 Hello, and thank you for joining us today on this 

 panel discussion focusing on Lyme disease. With the recent explosion of growth in the tick population, states and providers that have not seen cases of Lyme disease in the past, are now being confronted with the illness. Moreover, the fact that some individuals experience lingering symptoms, beyond their initial course of antibiotics, has sparked international debate among experts and advocates alike over why this is occurring, and what should be done to help these patients. Today, we have brought together a panel of experts on both sides of the debate, to better understand their perspectives, and to shed light on the impact the controversy is having on patients and on the medical community.

I am Dr. Peter Salgo, and I'm a professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and I'm the associate director of Surgical Intensive Care at New York-Presbyterian Hospital. Participating today on our distinguished panel are Dr. Robert Bransfield, private practice in psychiatry, in Red Bank New Jersey, and associate professor of Psychiatry at Rutgers Medical School; Dr. Samuel Shor, president of the International Lyme and Associated Diseases Society, and associate clinical professor at George Washington University Health Care Sciences in Reston, Virginia; Dr. Leonard Sigal, past chief of the Division of Rheumatology and current clinical professor at Robert Wood Johnson UMDNJ Medical School, and founder of Gateway Immunoscience in Stockbridge, Massachusetts; and Patricia Smith, president of the national nonprofit Lyme Disease Association, which raises money for research, education, prevention, and patient support. Patricia is also a member of Columbia Universityâ€™s Lyme and Tick-Borne Diseases Research Center Advisory Committee. Shea's a member of the Congressionally Directed Medical Research Programmatic Panel on Tick-Borne Diseases.

Welcome to all of you joining us here today. Why don't we get some of the basics established right off the bat? Simple question: What's Lyme disease?

 Lyme disease is the most common vector-borne or tick-borne illness in the United States and in Europe that is caused by a spiral or spirochetal organism by the name of 

 complex. That being said, most of us in the field agree with the acute phases of Lyme disease, where it can present with an acute, viral-like illness. What is more contentious is the concept of chronic Lyme disease, which we'll get into.

 We're certainly going to get into that, but just for the sake of establishing some definitions: this is a tick-borne disease. It's a spirochetal disease; it causes illness, and it causes a lot of symptoms. We'll explore them as we go along. That being said, where is Lyme disease found?

 Well, the current studies seem to indicate that Lyme disease is found in almost 50% of continental United States counties at this point in time, and that's an increase of 45% since 1998. A lot of the concentration is in the Northeast and the upper Midwest. However, Lyme disease is found in 43 states, but part of the problem of that whole situation of looking for the ticks is that not enough money is being offered to states to do surveillance to find out, 'Where are these ticks?'

Understanding Lyme Disease and Where It's Found

 Is it fair to say that, whatever the minute details of this cycle are—whether or not deer are the ‘no-tell motel’ for the ticks&mdash;to get people infected, you need people? You need 

, you need ticks, and the ticks need to have blood meals, which eventually gets them infected, and they eventually bite people.

So, if you walk to the edge of my backyard, to the next property, there are a gazillion ticks. And every time I go out, when Triver comes back, I have to pull lots and lots of ticks off her. There they are.

 If I may just add to that—you normally need ticks, but if you have a pregnant woman who has Lyme disease and that woman has not been treated, there’s a chance that it can cross the placenta and cause death of the fetus.

 Fair enough. But that’s why everybody is talking about deer, mammals, ticks, 

, and spirochetes; it’s all part of the very complex, interrelated issue.

 Right, with one other qualifier—the co-infection component. Co-infections can create a more clinically robust presentation, and, according to work in New York, the 

, and probably other co-infections actually contribute to the dissemination of those more widespread, infectious etiologies.

 Just when you thought you understood this, there’s another wrinkle to it all. But, before we leave this topic, let’s set the table again. How many folks, each year, get diagnosed with Lyme disease?

 Well, there are confusing statistics. The surveillance criteria report that there are basically about 30,000 people-per-year affected. However, when you look at the testing, there are over 3 million Lyme tests done per year. So, those 3 million Lyme tests yield 1 in 100 patients who meet the surveillance criteria. By other criteria, by research looking at insurance records through the [Centers for Disease Control and Prevention] CDC, there are over 300,000 people per year, and that was a study done a while back. So, it’s at least 300,000—probably quite a bit more&mdash;that we miss. The problem is the question about testing, which I’m sure we’ll get to later.

 Is one age group more at risk than any other age group?

 Yes, most decidedly. Ages 5 to 9 and 10 to 14 are at the highest risk for acquiring the disease, because, obviously, they are children. They tend to go in the woods and roam, and they don’t necessarily pay attention to their parents.

 Their parents tell them to stay out of the brush, and they laugh and do it anyway.

Finally, you mentioned misdiagnosis, or you alluded to it. How big of an issue is misdiagnosis, or an incorrect diagnosis, for this disease?

 Well, it’s a major issue if it’s overlooked early. Then, you can have greater disease progression and more serious neuropsychiatric problems, and I think that’s the greater area. That’s often what I see as a psychiatrist, and it’s very similar to what we think of in syphilis—where it starts as a rash and then, later, has other symptoms; and then, in the tertiary stage, it’s more of a neuropsychiatric illness.

