heard it, but I feel it was very important, about antibiotic stewardship. And I think I have her words written down fairly accurately. She was talking about antibiotic resistance and prophylactic use of antibiotics in our food, to just be aware of that in this whole grand scheme of things.

Lise: That's a factor that should not be ignored and it has been given weight in the past. You can't completely forget about it going forward.

Okay, going back to WebEx briefly, is there anybody else?

Operator: There are no further comments registered at this time.

Lise: Okay, thank you. Where are we here in the room? Over on my left, go ahead.

Female: [03:35:37]

Hi. We talk a lot about the need to do, you know, scientific studies, but given the complexity of Lyme disease, we know every single case is different. How do we plan on moving forward with, you know, isolating one variable, two variables? I mean, I think it's something that's rather impossible. We know everybody's case is different. So I feel like we talk about having to do these studies, but I don't see them ever being possible, so-and in the meantime, patients are caught in limbo and there's just going to be more of them. So I think we can't wait to have these double-blind, you know, randomized controlled placebo studies, because the cases are simply too complex. There's different co-infections, different systems affected. So I don't know if this model that we think is this, you know, gold standard really can apply to an issue as complex as Lyme disease co-infections and other related issues.

Lise: Okay, thank you. So again …

Urgency of treatment balanced against the needs of science, and how do you reconcile those so that you don't make the treatment wait for years and years and years while you're getting the perfect study done?

I'd like to hear from people who have not spoken yet before I go again to people who have spoken. Go ahead.

Female: [03:36:51]

There's been quite a bit of discussion in the stories yesterday and also today about the amount of disability that people have suffered from this disease or from whatever disease that they have, recognizing that we may not be sure on what the etiology is for some of these conditions. But there is a standard, acceptable approach for assessing disabilities, regardless of the diagnosis, and I think that needs to be implemented.

Lise: Right, the statements around it being recognized as a disability. Mm-hm. What else? Okay, over here, I guess. Go. Sorry, microphone is on its way.

Female: [03:37:37]

Like many other illnesses, patients should be included in developing the-be included in the process of developing a care plan for them, and patients should also be given the right to make an informed decision. So therefore, they should-like, because there's controversy. There's no clear answers. So therefore, they should be informed of the dangers, the risks, the pros and cons, and they should be included in making that decision on what treatment to pursue.

Lise: Okay, thank you. Anything else that we've missed? Okay, so here's-oh, did I miss a hand? Right here, okay. And another one on the right afterwards. Go ahead.

Female: [03:38:35]

Just as we've talked about the need for research with regard to treatment, we've also discussed the need for additional research for diagnostic tools, and I think that's something that we really need to deal with because while the studies are years and years and years away from actually having a resolution, a decent test that would be more informative, we do need some form of interim solutions and (inaudible) …

Lise: For diagnostics as well?

Female: For diagnostics as well, yeah.

Lise: Okay, so it's not just interim solutions for treatment, it's also interim solutions for diagnostics. Did I see a hand up here on the right? Yes, go ahead.

Female: [03:39:18]

Yeah, I'll try to be clear. I'm coming from a different viewpoint, I think, but I strongly feel that a strategy should include, because of the excessive strain and emotional impact of this disease on so many people for so long, that it should include both validation by the way you are sick, "We recognize that," and also extra emotional support because it isn't just the physical and financial, but excessive damage that requires people to get that support because you can't actually get better if all you get is a pill or, you know, physical something.

Lise: Okay.

Female: You need the nurturing as well to get you through it.

Lise: [03:40:06]

Thank you. I have been told that I need to wrap it up now, so I promised 5, but it's five to 5 and we're going to stop here.

What I'm going to report on tomorrow, very consciously, is not your recommendations for going forward, but I'm going to pull from everything you said in this last analysis on your description of the situation, okay? Keep your notes, bring them tomorrow, keep me honest, and we'll continue the conversation tomorrow. So tomorrow, we're shifting into, you know, if we got it right, what would it look like and how do we get there? So hopefully, tomorrow is going to be really a very powerful conversation for moving forward.

Thank you so very much. I have been amazed and impressed with everything I've heard today.

Have a good evening. See you tomorrow morning at nine o'clock.

At nine in the morning, then, we will start again with a conference here.

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