2016 Lyme disease conference welcome remarks and plenary presentations

Prevention, identification, treatment and management of Lyme disease

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

Audio Recording


Dan: [00:00:00] Good morning.

We have people joining us by WebEx, and I'm going to be asking the operator to queue all of the participants who are with us here today on WebEx.

Hello ladies and gentlemen. My name is Daniel Normandeau.

My name is Dan Normandeau, and I have the privilege of being your facilitator over the next two days for this conference. Very happy to be here, and we welcome people from right across the country, who've come to join us in this critically important Conference to develop a federal framework on Lyme disease.

Obviously, this is a conference to develop a federal framework for Lyme disease and we are here to work together over the next two days.

There's available interpretation. French is on the second channel. English is on Channel 1. There are interpretation devices. We expect that people will be speaking in both official languages, so please feel free to do so.

Before we start, for those of you who were with us last night, and heard the stories that people shared with us, of courage, determination, and wisdom-before we start this day and get going on our conference, which I will describe momentarily, please join me in giving them a real loud hand of applause for their major contribution last night.

A few administrative messages before we go. One: ladies' washroom-the automatic door opener is not working, but the folks here at the conference centre are on it. The second point: there's a Wi-Fi network, and the network name is, "govconfcentre." G-O-V-C-O-N-F-centre, and the password is "Spring2016." I thought it was going to be "Spring2017" because I thought we skipped spring this year and went back to winter. But that's another issue.

As you know, there are independent filmmakers in this room. One, there's our video feed that's going to the overflow room. But there's another independent filmmaker who's putting together a documentary. If someone should not wish to have their image recorded, please advise the cameraman directly, and he will ensure your image is not captured.

Ladies and gentlemen, today and tomorrow is a unique opportunity for all of us. It's time to work together, to bring together expertise, our experience, our journey, our stories. And I would encourage all of us to approach our work over the next couple of days with respect, to listen deeply to each other for understanding, and as I mentioned last night, to be hard on the issues and soft on the people, and to approach our work with a positive approach. This is an opportunity to build a framework that will improve what it is we're all experiencing today.

The agenda and program that we will be following over the next couple of days is really in three parts. The first one is, last night we appreciated people's journey, their experience, and of course that will be recorded and will be accessible online in the next few weeks, as soon as we can get the technical issues addressed. But they will be available to all of you.

Today is really about putting the body of evidence on the table, and hearing from the experts on their view. The overview of Lyme disease, of course, which will hear this morning, and this afternoon, in the smaller breakout sessions, we'll be focusing on individual themes that include surveillance and the other two themes that you find on your agenda.

What we'll be doing this afternoon is giving you an opportunity to really dig deeper in terms of the thematic issues, so that you can have the opportunity of really engaging with those experts and really finding out what the body of experience and expertise really has to offer at this point, so that we can actually be informed for our work tomorrow morning.

And our work tomorrow morning is really with a view to harnessing all of the experience and expertise that you're having to provide in this room, so that we can hear your ideas on what you think should go into a federal framework. All the various elements, the issues that you think need to be addressed, we'll be inviting you tomorrow morning to really share all those.

And then tomorrow afternoon, as we conclude the conference, it will be to bring all that body of knowledge and experience and contribution on your part to inform the development of the framework.

And it's going to be an extremely insightful conference. We have all of the experience in the room, all of the expertise that's required. And to launch this conference, it is my deep pleasure to introduce the Honourable Jane Philpott. That's going to be a double applause.

Dr. Jane Philpott is a family physician, for those of you who don't know, and was the Chief of the Department of Family Medicine at Markham Stouffville Hospital. She was also an assistant professor at the University of Toronto in the Department of Family and Community Medicine.

And of note, between 1989 and 1998, Jane worked in the West African country of Niger, where she practiced general medicine and helped to develop a training program for village health workers. In 2004, she founded Give a Day to World AIDS, which has raised over 4 million dollars to help those affected by AIDS in Africa.

Ladies and gentlemen, please join me in welcoming the Honourable Jane Philpott.

Jane: [00:06:12]

Thank you very much for the kind introduction and for the wonderful opportunity to be here at this conference. This is a fantastic event. I am thrilled to see the response, and hello also-I don't know where the camera is actually, but to the folks who are watching from-I guess there's an overflow room and some 400 other people that are signed up to follow the conference online, which is absolutely fantastic.

This is an extremely important step, this event that is taking place over the next couple of days to build a federal framework on Lyme disease, and I want to acknowledge the conference planning committee who have done so much hard work, over such a long period of time, to put together the event that we are all enjoying today.

And I cannot help but thank my fellow Parliamentarian, Elizabeth May, who as you all know, is such a hero on this matter for her incredible hard work and leadership on the matter of Lyme disease in Canada. And particularly, her excellent work in introducing the private members' bill which has led us to here today. The private members' bill that asked for respecting a federal framework on Lyme disease, so a big thank you to you, Elizabeth.

This is what all conferences should be like: when we get together and we have the voices of everyone that is affected. I think it's fantastic that we've brought together scientists, that we've brought together patients and policy-makers, and all of those who need to have a voice as we go forward. This is an opportunity to bring those voices together, to hear from Canadians across the country, and I suspect we're hearing from international partners as well. It's so important that we have discussions like this to develop a federal framework, so that we are guided by the needs and concerns of those who are most affected by Lyme disease.

I'm delighted to hear reports about last evening. I gather you had a fantastic public forum. I hear that the stories were heart-wrenching and profound, and I'm so pleased that so many of you had the opportunity to share those stories. Many of my colleagues I know were here and were deeply moved by the stories that they heard.

And over the next few days, this will remain a public, open event, and I certainly encourage you to share the ideas that you're learning about here with your colleagues and friends across the country.

We all know that Lyme disease is a serious illness. There is no doubt that it is spreading across Canada. There is no doubt about the challenges that we face. Initial symptoms can differ from person to person, which makes it difficult to diagnose. And early identification, as many of you well know, is critical to successful treatment and prevention of serious health issues that are associated with the illness.

That's exactly why it's so important that we bring together researchers, medical experts, patients, and concerned Canadians. All of us here today know that there are challenges as we face Lyme disease in this country. There is no doubt that we need much more research to better guide diagnoses. We need better surveillance and we need more education and awareness to inform both the public and practitioners about this infectious disease.

This is, not surprisingly, exactly why we need a federal framework on Lyme disease. As you will recall, the framework is going to focus on three key areas. Number 1: establishing a national medical surveillance program to properly track the incidents rates as well as the economic costs of Lyme disease. Number 2: the need to establish guidelines-guidelines for prevention, identification, treatment, and management and sharing best practices across the country. And number 3: the creation of standardized educational materials that will increase awareness about the disease.

I am sure that this conference will result in an excellent collaboration of all the people here and that it will allow some of the excellent work carried out to continue. As you may know, over the past three years, the Public Health Agency of Canada has implemented its Action Plan on Lyme disease. We partnered with the provinces and territories to provide Canadians with the information they need to protect themselves. We are also monitoring places where the disease is emerging and segments of the population that are most at risk.

We are also working closely with Canadian Institutes for Health Research to explore new science and research to be able to better detect, diagnose, and treat Lyme disease. In the last four years, the Canadian Institutes for Health Research has invested more than $2.8 million toward Lyme disease projects, and I hope that there will be much more research to come.

We are telling health professionals to be vigilant in diagnosing Lyme disease and reporting cases back to the local public health authorities. All of this work, we know can continue to be improved upon and we need to enhance it together. Over the next two days, you will be taking part in this very important opportunity to discuss the latest science on Lyme disease, to develop suggestions for consideration in the federal framework for Lyme disease.

As you know, the framework cannot be written overnight, but this conference is an essential and important step in getting there. All of the information, feedback, ideas, and opinions that are generated at this conference will be fully considered as this federal framework for Lyme disease is developed. Ultimately, the outcomes of this conference are going to help protect the health and well-being of all Canadians. And that is something that we all need to be proud of.

So, I thank you once again for the effort that it's taken for you to join us today. I wish you a wonderful conference, and I look forward to hearing all about it. Many thanks.

Dan: Please join me in welcoming Elizabeth May, Member of Parliament, Green Party of Canada.

Elizabeth: [00:12:49]

I'm just setting my clock because I have time limits. First, let me start by acknowledging that we're around the traditional unseated territory of the Algonquin of Golden Lake, Meegwetch. And as-coming from Saanich peninsula, Saanich people would say (indiscernible): "With respect and honour to be here."

And it's deeply overwhelming to be with so many of you who are the champions and heroes of the fight on Lyme disease. Many people have asked me, over the last number of years, since I took up the idea of finding a way, as an individual Member of Parliament, to make a difference to help the people I knew who had Lyme disease, how I got started, how I got interested in this as an area that needed attention.

