Dr. Donta: We are here because we have a problem and this problem is not going to go away. I don’t think the guidelines have to be all scrapped when I was on the first panel in 2000 and we reviewed the information and the additional information since then there were difficulties with how do you come up with guidelines when there are so many areas that are not as well defined. We knew the peak of the iceberg we still know the peak of the iceberg but like a bell shaped curve there are these other areas and as one of the questions was how do you diagnose a patient who is seronegative as having a Lyme currently we don’t have that ability, we hardly have that ability. Now, you have my presentation from the core of the application the information I have also submitted and I’m just going to focus on two areas of the guidelines, the area called post-treatment and how does that compare with chronic lyme disease and treatment specific questions. Post treatment, and I think the guidelines committee try to be as precise as they could in focusing on what it is that is known and so they took a group of patients and said where patients were treated and they still had symptoms afterwards, how do we document whether they still have lyme disease or not and I think that remains a problem area and I think a more recent paper by one of the members trying to distinguish post-treatment from chronic lyme disease. I may not be the smartest doc but I’m also not that dull either as far as trying to distinguish clinical symptomatology based on a series of clinical observations, I’ve had a career in basic research but I also spent a lot of time on clinical research as well. When you look at how chronic lyme disease is classified it changed from stage 1, 2 and 3 to earlier disseminated and late. And the chronic wasn’t put there because I think it was difficult to know what to do, the late it does seem to be a fairly well defined you get big arthritis primarily or you get a meningitis or you get a cardites and when you look at the responses the [Inaudible] [00:02:42] responses are very robust and these patients do quite well with little or no treatment and I think when you compare them with chronic lyme disease or call it whatever you want it, persistent and the issue is going to be how do you know if there’s an infection, I’ll address that in a few minutes. But when you look at the criteria you fall into this category and not just make up criteria like the old Jones criteria automatic fever you are major or minor and so you have fatigue muscular skeleton and [Inaudible] [00:03:19] and you have minor criteria so called minor criteria and then we’ll talk about the diagnosis and minor symptoms are not so minor to the patient that have disturbance that have jaw pain we have subjective symptoms but very few, if any, objective signs and that’s been I think one of the big stumbling blocks as to how to proceed here so they go to the dentist with jaw pain and go to the cardiologist [Inaudible] [00:03:47] they go to the neurologist cause they have seizures. When you look at the definition of chronic fatigue syndrome, when it was redefined and you have four out of eight and you look at the definition of fibromyalgia and having being involved in the BA system for a number of years and helping to conduct a couple of treatment trials with veterans on this the definition of [Inaudible] [00:04:11] was patterned after chronic fatigue syndrome because they had those symptoms and we still don’t know whether this illness just as with chronic fatigue syndrome just as with fibromyalgia is this a single causation probably not, it’s a symptom complex like if you have pneumonia you have to still sort it out what the cause of that particular illness is and when you put this all together you can’t distinguish chronic lyme from fibromyalgia from chronic fatigue from [indiscernible] [0:04:43] illness or from post-treatment lyme. Now post-treatment lyme