 Not necessarily. Coincidently, syphilis is another spirochetal disease, so there’s some interest there as well.

Lyme Disease: Who Gets It?

 Let’s progress right on, then. What are the symptoms? If we’re going to make the diagnosis, whether it’s correct or not, we’re going to test for it. Clearly, something is going to trigger you to go looking for this. What are the symptoms associated with the initial acute Lyme disease?

 The initial acute presentation is a flu-like illness that occurs within 3 days to 3 weeks of the tick bite. That may or may not involve a rash. Most people think of a bullseye erythema-migrans rash but, in some studies, on average, 50% of people did not develop that rash.

 So, good luck using that as an absolute marker.

 Right, and the majority of people with bona fide Lyme disease don’t remember a tick bite, so it’s a challenge in that respect as well. There’s a seasonality to it, such that the time between April, May, and September is the peak of the tick nymph feeding, and that’s when it’s most common to develop this flu-like illness—sore throat, low-grade fever, and muscle aching. Without treatment, it will resolve on its own. The problem with that is that it can then result in more chronic manifestations that are well recognized.

 We’re going to go on to talk about that as well.

 The term “chronic” is often used and, perhaps, sometimes misused. There are later manifestations of Lyme disease that are not necessarily chronic. There are chronic manifestations of illness that are a matter of debate, and I’m sure we’ll return to that in a moment.

 Well, “later” means it follows the tick bite, possibly when the erythema-migrans, if they’re infected, happens. So, the classic description of Lyme disease—and a lot of people have difficulties with this&mdash;is that there’s early disease and then there’s late disease. And the term “late” was what was originally used to describe cardiac disease, neurologic disease, and musculoskeletal manifestations, which don’t necessarily persist&mdash;which would be chronic. They occur later. So, I think there’s less of a value added to it.

 I think the syntax makes a difference, and I do want to get into it, because if what you mean by chronic is that there’s persistent infection, that needs to be treated. If it’s late, which are not necessarily active infections but some sort of immunologic response, that’s different as well.

 Well, there’s a distinction between chronic infection and chronic symptoms. And, in most diseases, chronicity usually means after 6 months—if something is there for 6 months. That’s the way a lot of diseases are categorized.

 And what are the psychological issues here?

 Well, the more common things, or the earlier symptoms, are an increase of milder cognitive impairments, slow processing, hypersensitivity to sound and light, and then, executive functioning problems. And then you can see depression, anxiety, and sleep disorders. You can see suicidal risk, and you can see much more extreme things. Now, you’re looking at things that evolve years after the infection. So, this is the later stage manifestation of the disease, and that’s usually in the people who I see, people who are 10 years out.

 I’d like to make a comment with respect to chronic active infection. I published a paper in 2011, whereby I believe I provided clinical evidence that was statistically significant. The majority of my patients—209 patients who had blood tests that were negative for 

, but who presented with the international case definition of chronic fatigue syndrome and other markers that were suggestive of infection—were treated with antimicrobials, and 62% improved to a statistically significant degree to a 

Early Vs. Late Lyme Disease Symptoms

 Since you brought up diagnostic criteria, how on earth do we make the diagnosis? We mentioned a blood test. What are the guidelines in terms of how you work this up? What are you looking for? What is essential to make the diagnosis?

 The classic [Centers for Disease Control and Prevention] CDC and [Infectious Diseases Society of America] IDSA guidelines use something called a 2-tiered system. The 2-tiered system involves a screening test called ELISA (enzyme-linked immunosorbent assay). If that ELISA test is positive, it is followed by a confirmatory Western blot test. They’re just 2 different types of technology. One is more sensitive, the other is more specific. In the setting of HIV, whereby the ELISA test is 99.9% sensitive, the Western blot is in the order of 98% specific. In the setting of Lyme disease, it’s about 50%, in the 2-tier. The 2-tiered system, cumulatively, is about 50% sensitive across the board.

 You’re basically telling me that the blood test isn’t so good?

 Correct. And the statements that it’s highly sensitive in late neurologic neuroborreliosis, are, in large part, based upon a study by Dr. Allen Steere, published in 2008. In order to be included in that study, in that analysis, you had to have had 2-tier positivity.

 If I understand you correctly, 50% may not. Then, you’re left up in the air about this.

 Correct. You’re dealing with a number of individuals who are very ill and, in fact, there’s a component of this that we’ll talk about in more detail. There’s immune suppression that can occur, and the sicker you are—this has been published as well&mdash;the more likely this antibody immune response will not be shown. So, the sicker you are, paradoxically, the more likely you’ll be overlooked.

 That’s not unique to Lyme disease. TB does the same thing.

Let’s get back to this issue of sensitivity and specificity. The question, then, is, what’s the gold standard? Because, in order to say that a test is good or bad, you need to have a gold standard as to what the disease is.

 Right. Unfortunately, the gold standard is not sensitivity. The gold standard might be considered a culture.

But, when you say 50%, what you’re saying is that, depending upon how you define Lyme disease, only 50% of those people will be positive by testing.

 Right, but if you’re going to use what you perceive as the gold standard of the technology that exists today, the 2-tiered system, and claim dogmatically that it is highly sensitive, when you’re skewing your population by including only those who are positive, then that is not accurate.