And so I want to start by saying it was Brenda Sterling in Pictou County, when I was a neighbour, who said that she had Lyme disease. You know, you don't really like asking someone in a wheelchair, who seems to be permanently disabled, why their permanently disabled. And I asked her.

And then she told me, "I have Lyme disease."

And I really didn't believe it. I was stunned. I didn't know that people could end up in wheelchairs. Nicole, I didn't know then that people could end up in wheelchairs with Lyme disease. And Brenda told me about her struggle, and about the stories that you all know. We heard dozens of them last night, of being told, "No, you can't have Lyme disease. We don't have Lyme disease in Nova Scotia."

And then we heard last night how many patients were told, "We don't have Lyme disease in Manitoba."

"No, we don't have Lyme disease in Alberta."

"No, you're wrong. You can't have Lyme disease. We don't have Lyme disease in British Columbia."

So it was the stunning similarities in the stories that made me think, "This is not just a random bunch of coincidences that I keep meeting people who have the same experience. Something's going on here and it requires a public policy response, and if I can do something about it, I will."

So I want to start again by thanking deeply all of the Parliamentarians who did this. This is the ultimate non-partisan issue. I want to thank the interim Conservative Party leader Rona Ambrose, our former Minister of Health. If she hadn't decided to let people support my bill in her party, it certainly would never have passed, certainly wouldn't have passed unanimously. So, I'm very grateful to Rona.

I'm hugely grateful to our new Minister of Health, Jane Philpott, herself a medical doctor, and I think, you know, "You're now Canada's doctor." And I think you've got great bedside manner. I feel good about you as our minister, Jane. I got a-really grateful.

So, I also want to thank Members of Parliament who aren't in this 42 nd Parliament, but who helped a lot: Conservative Terence Young, NDP Libby Davies, and currently in cabinet, also our current Minister for Science was a huge help in helping me with this bill, the Honourable Kirsty Duncan, who's now Minister for Science.

It is a non-partisan issue, but we have together, and I think we do have the right spirit, starting out today for a two-day conference knowing that the conference is not the goal of the bill. The goal of the bill is the federal strategy, which I had in the first draft of the bill called for a national strategy, a framework for Lyme disease with a focus on the patients.

That's what came out last night in the discussions. I remember Debbie McCann calling in from New Brunswick and saying, "We've got to stop treating this as a debate, about one opinion versus another opinion and in the middle are the patients. This has to be about the patients." And I think if we can keep our focus there, know that people have gone through hell and back for no good reason without getting answers.

But for the next two days, park the anger, try as hard as you can to listen and figure out how do we work together from here on forward to ensure that the Federal Department of Health, the Public Health Agency for Canada, can get the cooperation from the provincial departments of health. Right across this country, we need medical doctors to work with their patients, to work with the research agencies, to work with the departments of health and the official accrediting bodies for doctors, because I have some very specific goals that we must not lose track of.

We must put an end to the status quo. We're Canadians who are sick, are forced to go the US, lose their homes, lose their savings, lose their pensions. This has to end. Our Canadian healthcare system has to take care of everyone. And no one with Lyme disease should be stigmatized anymore.

With that, I just want to add for everyone here that now it is the patients with Lyme disease, we are together in solidarity, everyone together for the big-for the great challenge of Lyme disease.

We can confront this huge challenge with knowledge, and this conference is not the end. I want you all to know that I will never stop working on this. I have faith in this process, that it will remain inclusive and transparent, and you have my word. I won't let go of that. Thank you.

Dan: Thank you very much, Mrs. May. We'd now like to hear from Mr. Jim Wilson, President of the Canadian Lyme Disease Foundation. Jim, the floor is yours.

Jim: [00:18:41]

Welcome, everybody and thank you for coming, both those in person and everybody who is out there online. I wish to thank Minister Philpott for taking the time to come this morning. I know you have a very busy schedule. A special thank you to Elizabeth May and all those who helped bring Bill 442 into law, including Brenda Sterling from Nova Scotia, Nicole Bottles and her mom Chris Powell, David Coverly from British Columbia. David is a previous opposition-party health critic in the Province of BC and now a director on the board of the Canadian Lyme Disease Foundation. And to all of those others who contributed.

Patients have been waiting 27 years to be given a voice. Since the formation of the first Lyme Borreliosis Society in Canada, the Lyme Borreliosis Society of British Columbia, formed by Diane Kendree in 1989, followed a year later by the Lyme Disease Association of Ontario, formed by John and Kit Scott. Thank you to all those Members of Parliament and the Senate who unanimously enabled this bill to be brought into law.

This conference can be seen as only the starting point from where we must move on. But this time, the patients and their experts must be seen as equal partners in all aspects, including guideline-writing, diagnostics, treatment, prevention, surveillance, and what research our tax dollars should be funding. We need to truly identify the burden of Lyme Borreliosis currently within our chronically ill population and to find better ways to identify future victims of the disease.

Patients in our country cannot afford to throw away another 27 years. Canada is better than that. Currently, only select people through secretariats are privy to the flow of information that goes to our deputy ministers where, at the provincial levels, where the actual healthcare delivery model is set. There is no mechanism in place currently for the victim and their experts to evaluate the quality and the accuracy of the information flowing through these taxpayer-funded secretariats, and that needs to change.

Here we are in 2016, and Canada has no idea how many Canadians now, or over the previous decades, contracted Lyme disease because the protocols in place for testing and clinical diagnostics have had big gaping holes and still do. The conference has to-has so much potential to grow ethical, transparent science and discussion, but it will require not only the support of government, but government must put in place a mechanism of oversight to see that the patients and their experts are seen as equal partners at the table. We must have a say in how healthcare on all matters Lyme Borreliosis are delivered.

So that means we are there on every panel, not with token membership, but as equal partners. There can no longer be a community panel and then an expert panel where the expert panel has all the say in the end. And it's that expert panel who gets to decide who gets diagnosed and who gets treated. And the community has no say in that end result, and that has to change. That approach fails everyone as it breeds bias and self-serving policy.

Currently, government communications and marketing staff have more input than the ultimate end-user: the victims of Lyme Borreliosis policy. There is something terribly wrong and yet very telling with that. Canada has to stop endorsing American policy and guidelines and imposing them upon Canada. We have very different medical systems and our structure as it is now, makes it too easy to introduce bad policy overnight coast-to-coast in our social system. And it creates a one-focus, single-direction, tunnel-vision medical bureaucracy.

We have at least as much strain variation in Canada as anywhere in the world. Plus, we are a large country, spanning coast to coast to coast. We can no longer define Lyme Borreliosis by serology, and Dan Gregson-who you'll be hearing from next-last evening mentioned his background with AIDS and HIV. There, nothing changed until heterosexuals began getting sick. Then things started to happen. With Lyme disease, it required politicians' families, physicians, and scientists getting sick. We are sadly, finally here. We can do it in Canada, for Canada, and this conference is the first step. Thank you.

Dan: We're going to hear now from the medical community, Dr. Daniel Gregson, who's the past President of the Association of Medical Microbiology and Infectious Disease Canada. Dan?

Daniel: [00:24:51] Thank you. I want to start by thanking everybody who got up and spoke last night. Unfortunately, we were in three rooms and I can only hear about 27 people. I did hear all of your suffering, both the physical suffering and psychological suffering, the financial suffering that some of you or all of you've experienced over the last decade or so. And it truly is-I truly am moved by that suffering. I tell you that, that's for sure. I know that my members are moved by that suffering.

With regards to my prior experience with HIV, the vast majority of my patients were gay. I treated them long before there was any federal framework on HIV. I care for my gay patients. I care for all my patients. And I'm a little bit upset about the insinuation that I don't care for gay people. I do. I have gay friends. I know transgender people. That is not who I am.

In any case, I'm here now on behalf of the Association of Medical Microbiology and Infectious Diseases Canada, to welcome you all: patients, the delegates, and the experts to this meeting to assist the Public Health Agency of Canada to develop a federal framework for Lyme Disease in Canada.

So, our association is a non-profit association. We receive no government funding, we receive no industry funding other than support for our annual meeting, and we receive no funding from external companies or governments, so we're not funded by the IDSA. We receive no funding from European agencies and things like that.

We're really a group of specialists, over 500 of us, who develop our training in infectious diseases and medical microbiology and other scientists who are involved with research and treatment and caring for patients who have been affected by infections of all types, not just Lyme disease. We operate diagnostic laboratories, we provide expert advice to patients, to our colleagues, and occasionally to the government, not very frequently, on how to manage and control infectious threats that affect the health of Canadians.

Our members deal with issues ranging from assisting with emerging infections such as Ebola. Some of my members were in West Africa during their last major epidemic. Managing chronic diseases from infections like Hepatitis C and HIV. And then also evaluating and introducing new diagnostic tests in our laboratories to ensure that the diagnoses that patients get for all infectious processes are the best ones based on best evidence. And we also introduce new treatments.

