Dr. Baker: So Dr. Shapiro.

Dr. Shapiro: Thank you very much. It’s a pleasure to be here. What I plan to talk about, the guideline for management for tick bites that we came up with, some general comments about studies of outcomes of patients with Lyme disease, some about chronic Lyme disease and antimicrobial treatment, long-term for chronic symptoms.

Dr. Baker: Dr. Shapiro, did you say who you representing?

Dr. Shapiro: I’m sorry. I’m representing the original panel for the Infectious Disease Society of America, both the 2000and the 2006 guidelines.

Dr. Baker: Thank you very much.

Dr. Shapiro: So the recommendation about managing tick bites in the guidelines are to avoid exposure to bacterial ticks in endemic areas. Antimicrobial prophylaxis, a single 200-mg dose of doxycycline was recommended not routinely but only for patients greater than or equal to 8 years of age and who are bitten by nymphal or dog I. scapularis ticks that were attached for at least 36 hours and prophylaxis have to be started within 72 hours in an area where the local rate of infection of ticks was at least 20% and doxycycline which is the drug though shown to be effective is not contraindicative. This is largely based on the VEST study which was a clinical trial of treatment for tick bites or randomized trial in Westchester County, New York where there is a high rate of endemic disease, in persons over 11 years of age, to remove the tick within the previous 72 hours. Now, on this study, the ticks were identified by a medical group of entomologists, we will get back to that, and they received either 200 mg of doxycycline in one dose or placebo in a double-blind manner. The results are shown here. One of 235, 0.4% of those who got doxycycline developed Lyme disease compared with 3.2% or 8 of 247 who received placebo. Incidentally, that one person that Dr. Bolton said did zero convert. One person who received treatment as the people in a number of other studies in Russia who received doxycycline prophylaxis got the disease, they all zero converted. So the overall protective efficacy was 87% which was statistically significant with a fairly wide confidence of about 25 to 98%, but there were some problems, there were high risks of minor adverse effects. A lot of the patients had nausea and vomiting. All infected patients developed erythema migraines. There were no asymptomatic zero converters. They all had blood drawn soon after. Nearly 20% of the subjects had another tick bite there in the 60s followup. I just

want to make a point. You cannot extrapolate the use of one dose of amoxicillin to the younger children as the antimicrobial kinetics are quite different. Finally, the risk of Lyme disease it was low, only 3% in the placebo group and it was all erythema migraines which was easily treated and you know where the tick bit you when you removed it. So it was a low even in this very highly endemic area.

There is no new scientific information since the guidelines were written that would suggest a change of name. I just want to address one or two of the points that Dr. Bolton made. I already talked about the fact that in fact, in humans, patients who develop doxycycline or receive doxycycline and went on to get disease, they did in fact zero convert. He spoke a lot about the mouse model. Mice are quite different. The antimicrobial kinetics of doxycycline is different. It is much shorter and in fact, when mice were bitten by a single infected tick, received a single IV dose of doxycycline, 100% of them got better and that IV dose corresponds closer to what an oral dose of doxycycline would be like in humans. Finally, he made a point of PCR positivity. Being PCR positive doesn’t mean that you have viable organisms. You can have PCR positivity for a long time after you killed the bacteria. Okay, let me move on.

Dr. Baker: What about the studies of the assessment of long-term outcomes?

Dr. Shapiro: Well I will agree with some of the other speakers. It is very difficult to conduct a good study. This will be an ideal study. Obviously, you cannot do it. You take a representative population and randomized some to get Lyme disease, some to get no Lyme disease, and follow both groups forward in time to determine an outcome. Nobody would suggest doing this. Obviously, this will be unethical. So what ends having, is what we have something like this. We have a bunch of individuals who have a baseline state. Some have comorbid illnesses, others injuries, and so on. A diagnosis of Lyme disease was made. Once you question the accuracy of that diagnosis, they receive a variety of different treatments. Subsequently, comorbid illnesses may occur. Injuries may occur. Multiple other factors are playing. There is stress, there is publicity, medically unexplained symptoms may develop, the normal process of aging, and then at some point, somebody assesses outcomes. So it becomes quite difficult.

Is it valid to attribute abnormalities in such studies to Lyme disease? Well, there are a number of potential problems. First of all, the accuracy of diagnosis. There is something called

protopathic bias where somebody is diagnosed as having Lyme disease because they have a symptom. We’ve heard a lot about that today. I think you heard from Barbara Johnson why you need to have some criteria in making a diagnosis of Lyme disease besides just symptoms.