If you’re only including people who are positive, then the sensitivity and specificity is 100%.

My only point is—and I don’t want to argue about what the gold standard is&mdash; depending upon what you consider to be the gold standard for saying that this group of patients has Lyme disease, the sensitivity and specificity of the assays, assuming they’re well done, will be different.

 Let’s do something else, if I may. Let me refocus just a bit, because the lab testing is contentious. I think your point is well taken, which is, if you say the lab testing is missing this disease, then you have to have at least some other way to define the disease other than lab testing, right?

 So, what else do you do to make the diagnosis?

 Well, this is similar to what happened in the 1960s in psychiatry. We had a phrase, “psychoneurosis.” Different people thought of psychoneurosis in different ways. Then, we had the DSM (Diagnostic and Statistical Manual of Mental Disorders), and the DSM helped better define various disorders.

Now, with infection, you think of PCR, culture, and antigens as proof of infection. The problem with Lyme disease, is that it’s a microbe that suppresses and evades the immune system. You cannot rely on an immune-based test for an organism that suppresses and evades the immune system.

 But we do have, certainly in medical history, plenty of experience in immune-suppressive diseases for whom lab tests work. Let’s go back to HIV, which is a classic immune-suppressive disease for which ELISA and Western blot does work.

 It’s 500 times more reliable than with Lyme disease, based on a recent journal article that was published by Michael J. Cook. Even though it does suppress, that’s a better test than what we see with the 2-tiered testing.

 How else would you make the diagnosis? First of all, let’s get some basic medicine.

Can I just return to immunosuppression a bit? If 

 were truly an immunosuppressant organism—and let’s assume for a moment it’s B-cell function, it’s antibody production&mdash;then, wouldn’t you expect to see these people with more infections?

They have positive blood tests for other diseases.

 Not to the degree of HIV, because the degree of immune suppression with HIV is far in excess. This is a subtle, indolent infectious process that’s been shown to actively suppress.

The problem with this immunosuppressant claim is that HIV is a much better immunosuppressant by destroying T cells, and yet the blood test for HIV is positive.

 I want to leave that just for a minute. We’re going to get back to it, I promise you we’ll get back to it.

Reliability of Lab Testing for Lyme Disease

 Let’s make the diagnosis by simple, basic medicine. Geographic considerations, you’ve already told me that it’s more widespread than it’s thought to be. Are there some areas where there’s more likely to be Lyme disease than others?

 Yes, according to the studies out there, that is true. However, unfortunately, many researchers feel that Lyme disease is actually far more widespread than the map shows. They are doing research in the South, for example, looking at the fact that it might be the Lone Star tick (

) that is actually carrying the disease. There has been research done by Kerry Clark at the University of North Florida in this area. So, I don’t think we can limit it, but yes, there are what are called high-incidence states; that’s the term that the CDC uses.

 It tends to be—right now at least&mdash;northern tier, the Northeast, and maybe spreading West.

 There’s one interesting disparity when you look at human studies versus dogs. With dogsandticks.com, you see different geographical patterns. For instance, Colorado has a lot of dogs that are infected with Lyme disease, but people aren’t. So, it doesn’t exactly make sense that, maybe, the veterinary statistics are more accurate than the human statistics.

 Maybe people are getting missed or maybe the dogs are overdiagnosed.

 Or maybe the dogs are invading an area that people just don’t go to.

 Right, because dogs are always in the brush. But that being said, I just want to nail this down before we go further. We’ve got geographic considerations; we’ve got some veterinary considerations. If you want to make this diagnosis, without the blood test for a moment, you’ve got to do a history and a physical. What are you going to find?

 Well, in keeping with that question, it involves the art of medicine and clinical judgment. You’re using risk factors for exposure. Those risk factors for exposure involve travel or location within a high-risk environment, recognizing that you can still contract the disease in low-risk environments. But it is a risk stratification. You’re exposing yourself to a habitat that is high risk: grassy areas, low brush, that type—such as walking through the backyard.

 Mind you, I’m not coming to your house any time soon.

 And then you have a clinical presentation.

 It is consistent with the disease. Now, the challenge with that is this is the new great imitator, and it is also felt to be a neurotropic condition. Neurotropism means it’s drawn to the nervous system. So, for example, in the chronic fatigue syndrome paper that I published, chronic fatigue is one of the most common clinical presentations of the condition that has not been treated, and frankly, in some presentations that have been treated. But that’s another set of issues we’ll get to.

There are arthralgias, arthritis in a migratory pattern, very often. So, it goes from one joint to another with or without inflammation. The nervous system, whether it be neuropsychiatric or cognitive—the autonomic nervous system&mdash;is very often involved, and what I mean is the part of the nervous system that controls unconscious function: blood pressure control when moving from a lying to a standing position. Sleep&mdash;fractured, nonrestorative sleep&mdash;is a very common phenomenon, so you look at the complex symptoms with which an individual is presenting. You look at the risk factors for that individual’s exposure. Tests may be supported, but not required, because they're relatively insensitive.

 The key thing with any medical diagnosis is pattern recognition.

