11 Why Aren't Persisting Spirochetes Enough Evidence Of Infection?

On the heels of Embers et al having published their statement on PLoSONE, a number of patients are already questioning its content.

Some are claiming that Embers et al statement about how their findings should not be used to oppose current IDSA treatment guidelines for Lyme disease is something they were asked to write - rather than something the authors included on their own.

I don't know. For this claim - whether it's true or not - I have no evidence. However, one thing I do know is that there are solid scientific reasons which back the need for more research on spirochetes which survive after prolonged antibiotic treatment.

The question, of course, which weighs heavily on every patient's mind has been this one:

Why aren't persisting spirochetes enough evidence of infection?

It's become a political hot button question, and it's a scientific question. But most people think that as long as the spirochetes Embers found are alive and metabolically active, that is enough evidence to state that yes, Lyme disease is a chronic infection - let's stop all this nonsense right now and change the treatment guidelines!

Given my own experience and how longer than standard treatment helped me improve, I totally get this. I've been there, done that - and I think that a standard course of antibiotic treatment does not work for everyone. Particularly if there is a delay in proper diagnosis and treatment. Particularly if a coinfection is present. Particularly if there is some abnormality in one's immune system.

But if you are a scientist and you are researching this phenomenon of persistence - whether you as a scientist suspect these spirochetes can cause persisting infection or not; whether the above claim by other patients is true or not - you will be called upon by other scientists to support your findings.

It isn't just going to be the IDSA or the ALDF or other organizations which deny the possibility of persistent infection as a cause of chronic Lyme disease which are going to want to know the outcome of your study.

It's going to be the American Society for Microbiology (ASM) that wants to know the outcome. It's going to be researchers in Europe like the Brorsons who study the "cyst" form of Borrelia burgdorferi and want confirmation of their own findings about persistence.

It's also going to be universities and health departments and many different organizations which may not have any particular position on whether or not Lyme disease can be chronic who will want to know the outcome of your study.

They're all going to want to know the outcome of a study such as Embers et al, so these researchers must be certain about what they found and its significance, and conduct additional research related to their findings in order to confirm them.

They must find evidence that no one can argue against - even the most skeptical - if they are to support their own hypotheses. And it may be that at this stage they genuinely do not know what to make of these persistent spirochetes and not only their ability to cause disease - but how they cause it.

I can easily imagine that Embers et al is being very cautious about the interpretation of their results and wanting further studies as easily as it is for other people to imagine that Embers at al were somehow instructed to downplay the significance of their spirochetes surviving antibiotic treatment.

Why do I say this? I say this because I have learned a few things about these stealthy bacteria and think there is good reason for Embers et al to be cautious about the interpretation and approaching their results either way.

Borrelia burgdorferi spirochetes, plasmids, and infectivity

After doing some research on this issue, the issue of whether or not these spirochetes were infectious and pathogenic or not is a more complex issue than it at first appears.

First, here's a refresher of some basic microbiological definitions. (Bear with me, I'll try to get through this part quickly.)

Infection = the replication of organisms in the tissue of a host; when defined in terms of infection, disease is overt clinical manifestation. In an inapparent or subclinical infection, an immune response can occur without overt clinical disease.

Colonization = A carrier (colonized individual) is a person in whom organisms are present and may be multiplying, but who shows no clinical response to their presence.

Pathogenicity = The pathogenicity of an agent is its ability to cause disease; pathogenicity is further characterized by describing the organism's virulence and invasiveness.

Virulence = refers to the severity of infection, which can be expressed by describing the morbidity (incidence of disease) and mortality (death rate) of the infection.

Invasiveness = invasiveness of an organism refers to its ability to invade tissue.

Now that we're past these definitions, I'll cut to the chase and say there are two important things to know upfront:

1) During in vitro passage or certain stressors, Borrelia burgdorferi can lose some of their plasmids. How soon this happens varies depending on the strain and particular isolates of Borrelia. 

2) When Borrelia burgdorferi loses specific plasmids with specific genes on them, it can lose infectivity and pathogenicity. It should be noted that specific genes for specific purposes can show up on different plasmids on different strains. (For example: Bb strain N40's VlsE locus is different from the one found on commonly studied B31, and it shows up on a different plasmid than on B31.) 

The essential bit of information here is that the loss of a particular gene or set of genes can affect spirochetes' ability to cause infection - and even if these genes are lost, spirochetes may still survive for a while. They can become attentuated or less infectious.

Numerous studies on Borrelia burgdorferi's plasmids have shown that lp28-1 is a linear plasmid which makes Borrelia burgdorferi infectious. VlsE genes found on lp28-1 are thought to be essential for mammalian infection with Borrelia burgdorferi.

When the lp28-1 and yet a different plasmid, lp25, are missing from spirochetes, they are unable to infect mice. The lack of lp25 completely abolishes infectivity since this plasmid encodes a gene (bbe22) which is essential for Borrelia burgdoferi's survival in mice.

Spirochetes which lose lp28-1 plasmids will still live for a while - but the immune system tends to mop them up in a few weeks without antibiotic usage.