I have a colleague I refer patients to (indiscernible) infection, and we're on that cutting edge of making people's lives better.

I'd like to thank Health Canada and our Minister, Jane Philpott, and Dr. Taylor for organizing and funding this meeting. We think it's a very important meeting for you and for us to find some common ground. I guess from my perspective, what we need is science. What we need is science. What we need is science.

Our members see this conference as a major opportunity for Health Canada to developed evidence- and science-based frameworks to deal with this important health issue, and I wish you all the best for the conference. Thank you.

Dan: Okay. Ladies and gentlemen, we're going to be shifting gears. We're now going to begin to hear from the experts who have something to share with us. There are four of them, as you can see in your program, that we're going to hear from this morning. They each have 20 minutes, and with an opportunity following the health break, after we've heard from all four of them, to exchange with you in a discussion, questions of clarification, and so on. We will open the floor to questions to you people in the main room, as well as those in the overflow, and I know that there's also provision for those of you joining us via WebEx.

So because we will be holding a panel discussion following each of the presentations-following all of the presentations. So I'm going to be inviting you to note your questions as you're hearing the speakers, one after the other, and we'll ask you to keep them until after the health break.

So it's now my pleasure to introduce our first speaker, Brian Fallon, who's going to talk to us about a brief history of Lyme disease and the review of the US clinical trials. He's a Professor of Psychiatry, Director of Lyme and Tick-Borne Diseases Research Center at the Columbia University Medical Center. He's a Director as well as of the Center for the Study of Neural Inflammatory Disorders and Bio-Behavioral Medicine in New York State Psychiatric Institute. Ladies and gentlemen, please join me in welcoming Brian Fallon.

Brian: [00:29:50]

Thank you so much for inviting me. I'm honoured to be here and I think this is such an interesting process. I hope we can all be helpful to it. Bonjour, and I wish I could say this in French, but it would be very slow in French and not very content-filled. Okay, so I'm going to briefly talk about the history of Lyme disease-how do I move forward? This? Okay-and a review of US clinical trials. I am getting a small grant from Oxford Immunotec, but I'm not going to be talking about their products here. And I will not be referring in my talk, as I said, to any product by Oxford Immunotec. Okay.

So, this is the outline of the talk. Two key early pioneers, who I'll describe briefly, and as-this is a very personal view of Lyme disease. I sort of see it in three eras. 1976 to 1990 was a time of great openness and discovery in trying to figure out what Lyme disease really is, what the many manifestations are, what the proper diagnostic tests were or some beginning preliminaries on diagnostic tests, and certainly describing the full many, many different manifestations of Lyme disease. So, if you look at that early literature, it's quite informative and fascinating.

And then in 1990 to 2008, I saw as a period of narrow definitions and retrenchment. And that was done for a good reason. So, it was done because the Centers for Disease Control wanted to create really good surveillance criteria that could monitor the spread of disease over time, and in order to do that, you needed objective, clinical criteria and you needed a good diagnostic test. So, things became narrowed down. One of the mistakes that was made, I think, during that time was the clinicians started to the use the surveillance criteria as their only criteria for diagnostic determination. That's not what the Centers for Disease Control was recommending, but that's what some individuals did.

And then 2008 to present, I see as a time of renewed discovery and exploration. And that's because of the great advances in biotechnology, that's because of a number of studies that have come out, and it's a time of great hope. So for patients here, I think you should be encouraged and happy about what you're going to be seeing in the next years because it'll make a huge difference for you.

So, Willy Burgdorfer is this charming, happy guy who was the Swiss tick surgeon in 1982 who discovered that it wasn't a virus, after all, inside ticks that was causing the disease. But rather, it was a spirochete. This spirochete was named after him. The treatment had evolved into antibiotics, but initially they thought it was anti-inflammatories, and it really helped to enhance the recognition that what we have in the United States is pretty much the same with important differences to what was going on in Europe.

Allen Steere was the individual who was a young epidemiology researcher and rheumatology at Yale who identified and described the first cases of Lyme arthritis among children and associated it with a rash. He also has over the years researched the role of autoimmunity, identified genetic risk, identified an autoantigen, and he also importantly reported in the New England Journal of Medicine that not all cases meet the CDC surveillance criteria. So, one out of five cases would be missed if you strictly applied the CDC surveillance criteria.

He also reported that antibiotics may not always lead to a cure, and that's been a lot of his work on Lyme arthritis. But he also reported a small number of cases of children who had visual problems associated with Lyme disease. One poor child who became blind as a result of increased intracranial pressure. And my interest as a psychiatrist and neuropsychiatrist is on brain imaging, and he was one of the first to report brain blood-flow deficits in Lyme. So, he's done a lot of interesting and important work.

And I also want to recognize my colleague Dr. Dattwyler here, who is one of the early pioneers, as well, who did some of the original pivotal studies on the treatment of early Lyme disease in the 1980s.

So, we're here on the upper left. You see a cluster of unexplained childhood arthritis was Polly Murray. Mothers have had a huge influence in shaping the study of this disease and she was the one who brought it to the attention of public health authorities. Then the spirochete was found in the tick in 1981-82.

Then a paper came out called "Lyme disease, the new great imitator." And why was it called that? Because syphilis was described as "the great imitator" because it had so many different manifestations. Andy Pachner wrote this paper. He was a neurologist and he was very impressed with the fact that sometimes-not often, rarely-you can see cases that look like multiple sclerosis, or in one case in that paper, a childhood onset OCD after Lyme arthritis.

And then the CDC adopted the two-tier criteria, which I know that Dr. Dattwyler will be talking about. The genome was sequenced, and that was very important and very helpful. It later enabled them to look at The Iceman who was 5,000 years old-actually had spirochetal DNA.

And then in 1998, the vaccine came out, LYMErix. Very important and big effort to create that vaccine, but the problem was, it wasn't 100 percent protective for everybody who took it. It required lots of booster shots, and there was concern among patients that maybe it initiated some arthritic problems and neuropathic problems. So, the popularity of it declined, and as a result, people stopped taking it. SmithKline took it off the market.

And then there were the Lyme clinical trials, which I'll be talking about shortly. And then in 2008, an article was published out of Steve Barthold lab in the UC-Davis where he documented the persistence of the Borrelia spirochete after antibiotic treatment. He's a preeminent researcher, a member of the Institute of Medicine, and when he writes something, people pay attention. And it actually had been written by Dr Stravenger in an earlier report among beagles in 2000, I think it was-1999-but that was largely ignored because he was a post-doc writing a paper and he wasn't as recognized.

But what was important about that is that suddenly it opened up the thought processes-that maybe it is true that some patients out there do have persistent infection. If it's occurring in the animals, perhaps it could also be occurring in the humans. So, as a result, research opened up and as a result, people like Dr. Zhang and people like Dr. Lewis are studying persistent Borrelia.

And then the CDC came out and reported that there are 300,000 new cases of Lyme disease each year, which was an increase from the 30,000. And that was really important because it led a lot of diagnostic pioneers to put more efforts into developing new diagnostic tests, because by doing so, they might develop the next great diagnostic test, which would be great for public health and also great financially. So it was a good thing for everybody. It allows people to get grants and recognized as the severity and importance of the disease.

And then as we all know, systems biology and the "-omics" revolution has been hugely important. It allowed us to study things in ways that we weren't able to do before, and if you collect samples very carefully over time and longitudinally, you can see what's different in those patients who have persistent Lyme symptoms versus those patients who recovered. And you can look at the DNA and the RNA and the proteins and metabolome, and by doing so, perhaps we'll be able to develop better tests, and perhaps we'll be able to understand the pathophysiology and devise better treatments. So that's super exciting. So it's really a great time in the research opportunities for Lyme disease and for patients.

So, now in my next seven minutes, I'm going to review all the clinical trials in the US that we've done on Lyme disease as well as talk about one trial that was recently published in the Netherlands.

So, in the US, there were two symptom-specific studies: one from Columbia, one from Stony Brook. The one from Columbia looked at Lyme encephalopathy-that's one that we did. The one from Stony Brook focused on post-Lyme fatigue. And then there were two heterogeneous-symptom studies that were of the same study-design, but there was a group of seropositive and a group of seronegative patients out of the New England Medical Center. And then there was also a heterogeneous symptom study in the Netherlands.

And the reason why I'm focusing on what's homogeneous and what's heterogeneous is because it's super important if you're designing a clinical trial, and you're including people in the study who have a heterogeneous group of symptoms, you may not be able to show a treatment effect. Whereas if you focus on a particular problem, enroll people based on the severity of that particular problem, you're more likely to see a treatment effect.

So, I'll quickly go through our study at Columbia, since I know it the best, and our goal was to assess brain structure and function and to assess improvement in response to 10 weeks of IV ceftriaxone versus placebo.