You do a thorough assessment, you take a thorough history, and you do the old-fashioned medical school review of systems that we were taught to do that’s boring and tedious. That’s how you have to do it.

 But if I believe him, the review of systems for Lyme disease is essentially positive.

 No, no, I ask over 300 questions whenever I see a patient with Lyme disease. And I look at each one with a baseline or course of illness, and I have to do a very thorough review of systems. You see a certain pattern that evolves; it’s a multisystemic illness that can evolve over time. There aren’t too many multisystemic illnesses like this, so you look at what other pattern it correlates with. For every other setting in medicine, you do a thorough workup and review of systems. You don’t just rely on 1 piece of evidence, just 1 lab test. Why should Lyme disease be an exception?

 But we’re talking about a very broad spectrum here. My colleagues are talking about people who are very ill for a long period of time and have symptoms that have somehow evaded prior clinicians. There are people, on the other hand, who present with erythema-migrans. That’s pretty obvious. We can’t use that as the gold standard, as you pointed out, but it’s pretty obvious. If somebody comes in with a facial palsy in an endemic area, your index of suspicion is very high. That is something that is reversible with antibiotics, relatively quickly. These are all obvious things: lymphocytic meningitis in the proper setting, a heart block that progresses from a first- to second- to third-degree block in front of your very eyes. I don’t know of anything else that does that, and that’s also potentially very responsive to antibiotics, and relatively quickly.

And of course, arthritis, the monoarthritis, is not very painful, but it has a very large effusion. That’s quite often Lyme disease in the proper geographic setting and proper individual setting. And then, we move on to all of these less well-defined, very troublesome, and very difficult-to-identify-a-cause symptoms. There, the index of suspicion has to be high enough for you to actually say, “Well, I don’t know that this is Lyme disease, but if it is, I want to make sure that this person is treated.” We’ve all seen patients where it’s a balancing act, and you’re saying to yourself, “Gee, I’m not sure, but do I really want this person to walk out of this office without having been treated appropriately for Lyme disease if I think there’s a reasonably high level of likelihood?” The question is, what’s the reasonably high level of likelihood?

 And that’s a difference of opinion between different providers.

 I’d like to take that concept one step further. If I feel that, clinically, an individual raises to that level of suspicion where I’m concerned, then I will try a therapeutic trial of something like minocycline, 100 mg twice a day, for a month and see what kind of response they have. Are they getting better? Are they getting worse? When they get worse, there is a phenomenon called the Jarisch-Herxheimer response, which is an inflammatory response that is related to an introduction of, or change in, antibiotics that was characterized in syphilis.

 I was just going to say, yet another spirochetal issue.

 When you said minocycline, did you mean minocycline or doxycycline?

 I use minocycline. I prefer minocycline because of its CNS penetration improvement.

Are you aware of any proof that Jarisch-Herxheimer reactions can occur after the first, second, third, or fourth antibiotic?

 There are studies that support the finding of Jarisch-Herxheimer in 

 There’s no question about that, but my question is about how there are patients who say, “Well, I’ve had multiple Herxheimers.”

 And I’m not aware of there being any proof that that phenomenon really occurs after the first, second, third, or fourth course of antibiotics.

 In the paper that I published, I do describe that.

 We’re going to get back to this. I promise you we’ll get back to it.

Challenges in Making a Lyme Disease Diagnosis

 My concern as a clinician is that, when you start describing everything as a potential consequence of a particular disease, now you’ve taken away diagnostic specificity, right? If everything can be caused by it, I don’t know what to make of that.

 It can be specific patterns. There are only 3 specific symptoms: the expanding erythema-migrans rash, acrodermatitis chronica atrophicans (ACA) rashes, and ACA deterioration, which you rarely see; I’ve seen it a half-dozen times. The skin gets paper thin in the wrists and the ankles. And Hyperacusis, which is that loud noises can cause nausea, sometimes vomiting, and dizziness, you only see [this] with syphilis and Lyme disease; those are the only 3 truly specific things. Here’s the problem. Diseases that are easy to find, we’ve already figured them out. What we’re left with are the things that have multiple contributors, multiple pathophysiologic pathways, and multiple manifestations. So, 2 new patients end up with exactly the same symptoms. We have to have a different disease model for complex diseases that is different than what we’re used to having, where the disease is a simple clear thing that you can diagnose with one process. We have to think of the statistical probability of symptoms and pattern recognition. It takes a more complicated way of adding all this together.

 And you’re not talking about actually making a calculation of statistical likelihood. This is all that is going on in your brain.

 Are there other tests that we could do? We’ve got the ELISA test. We’ve got these other 2 tests. What else is out there that can help you nail this?

 We’re involved in the study of 2 tests that are very promising. One is called the Nanotrap, which looks at a highly specific protein called OspA that is found across multiple strains of 

. And what this technology does is super concentrate, in a urine sample, the presence of this protein and then further tests it, and, it’s 1000-fold more sensitive than the standard Western Blot. In our 2015 paper that was published in the 

, in the preliminary erythema-migrans patients—who are very often negative in the ELISA test because they haven’t had the time to respond immunologically&mdash;24 out of 24 were positive with the Nanotrap test.

