Dr. G Wormser: Well Good afternoon Panel. Thank you for inviting me and I am, I was the past chair person in the 2006 IDSA guidelines and Chief of the infectious diseases of US medical college since 1981 and I am vice chairman of the Department of Medicine and I am founder and Medical Director of Lyme disease diagnostic started in 1988. My talk today is going to encompass these three areas and some background information on the 2006 IDSA Lyme disease guideline, our discussion of some of the recommendations in the guidelines and a comment from me on whether revisions are required and perhaps in miscellaneous. First of all these guidelines were directed to Lyme disease in North America as you can see from this slide the Lyme disease in Europe is so much more -- a bit more complex it is associated with more species of Lyme Borrelia and slightly different clinical manifestations and some issues have been touched on related to differences in diagnostic approach.

In comparison to the 2000 IDSA guideline, these were the differences we advised treatment of selected ticks and as that’s been discussed and we added treatment for Acrodermatitis chronica atrophicans and borrelial lymphocytoma those are European manifestations, [Indiscernible] [0:01:47] that in because people may travel back and forth to Europe and we felt that we should at least cover that somewhat, we had advised on clinical assessment, we added a formal definition of Post Lyme disease syndrome for purposes of potential research study, we tried to understand better what’s going on with regard to Post Lyme Disease syndromes which has been a topic of great interest to the group, we also added guidelines for the diagnosis treatment and prevention in Human granulocytic anaplasmosis and babesiosis because these are well documented infections that can be transmitted by the same deer tick.

The 2000 guidelines had panel had 12 authors, 2006 guidelines had 14 authors and 16 consultants as this been alluded to by others that’s kind of increasing size from 15 pages to 45 pages including the 8 pages devoted to Post Lyme Disease symptoms and the question of persistence or not. The reference list swelled to 405 from 99, this was the current 2006 guidelines panel. You can see that there are quite a number of new panelist added. You can see Dr. Steere was a panelist to describe this illness and he has done continually extra research in the area, we had investigators from all three of the Post Lyme disease treatment [Indiscernible] [0:03:31]. Although we didn’t have Dr. [Indiscernible] [0:03:33], we did have Dr. Dattwyler, who was a co-investigator and coauthor of that study, we had Dr. Klempner of course he did two other personal investigator two of his studies and you can see that the people on that panel are highly regarded with regard to their experience and research productivity in the area of Lyme Disease and other related tick borne infections.

We recommended basically a 10 to 28 days course of antibiotics simply with either one of those three oral agents listed Doxycycline, Amoxicillin or Cefuroxime or one of three Parenteral Agents Ceftriaxone, efotaxime or Penicillin. The vast majority the recommendations regarding any manifestations of Lyme disease those particular antibiotic was favored, the evidence through the quality of evidence that we relied on was basically what has been the standard for other guidelines produced by IDSA level one evidence for example required at least one properly randomized control part and of course you are very familiar with level two and level three, with regard to this specific recommendations, we recommended Doxycycline 200 milligrams single dose as a potential therapy for selected tick bites, level one evidence and we recommended 14 to 21 days course of antibiotics with an average duration of the 14 days as a standardized the recommendation but the range could be 14 to 21 and even 10 to 21 if we used doxycycline for

which there are at good data. Level one, granule nerve policy, level two to three, we don’t have many systematic studies of granule nerve policy, especially in North America it’s hard to get level one evidence for that particular indication, Managiatias level one evidence Cardiatias level three again we have so few cases the Lyme disease cardiatias its very remote which you are going to see high level one evidence for that particular manifestations. recurrent of arthritis level one evidence for recurrent arthritis again not that common a condition a refractory arthritis as you heard from Dr. Steere again not that common enough condition that’s likely to be randomized double mind perspective studies.

Late Neurologic Lyme disease again extremely rare in this day and age. Post Lyme disease syndrome level one evidence. Now the guidelines specifically states that it’s important to realize that guidelines cannot always account for individual variation among patient, they are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA considers appearance to these guidelines to be voluntary very explicitly stated you can’t miss them – can’t miss that statement you might have missed this statement though which we think was prominently placed in the guidelines regardless of the clinical manifestation of Lyme disease complete response of treatment may be the delayed beyond the treatment duration study after, study after study has shown this, relapse may occur with any of the regiments, patients with objective science of relapse may need a second course of treatment, we only recommended unlike a many of the ideas and guidelines we only recommended generic drugs that are no longer under patent protection and short courses, we recommended against extremely prolonged or multiple repeated courses of therapy, we only recommended generic 2-tier test and did not recommend any particular serologic test or test kit , we did not even comment on use of a commercial vaccine since none exist since 2002.

