Dr. Baker: Thank you very much and we will go on to Raphael Stricker, is it Stricker or Striker.

Dr. Raphael Stricker: It’s Stricker.

Dr. Baker: Okay thank you.

Dr. Raphael Stricker: Thank you Dr. Baker my vision isn’t as good as Dr. Philips I am going to try to use my computer to read my slides and I will try to press both buttons at the same time. So I am the past President of ILADS and I want to thank IDSA for inviting me to speak here today. My mission is to review the problems with diagnosis and treatments of Lyme disease in the IDSA guidelines and I am going to be covering four topics, it’s a good thing I have this one is the laboratory diagnostics, test requirements and restrictions on the use of clinical judgment in Lyme disease, the second is the impossibility of persistent infection in Lyme disease, the third is the challenge to early Lyme disease treatment duration and finally challenge to late neurologic Lyme disease treatment and to just give you an overview and several of the panel members including Dr. Medoff as well do you think these guidelines just need a little bit of tinkering or do they really need extensive revision and I think that the message that these guidelines give are shown on this slide, Lyme disease is easy to diagnose, Lyme disease is easy to treat, persistent infection falling short course antibiotic therapy is "highly impossible" and also the alleged danger of prolonged antibiotic therapy in patients with Lyme disease and I think that because the guidelines give this message they really need an extensive overhaul to change that message. So first let’s go to the challenge to the laboratory diagnostic test requirements and restrictions on the use of clinical judgment and the guidelines take clinical findings are sufficient for the diagnosis of erythema migrans but clinical findings alone are not sufficient for diagnosis of extracutaneous manifestations at Lyme disease. Diagnostic testing performed in laboratories with excellent quality control procedures is required for conformation of extracutaneous Lyme disease, so let’s look at how these laboratories are doing with their testing for Lyme disease.

A study by Bakken et al published in 1997 comparing interlaboratory variation among five hundred and sixteen participants in the Wisconsin State Laboratory of Hygiene, College of American Pathologist, Proficiency Testing Program reached the following conclusion. Our data indicated that the sensitivity and specificity of the currently used test for Lyme disease are not adequate to meet the two tier test approach being recommended and because of the poor performance of these tests the study went on to say in conclusion our result suggest that stronger measures needs to be taken by the Food and Drug Administration to control the quality of commercial available Lyme disease and right on queue a study by Brown et al published in 1999 from the Food and Drug administration reviewed studies of Lyme disease test performance published through 1998 and reached the following conclusion. Given the result seen with different manufacturers test kits interlaboratory results predicatively show poor agreement, a testing for laboratories which used either IFA or ELISA indicated that neither interlaboratory or intralaboratory testing were reliable so to back this up a study from a

Hunfeld et al published in 2002 involving three hundred and thirty seven microbiology laboratories in Europe reached the following conclusion. Quantification of test results reporting of specific and blot band showed high variability, moreover for some assays a high number of false positive and false negative result, test result were reported by the participants. In view of our results further standardization of Lyme disease serology is not just desirable but it’s urgently needed, moreover stronger criteria for the validation of available test kits must be applied and finally a review by Stricker and Johnson published in 2007 of North American case control studies of commercial two tier Lyme testing reached the following conclusion.

The two tier testing system endorsed by the centers for disease control has a high specificity ninety nine percent and yields few false positives but the test have a uniformly miserable sensitivity fifty six percent, they miss eighty eight of every two hundred patients with Lyme disease. An updated analysis including more recent studies found that the sensitivity of the two tier test system was even worse at forty six percent and this sensitivity is far below the ninety five percent cutoff required for an accurate diagnostic test and much worse than the ninety nine point five percent sensitivity of commercial HIV testing and to show you this in tabular form, these are the studies included and I want to point out that they were all studies after 1993, they did not include the older ELISA and IFA test that were referred to by previous speaker, there were eight studies involving four hundred and thirty five patients and nine hundred and fifty one controls as you can see from the slide the specificity was great ninety nine percent but the sensitivity was very bad forty six percent inadequate for a diagnostic test.

Now you have heard from previous speakers that this testing the two tier testing maybe good in certain stages of Lyme disease and this is a version of a previous slide that look much nicer before from Dr. Johnson that was presented at the [Kadian] Lyme Consensus Conference in 2006 and you have heard that in the late Lyme disease the two tier testing does a lot better, ninety seven percent, a hundred percent sensitivity in late arthritis related neurologic disease. But as several of the panel members have commented there are some problems with these results. One is that this is a very small number of patients thirty three patients with arthritis, eleven patients with neurologic disease and there is in fact circular reasoning in this type of study which was admitted by the authors of the study who sad that for a late disease the case definition requires at least one late manifestation and laboratory conformation of infection and therefore the possibility of selection bias toward the act of samples cannot be discounted so there is this kind of circular reasoning that you need a positive test to be included in this group and then the test has a hundred percent sensitivity.