There are other potential biases we call reporting bias. A patient labeled as having had Lyme disease, may be more likely to recall or to report minor symptoms or problems that subsequently occurred in articles of all the publicity with Lyme disease has received. In addition, there is investigator bias. Persons investigating outcomes in some studies are not blinded. Finally and I think this is very important to understand, the potential of problem with multiple outcomes. In many studies, including the randomized clinical trials, not just observations that I’m talking about, multiple outcomes have been reported even though sample sizes are calculated for statistical power for just one outcome. Typically, we set the probability of finding one outcome being statistically significant at 0.05. However, if ten outcomes are reported, the probability by chance alone that any one association will have a PE less than 0.05 is 40%. If 20 outcomes are reported, there is a 64% probability that one will be less than 0.05 by chance alone. So drawing conclusion based on such post-hoc analysis is not valid, pure and simple. I think it’s important to remember that when you hear people talking about multiple different outcomes and if you dig through this, you’ll found this statistical association.

Okay, chronic Lyme disease, what is it? Well, it is hard to find a real definition. It seems to be that somebody says or the patient decides that here she has it. I think from some of the literature you’ve received and studies that were done in many, many different major medical centers, the majority of patients labeled as having chronic Lyme disease have no evidence of having had Lyme disease either currently or in the past. No credible scientific evidence. Most do have chronic symptoms, sometimes severe and disabling symptoms, but no objective signs of Lyme disease or often of any other disease. A minority of patients with chronic Lyme disease do have some evidence of having had Lyme disease. If the symptoms persist for more than six months after antimicrobial treatment, we have turned this condition post-Lyme disease syndrome. Again these patients primarily have nonspecific symptoms such as pain, fatigue, and so on, without signs of ongoing infection or inflammation as this group of patients primarily and whom the randomized clinical trials have been done because at least there is some evidence that at some point, they had Lyme disease.

Are patients suffering? Yes, absolute, many are suffering. Personally, I think doctors are part of the problem. Why is that? Well, doctors, I think in general, are pretty good at treating diseases. We have a diagnosis. We know how to treat it or we can look it up. We’re quite poor at managing symptoms without a diagnosis. There is a growing literature. It is now called medically unexplained symptoms which I think many patients have and I think you have some of the references to it. I can understand the frustration of many patients. When you say to somebody that it is not Lyme disease, it doesn’t solve their problem. Many people hear somebody saying, oh this means it’s all in your head. There’s a negative stigma associated with medically unexplained symptoms and there’s a growing literature that many doctors had negative feelings about such patients that influence their management, not even necessarily at the patients but they feel themselves unskilled and incapable of managing the problem and so they’re not very good at it.

As I said, there are a number of good articles on medically unexplained symptoms. There are excellent reviews, one written by Dr. Hatcher in the British Medical Journal, another by Smith in the Journal of General Internal Medicine. In fact, I think that whole edition of the journal of the general internal medicine is dedicated specifically to medically unexplained symptoms.

So yes, people are suffering and we have a great deal of concern and sympathy for them. That’s why I and I think many of the other members of the panel went into medicine to try to help the patients. Does this mean that we should abandon the scientific method and evidence-based medicine to address the problem? Absolutely not. There is no scientific evidence that active infection with Lyme disease is the cause of chronic medically unexplained symptoms and I think, referred here and you probably will hear more in the future, criticisms of some of the studies that have been done, which is fine. It’s very hard to conduct a good study. I certainly have never conducted a perfect study. I think the burden falls on persons to prove that in fact long-term antibiotics are effective in a scientifically controlled manner, even if you believe in some of the criticisms which may or may not be valid.

Okay, so the scientific evidence at the time that the guidelines were written, randomized clinical trials of patients with post-Lyme disease syndrome showed that long-term antibiotic treatment had no or minimal benefit and substantial risks of adverse effects. We know that long-term antibiotic treatment is associated with serious,

sometimes even fatally adverse side effects. We know that long-term antibiotics select for antibiotic resistance super bugs that are a threat both to the patients and to others in the community and we know that they are expensive. Furthermore, patients who received these long-term antibiotic treatments not only do not benefit but also do not receive the treatment for the real problems that they should be getting. I also want to point out that symptoms are very labile. In some of the studies, more than 40% of the patients who received placebo improved. So anecdotal reports that we’ve got the antibiotic, and we got better, really, you need a controlled study for scientific validity. At the time the guidelines were written, the scientific literature clearly showed that the risks of long-term antibiotic treatment far outweighed any potential benefits. This has not changed. On the contrary, I think there’s more evidence.

Let me just talk about a couple of subsequent publications. One is by Dr. Fallon who I believe is speaking next, perhaps. He conducted a study supported by the National Institutes of Health. It was a double-blind, randomized controlled trial in which patients had to have been treated already for, I believe, it’s three or four weeks with ceftriaxone and then had, I think, another 3- or 4-month period and then were enrolled and they received either ceftriaxone IV for ten weeks versus placebo.