These patients met highly conservative criteria for Post-Treatment Lyme Syndrome-so the crème of the crème of rigorous diagnostics for these patients. They were treated for 10 weeks and then their primary outcome was at 12 weeks and we looked to see if they sustained their response without antibiotics to the 24-week endpoint.

It was a small sample size, unfortunately, because our criteria were so rigid and so conservative. It was enormously hard to find patients who met these rigid criteria. Twenty-three got randomized to IV ceftriaxone, 14 to placebo, and we also had 18 healthy controls. We didn't give them antibiotics of course, but the reason we had them was to monitor neurocognitive change over time. Because if you give the same test, over time, they'll be a practice effect, and people will get better.

So, one-the main point is that my study included people who were particularly chronic. They had a mean amount of prior IV of two months and a mean amount of prior oral of seven months. Obviously if we had enrolled patients who had much less antibiotic treatment, they'd be more likely to respond to treatment than if they had as much as these patients had.

On initial finding in this study, they only had mild cognitive deficits, they had mild psychiatric issues, but they had very significant pain, fatigue, and physical disability-and I'm going to quickly pass through this. This is the main outcome where you see the lime-green arrow is pointing out to the drug group in black, and the spotted line is the placebo group. You see the drug group making an improvement to a greater extent than the placebo group, but it did just went slightly above the range of statistical significance: 0.053. And then they lost all their gains when it came to the next three months.

So in terms of conclusions, I couldn't-I had to say that 10 weeks of IV antibiotics does not lead to sustained benefit. Because it didn't. There was no difference between the drug and the placebo group for sustained benefit.

However, if you look at the secondary outcomes, which were fatigue, pain, and physical functioning, well you see at the arrow there, under "Fatigue," is a wide difference between the placebo group and the drug group. The drug group dropped to a greater extent than the placebo group. If you looked at the bottom two lines, there's no difference between drug and placebo. And why is that? It's because they started without much fatigue. And then next you see a wide difference in the drug and placebo group among people who had high levels of pain, but no difference between people who had low levels of pain. And the same was true for physical functioning.

So if you're more severe when you enter the study, on the outcome of interest, you're going to possibly see a treatment effect.

Were there objective biomarkers that differentiated the Lyme patients from the controls? We looked at global cerebral blood-flow and there was a difference. The patients had more difficulty, vasodilating in response to a vasodilatory challenge. So, there was some compromise of their vascular flow, and they had areas of deceased metabolism, primarily in their temporal and parietal cortex compared to age- and sex-matched controls. We could not find any blood markers that were associated with response to retreatment, including the endcase CD57, including inflammatory markers, including the IgM Western blot, including titers for other infections.

We did find, as I mentioned, that those who were worse, clinically, did better with treatment. So the strengths and limitations of the study: rigorously defined patients, excellent study retention. The weakness was a small sample size. It was severely underpowered to show any treatment differences.

Would a less treatment (indiscernible) sample have done better? What alternative and safer non-antibiotic therapies may enhance patient response? What was the mechanism? Was it antimicrobial? Was it glutamate modulatory? Was it anti-inflammatory? We know that ceftriaxone does modulate glutamate. So, my recommendation is that clinical research trials should focus on more homogenous populations recruited for severity level.

So, I'll just briefly go through a couple of other trials.

This was a wonderful study. I really like this study out of Stony Brook because they recruited primarily for fatigue. Everybody had to meet a certain cut-off for fatigue to enter the study. They had three outcome measures: fatigue, reaction time which is a cognitive test, and OspA in the spinal fluid. But on only one, fatigue, were the patients uniformly impaired.

They got one month of IV ceftriaxone and then they were followed six months later to see what happened off of antibiotics. And lo and behold, the ceftriaxone group, 64 percent of them responded versus 18 percent of those on placebo. That was a significant difference. There was no improvement in cognition that was different between the two groups, but they only had mild deficits to start with. There was no change in OspA, but only nine of the 55 patients had OspA. So, that was a meaningless outcome measure.

So there you see that there was even a biomarker of treatment response, which was whether or not you were IgG Western blot positive at the time of study entry. Of those who were enrolled, 80 percent benefitted from the treatment compared to 13 percent on placebo.

And then when I was writing my manuscript for the Journal Neurology, the reviewers asked me, "Please analyze your data using the exact same enrollment criteria that the Stony Brook study used, and see what you come up with. And analyze it the same way."

And as you can see-from the left and the right-left is the Krupp study, right is my study. The results were identical in terms of improvement and fatigue. So when you have a second study done by a different group that corroborates the first study, it gives greater credibility, of course, to the findings from the first study.

I want to recognize the Infectious Disease Society of America does not agree with the way I've just presented this data. "Antibiotic therapy," they say, "has no proven benefit for PTLDS, Post-Treatment Lyme Disease Syndrome."

The British Infection Association says, "Studies of prolonged antimicrobial treatment have not shown sustained benefit."

The European Federation of Neurological Society says, "American trials have demonstrated that additional prolonged antibiotic treatment is ineffective in Post-Lyme Disease Syndrome."

So, I'm raising this as a point of discussion for later. But if you look at these studies, I don't see why that's so difficult to see that there's an improvement associated with repeated antibiotic therapy. This is not extended. This is repeated antibiotic therapy. And the effect size-which is important in clinical trials, to say, "Is this meaningful?"-was moderate to large. And I can tell you for drug studies for fibromyalgia and the drugs that are FDA-approved in the United States, the effect size is mild in size. So these were moderate to large in effect sizes.

Now, there was a very significant study, the Kleppner study, which was the largest study in the US, which was negative. It was a study of seronegative and seropositive patients. They used a measure of functional impairment, but they did not recruit based on a certain cut off of functional impairment. It was a carefully done study, they were hoping to show benefit with 30 days of IV ceftriaxone and 60 days of oral doxy compared to placebo.

But there was no difference in the primary outcome of physical and mental functioning. And there was no difference in change for cognition or depression. So the strength of that study compared to the other studies was that it was really a large sample size. Limitation was the heterogeneity of the patient sample.

This is the Netherlands study, which was just published in April, and this was a randomized trial of longer-term therapy for symptoms attributed to Lyme disease-huge study. You have to give them credit-280 patients. Only one third had objective clinical markers of past Lyme disease, so that was unusual. I don't think that would ever get funded by the National Institute of Health. Two-thirds had possible past Lyme disease with non-specific symptoms with a positive IgM or IgG Western blot.

So, because they included a very heterogeneous group, we don't know how many of those patients truly had past Lyme disease or didn't, because you can have false-positive IgM Western blots. And oddly, 11 percent of the people in this trial had never before been treated for Lyme disease. So it was truly a mixed, confusing group.

Okay, two minutes. I'm pretty much done. So everybody got 12 weeks of IV ceftriaxone followed by oral placebo, oral doxy, or oral chlorithro and hydroxychloroquine. Because there was no placebo during the first two weeks, this study cannot state whether or not repeated antibiotic therapy was helpful. And there was no benefit seen for extended antibiotic therapy beyond the first two weeks. But again the heterogeneity of the sample makes it very hard to know what to conclude from this study.

So, I want to highlight the difference between efficacy versus clinically recommended. Krupp's study showed efficacy, but she concluded it wasn't clinically recommended. Why? Because of side effects associated with IV antibiotics. That doesn't mean it didn't work, it just meant that we need a safer treatment.

So, the conclusion guideline committee should include a statement indicating that retreatment with IV ceftriaxone has been shown to reduce fatigue and Post-Treatment Lyme Disease Syndrome in two US trials. Treatment with fewer side effects are needed. Other treatments also are needed for those who are no longer benefitting from antibiotics, and there are many patients who have ongoing symptoms despite quite a good course of treatment with antibiotics. Thank you for your attention.

Dan: Thank you. Thank you very much, Brian. The next presenter will be Ralph Hawkins, and he's going to be presenting on Lyme disease from the perspective of a general physician in active clinical practice. Ralph is the Clinical Associate Professor of Medicine, the University of Calgary, South Health Campus Hospital Site, where he's the Lead for the Division of General Internal Medicine. Please welcome Ralph.

Ralph: [00:49:52]

Thank you. Merci beaucoup. That's the only French you're going to hear from me, I'm afraid. I'm not bilingual, functionally. It truly is a pleasure to be here to talk to you all. I'm talking from the perspective of a general physician. So, I have had a past background as a family doctor. I'm now a clinician in internal medicine, so I provide my comments from the perspective of the 35,000 primary-care physicians and the 3,000 general internists in this country.

My disclosures slide is here. I have no grants or research support. I serve on speakers' bureau for a few of the major pharmaceutical companies, mostly in areas of Metabolic syndrome, hypertension, and diabetes. The other disclosure I'd like to give is one that we're held to by the Canadian Medical Association Code of Ethics, and that is the recognition of a responsibility to give generally held opinions of the profession when interpreting scientific knowledge to the public. And when presenting an opinion that is contrary to the generally held opinion, to so indicate. And most of what will follow is going to be a departure from what most of the physicians I believe would probably hold to.