 Let me play the devil’s advocate and say that when you make a test sufficiently sensitive, it may become insufficiently diagnostic. That is, everybody turns positive.

 It’s highly specific, and as far as the authors of this study feel, the false positivity is very low.

 But does that mean that you’ve been exposed or that you’re actively infected?

 It’s an antigen, so you’re actively infected. There are studies to show that an infection should be cleared and no antigen should be present within 72 hours of that infection being cleared by the body.

 So, the obvious question that comes to mind is, if somebody who’s positive by that study is given appropriate antibiotics, improves clinically, does that study then become negative?

 Yes, it has. And, in fact, I provided the test to 100 patients with chronic disease, 42% of whom were positive, and 1 of whom was an MS patient who was symptomatic when she was first studied and asymptomatic when she was subsequently studied. She was positive initially and negative afterwards.

 All this suggests that patients with ongoing Lyme disease-related issues—and I’m being very careful with the syntax&mdash;often wind up with a lot of different doctors, a lot of different clinical situations. The provider path here is an issue.

 Can we just return to testing here for a moment?

Because that is a fascinating new technology. There is a polymerase chain reaction that’s available. It’s not often used, and it shouldn’t be used. It’s a research tool, but it’s not the sort of thing that the average clinician should be ordering. There was a technology that the late Michael Brunner and I worked on back at Robert Wood Johnson University looking for immune complexes. An immune complex can only be formed if there’s an antigen and antibodies against it. So, we concentrated on immune complexes, broke them up, and then looked for an antigen, OspA, as well as an antibody against 

. We found it to be a remarkably useful tool in diagnosing people who had active infection, some of whom were seronegative, and people who had been treated and were now asymptomatic, because they had been treated appropriately and gotten rid of the 

. The problem is that it’s a tedious sort of technology: very useful, but not easily done. And so, that’s what we’re looking [at] for now: a technology that’s sensitive and specific, which is a very difficult balance to manage, and a technology that can be ramped up to make it a commercial tool.

 We are actively involved in the FDA approval of erythema-migrans patients, to the goal of having a CLIA-waived in-office test with that technology. We have to keep in mind we’re 24 months away from that, but that’s the goal.

 Wouldn’t that be great. We wouldn’t be having this broadcast if we had the Lyme disease test.

 There are other things we could talk about.

 I’d like to address this issue because it’s frustrating sitting here. I’ve been involved in this setting for 33 years, and I look at what has happened. You can all talk about these tests, and I certainly was going to bring up what Dr. Sigal mentioned because we had funded Dr. Schutzer at UMDNJ, who initially looked at those immune complexes. He actually proposed that test to the CDC, and they didn’t want to hear about it.

 Well, that’s a good question. What I’m saying to you is that the CDC is very reluctant to move on to new technology. I’ve been invited out there, twice, to Fort Collins. We’ve brought it up as advocates. The physicians have brought it up; researchers have brought it up. They want to stick with a 2-tier, antiquated test that, again, is probably missing at least 50% of our patients. So, for a lot of what we’re talking about, in reality, we’re not going to accomplish it unless the CDC moves off the dime.

Emerging Tests for Lyme Disease

 I want to come back to the problem that we don’t have a test, for whatever reason, and we don’t have this wonderful magical machine where we can put the blood in and determine, bing, Lyme disease, boom, not Lyme disease. And so, we wind up with people with all sorts of multisystem issues. They must go through provider, provider, and provider. This pathway has got to be crazy.

 The record that I saw was 57 doctors. Now, that was a case 20 years ago, and I was actually Dr. 58. He’s doing well now. I treated the psych symptoms, which weren’t being adequately addressed and contributed toward disease progression, and he did have another doctor who was treating him with some modest amounts of antibiotics. Now, he’s fine, but he just wandered around for a while. You don’t see that now. Now, maybe someone sees a few doctors. The average might be 5 doctors, according to 1 study. I think there’s more of an awareness than there used to be years ago.

 Well, it depends on where you are located. If you’re located in a state that’s now considered low incidence, the problem patients have is that they go to a physician, they may have all the symptoms—sometimes they even have an EM rash&mdash;and yet that doctor will not consider Lyme disease, even as a part of the differential diagnosis. They are told, “We don’t really know what you have, and maybe you need to see a mental health professional,” which seems to be a universal excuse.

 Well, yes, but it’s happening time after time, and it has been happening for decades with our patients.

 And what’s really frustrating is that patients will walk into a doctor’s office with papers. They’ll say, “I’ve looked at the internet, and this rash that I have looks very much like this. I think I have Lyme disease.” And there’s none so blind as he who will not see. There are lots of clinicians like that who won’t listen. It’s very frustrating.

 What comes to mind is, somebody walks into a doctor’s office in New York and says, “I have symptoms consistent with San Joaquin Valley fever,” and the doctor in New York says, “No, you don’t, this is New York.” But why not?

 But this is different with Lyme disease because there are so many cases and it has such a contentious history. Our patients have to fight every minute of every day of their lives while they’re in tremendous pain. And by the way, that was missing from the symptom list, and it’s one of the things patients say to me most often: “Why don’t they have the massive pain that we are in on the symptom list?”