So now this slide also presented by Dr. Johnson at the Canadian conference shows very eloquently all the problems with two tier testing, its insensitive in a QDM and possibly in early neurologic disease lacks antigens expressed only in mammals, its complex technically demanding and costly, its hard to standardize reading western blots requires judgment and experience, western blots are only semi quantitative, faint bands are difficult to interpret they may require two blood samples, appropriate use of IgM blots requires knowledge of the date of disease onset and IgM blots are less specific than IgG

blots and some labs are inexperienced in properly setting blot development cutoffs and all of these problems are reflected in, you know different way on a PC, in this statement from Aguero-Rosenfeld and colleagues you said relatively few studies using currently available commercial tests have evaluated the performance of the recommended two-tier testing on well-characterized sera from patients with extracutaneous manifestations of Lyme borreliosis. Comparison of sensitivities and specificities between studies is difficult due to the use of different antigen preparations and test methods and inclusion of sera from Lyme borreliosis patients with undefined disease duration and treatment history so this testing is very difficult to interpret.

Now for those of you who do AIDS work you may know that the best way to evaluate an old AIDS treatment is to look at a new AIDS treatment and the same thing goes for Lyme testing so this is a study also presented by Dr. Johnson in Canada looking at the C 6 peptide ELISA and comparing to the GTR system that we have now and if you look at the bottom line this was a fairly robust study two hundred and seventy five patients and the sensitivity of the two tier testing as you can see here was a mere a sixty two point five percent again inadequate for a diagnostic test. The interesting thing about this slide you have heard from some speakers that in late Lyme disease there is a hundred percent sensitivity well in this group of patients and they had ninety one who had late Lyme disease the sensitivity of two tier testing was only eighty one percent so not the hundred percent, ninety seven percent that you heard about before not really that good. Now for those of you who think that the C 6 peptide has a vast improvement this slide is not very encouraging, you can see that the overall sensitivity for the C 6 peptide was only seventy seven point eight percent so that may not be a big improvement on the current system that we have.

Now why do we have this problem with two-tier testing, well the IDSA guidelines were why on the CDC surveillance criteria that you heard about before for the use and interpretation of Lyme testing. The CDC in turn sites to pivotal studies to support the current commercial test system, one by Engstrom et al for positive IgM results and the other by Dressler et al for positive IgG results, Engstrom and Dressler pegged positive test results to high specificity, ninety two to ninety four percent and ninety nine percent respectively at the expense of sensitivity in those studies that was forty four to seventy five percent and eighty three percent and thus the two tier surveillance test system although highly specific will act to the sensitivity required for in accurate diagnostic test.

So the next question is should Lyme testing, should this inadequate Lyme testing take precedence over clinical judgment and this gets back to the issue of positive predictive value of Lyme testing which you have heard about from other speakers, the guidelines state that regardless of the nature of the symptoms a low positive predictive value can be anticipated if serologic testing is done for patients who do not reside in or travel to a geographic area where Lyme disease endemic. Now there are two problems with this statement, one was articulated by [correct lead] in this review of laboratory testing for Lyme disease and that article says because Lyme disease insulin rates and vector abundant is very widely between different geographic areas it can be difficult for physicians to have sufficient information to allow accurate assessment of probability of

Lyme disease for individual patients and the other problem is shown more graphically on this slide, this is a study by Brownstein et al looking at the distribution of [exody] sticks over the next seventy years and influenced by the changes in a climate and global environment and if you look at the pink portion of this slide virtually the entire eastern part of the United States is going to be tick habitat over the next seventy years so it will be impossible to say that the patients has not been in an area where they were not exposed to Lyme disease from these ticks and this is a big problem with determining positive predicted value.

Now turning to the challenge to impossibility persistent infection you have heard a lot about this from Dr. Phillips, the guidelines state that the notion that symptomatic chronic deeper burgdorferi infection can exist despite recommended treatment courses of antibiotics in the absence of objective clinical signs of disease is highly impossible and I want to remind you of something that Dr. Luft said in passing which is that Lyme disease is really zoonotic infection and these types of infections are programmed to be chronic infections and therefore its not surprising that this organism has a number of mechanisms for chronicity and they are shown on this slide and I don’t have time obviously in this talk to go into these mechanisms in detail, I refer you to the source material to read more about these mechanisms of persistence and these mechanisms are responsible for the persistence infection that’s been documented in numerous cases as outlined by Dr. Phillips like they are shown here partly on this slide and so its highly possible that Lyme disease causes persistent infection in patients who have persistent symptoms.

