Peter L. Salgo, MD: 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.
Samuel Shor, MD, FACP: Correct.
Peter L. Salgo, MD: Is that prima facie evidence that it was an ongoing active infection?
Samuel Shor, MD, FACP: 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—then that argument would be not supported.
Peter L. Salgo, MD: But that would be directly time-correlated to the administration of antibiotics.
Samuel Shor, MD, FACP: 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.
Peter L. Salgo, MD: I don’t know about the evidence to support that.
Leonard Sigal, MD: Oh, there’s plenty of evidence.
Peter L. Salgo, MD: There is?
Leonard Sigal, MD: Yes, absolutely.
Samuel Shor, MD, FACP: 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 Borrelia burgdorferi infection.
In a recent study that was published, Hodzic infected mice and then used Borrelia-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 Borrelia-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 Borrelia.
Peter L. Salgo, MD: 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?
Samuel Shor, MD, FACP: Clearly not in those 2 studies, and arguably in some other settings, to extrapolate from that.
Peter L. Salgo, MD: 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—chronically infected? Or are they simply cleared, but having a distinct, long-running immune response?
Samuel Shor, MD, FACP: There’s a mix. There are over 100 strains of Borrelia, 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…
Leonard Sigal, MD: What do you mean by toxic?
Samuel Shor, MD, FACP: This was in the SLICE study: the chemokines and cytokines are elevated, and so that can relay to inflammatory response.
Leonard Sigal, MD: Those are chemicals made by the inflammatory reaction of the host.
Samuel Shor, MD, FACP: Correct.
Leonard Sigal, MD: I just want to be very clear about that, because there’s no evidence to suggest that Borrelia burgdorferi makes a toxin.
Samuel Shor, MD, FACP: No, no.
Leonard Sigal, MD: OK, I just want to be clear on that.
Samuel Shor, MD, FACP: 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—that can create the same process.
Peter L. Salgo, MD: 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?
Samuel Shor, MD, FACP: Correct.
Peter L. Salgo, MD: 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.
Samuel Shor, MD, FACP: 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.
Peter L. Salgo, MD: In other words, an absence of data, an absence of…
Leonard Sigal, MD: Good scientific studies.
Peter L. Salgo, MD: Good scientific studies.
Samuel Shor, MD, FACP: 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.
Leonard Sigal, MD: What do you mean by not fine?
Samuel Shor, MD, FACP: When you say that the 2-tiered system is sensitive enough, that’s not fine.
Leonard Sigal, MD: 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.
Samuel Shor, MD, FACP: Yes.
Leonard Sigal, MD: 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—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.
Samuel Shor, MD, FACP: 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.
Leonard Sigal, MD: Yes, that’s a topic of discussion.
Samuel Shor, MD, FACP: From my standpoint.
Leonard Sigal, MD: Exactly.
Peter L. Salgo, MD: And we’re going to get to that.
Robert C. Bransfield, MD, DLFAPA: 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.
Leonard Sigal, MD: 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—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.
Samuel Shor, MD, FACP: Theoretically, it’s possible.
Leonard Sigal, MD: 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—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?
Robert C. Bransfield, MD, DLFAPA: We could get back to pattern recognition and what pattern of clinical symptoms, signs, and findings best explain that complaint.