 A lot of neurologic pain, musculoskeletal pain, and arthritic pain, and they are very high levels of pain. That is not looked at as being part of the picture, and it needs to be. When these people do come in with papers, I give them credit. They come in with studies. You know why they come in with studies? Because otherwise, oftentimes, they’re not able to get diagnosed. I talk to patients who have seen 20 physicians over the years. We had a renowned oncologist in the field for many years who had nothing to do with Lyme disease. And what happened? He developed problems and he was very physically fit, etc. No one could diagnose it. He has now written a book. He lost his heart. He had to get a heart transplant because—by the time he finally got diagnosed with Lyme disease and got treated&mdash;he got better, but his heart just didn’t make it. He is absolutely appalled because now he sees. He saw doctor after doctor, and many of these doctors were his colleagues.

Trials and Tribulations of a Diagnosis for Lyme Disease

 Most patients who have Lyme disease get diagnosed with Lyme disease, get treated for Lyme disease, and clear the infection quickly. Somebody comes in with the symptoms of infection, which has been associated with a Lyme disease diagnosis, they get antibiotics. Most of them get better. Is that fair?

 It depends on the manifestation you’re talking about. If you’re talking about erythema-migrans, I think everybody on this panel would agree: if somebody comes in with erythema-migrans, you give them antibiotics for however long you decide you want to treat—2 weeks, 4 weeks&mdash;and most of those people will get better.

 The majority will, but in John Aucott’s SLICE study, 39% at 6 months were still ill.

 And he did not look at markers for activity of disease. So, I’m not saying by that statement that they were all still infected, but I would argue that, given the studies by Embers and Hodzic, etc, there’s persistence. There’s evidence in the literature of persistence through the standard antimicrobials.

 The very first descriptions of Lyme disease being treated with antibiotics in the United States—because it was treated with penicillin in the 1950s in Sweden&mdash;the first evidence of antibiotic sensitivity, from Allen Steere and Stephen Malawista, supported that a significant proportion, up to 50% of patients, was still symptomatic in some way for as long as 6 months after their treatment.

 Right. But the question is, how many of them are actually infected, and that’s to be determined.

 There were different studies. There were 2 that showed 28% had significant symptoms; one showed 63%. So, there’s a variation. Again, it gets back to definition that people don’t agree on. I think there are some people who get infected, have a natural resistance to it, and even without treatment, they do okay.

 And they may carry it in a latent way for years. And years later, it appears after an auto accident or something in their body, something like chicken pox, where it comes up as shingles. I think the co-infection is a complicated thing. It can be a complex interactive infection, not all of which we understand—coinfections with other tick-borne pathogens, or non—tick-borne pathogens that might be in the body and are opportunistic, like viruses.

 Let me put it as clearly as I can, because I think we want to parse this out. If you have an initial diagnosis, let’s say we’ve made the diagnosis of a 

 infection. We’ll call that Lyme disease, the 

. They treat it with antibiotics, and let’s say, for the sake of argument, that this person then continues to have symptoms. Are a significant number of people continually infected or are their symptoms merely autoimmune manifestations of a previous infection, the infectious portion of which is now gone?

 I have to disagree with you when you use the term “autoimmune.”

 Or an inflammatory reaction. Autoimmunity is a very specific phenomenon

and there’s no evidence to suggest that patients with Lyme disease have autoimmunity based on prior 

 Let me try this again. I told you this was going to get interesting. If we talk about these ongoing symptoms after what should have been—theoretically, perhaps not&mdash;an effective course of antibiotics, is it that there is active infection that is persistent or is it that there is an inflammatory response? Is that fair that it is not related to active infection but is something related to the previous infection that’s ongoing?

 And there’s a third potential phenomenon, and that is, a person has Lyme disease, the person is treated—whether or not they still have active infection or debris is not the issue&mdash;but they have something else that is not related to Lyme disease. As an example, there’s a recent paper by Allen Steere’s group at the Massachusetts General Hospital where patients with Lyme disease that has been treated and apparently cured have developed rheumatoid arthritis, have developed psoriatic arthritis, and have developed what’s called seronegative spondyloarthropathies, like ankylosing spondylitis. There’s no evidence to suggest active infection. These people meet American College of Rheumatology criteria for those diagnoses, and they don’t respond to antibiotics.

 But is that related to Lyme disease? People get these diseases who don’t have Lyme disease.

 It’s a comorbid condition. Let me go back to your immune issue. It seems like there’s provocation to the immune system.

Now, with a normal infection, you get early inflammation, then adaptive immunity, and that’s it. And then you’re fine. So, with this, what seems to happen is inflammation persists, there is an adaptive immunity, and there may be some autoimmune-type symptoms that persist in some people.

 Because you see some things; for instance, obsessive compulsive disorder. And you can see an abrupt onset that may follow 2 weeks after an infectious exposure.

 So, that’s tissue damage, that’s inflammation. There are any one of a number of potential explanations, but as an immunologist, I don’t see how you necessarily implicate autoimmunity as being the underlying mechanism.

 I think it’s less common than inflammatory mechanisms.

 But what evidence do you have that there is autoimmunity?