The third challenge is to the early Lyme disease treatment duration and here the guidelines say that each of the recommended antimicrobial agents has been shown to be highly effective in the treatment of erythema migrans and associated symptoms in perspective studies. So what are these antimicrobial agents, well the guidelines say that Doxycycline, Amoxicillin or Cefuroxin for fourteen days is recommended for treatment of adult patients with early localized or early disseminated Lyme disease associated with erythema migrans. For Amoxicillin none of the trials sited by the guidelines used Amoxicillin alone for less than twenty days and likewise for Cefuroxin all three of the sited trails implied a twenty day Cefuroxin treatment regimen so the recommendation to reduce treatment duration for Amoxicillin, Cefuroxin to fourteen days lacks explicit evidence that effectiveness is maintained with the shorter regimens in this portion of the recommendation has to be revised.

What about Doxycycline, these were the studies looking at early Lyme disease treatment with a twenty to twenty one day course of Doxycycline and as you can see that the first study doesn’t look bad a five percent failure and the smallest number of patients but look at the other studies and the failure rates on the right. Nineteen percent, twenty two percent, forty percent, thirty two percent, this is not necessarily effective treatment for early Lyme disease and if you look at an even shorter course of Doxycycline this is ten days in few studies the failure rates were even worse forty six percent and thirty one percent again this is based on an intend to treat analysis which as those of you who do AIDS work know its the goal standard for analyzing these kind of studies.

So what about, now what about longer follow up on these patients and this is a slide that Dr. Wormser is very found of presenting, showing the response to ten days of Doxycycline over thirty months and as you can see from this slide the response looks great ninety percent of patients got better with a ten day course of Doxycycline but the problem with this study is that it had sixty one patients in the treatment arm and by thirty months half of the patients had either dropped out or been excluded and that’s the basis we are saying it goes to a ninety percent success rate. If you look at an intend to treat analysis of the same group of sixty one patients you can see that the success rate is only forty six percent which is a lot different from the ninety percent that’s shown on the initial study.

The fourth subject is the challenge to late neurologic Lyme disease treatment, the guidelines say that response to treatment is usually slow and maybe incomplete and re-treatment is not recommended unless relapse is shown by reliable objective measures. Now the problem with this recommendation is that its based on four label trials involving ninety six patients who had variable durations of Ceftriaxone treatment and in fact the outcomes in these patients was really poor only sevens to thirty five percent returned to their premorbid baseline, so the recommendation against further treatment is really not supported by the outcomes in the studies and along those lines I want to show you some evidence about the risk of treatment in the patients receiving IV antibiotics because there has been a lot said about that during this hearing and this is a table that shows the published randomized control trials of IV antibiotic or placebo treatment for chronic for Lyme disease, there are three hundred and sixty six patients who received an average of thirty eight days of either IV antibiotic or placebo, this corresponds to over eleven thousand days with an intravascular device or an IVD, there were fifteen patients out of three hundred and sixty six who has significant adverse events for an adverse event rate of four percent and this corresponds to an adverse event rate of one point three per thousand IVD days which is really no different from other studies of other diseases using this kind of therapy or IV therapy and also if you look at the difference between patients receiving IV antibiotic versus the patients receiving IV placebo there was no difference in the complication rate. So it does not look like using IV antibiotics makes this so much more dangerous treatment.

Now I want to say a few words about the systematic errors and misleading statements in the IDSA guidelines, there are and they are shown on this slide, exaggeration an example of that is the guidelines say that the vast majority of patients with early neurologic cardiac or arthritic symptoms of Lyme disease have a certain outcome, this translates into something like sixty to sixty five percent of patients so this is definitely an over statement, we have already talked about the circular reasoning to find a condition to the positive test and then saying that the test has a hundred percent sensitivity and then you have heard more about small sample sizes, data selection and reliance on expert opinion. These are more reasons why these guidelines need to be robust.

So in summary science does not support the inadequate diagnostic testing for Lyme disease recommended by the IDSA guidelines. Science does not support the inadequate treatment of Lyme disease recommended by the IDSA guidelines, persistent infection

causing persistent symptoms is possible in chronic Lyme disease and prolonged antibiotic treatment is relatively safe and justifiable in chronic Lyme disease thank you very much.