The target was to enroll 45 patients with Lyme encephalopathy as he told us and they were randomized 2 to 1 to treatment versus no treatment. Outcome was performed inside a memory test. He screened 3,368 patients but in the end, only 37 patients met criteria and were enrolled, only about 1% of those screened. I think that tells you something right there. Of the 37 patients who were randomized, 5 withdrew in the first 12 weeks because of adverse side effects and three others had medication terminated because of adverse events. At 24 weeks, there was no statistically significant difference in memory scores between the treatment groups. This is a quote from Dr. Fallon’s article, "Therefore, considering both the limited duration of cognitive improvement and the risks, 10 weeks of IV ceftriaxone and then 14 weeks of no antibiotic is not an effective strategy for sustained cognitive improvement."

There is another subsequent publication that I haven’t heard anybody talk about yet by Dr. Azzi. This was published in European Journal of Clinical Microbiology Infectious Diseases in 2007 and was a double-blind randomized control trial. It had 145 patients. There were patients with disseminated Lyme disease, many with neurologic disease. All were treated with three weeks of ceftriaxone IV. They were then randomized to receive either

amoxicillin or placebo for additional 100 days. The outcome was a visual analogue scale of how they felt symptomatically that was completed by the patients. Subsequent results determined that one year with that vast majority rated their outcomes as good. There was no statistically significant difference in the outcomes of those who received long-term antibiotics versus those who received placebo. So this is another study conducted in Europe where neurologic Lyme disease is much more frequent than the US and it confirms defining the US studies that long-term antibiotic treatment is not beneficial.

I was going to talk about a publication by Dr. Kenny, but I don’t think I will just in the interest of time. I am going to go right at my conclusions which basically clearly, many patients are suffering and we all very concerned about that. However, there is no credible scientific evidence that the cause is persistent infection due to Lyme disease. Indeed, the overwhelming scientific evidence is that long-term treatment with antibiotics is not beneficial, but it is associated with substantial cause and serious risks and serious adverse side effects. There is no scientific justification for changing the current idea, say recommendations, related to the duration of antibiotic treatment Lyme disease; however, I strongly feel that additional research about how to help persons suffering from medically unexplained symptoms is very important and indeed, I do have another couple of minutes, nobody is saying that Lyme disease, the patients who did have Lyme disease and went out to have this chronic symptoms, perhaps Lyme disease does have something to do with that. Perhaps I mean many of you have been around long enough to hear, we used to get called up at time about chronic mono. That was a major problem. I have not heard a call about chronic mono for years and years. Everybody now has chronic Lyme disease. It is possible that there is some group of patients who have a genetic susceptibility to go on and develop some of these symptoms following certain infections. I don’t know. However, what it is clear is that it’s not active infection, ongoing infection with live organisms for which antibiotic treatment is indicated. Indeed, the overwhelming evidence is the risks far outweigh the potential benefits, which is how the panel came to its conclusions. Thank you very much.

Dr. Baker: Thank you, Dr. Shapiro and thank you for staying tea time. We do have time for questions from the panel.

Dr. Lantos: Yes.

Dr. Baker: Dr. Lantos.

Dr. Lantos: Given some of the mythological limitations pointed out by you and previous speakers and the respective trials, do you stand by the grading of evidence for the guideline recommendations. Is it an E and is it a 1?

Dr. Shapiro: Yes, I do because for example in the company trial, I forgot who was one of the speakers who said that the samples that the numbers of subjects were small that’s because they have a predetermined outcome which many people thought about for a long time as about including the person I think who develop the SF-36 and felt that it was a valid outcome. They had independent biostatisticians, independent groups reviewing the data who concluded that it should be stopped because why go on and subject patients to this if in fact the chance to find it difference in the end is only 3% during their planned interim analysis. So, the answer is yes. I think that was completely valid.

Dr. Baker: Other questions. Dr. Medoff.

Dr. Medoff: So, I was struck in the guidelines about the statement that the symptoms of chronic Lyme disease were no different from the general population, do you think that it does its service to the patients who we all agree some of them are very sick and very ill and certainly sicker than one would see in the general population?

Dr. Shapiro: Well, I have to see the exact statement but let me make one thing clear for example in some of the studies we talked about where people have said the severity of the symptoms are just similar to the people who have severe congestive heart failure etc., etc. Those were entry criteria to get into the study. So it’s not as though that they pick a random sample of patients with Lyme disease or chronic Lyme disease and they all have these. So generalizing that degree of severity to all such patients I think is incorrect, that was an entry criteria. I do not agree that—I think there is a bell-shaped curve and I think that many of the people that we hear about are on the far end of the bell-shaped curve who have severe and disabling symptoms as I said. Clearly, not the general population doesn’t have severe and disabling symptoms all the time. So, there is a bell-shaped curve. So I would not say that everybody who has chronic Lyme disease is similar to general population, certainly not.

Dr. Medoff: Perhaps the statement like that sort of raises the eyebrow of people who suffers.

Dr. Shapiro: I can understand that if it says that would be a mistake.

Dr. Baker: Thank you very much, Dr. Shapiro. While Dr. Fallon is going to the podium, I want to thank Dr. Shapiro as a person who is on two previous guideline panels for recognizing how many patients are suffering and the need to find out the best way to alleviate their suffering.