Now I would like to talk about symptoms that occur in patients with Erythema migrans for example our other manifestations of Lyme disease after conventional courses of antibiotic therapy, now one of the problems in the studies of this question and you can see how much how important this question is with regard to the discussion that has occured today, all the studies they had controlled groups, helped the control groups or a retrospective studies that have been published up to this point of time, when the, and the older studies by and large in which the diagnosis and the treatment of the patients of Lyme disease would not need current standards, but any way I want to show you the frequency of symptoms. Here is a study of n=160, and n=167 and n= 212, 15 percent fatigue, 16 to 18 percents of headaches, 27 percent to 24 percent joint pain or muscle aches 19 percent, Paresthesias is 13 to 19 percent, concentration problems up to 13 percent these are in occupations for Lyme disease, these were the healthy control in the study it’s important to point that out.

So consequently the question comes up how do you meaningfully address whether patients who would have Post Lyme disease symptoms with benefit from an additional course or courses of antibiotic therapy and then Dr. Klempner in a study that’s been discussed studies two studies that have been discussed in quite a bit of detail here to find for his study that Post Lyme disease syndrome had to have an objective clinical manifestation of Lyme disease such as Erythema migrans that was treated with antibiotics. The patients then had to have or develop subjective symptoms that interfere with functioning in particular musculoskeletal pain, cognitive impairment, radicular pain, paresthesias or dysesthesias. Fatigue was not a criteria in that particular study but almost every patient had severe fatigue, symptom on set within six months of

the original diagnosis, these objective symptoms had to begin within six months of the original diagnosis and persist for at least six months and they had to interfere with function, so important to point that out because in many studies and including the study I have the largest study of culture confirmed patients with Erythema migrans that we have been following now for over ten years of large cohort over 200 such individuals, unequivocally diagnosed by culture and I can tell you that these ten percent of patients who have these subjective symptoms that, that we find in this group year in year out there are not functionally disabled by any means and the fact that’s one of the reasons that it was so hard to recruit patients for this study that the majority of the symptoms there are associated truly with having had Lyme and getting treated are not functionally disabled for the majority of the patients that we see at least not that they can’t be, they can be but it’s an important comment because people make much of the fact that the patients will refer to these studies and have obvious functional pyramid but in a sense its circular reasoning and any way as you know the outcome of this study was that, by the third of patients in the antibiotic therapy groups improved, about a third stayed the same and about a third worse and it was no benefit.

Now somebody -- some have said and I know we are not suppose to try to rebut speakers, but some of things that Dr. Fallon said I would be happy to try to rebut it some point with regard to the issue the team as a mission and I think it’s a little this ingenuous to say that Dr. [Indiscernible] [0:12:08] paper sort of reluctantly concluded that the ticks shouldn’t be treated with IV antibiotics because even in the abstract they said because fatigue and non specific symptom was the only outcome that improved and because treatment was associated with the adverse of that this study does not support the use of additional antibiotic therapy with Parenteral receptor action in post treatment persistently fatigue patients. I don’t have to -- what could be more clear cut from the authors of this study that they didn’t feel the risk outweigh the benefit outweigh the risk. Anyway, in regarding the [Indiscernible] [0:12:45] study this is the really then a very crucial part of the study that’s underemphasized, it in the great detail that I mean the congress study tried the great attempts that the congress study made that tried to document persistence of infection by PCR and culture during the course of that study, on multiple occasions in the volunteers and in no case was there a positive PCR or culture. So I have to say that I was I think Dr. Weinstein talk was very insightful, because what is are or the explanation the Post Lyme Disease symptoms? Well as Dr. Weinstein has so elegantly said maybe it’s the same is the medically that mean the medically uncertain symptoms that are occur in the general population may be it’s the same as the Post infectiously grow that occur with less now or was fever virus or Epstein-Barr virus.

Clearly a lot of the post infectious equally have one thing in common, they all in general the sickest patients really key donors are the most likely to have the Post infectious subjective symptoms equally and that’s an interesting potential clue. One study on Lyme disease in particular suggested the pre infection emotional state affected the outcome, Co-infection is a possibility and in fact in one study with a untreated patients with in babesiosis there was more evidence of fatigue greater than six months in patients who had Co-infections with the babesiosis is compared to those that had Lyme disease alone.

However none of those patients with babesiosis received any treatment for and I can say that the Post Lyme disease treatment studies of pulmonary look carefully for evidence of Co-infections it

couldn’t explain the symptoms on that basis and in fact given the duration of the symptoms it would be very unlikely.