I have no disclosure of commercial support and I really don't know what the commercial support for this meeting is. I imagine it's none, and I have no mitigating potential biases to report.

I'd like to report on behalf of one of my patients. We refer to Lyme disease sufferers as patients because the word "patient" actually derives from the word "to suffer." I think Dr. Gregson was quite eloquent last night when he talked about his experiences over 33 years with HIV patients. And it was quite palpable the suffering, as a physician, that he expressed in dealing with those patients. I graduated from medical school 35 years ago, and I continue to suffer with my patients when they have setbacks and drawbacks. I'd like to report about this patient, "TS." I have her permission to provide this case history.

The picture that is depicted is the day that she got her tick bite in Calgary, Alberta, within the city limits. She's an athletic, healthy young mother. She did have an arthropod bite below her scapula on April 19th, 2015. She recognized the bite later in the day. After a few days, she developed a rash that was larger than a loonie, and it expanded over the course of several days. And as most young, healthy individuals, she did not seek medical attention.

May 27th, about five weeks later, she was admitted to the hospital, our hospital in south Calgary, with persistent headache, dizziness, blurred vision. She was collapsing spontaneously and unexplainedly at home. She'd been in the hospital for 10 days before I got involved in her care and consultation. No diagnosis had been established at that time and she had new symptoms that include generalized arthralgias, diplopia, parethesias of her limbs.

And her provincial screening for Lyme had been done and was negative. Her C6 test was reportedly negative, drawn seven weeks after her incipient bite. The infectious-diseases specialist at that time advised her that Lyme disease had been ruled out by serology, and this is the notation from the medical record.

This is the two-tier testing that the Centers for Diseases Control recommend for testing for Lyme disease. And this is the methodology that's employed in the province of Alberta. The first test is a screening test such as a C6 immunoassay. If it is positive or equivocal, you go on to have a Western blot study, but if it is negative, you are advised to consider alternate diagnoses, or to have the test repeated several weeks later if your signs and symptoms persist.

We talk about two-tiered testing in Canada, but the two tiers of two-tiered testing are not done on 98 percent of people because the ELISA is only going to be truly positive in those who have Lyme disease, and it's going to be falsely positive in those where the test has false positivity. So most patients don't have two tiers of the two-tiered testing. So our persistence of the terminology that we use two-tiered testing in Canada is actually a falsehood. Truly, most people have one-tier testing.

Could I have a slide 36, please?

I've warned the people at the back that we're going to try and bring slides up in a different fashion and hopefully this works and if it doesn't, I'm sorry.

So-that's the one.

The C6 test is a patented test by Immunetics. This is their product monograph. If you look at the enlarged version of the product monograph, you'd be able to read all that is here. But the C6 test's intended use, as licensed in Canada, advises that negative results, either first or second step, should not be used to exclude Lyme disease. So we are using the C6 test as part of two-tiered testing explicitly against the licensed, intended use of the product. The intended, licensed use of the product is for it to not be used in this fashion. I'm sorry to you in the back-could we go back now to slide 9?

I neglected to mention as part of my preamble: if this sounds a bit legalistic, I do have a Master's of Law degree from Newcastle, and much of my thinking regarding Lyme disease is actually coloured by my experience with my medical-law degree.

Just going to move past these couple.

The two-tier testing that we're talking about as an acute study only has about 45 percent sensitivity. If we employed acute and convalescent serology rather than this acute testing, we would see an improvement in the ability to identify acute Lyme disease in the 75 to 80 percent range. I know that Dr. Dattwyler is on record from years ago as recommending acute and convalescent serology rather than relying upon the two-tier testing. And I think that that is an appropriate approach that we should perhaps be teaching primary clinicians.

Sir William Osler, the father of modern medicine. William Osler was a professor at Johns Hopkins University in 1912, when my grandfather graduated from Johns Hopkins. So my grandfather was actually a student of William Osler's. He's famously known to say, "Listen to your patient. He's telling you the diagnosis."

Well, the stories that we heard last night reflect dismissiveness, clinical arrogance, condescending patient-contact, prejudicial treatment, humiliation. That just about brought me to tears then, it's just about bringing me to tears now. The Canadian Medical Association Code of Ethics is something that we should adhere to as physicians. I apologize. I'm nervous as hell.

So there are fundamental requirements that the Canadian Code of Ethics oblige us to uphold. I'm going to read to you the first three fundamental responsibilities. This is number 1, 2 and 3 in our Code of Ethics.

Number 1: Consider first the well-being of your patient.

Number 2: Practice the profession of medicine in a manner that treats the patient with dignity and as a person worthy of respect.

Number 3: Provide for appropriate care for your patient even when cure is no longer possible, including physical comfort and spiritual and psychosocial support.

The stories last night did not reflect that. We as a medical community in Canada are failing our patients, and we as senior physicians are teaching our junior physicians this bad behaviour. We need to not teach our junior trainees this dismissive, disrespectful behaviour, please.

Dr. Gregson suggested that we need science and science and more science. I would add to that we also need care and compassion and clinical competence, please.

So my patient, TS, was started on oral doxycycline and her serology was sent to the State University of New York lab at her expense. Her C6 was negative just as it was in Canada, but she had interesting findings on her blots. And her blots showed that she had a positive IgM, drawn seven weeks after her bite. She had 10 positive bands on her IgM. She had five positive bands on her IgG, but this was declared indeterminate because only four of those five bands were bands that have been arbitrarily defined as being CDC-positive bands.

Faced with this information, our local infectious-disease specialist said, "This is all false-positive because the C6 is negative."

The rationale that was employed to say that Lyme disease had been ruled out: "Alberta's non-endemic. We don't have ticks that carry Borrelia in Alberta."

That's false.

The patient did not specifically identify a tick as the source of the bite. Well, that's common in Lyme disease sufferers. A tick, or observing a tick biting you, is only seen in perhaps 20 to 40, maybe 50, percent of cases. The rash described as "not typical for erythema migrans"-we didn't show it to a doctor. We didn't have picture of it. So, it was dismissed.

The duration of the tick bite was too short to transmit the disease. I hope to be able to address that at some point in the discussion because this idea that a tick needs to be attached for 36 hours or 48 hours is, in my view, foolishness.

My specialist in my hospital advised that because the C6 was negative, we should never have sent those studies for Western blot study. The reported IgM was positive, but because it was more than four weeks after the bite, it should be considered negative and not positive. The IgG Western blot was negative according to criteria developed by the CDC in 1995. I'd love to talk about those criteria. I've got seven minutes left-we'll do that some other time.

And system persistence following her antibiotics means that she probably didn't really have acute Lyme disease. She had something else, probably has Chronic Fatigue Syndrome or maybe she's depressed or what have you.

Could I have slide 44, please?

Oh yeah. We have to provide a little bit of difficulty for the people at the back, I'm sorry.

So, in my view, we're not being helped by the National Laboratory, either. The National Laboratory published their guidelines for the Canadian Public Health Laboratory Network, and here is how the Canadian Laboratory responds to Western blot testing.

"A Western blot that fails to meet all of the criteria set out by the CDC Working Group would be reported as negative."

So if my patient's serology had gotten to the National Lab, because it was four and not five bands positive, according to this, it would be reported as negative. The National Lab specifically does not report band patterns, and this is one of the reasons why we can't rely on a negative report from the National Lab. We have to send the specimen somewhere where we get a band pattern reported to us, always at patient expense. If the National Lab of Canada would simply report band patterns to us, I would be able to abandon that clinical practice.

And when the serologic testing requested for Lyme, the screening test positive, subsequent Western blotting is negative. They will simply report that it is negative. Again, when serologic testing is requested for Lyme and when the initial screening test is positive and the subsequent Western blot confirmatory test is negative, specimen should be reported as negative.

Western blots lose sensitivity over time. These tables come from the product monographs of the IgM blot kits and the IgG blot kit, and it identifies the failure of the IgM Western blot serology after the first two or three months. And it reports the failure of sensitivity of the IgG after about the first year, with an 81 percent sensitivity for the IgM after the passage of the first year, and the upper limit of the confidence limit being in the 90 percent range. So it is mathematically and scientifically impossible for the two-tier test to have a sensitivity higher than 90 percent in people who have been sick longer than a year.

Could we have slide 15, please? Sorry, I blew it-57. Slide 57, please. I'm so sorry. We submitted these slide kits a month ago, and I've done some sorting of how I want to present the data. I'm just wrapping up here.