Well, people found antibodies. But the timing goes, for instance, 2 weeks after infection, where there’s an abrupt increase. This is most prominent with some of the OCD cases, where there can be a sudden increase of symptoms that can correlate with when antibodies are produced. That would suggest it.

 Not for sure. But let me get back to the greater point that I wanted to make: that it’s more the immune provocation symptoms, whatever we call them, that are associated with the manifestations of the disease. And if the immune system is being provoked, something is provoking it. Now, it might be infection, it might be something else.

 It could be debris from the organism. That has also been described.

 Yes, but it seems like it’s cleared rather quickly.

 I must disagree with you. Linda Bockenstedt and her group at Yale have demonstrated quite clearly that when you take mice and treat them with antibiotics, there’s no live organism left, and yet there’s debris that persists—

-derived debris—which is going to be a proinflammatory nidus.

 I don’t think it would last that long, and you see this persistent inflammatory reaction associated with symptoms. Now, it does seem like the people who have been adequately treated don’t have disease progression; it’s more static. They have the same symptoms they had; they don’t keep getting worse. But there’s this other group that keeps getting worse and worse with time. The symptoms they have get worse, and they get new symptoms. The disease keeps expanding with time. So, therefore, you’re thinking that something is provoking the immune system and increasing over time. What is it? Now, persistent infection is one of the possibilities. We can consider other possibilities, too, but that’s what concerns us.

Lyme Disease: Theories for Longer-Term Manifestations

 If I understood you when you spoke earlier, you said you had a group of these patients, you treated them with antibiotics, and a fair number of them got better.

 evidence that it was an ongoing active infection?

 In general, yes, one may think that there’s an anti-inflammatory effect that antimicrobials have. But if you think that a Jarisch-Herxheimer response is an inflammatory response— and many of them had that&mdash;then that argument would be not supported.

 But that would be directly time-correlated to the administration of antibiotics.

 Correct. But what I’m saying is that there are some who argue that with the chronic use of antimicrobials, clinical benefit is due to the anti-inflammatory, not antimicrobial, effect of those antibiotics.

 I don’t know about the evidence to support that.

 But what I’m suggesting is, if you’ve got someone who develops an inflammatory response in the setting of introducing those antimicrobials, then that would argue against there being an anti-inflammatory therapeutic gain. That being said, when we are tracking folks we’re using metrics that are carefully identifying their clinical course, let alone subjectively: “How are you doing? You’re feeling better?” “I’m having less joint pain, etc.” We’re not willy-nilly sending them off for 6 months and having them come back regardless. I wanted to argue with respect to the study of perpetuation and transmission persistence of 

In a recent study that was published, Hodzic infected mice and then used 

-naïve ticks to feed off those infected mice. And this was after a course of antimicrobials that should have cleared the infection. But after that course, the ticks then fed on 

-naïve mice and they infected them. So, that’s a xenodiagnosis that was able to prove that the antimicrobial regimen that was used, that should have cleared the infection, was unable to do that. Embers did that with Rhesus monkeys: 12 Rhesus monkeys were infected. They used the same study protocol and got the MBCs that Klempner had used in his NIH trial. After a period of time, the animals were sacrificed, and all 12 were culture-positive for 

 If I understand that argument correctly, what you’re basically saying is that what we think may be antibiotic sufficient to clear the infection, is not?

 Clearly not in those 2 studies, and arguably in some other settings, to extrapolate from that.

 So, that would argue for a different approach, different antibiotics, and a different course of therapy. But this does not necessarily get to the question of, are all patients 6 months out with symptoms—whatever those symptoms may be&mdash;chronically infected? Or are they simply cleared, but having a distinct, long-running immune response?

 There’s a mix. There are over 100 strains of 

, and they don’t all do the same thing. There are a ton of co-infections, and they don’t all do the same thing. People have genetic makeups: they’re not able to clear infections the same way, and they become toxic in different ways. That lends itself toward some of the conversation we had before: what perpetuates disease? In some people who are not infected, they’re toxic and unable to clear ongoing…

 This was in the SLICE study: the chemokines and cytokines are elevated, and so that can relay to inflammatory response.

 Those are chemicals made by the inflammatory reaction of the host.

 I just want to be very clear about that, because there’s no evidence to suggest that 

 I’m not suggesting that’s the case, but it’s the host’s response to the infection, whether it’s an ongoing infection or residual of a past infection. There’s something called “mast cell activation syndrome,” which we’re just beginning to hear about, where there’s a large crossover of mast cells or immune cells that produce not only histamine, but other chemicals—cytokines, chemokines&mdash;that can create the same process.

 What comes to mind, as an analogy, is that not everybody who gets strep throat and is untreated goes on to get rheumatic heart disease. Some do, right?

 And that rheumatic heart disease then persists, even after evidence of active infection goes away. So, this seems analogous, but the other problem is, how do you work it out? It has been pretty well worked out for strep throat and heart disease.

 But the problem is markers. It’s biomarkers, and that’s the emphasis that John Aucott, with the Nanotrap, and others are trying to identify. How can you identify what’s going on? Is it active infection? That has been the major bugaboo in the field.