What about the animal studies you have heard comments about these animal studies then they might refer you to a recent review that I help to write on the subject first of all the animal studies for whatever their worth and they may be important have variable results some of the so called antibiotic failures were based on PCR and serodiagnosis, not culture and not clinical point, mind you in the transmission experiment where they transmitted the viable, but not culturable Borrelia post treatment to skin mice [Phonetic] [0:15:41] that are very susceptible for developing [Indiscernible] [0:15:44] and inflammatory clinical manifestations, none of the mice [Phonetic] [0:15:47] had any evidence of information or clinical manifestations.

A very serious not to be ignored from the point of view in fact of these doctors is that pharmically dynamic issues were not considered in any of these treatment sector or not considered adequately. In the relevance to Post the Lyme disease or Post Lyme disease syndrome was really not established as Dr. Feder wrote with 28 other co authors in a New England Journal Paper about chronic Lyme diseases which I think the panel should read they have it later is that a central question is not whether few spirochetes might might persist after antibiotic treatment but really whether clinical disease can be attributed to their presence. What about persistence of Borrelia burgdorferi in humans after antibiotic treatment, well in US studies numerous once existed do not demonstrate persistence like with two clinical trials.

For example the few reduce suggest persistence or either unconfirmed or when tried to be confirm they actually couldn’t not be replicated on multiple occasions it’s very important as you read the literature in this area and undoubtedly you have learnt, you have a lot of literature to think about PCR and culture essays can be false posses isn’t it, even culture well documented we’ve had false possess even in our laboratory, we play the most experienced laboratory in the country in doing cultures. PCR well documented you should obviously look to see whether the PCR used multiples that whether they sequence the [Indiscernible] [0:17:36], whether they tried to amplify multiple targets to see how convincing the results really are, was re-infection excluded as was brought up by one of panel members and it was a question.

Strain, but Borrelia burgdorferi should be the same right we have that can persistent infection the initial strain in the follow strain should be the same, this is my conclusions which they weren’t in the study that was cited and one of the stage that was cited, it is not been established that the frequency of Post Lyme disease symptoms exceeds that in general population that may seem surprising that this panel given the arguments that have been discussed here about the whole subject in fact there are two prospective studies now, two prospective studies they have now included control tips one is published, one is in press, neither one showed that the frequency of this Post Lyme disease subjective symptoms exceeds out of control groups, healthy control groups. Incredible scientific studies have failed to find evidence of residual Borrelia. burgdorferi, I have to emphasize the word incredible and reproducible and confirmable that failed to find evidence of residual Borrelia burgdorferi infection post treatments, especially in North America and treatment trials have shown potential harm without sufficient benefit to justify for longer repeated courses of antibiotic therapy as indicated by all the authors of these studies so what is my comment I may need to update or revise the guideline this may surprise you I can [Indiscernible] [0:19:12] there be an update after three years and I can tell you where nobody’s mentioned it.

In the babesiosis section there is an important article that came out about the importance of the little bit longer therapy than we recommended for patients who are highly immune compromise with the babesiosis at least six weeks of treatment is recommended now and if you are going to tweak the guidelines that would be an area to consider. Thank you very much.

Dr. Baker: Thank you Dr Wormser questions now from the panel. Dr. Lantos

Dr. Lantos: Still on some of our speakers today in particular Ms. Garcia and Ms. Johnson have well articulated that very strong feelings on patients who suffer chronic symptoms and the people they represented their organizations and my perception has been that irrespective of recommendations either respective of scientific truth these groups feel alienated by the content and the language of the guidelines. What’s your feeling about them as a diplomatic tool as a communicative body as oppose to just a clinical guideline and you think your language can be modified in future, iteration of the guidelines.

Dr. Wormser: Yes. How is that?

Dr. Baker: Well just making a comment as somebody who got a degree in English for example one of the criticism of the guidelines today was the use of the word vast majority and that percent cited was two thirds, I always thought that you never needed to exaggerate when you were using a percent you did need to modify of just said majority if it’s more than 50 percent it’s a majority and then you can list the number and make your own decision.

Dr. Wormser: Well also I have been you have one side of that two thirds.

Dr. Baker: Sure.

Dr. Wormser: You hear my side whether what we thought the percentage was.

Dr. Baker: And so.

Dr. Wormser: We wouldn’t have used two thirds as vast majority as a rule.

Dr. Baker: So what would you.

Dr. Wormser: 90 percent.

Dr. Baker: Okay and are there other questions I know it’s been a long day panelist, but I can’t believe you’re out of questions, I guess I will have believe it and I have heard from a couple of our panelist Dr. Wormser said that they like to recall other people for questions, other our presenters who are still here so thank you very much for your presentation and don’t leave the room.