you can say it’s a benign term but it implies that treatment is done and from my perspective there is nothing about post-treatment that makes it after infection and we’ll get into the specific issues about antibiotic one of the first patients that I ever saw had been treated with Doxycycline had gotten some better and then he relapsed and the question was how do you really know. Well by chronic definition of post-treatment is he’s already had his treatment and what’s left can’t possibly be due to persisting infection but I’ll come back to that. As far as the laboratory criteria tests were developed and they are wonderful they are specific for patients who have the alego arthritis some with meningitis but when you get that the patients with this chronic form of the disease you don’t have those same criteria the criteria that were developed were of objectives lyme positive when the question was asked before about how come there are so few patients in that group that’s the few patients in the neurologic group or the chronic fatigue group, those patients were not included in the analysis and if they were, those results weren’t reported and I’ll show you some information, your rare western blocks now why is it down at the IGM with cutback and we don’t report all the bans. Are physicians not capable of trying to locate laboratory tests and decide how do I interpret them? So the idea of cutting back on the IGM activity because maybe it’s false positive in chronic disease, I don’t know how to interpret it in chronic disease that doesn’t make it right. So in the beginning until the two-tiered system came about laboratories would routinely report all the bans and I think that still needs to be the case to have all the information. And when we look at, this is from a pediatric study that we’ve done that’s very difficult to get published because how do you prove they had lyme disease. But taking patients who had teak bites had rashes versus those that didn’t have a teak bite but had a rash and others and putting them in a group it fit with the symptom complex don’t have anything else that can be discovered you find that a number of them have IGM reactions to various proteins and they also may have IDG reactions, not everybody. And when I compare that group of patients whose EIA are positive on this axis there with people who had IGM or IGD responses and in this case I’ve taken the liberty of defining an IGM positive as having two or more reactions where an IDG positivity is two and one of which has to be specific and I’ll get into that in just a second. You find that you rarely have western block negative for IGM or IDG and the lights are positive but in this group of patients whose titus are negative you have 33% in whom you have no IGM or IDG reaction so how do you know they have lyme disease? When I first saw my first patients when I was in U-Con health center in the mid to late 80s and we established a lyme clinic there I didn’t know what the results were going to be and based on the clinical picture I tried to imagine who’s going to be positive, who’s going to be negative. Western blocks were just being developed in laboratory medicine, the lab was part of that and YMC was doing some stuff spreading later information with chronic lyme was against RPC so things were being developed and I’d go up from the clinic up to the lab and correlate between the patients and their responses and it became pretty apparent that I couldn’t distinguish who was going to have an IGM positive who was not, who was going to have an IDG positive who was not. But what I did gather was the information is that the less objective sign the more difficult it was going to be to have a CDC positive definition of two or more or five out of ten of the other so it became that this tool that arise especially in the western block became an adjunct to the clinical diagnosis as all laboratory tests I think we primarily make the clinical diagnosis and you both look for inclusive criteria and exclusive criteria

but the western block is frequently very positive in patients with chronic lyme disease where the [Inaudible] [00:10:02] not necessarily and indeed is not a great marker we don’t use antibodies to follow the course of the infection but because this is kind of a more prolonged illness I could see in the patients and this is from our [indiscernible] [0:10:19] published paper that you have as well that patients who are symptomatic were more likely to have IGM reactivity and when they became asymptomatic with treatment the IGM reactivity disappeared and they either kept their IDG reactions or they lost even in the case of 22% they lost their IDG reactions. MRIs have been done on these patients and while that doesn’t prove that the spots the TC signal enhancements that are seen and in my observations are they are only seen in about 15% of times and there’s this issue how do you know if it’s MS how do you know if it’s lyme, how do you know if it’s something else, vasculities or something else and those are the difficult clinical questions we have to address. The brain specs scans on the other hand are positive in about 75% of patients, now these are selected patients in the sense that they said my memory isn’t what it was or my mood is different and when we do that we find abnormalities in various parts of the brain in the course Dr. Fellons studies an institute has more specific information. So in this slide I demonstrate the severity and the location of the abnormalities and this was done in conjunction with collaboratives at U-Con center, Rhode Island Hospital Dr. Nottle and Abbas Medical center while I was there and the interesting and satisfying thing is that in terms of do you have something to follow, they tell me they are improving besides the patient saying I’m better or I’m not the specs scan are reversible and the people who are improving. Now when the specs scan turns negative that doesn’t mean your symptoms are all gone but by and large it’s a soft collator and this case somewhat objective. Now I want to spend the remainder of the time getting in the issue of antibody treatment. In vitro we have a sensitivity/variety of antibiotics but knowing something about pharmacology infectious disease when you look at the antibody it’s not enough that it sensitive in vitro it’s got to be able to get to where the action is. So without knowing exactly is there’s persisting infection people have tried a variety of antibiotics and have come up with interesting albeit desperate results times. So one of the interesting things that I’ve come back to is how come azithromycin as Dr. Laff addressed azithromycin aren’t very effective and in Dr. Steers original studies of about 20 people in each of the group the Tetracycline seems to work well but the azithromycin didn’t that good of a job in that, and I was wondering about that but before I get to that I want to address whether there is statistical operations in the trials that were done especially the Campton trial, I’ll accept for the moment that there wasn’t a problem and these people did not respond whether they were seropositive or seronegative. So as I wrote in that letter to Ringler general about it that proves that that trial of one month of Cetriaczone followed by two months of Doxycycline didn’t work but does that mean you stop there? You have a cancer treatment trial and something didn’t work and you say I guess it doesn’t work. Now each antibiotic is not the same as the next antibiotic, we don’t use the same antibiotic for every condition. So why is it, I was curious, why is it that that happened and I kind of new at the beginning of the trial that Doxicycline was going to be in trouble. But first of all as far as the design one month of Cetriaczone followed by two months of Doxycycline wait a minute, we are mixing apples and oranges here I don’t know if that means three months of Cetriaczone would have been better, there was apparently some questions about whether they should have an IV for three