I think, you know, based on my legal background I think we need to look at the evidence of the presence of Lyme disease with a different lens. And the different lens I think we need to use is a lens that I take, again, from the law. We need to look at cases where Lyme disease is definite. These are the criteria that have been already established by the CDC, where there is clarity that you have a positive two-tier, or you've got a positive culture, or where your spirochetes are observed by a dark-field microscopy, or where you have a single-tier IgG Western blot study that meets all of the criteria-definite Lyme disease.

But I think we need to expand that. And patients like mine, who doesn't meet the CDC criteria, but I think by every lens that you can apply has probable Lyme disease, should have the diagnosis of probable Lyme disease. And I think we should expand that further and say that if people have a plausible cause for Lyme disease, that should be considered as well.

I take that from the Canadian Rules of Law. These are the rules for evidence in the Canadian court system. The preponderance of evidence, the likelihood, that more likely than not, a person has Lyme disease. We take an example that it's in common circumstances right now: OJ Simpson. OJ Simpson was found not guilty by a court, but I think the court of public opinion has identified that he is probably guilty of murder. And that is the type of tests that are used in courts of law. He was guilty when there was a civil trial based on preponderance of evidence. We can talk about the different types of evidence during the question-and-answer period.

So, what should a Canadian framework include? I think we need to include different definitions for epidemiological surveillance and actual clinical treatment of patients who suffer the effects of Lyme disease. We need support for research. We need the government to fund basic research, scientific research, bench research, clinical research. We need to help patients. We need to maintain an open dialogue. I have great respect for people who have different opinions on this than I do, and I acknowledge that my opinions are in the minority. But I think we need to have a dialogue about the ideas in order to move forward.

My patient is doing well. She was treated aggressively for Lyme disease because I believe she had probable Lyme disease for reasons that I talked about. She is doing well. I hope that we can afford this type of treatment to more Canadians and thank you for listening.

And thank you to the girls at the back for flipping the slides around.

Dan: Thank you Ralph. Clearly, you have a friend and supporter in the slide-changer at the back. She's going to get a trophy from you at the end of the day, I know. So thank you for all your great work. Thank you very much.

Our next speaker is going to be Raymond Dattwyler, who's going to be talking to us about lab diagnostics of Lyme disease-past, present, and future. And Dr. Dattwyler is a Professor of Microbiology/Immunology and Medicine, at the School of Medicine, New York Medical College. Please join me in welcoming him very warmly.

Raymond: [01:11:03]

I was hoping there'd be a pointer because I have very complicated slides-that I could actually point out some stuff.

Okay. Thank you.

I have to tell you about my conflicts. I have patents. I have deals with Bio-Rad and Cyagen, and I own a biotech company. So, some of this stuff-the patents are held by that biotech company.

I've been in this business a long time. I actually started doing Lyme disease in the early 1980s and I was on the CDC panel that wrote the two-tier guidelines. I can actually tell you some of the problems with that right now.

So, if you look at the history of Lyme disease diagnosis, well it really started when they found-Willy Burgdorfer and Jorge Benach-people found the organism. And they began to culture it. So you could make crude tests based on cultured bacteria, and you could grind it out and put in on an ELISA plate. And that was really how it started.

But that test had a lot of false-positives. So, you began to say, "How can we make this better?" because the predictive value, the ability of a positive test to predict someone really had it, was poor. So Allen Steere's group came up with what's called the Dressler criteria, which is Western blot criteria. And CDC got a bunch of labs together, and had a contest, and three labs determined that the Western blot criteria actually improved things. The big problem was false-positives. So, the two-tier system was established in the mid-1990s. And we got the C6 later on at the end of the 1990s, and we continued to try to define the proteins and, we call them antigens, of Borrelia burgdorferi.

So, we're still using that criteria that was developed in the 1980s and 1990s. There's a lot of problems with that. First of all, whole bacteria, it doesn't matter what bacteria it is, they contain antibody-binding sites. And the definition of an antibody-binding site is an epitope, so you'll see that term throughout my lecture, that are common to all bacteria. These are non-specific, so you get a mouth infection. Or you get an E coli urinary-tract infection. Got to make an antibody response against whatever organism you're infected with. You can pick that up in those Lyme tests.

The other thing is that cultured Borrelia burgdorferi will lose a lot of the genetic material that it needs to make the proteins. So those early tests that were based on cultured Borrelia burgdorferi, a lot of them became empty bags after a while and they lost their antigen. So they had lousy sensitivity. And the other thing that we realize now is that not all of the important proteins of Borrelia burgdorferi are expressed in culture. Some of them are only expressed in the mammal, whether it's you, or whether it's a white-footed mouse, or whatever. And that is what we didn't realize when this was put together. This does not have in-vivo expressed antigens in there, and it also has cross-reactive proteins in there.

So, we didn't have good definitions of what was in those Western blots. Those are just bands on a gel. So when you look at it, the sensitivity of the two-tier system, as reported, is not that great in early disease, especially. So early disease, you're looking at 30 to 40 percent, and it doesn't matter whether you see six or any of the others. It's later in the course of the disease that these tests get better.

So, another thing that's very important to realize when you do Western blot. Western blot is called a 1D gel: one dimension. You're looking in a band, but if you look at a 2D gel, a 2D is going to pull these proteins apart. Many areas of these bands, there's more than one protein in that 1D gel. And that's important because if you look at just, for instance, 31-some labs say 31-specific-so you got 31 bands, you got Lyme disease.

Well, there's a big problem because that other protein in there, which is expressed in Borrelia burgdorferi is expressed in all gram-negative bacteria. So you have a urinary-tract infection, or with E coli, or something like that, you can have that band, and a Lyme Western blot will pick it up. It's not specific. This gives you an idea of the complexity, which was not addressed in those CDC things.

So, if you look at what's on there. The blue are the antigens associated with the Western blot. You'll notice, some of them I've starred. Each one of the ones I've starred is highly cross-reactive and a protein that cross-reacts with a lot of other bacteria. It decreases the specificity of this assay.

And cross-reactivity-this is some examples. Greater than 40 percent of individuals with no history of Lyme or from places like the desert southwestern United States, will have a positive 41-band. Why? The answer is because all bacteria with flagellas-that's the little tail that wiggles around and makes them move-cross-react. The 60-KD band, greater than 16 percent of normal people, will have positive. That one I pointed out that's BBO 323 is also cross-reactive.

So, what we have is we have a real problem when we use cultured, whole substrates for either Western blots or first-tier assays. And it's an example of flagellum. If you look at the protein, there are parts of it which are highly cross-reactive with all other bacteria flagellum, but there are parts that are specific to Borrelia burgdorferi. And you can use that as a tool, and that's one of the things that we did to try to define, "How can we make things better?"

If we look at P66, which is one of the bands on the Western blot, and this is complicated, we looked at all the different epitopes of it, and they have epitopes which are cross-reactive with people with healthy normals with other diseases, and it's a problem.

And we-I'll skip this one.

So, what can we do? And the answer is, we can look at the proteins of the bacteria that causes Lyme, and define what are the antibody-binding sites that make it non-specific? Get rid of them, and just use the areas where those epitopes are pretty unique to Borrelia burgdorferi. And doing that, we conceptually can improve both sensitivity and specificity.

Now, the first assay that actually did that was C6 assay. C6 assay is an epitope of VlsE, which is a big outer-surface protein that's only expressed in vivo. And it is pretty good. Probably the best single test out there, although it's not perfect. One of the things, it doesn't bind IgM very well, and VlsE, the parent protein is not expressed until after the establishment of infection. So, the human immune system doesn't see it straight away. It takes a while to see it. And people like that.

That's too complicated-that's too complicated. I'm doing this. I'm skipping slides because I want to keep in the time limit.

So, what we can do is, we can use peptides containing epitopes that are specific for Borrelia and try to make a better assay. And in fact, we've done that and right now, they're in trials. Bio-Rad, which is a big pharmaceutical company that makes a lot of tests, is putting together a study so they can take it to the FDA and try to do it.

So, no matter how good we make serologies, there's certain problems. It takes time to make an antibody response. So, you get bit by a tick, I draw your blood, you haven't got antibodies. First, you make IgM, and that takes a week before you start getting a lot to measure. Then you make IgG and that takes another week. The other thing too is that once you make an immune response, especially for IgG-you have a mature immune system-you can keep that forever. So, antibody levels do not correlate with treatment outcomes. You'll be seropositive for the rest of your life, and it doesn't mean you're still infected. It just means you're what? It means if you had mumps when you were five-I draw your blood, you have anti-mumps antibodies. You don't have mumps, you had it. So that's an important thing.

And another aside, after treatment, your tendency is-and many people, for those antibodies to fall away, but it's not predictive of anything. So, some it does, some it doesn't. That's why when you look at those studies from those package inserts, those were all treated patients. And most of them were erythema migrans, and they're fine, and it's not very predictive of anything.