Dr. Baker: Thank you Dr. Stricker, questions from the panel, Dr. Madoff.

Dr. Medoff: I am just curious about exactly what you mean by clinical judgment and what criteria do you use to make a diagnosis for chronic Lyme disease?

Dr. Stricker: I think there are a number of symptoms that are consistent with chronic Lyme disease and again I think you have to make a distinction between screening for this disease and also the patient sitting in your office who has just come back from a vacation in Cape Cod and has a number of symptoms that may not be hard evidence of the disease but together I suggest that there maybe something like Lyme disease and then there are tests that can be done that to support that diagnosis and we can discuss that more if you like but I think that Lyme disease as well as the CDC says is a clinical diagnosis and you have to use your clinical skills to make that diagnosis -.

Dr. Medoff: Could you tell us what those other tests are?

Dr. Stricker: I mentioned that the testing endorsed by the CDC and IDSA is based on a certain criteria from the Engstrom and Dressler studies, there are other criteria also from the Engstrom study and the study by Ma that was referred to previously that give a different diagnostic test criterion or a set of criteria for a positive test and those tests are done by labs that are proficient in testing for Lyme disease, they have a very high sensitivity and a very good specificity and that can be used now. Also there are newer tests coming along, Dr. Luft is working on a proteomic system along with Dr. Barber as well, that testing will probably be much better but that’s in the future.

Dr. Baker: Dr. Charini did you have a question.

Dr. Charini: Yeah its you mentioned the backend study from 1997 and unfilled study that was done in Europe to the variability of different labs with – regard to the two tier testing, are those data’s still valid or things that you grew – and the data from Europe maybe not as relevant?

Dr. Stricker: That’s true because there maybe different strains that they are testing for however those data are using the exact same test kits that are used today, the Mardex kit, Immunetics kit, all those tests are the same today as they were in ’97 and nothing has changed.

Dr. Charini: Is there any monitoring of variability among that?

Dr. Stricker: I have not seen a follow up to those studies so I don’t know.

Dr. Baker: Dr. Sanders.

Dr. Sanders: I know for time reasons you had to skip over this area but going back to the apology of burgdorferi I haven’t seen that same description in the course relative the other Borrelia that cause tick-borne relapsing fever or louse-borne relapsing fever in fact what I think I have seen described is that as the antigenic variation, as the antigenic shifting goes through its cycles the body clears that why would this be different and its suppose as relevance.

Dr. Stricker: I am not sure how well those spirochetes have been studied compared to Borrelia burgdorferi but I know that the Lyme spirochetes has a large number of functional genes, most of them have unknown function and probably that confers much more of a potential co resistance to the Lyme working that’s the probably the best answer I can give you.

Dr. Baker: Dr. Lantos.

Dr. Lantos: You had mentioned that in the before clinical trials that the adverse event rate was similar in placebo group as it is in the blood group, correct me if I am wrong but the adverse events were reported for both seasonal Lyme infections so these are not facts that we would expect to see in he who don’t have central lines right?

Dr. Stricker: That’s correct, but the point is that the effects, that the side effects from the treatment did not significantly increase the risk of just having intravenous catheter and in fact one issue is that getting the antibiotic may have decreased the complications of the catheter because Lyme infection was one complication which was not seen in most studies with Ceftriaxone.

Dr. Lantos: But if the alternative is no catheter right and you would not expect to see the adverse events?

Dr. Stricker: That’s true you would not see the four to five percent adverse events that you see in those studies if you didn’t have a catheter that’s correct.

Dr. Baker: Just one comment on your map, your map was as the location of the ticks in the left hand side of the US map and we have lots of ticks, Lone Star ticks in the Lone Star state and I just want to make a comment that I think a map with distribution of disease rather than distribution of ticks would have been more helpful in the presentation.

Dr. Stricker: I don’t think we really have that map over the next so projected over the next seventy years again that’s the good point of our study, the other thing about that study is that it only looks at the eastern part of the US it didn’t not look at anything else so -.

Dr. Baker: Well I was talking about now not in 2080 so the blue part of the map and maybe Dr. Johnson can take back to the CDC that it would be nice to have at least for the recorded cases an updated map. A case map not a tick map, as we have lots of ticks but

not as much disease as in some of the other areas of the United States so thank you very much for your presentation.

Dr. Stricker: I just wanted to mention by the way Betty Maloney was responsible for a number of the slides in my presentation, I want to give her the credit.

Dr. Baker: Thank you