months and Doxicycline in that patient the first patient that I saw I noted that the patient didn’t improve they didn’t stay improved. I wondered, I’m old enough that I’ve used Tetracycline a parent compound and knowing that some of the pharmacology is that Doxicycline has a high protein bound level that’s why you don’t have to give it very often but on the other hand there might not be quite as much free drug to diffuse into the tissue and if this is an intracellular organism which I think it has to be in order to survive or persist if there’s an infection then Tetracycline which is in this case the high protein bound and you give a higher dose it might work and it indeed works and that’s the basis for the first publication I made on antibiotic treatment that involves Tetracycline. The second is the Cetriaczone that’s an interesting compound isn’t it, where is very active in-vitro and it does seem to afford some benefit of the transient and in my experience with patients it seems to help the first time around 2 to 4 weeks into treatment they start feeling better, 6 to 8 weeks they are feeling pretty good, you give it to them even through out the 12 weeks and after that they slip, slip, slip and some patients maintain some improvement basically I think they slide back closer to the beginning than our Tetracycline patients. So I wondered too how do we analyze that and how do I reconcile if I’m saying this is an intracellular infection why subjective reactions have any reactivity coz we know from experiments that involve the in vitro the teacher culture studies done by two or three different groups that if they infect the transient molecules there is no permanent and it’d be nice to have a permanent culture model of lyme early on infection so we can study a little more accurately to really see where it is to go and why there is whatever happened that when you do those studies, you find that Doxycycline doesn’t do anything to the bacterial as Tetracycline does and erythromycin does. And then comes along what a few years ago now, as part of the [Inaudible] [00:16:54] research there is an animal model and it suggests in doing a library search Cetriaczone is at the top of the list as an agent that percolates the [indiscernible] receptor which is thought to be at fault in causing an accumulation of [indiscernible] and neurotoxicity to that patient in that case it’s a mortar disease whereas lyme disease is pretty much a sensory disease but nonetheless I wondered is there a similar situation in lyme disease where maybe as a neurological path of physiology that there is an accumulation of a transmitter and that becomes toxic. So that’s an interesting question and that reconciles the difference we see is Cetriaczone working as an anatine or toxic agent. You can see any of these antibiotics working and if they are resisting infection or not and these are the tissue culture studies that I cited, now the last point I want to make is with micro lyte antibiotics. In-vitro they are very active but clinically when people were using them be it for MS be it [Inaudible] [00:18:10] it wasn’t very effective then in the MIC zone, terrific for these antibodies. Well there was a paper that was published in 1992 by Dr. Video Raul of the Pepsio Division at Marcelle and I went and gave the talk and discussed this with him and in his experiment he showed using a cosiellor tissue culture model whereas [Inaudible] [00:18:38] agents such as choloroquine, amentodine, and ammonium sulphate didn’t affect the viability of the organism and the middle curve is [Inaudible] [00:18:55] alone but in the presence of a lysosomotropic agent the killing was more complete and faster so a light bulb went off in my head about maybe that’s why the macrolide antibiotics aren’t working in the lyme disease because if they are in an acidic endosome the lysosomes or one of the later endosomes, we know that the macrolide antibiotics don’t work very well in acidic pH and if one of these agents help I can give ammonium chloride and I asked