So what else is out there? I can say we got a better serology coming. It's more sensitive in early disease, it's more specific, but it's still not the end. Metabolomics, Borrelia burgdorferi changes how your body utilizes certain things and that's a possibility. Transcriptome analysis, that's your immune system response to anything-is there unique markers in your responses that can do it? That's something. And these are really early-stage.

The other thing which I'm involved in is monitoring T-cell activity. When you make an immune response, you make antibody, that's B-cells, but you also make a T-cell response. And that's commonly used in TB and things. So, what are the advantages of T-cell responses? And this is more primitive work. Well, you get an early response, you can measure it faster than you can make an antibody response, and T-cell responses wane with successful treatment. So, the number of T-cells that are responding is dependent upon the presence or absence of infection. We know after a successful outcome, the number of activated T-cells contract and we can measure these substances called cytokines, which are proteins or substance that released by immune cells, and that's how they communicate. You can measure them.

So this is something we just published and it's based on what's called QuantiFERON technology. QuanitFERON is a TB test, and you measure the amount of gamma interferon, which is a cytokine produced by activated T-cells in response to an antigen. And like the B-cell stuff, we don't use whole proteins. We use peptides. We mapped the T-cell recognition sites on these proteins, too. And that takes a while. And this is an example of how you do a cytokine release assay. You just take some whole blood from a patient, incubate it overnight, spin it down, and measure the amount of gamma interferon or other cytokine we're working on other cytokines, too. And then you can then begin to get a picture of immune response.

And these are some of the target peptides from these target antigens that we used, and we specifically, again screen out highly cross-reactive T-cell epitopes. And this is a preliminary study which was recently published in which we took 29 patients, all with erythema migraines, and so these were very early patients, and what we saw was a fairly typical picture. Twenty-three had single erythema migraines, six had multiple erythema migraines-the usual things that you would expect to see in someone with an acute infection. And unfortunately, none of this is specific for Lyme except for the erythema migraines.

And then when we looked at the gamma interferon, what we found is that 69 percent of them were positive in this assay. That's much better than the serologic assays. At convalescent, we didn't get everybody back, but what we found is after two months, we had a marked decrease in the number of positives in that population. And everybody was treated and did well in this, so, all of these 29 patients were promptly treated and they're all well. And they were well at their two-month and six-month follow-ups.

So that is something that we're optimistic about and we ran C6 and Western blots on the same patient population, and it's clearly better than the C6, and it's really much better than the Western blot. The Western blot is something that was put in place, again to help get rid of all the false-positives that you have with whole Borrelia assays. And that is something that's a problem, that it was recognized at the time. But I can say, one should not do Western blot just by themselves because Western blots have their own problems. Everything has its own problems, and what we need, I think, is more basic science research, more support to get things better, but as scientist, and that's what I consider myself, I can tell you I am trying to make things better as are lots of other people. And the amount of progress that's been made from the 1980s to now is dramatic. And it's only with funding of research that it's going to get even better.

Now, you'll note I haven't talked about late Lyme disease. As Brian Fallon pointed out, it's hard to get those patients, because you need-to do these studies, you need extremely well-characterized patients, because it's too easy to make mistakes. When you're dealing with patient populations, you don't want to make mistakes. We do with the best intentions, and in the 1980s and 1990s, we were doing the best we can. But it's time, I think, that we start to move on from that 1980s-1990s technology, and to modern technology.

But the only way of doing it is not just-I think this is a good idea, you've got to understand how the immune system works and interacts with this infection, you've got to understand the bacteria, but that takes money. And for a while the NIH in the States, four years ago, they were only funding 8 percent of the grants. So, the politicians out here have to realize, you've got to spend some money. I'll stop there.

Dan: Thank you very much, Raymond. Our last presentation is going to be provided to us through WebEx. It'll be on Lyme disease diagnosed by alternative methods and similar syndromes, research approaches to take us forward. And that'll be given to us by Dr. David Patrick, who is a Professor and Director of the School of Population and Public Health at UBC.

Dr. Patrick, are you online and can you hear us? Operator, please.

Operator: [01:30:49]

One moment, please.

Dan: Thank you.

We will be taking a health break following this presentation.

Dr. Patrick, are you with us?

Operator: He'll be with you shortly.

Dan: Thank you.

Operator: Please go ahead, Dr. Patrick.

Dan: Dr. Patrick, welcome.

David: [01:31:13]

Thanks. Good morning.

Dan: The floor is yours, sir.

David: Okay, how do I advance the slides here?

Dan: Sorry. Say again?

David: I'm looking for a control to advance the slide-oh, I think I see it.

Okay. Good morning, everybody. I want to start by commiserating with any fellow West Coasters who got up at the crack of dawn to join the meeting and by thanking the organizers for getting us involved.

I have no commercial conflicts of interest with laboratories or pharmaceutical companies, and my research is funded by CIHR, NIH, and foundations.

I think I like the tone of the meeting so far. We're fundamentally here because people are feeling sick. There's no question that we have an epidemic of an illness that is debilitating a lot of people and we have to get to the bottom of it. And I think that's appreciated on all sides of this discussion.

I'm a big fan of Louis Pasteur. Now, he was the father of medical microbiology, and he said we shouldn't be justified in devoting further time to opinions which are not supported by serious experiment. Meaning, you have an idea, you test it, and if the idea doesn't quite work out, you move on to the next thing. And using that strategy, at the tail-end of the 19th century, within 20 years, 18 plagues that had harmed mankind for millennia were elucidated. I'm talking about TB, leprosy, typhoid, and so forth. And really, Willy Burgdorfer followed in this fine tradition of Pasteur's.

Now, we've heard from Dr. Fallon, quite accurately, that there are scientific problems with imperfect case definitions. So when we talk about a broad group of people with Lyme disease, or any other label really, it's possible that there could be several groups of people sick for different reasons within that grouping if we're not careful. And that imperfect case definition leads to the research problem of misclassification. It's like having apples and oranges in a fruit bowl. And that makes it harder to find differences between sick and healthy people. It also makes it harder to find good tests. And it makes it harder to test treatment options.

So, I've heard from Dr. Hawkins, he agrees we have a definite or undisputed Lyme disease category where even using standard reference testing and rock-solid clinical criteria-that's what we've got. Dr. Fallon's done a lot of work with people who are so diagnosed but who had long-term symptoms afterwards. The Post-Treatment Lyme Disease Syndrome grew. But I need to speak a little bit about what's going in the northwestern part of the continent where most people coming forth clinically have been diagnosed on clinical grounds alone supported by alternative tests, the validity of which is questioned by major reference labs. We'll call those alternatively diagnosed Chronic Lyme Syndrome just for now.

So, back to Pasteur, I have to agree with Fallon and Dattwyler, that what would he be doing if he were alive today? He'd be doing metagenomics, (indiscernible) sequencing for microbial discovery. He'd probably be spending a lot of time figuring out what's going in the gut microbiome as well. He'd be doing this post-gene expression thing, the transcriptomics that Dr. Dattwyler's talked about. He'd be looking at altered genes, the science of epigenetics. And he's also be taking a look at different ways to study antibody expression in the immune system. Basically, our research is using three of these: the metagenomics, the transcriptomics, and immunosignature assay to begin to get better ideas about what may be going on with Chronic Fatigue Syndrome and with people who have alternatively diagnosed Lyme.

Now, I had the pleasure of meeting Lyme advocates in BC back in 2010, and they put forward three main things to me: that Borrelia bacteria were everywhere in ticks in BC with plenty of strain variation, that specialty labs do a better job of finding Lyme disease than reference labs, and that people need more antibiotics than they get. Well, we all are going to discuss our different readings of the literature, but I can see well-designed studies that have refuted those findings, at least in the BC setting. But that doesn't change the problem, which is that we're still looking at large groups of ill people.

So, for example, in BC not only do we pick up a thousand ticks off healthy people or people who are ill, who've had ticks identified on them, we pick them up in the wild. And when you're looking for Borrelia there, you use a reference PCR primer that picks up the whole genus, basically. And we've tested it, and it'll pick up mayonii and that sort of thing. So that's what we do. We only get Borrelia in one in 200 ticks in the Northwest, which is way, way lower than what you've got in southern Ontario or Nova Scotia or down in Connecticut, right? So, it's important to bear in mind that we are looking at a different epidemiology out on the West Coast.

I also wanted to elaborate a bit on why a lot of the medical profession, the majority of Dr. Hawkins' CMA folks have difficulties with the alternate lab testing. I have to thank Dr Fallon for his forthright publication of his extramural evaluations of specialty labs in the States because it was clear that these specialty labs are actually not better at finding Lyme disease when it was there, and we had one specialty lab that used in-house interpretive criteria for Western blot that diagnosed fully 57 percent of healthy people, 23 out of 40 healthy people as having Lyme disease. Of course that's the approach. That has been used by most people seeking alternative testing on the West Coast.