 In other words, an absence of data, an absence of…

 So, what are you going to do for people who stand before you? You’re going to use your best clinical judgment in the setting of lab tests that are inadequate. One of the concerns that I have is the politicization of this. We’re saying the lab tests are fine. The lab tests aren’t fine, and until we recognize that the lab tests aren’t fine and that we have to look at things on a more global scale, then we need to move off the mark.

 When you say that the 2-tiered system is sensitive enough, that’s not fine.

 Again, I have to take issue with the premise that they’re only 50% accurate. But they are not perfect—I think we can all agree on that.

 There’s no question they’re not perfect. And so, quite frequently, a patient will walk into your office and have what you think is a constellation of findings that is highly likely—using your judgement and your statistical analysis&mdash;to be Lyme disease. I’ll tell you, having taken care of a lot of such patients, when you explain to them, “I think you should be treated with antibiotics: not because I can prove that you have Lyme disease, but because I think you might have Lyme disease and I don’t want you to deal with the consequences,” I’ve never had anybody turn down antibiotics in that setting.

 Right, and that’s very useful from a clinical standpoint. What’s the clinical response to that intervention? Are they getting better? Are they getting worse? And that’s a part of the clinical judgment that goes into, do I continue if they come back 4 weeks later? “Oh yes, I’m starting to feel better.” You don’t stop it, necessarily.

 I think the 2-tiered test is more useful if you had an infection a few months ago, but it’s of questionable usefulness if you’re looking at something 5 to 10 years old, for it to be a valid test. It was never standardized for later manifestations.

 The other problem is that you don’t know how long ago they got the infection. As an example, I saw a gentleman 15 years after an erythema migrans who came in with Lyme arthritis. He was very seropositive. If somebody comes in with something that is not clinically likely to be Lyme disease and you have the blood test that’s positive, you don’t know if there’s any relationship between the 2 or if this is one of those lucky individuals—I think they’re lucky&mdash;who get bitten by a tick, their immune response deals with, and they seroconvert because there is an organism inside and available to their immune system. But now, they’re coming in with something entirely different.

 Well, I think it’s more than theoretically possible. It does happen. But then the problem is, with whatever that manifestation—whatever that clinical problem&mdash;you as a clinician are faced with a dilemma. And that is, is it possible that this is really Lyme disease? Or is this true and unrelated?

 We could get back to pattern recognition and what pattern of clinical symptoms, signs, and findings best explain that complaint.

Exploring Controversies in Lyme Disease

 First of all, people with good will are attacking this all the time; we’re looking at this. Second, there are outliers on both sides. People who say, “This isn’t Lyme disease, it can’t be, you’re not sick,” and that you’re crazy, or others will say—and I’m not pointing to you, I’m just saying it’s the other side&mdash;“Look at this, Lyme disease can do anything. Therefore, since you’re in an endemic area, you have this, and Lyme can do this&mdash;wow&mdash;you’ve got Lyme disease.” There has got to be a middle course, right? And because there is no real consensus&mdash;I’m going to give you that there is no good testing, that we would rather have a better test&mdash;what is the impact on patients who hear this? This is medical noise. What do patients think when they hear all of this?

 I can tell you that patients are very frustrated, and many of them have had Lyme disease for decades—and despite what some people’s opinions may be, it started out as Lyme disease. The patients see the research out there that there are things now called persisters, which just don’t appear in Lyme, but also appear in other diseases. But does the establishment want to recognize these studies that are being done at places like John Hopkins and Northeastern University by great researchers? They are doing it in laboratory settings, and the plan is to go on with animal and human studies. They are looking at other types of antibiotics, combinations of antibiotics, and whether or not pulsing doses might help. And yet, no one wants to acknowledge that perhaps these people really do have Lyme disease and they say to themselves, “Well, I’m looking at this. Maybe I’m one of these people.”

 I was just going to address it, which is that you said 2 things that are very provocative.

One is the establishment—whatever that “them” might be&mdash;and that nobody wants to hear it. Who’s nobody?

 Well, I’ll be honest. After 33 years, I can say if it wasn’t for the International Lyme and Associated Diseases Society, most of the patients that I have seen across the country—children who have Lyme disease, and their parents&mdash;they would not have anyone to turn to, to try to help them figure out just exactly what they do have. And contrary to some opinions, these doctors do not always diagnose Lyme. It’s just that people go to them because they have signs and symptoms. Lyme disease appears to certainly be in the mix, and they may have a history of that. Now, just because they get 3 weeks of doxycycline, I certainly think that the literature has shown that that is not necessarily a situation where that will be clear.

 You’ll forgive me, but define no one: you haven’t defined the establishment.

Why Are We At Odds Over Lyme Disease? Exploring the Impact and Controversy

Understanding Lyme Disease and Where It's Found

Lyme Disease: Who Gets It?

Early Vs. Late Lyme Disease Symptoms

Reliability of Lab Testing for Lyme Disease

Challenges in Making a Lyme Disease Diagnosis

Emerging Tests for Lyme Disease

Trials and Tribulations of a Diagnosis for Lyme Disease

Lyme Disease: Theories for Longer-Term Manifestations

Exploring Controversies in Lyme Disease

Research Challenges in Lyme Disease

Lyme Disease and Long-Term Antibiotics: Help or Harm?

Reaching a Consensus in Lyme Disease

Improving Care in Lyme Disease