Dr. Wood and he said hyrdoxic chronic which is the safer of the chloroquine hydroxide chloroquine compounds would do it and [indiscernible] [0:19:31] but not as effective as hydroxyl chloroquine and when you look then at other organisms so this would not be the first one, not that we know this where organisms can be very terrific be it a typical micro bacteria be it [Inaudible] [00:19:46] the estoplasma and those are those studies. So in the final few seconds or minutes here we started doing observations and now probably several hundred thousand people we know when you use a combination of hydroxic chloroquine and azithromycin that people begin to improve sequentially depending how for how long they were sick before will determine how good an outcome we have and also how long it takes to begin getting better. I tried to, and there are some gender differences as well which might involve some hormonal retro action. I tried to submit this is as a possible controlled grant along with the Tetracycline grant and as I’m sure Dr. Bagel will attest there is no further money to go ahead and doing the additional trials. So I’m stuck I know am not in academic medicine anymore while I can still submit the grants and I think that they should be done to prove that we have, and I’m not the only one using this now, but there are numerous of patients who are being treated with these safe agents Tetracycline and I’m not talking about IVF drug zone I’m talking about Clorithemycin and Azythromycin relatively inexpensive antibiotics and they appeared to be working.

Dr. Baker: Dr. Donta I’m sorry I’m going to have to interrupt you.

Dr. Donta: Those are the conclusions and we need to further files and we need to go ahead and revise the guidelines to allow some questions about what we know and what we don’t know.

Dr. Baker: Thank you very much for your presentation I’d like that you put your future directions to my recommendations slide up but I’m going to turn to a brief question period from the panel starting from my left, Dr. Parsonnet.

Dr. Parsonnet: I have a question and forgive me if this is published or somewhere and I just haven’t seen it yet on the brains specs studies in the slide that you showed are there control patients in there as well?

Dr. Donta: The control population has 5% or less they are historical do not have any brain specs scan abnormalities that’s at U-Con medical center that’s historical controls but I wouldn’t have run a specs scan on a patient who didn’t have an illness or another illness like lupus. Maybe the scan some abnormalities that Dr. Fern can better address that particular issue but the answer to your question is not as hard as studying if it was presented in abstract form and I’m still in the process of trying to get it published.

Dr. Parsonnet: Okay thank you

Dr. Baker: So just to reiterate and clarify that these were patients with fatigue chronic pain syndromes who had these scans?

Dr. Donta: Right who thought fit with lyme disease based on [Inaudible] [00:22:43]

Dr. Baker: Okay, thank you. Dr. Madoff

Dr. Medoff: I don’t think anyone on the panel or anyone in this room will contest the fact that patients with chronic lyme whatever that is real, so are you saying the abnormalities on the specs scan are decade above the infection?

Dr. Donta: No and I think that that’s one of the issues when we ask is an antibiotic working as an antibiotic or is it doing something else and that’s an important question but the specs scan abnormalities [Indiscernible] [00:23:21] condition.

Dr. Medoff: There is evidence from West Nile disease that patients who have documented West Nile disease have a group of symptoms that are very similar to those patients with chronic lyme and they can be sick for months to years.

Dr. Donta: Right and a lot of these patients.

Dr. Medoff: they don’t have any evidence of persistent West Nile disease.

Dr. Donta: That’s true and a lot of these patients have had West Nile antibodies run but the treatment thing is that they seem to reverse and people can comment with improvement and don’t reverse in the patients who are not improving. It’s just another piece that maybe is worthy of more attention, we have precious few objective laboratory adjunctive studies to help us with trying to know what’s happening with clinical patients.

Dr. Parsonnet: And patients who are sero-negative who have or are thought to have [Inaudible] [00:24:30] lyme disease have there been formal investigations into their ability [indiscernible] general for instance vaccine androgens are these [indiscernible] by any of the patients.

Dr. Donta: Those patients are, I can’t speak about all of them but enough of them have normal immune responses to new muccaco vaccine or I have no reason to believe that they are immuno-deficient.

Dr. Baker: Thank you very much.