So what does this actually mean? This is the second slick figure you see. This-in BC let's say you got a hundred testing for Lyme disease, about 2 in a thousand test positive by referenced methods. Let's bump that way up to 10 in a thousand, for those of you who think these methods are to insensitive. One percent, that's this green person here. And that person's going to get picked up in probability by the alternative lab and it will also get picked up by the reference lab. Or according to Dr. Fallon's paper, for the most part. But the problem's this. You get 57 other people out of those 100 who are given a false-positive result for Lyme disease. That means two things. It means that your positive predictive value-your likelihood of actually having the disease if you've got that test positive in your hands-is less than 2 percent. It also means that this test was registering fully 57 percent incorrect results. So, if you want to save your money in terms of a test like that, you could flip a coin and get 50-50 results and actually get more accuracy.

So our concern and mine is that, as infectious disease epidemiologist, is that these tests are solid in the States for profit. The labs that have produced them will sponsor meetings attended by advocates. Advocates are sometimes more likely than to suggest mentioning the alternative test to people. More people might get the test, and then predictably, a few people with Lyme-this one person here-are joined by very many with a false-positive test. What does this do in terms of public perception? It vastly amplifies the perception of disease burden, individual risk, and, potentially, the demand for the test. In this we've got ill people, we want to get to the bottom of what's going on, but who benefits from this positive-feedback loop? Think about it.

I've also heard that one lab that was offering this kind of testing has changed its tune, doing things differently. But I also need to say that any Canadian lab reporting with this much error would be required to issue recall warnings to its clients, even if it did move forward with a change to the testing platform. And so, I agree with everybody. We need to keep it real here in Canada. We don't want to lower our standards by going with untried technology.

Now, diagnostic misdirection has its risks: delay in finding underlying cause, and we've seen that with MS and cancer, risks associated with certain treatments. All treatments have risks and you only want to take them when they're clearly a benefit. But I think also we're seeing the potential for exclusion from involvement in research that may come up with a better answer. Right now, there's a lot of investment going on by NIH and CIHR in Chronic Fatigue Syndrome, and so forth. What we need are similar efforts to bring in people who have had a diagnosis of Lyme by any methods.

I also think that this is a challenge for advocacy groups. I take my hat off to CanLyme for helping people be more aware of the emergence of Lyme disease in areas of Canada where it's come in, particularly southern Nova Scotia and southern Ontario. But I think you've also done a great job of indicating that we've got a large bunch of ill people here and bringing political attention to it.

But you also, in my opinion, have to say, "Well what if some of those people don't actually have Lyme disease? What if that's not the answer?" We've got to dig a little bit deeper to be sure that we understand what's going on with everybody. And I think we've got a heterogeneous mix here as some of the other speakers have talked about. So, is it more important that we be perceived as correct or that we find a better answer for some of those we represent?

So why would we research Chronic Lyme Syndrome or Post-Treatment Chronic Lyme? Well, people are sick and disabled. I understand the outrage and skepticism. I've seen what people are going through. But disagreement on cause should not cause people to be selected away from studies.

So, we've done a little bit of pilot work here in BC, not large studies, but trying to get into the "-omics" revolution with Chronic Fatigue Syndrome, with a group of alternatively diagnosed chronic Lyme. And I have to tell you, we looked very hard. We turned over the books in clinics for Post-Treatment Chronic Lyme in BC. And not surprisingly, in an area where Lyme disease, objectively diagnosed, is somewhat low prevalence, they were hard to find. So everybody went through a detailed clinical assessment, reviewed for case definitions, and consented for the study.

And it's really important-I'd like the press to take a look at this. Take a look at the Karnofsky score on the left-hand side there. You're looking at alternately diagnosed Chronic Lyme and Chronic Fatigue being down around 60. That's a level of disability that is not compatible with being able to work at a full-time job.

And these were ambulatory people who are able to come in. There are many people who can't come in for studies because they're too sick, so the physical disability was really clear. But all of these other scales, mental-health scales, actually didn't distinguish very much between people-arguing against the idea that this would be sort of in people's heads.

We did take a lot of time characterizing people with Chronic Fatigue and alternatively diagnosed Lyme. Every aspect of aspect of the history and physical exam, their lab testing, and they were very, very similar. And we also found that no patient diagnosed with Lyme disease by alternate methods could be confirmed by any form of reference testing, not just North American Western blots, but Western blots for European strains, a whole array serology for other tick-borne diseases. So, it's still worthwhile trying to find out what could be going on.

Now, those of you who are going to be skeptical about the reference test will say, "Well, the alternate test could be false-positive. That's right Dave, but couldn't the reference test be false-negative too?" So we sort of looked at those probabilities. As we pointed out, positive predictive value of only 2 percent with the alternative test based on Fallon's published study, and prevalences in the test population in BC would mean that 98 percent of the time with an individual test, you get a false-positive. So 98 times 98 all the way out to 12 times is 78 percent. It's pretty likely that we have a false-positive result explaining these findings.

But what about the reference test false-negative? Let's give Dr. Hawkins his idea that the reference test is only 40 percent sensitive. So, 60 percent of the time, if that's the case, you're going to come out false-negative. Well multiply.6 12 times, you get 0.2 percent. So it's not very likely, and in fact, it's 350 times less likely than the alternative test being false-positive.

So, where do we go from here? Metagenomics is the science of high-throughput sequencing to look for organisms in tissues. For example, we worked in blood, and I think you could well argue that we should be looking in a lot of other tissues in terms of future study. You've got to isolate the nucleic acid, you've got to run it through these sequencers, you get the data files, you've got to get rid of junk reads, you've got to get rid of the human reads, and then you can make comparisons between patients in terms of what can be found in the bloodstream or not. So, in our hands so far we're finding no big differences in blood, but that's probably not a big surprise to anybody here. It's just a preliminary foray.

Of more interest, particularly following what Dr. Dattwyler said, we're working with the Chiu Lab in UCSF on the transcriptomics, and this is the lab that has found and published a transcriptional signature for acute Lyme disease. I hope some of you saw that, but early on, you've got 1,200 differentially expressed genes which, again, might be a way of diagnosing Lyme even before serological tests can become positive. But I did get a report from Jerome Bouquet that basically none of our alternatively diagnosed Lyme people had this transcriptional signature.

So, once again, we may have false-positive diagnoses at least in BC. In the same hand, so we've been looking for differential expressed genes in Chronic Fatigue in healthy folks. Not finding a great deal yet, but we're still not done yet with all of the analysis.

I think one of the most promising technologies are these peptide arrays that allow you to take a look, not just at individual antibodies, but there's actually 320,000 peptides sitting on one of these chips. And it allows you to get an idea of the array of epitopes to which your antibodies are expressed. And we're finding interesting clustering within a Chronic Fatigue Syndrome group and beginning to get together with other groups to see if that's common. And we want to take a look to see if it could be common with some of the folks with alternatively diagnosed Chronic Lyme.

But where do these things really need to go? Well beyond small pilot studies, of course. We want to see multi-centre efforts, and something should come out of this meeting and in the way of a research agenda in that area. We need new cases to be identified within our large, population-based cohort studies. I don't know how many of you know, but we follow 150,000 Canadians, prospectively, for the development of cancer in Canada and the Canadian Partnership for Tomorrow. They have biobank specimens at baseline, and within this group, lots of people come down with various different illnesses: diabetes, Crohn's disease, indeed Lyme disease, Chronic Fatigue Syndrome. So, it's possibly actually with those biobank specimens within these studies to draw much better inferences about causation, pathophysiology, and so forth, for things that have been a mystery.

And I think, ultimately, what we want to do is make sure we invest properly in those things, and we do all kinds of the appropriate bio-banking, and you'll have ideas about the sorts of things that you'd want to see bio-banked. But not just blood, stabilized RNA, stool, hair, all sorts of things.

I'd like to just conclude by saying, really, if there's a consensus that solving problems for patients is more important than anything else. And I am reading that in absolutely everybody I've heard from, and it's far more important than our current complete agreement on theory. Then we'll increase the likelihood that the future research and care will be better than the past. And I'd like to basically conclude by thanking all of the study participants. It took a lot for the folks with alternatively diagnosed Lyme and Chronic Fatigue Syndrome to get in and to put their time in. It made a big difference. It took a lot of people to put together a research team and a lot of help from a lot of labs in order to get everything accomplished. And of course, this is where we hang out, and we hope to see any of you out there this summer or next winter.

Dan: Thank you very much, David.

Ladies and gentlemen on WebEx and in-person here in Ottawa, I'm going to invite you to take a 20-minute break.

Je vous invite à prendre une pause de 20 minutes.

We'll be starting, by our clock in this main room, at 11:15 in 20 minutes.

Je vous invite à prendre une pause de 20 minutes.

I will ask the speakers to be available at the front table. Thank you.

And David, we'll come back to you online.

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