Specific research on mutant spirochetes with a lack of the lp28-1 plasmid has shown the following:

"While the wild-type B. burgdorferi persisted in tissues for the duration of the study, the lp28-1− mutant began clearing at day 8, with no detectable bacteria present by day 18. As expected, the wild-type strain persisted in C3H/HeN mice despite a strong humoral response; however, the lp28-1− mutant was cleared coincidently with the development of a modest immunoglobulin M response. The lp28-1− mutant was able to disseminate and persist in C3H-scid mice at a level indistinguishable from that of wild-type cells, confirming that acquired immunity was required for clearance in C3H/HeN mice. Thus, within an immunocompetent host, lp28-1-encoded proteins are not required for dissemination but are essential for persistence associated with Lyme borreliosis."

To translate the above:

Normal Bb spirochetes infected C3H/HeN (mice which are specifically bred for the ability to demonstrate joint swelling and arthritic symptoms similar to those found in the average person who gets Lyme disease) mice and these spirochetes could not be cleared by the immune system despite the fact that these mice had a strong humoral response.

However, mutant Bb spirochetes which did not contain linear plasmid 28-1 were completely cleared by these C3H/HeN mice.

What's fascinating about this study is even though the mutant Bb spirochetes lacked lp28-1, these spirochetes could still disseminate. Only in severely compromised immune deficient mice (scid mice) could the spirochetes both disseminate and persist - acquired immunity must be functional in animals infected with such mutants in order to clear the spirochetes.

So, here is one example of how you can have spirochetes which are alive and metabolically active and  can even disseminate - yet they are no longer causing disease. In this instance, they were cleared by the immunocompetent mice without the use of any antibiotics within a mere 18 days. (I wish I were that lucky!)

More recently, other plasmids have been found to contribute to infectivity in mammalian hosts - such as lp36. lp36 is viewed as being another major contributor to persistent infection in mice, and spirochetes become attenuated when lp36 is removed.

Linear plasmid 28-1 and lp25 have a much longer history of their role in infectivity and pathogenicity, and they are two of the most studied linear plasmids thus far - lp28-1 the most because of its VlsE genes in strain B31.

So, keep this in mind when you think of the Embers et al study, and realize why this part of their paper on Rhesus macaques caught my attention:

"A few spirochetes grew in cultures of organ tissues collected post-mortem from each animal after  > 9 weeks, but we were unable to subculture any spirochetes from either treated or untreated animals due to their slow growth. We therefore pelleted these cultures to confirm their identity and test their viability by DNA/RNA analysis. Transcription was detected in culture pellets and the tissues of treated animals, indicating that the bacteria were metabolically active (Figure 6C, D). Figure 6D shows ospA transcription detected directly in tissues harvested from treated and untreated animals. We also hypothesized that persistent spirochetes may lose linear plasmid 28-1 (lp28-1), which encodes the VlsE antigen bound by the anti-C6 antibody. Transcription of a lp28-1 gene (bbf26) was verified in organ tissue from both untreated animals and one treated animal (Figure 6D).

In the case of Embers et al study on Rhesus macaques, one antibiotic treated animal was found to have evidence of transcription of a lp28-1 gene (bbf26 - protein; purpose unknown) from a sample taken from heart tissue (Fig. 6D) and that transcription should only be able to occur if the lp28-1 plasmid is intact and functional. lp28-1 is a linear plasmid which is very specific to infection both in vitro and in vivo, whether a tick or needle inoculation is used.

In Embers study, in addition to transcription of a gene from lp28-1, OspA transcription from lp54 was found in three treated animals. OspA transcription was detected in two tissue samples taken from the bladder and one tissue sample taken from the spleen. Additional OspA transcription was found in different organs in two out of three of the same animals using organ tissue culture pellets.

Overall, this sounds interesting and points to the possibility of chronic infection after antibiotic treatment.

 But if I have seemed cautiously optimistic about this study, it's because of a few factors*:

1) Only one treated animal had evidence of a infection where lp28-1 transcription was taking place - had more treated animals shown evidence of transcription on this plasmid, I would have been more excited. How long could spirochetes maintain these plasmids while being treated? What about lp25?

2) It is unknown to me if the genetic background and/or immune system of the treated Rhesus macaques somehow played a role in their inability to clear the spirochetes which remain after antibiotic treatment. (Refer to this post on HLA-DR types, read what's before and after the "=" signs, and you'll see what I mean.)

3) it is unknown to me how different the results would be if the Rhesus macaques had been infected using ticks instead of needle inoculations. It seems to make sense to me to do this study again using ticks because that mimics what happens in nature.

On the other hand, I find it very interesting that three animals showed evidence of transcription of OspA. Given how much inflammation people experience during Lyme disease - plus evidence of later stage antibody reactivity to OspA - it at least gives me pause to think about how often OspA has been a culprit for my own symptoms, directly or indirectly.

The only kind of spirochete
you don't mind getting close to.

So it's a mixed bag how I look at the results of the Embers Rhesus macaque study. I think it's a positive step in the right direction establishing what happens with spirochetes in their host after antibiotic treatment. And yet the unanswered questions for me seem related to the same unanswered questions the researchers themselves wrote in their paper.


Is There Anything Positive To Glean From Dr. Baker?


Of Dr. Baker's two major stated issues with the Embers study, the only one now left is whether or not the spirochetes which were transmitted by ticks to new hosts (xenodiagnosis) were in fact infectious. His other concern was over the use of ceftiofur in the study rather than ceftriaxone - however, the authors of the study have since posted a correction to PLoSONE stating that ceftriaxone - not ceftiofur - was used throughout the entire study.

If there are any remaining minor issues he has with the study, he has yet to share them on the Lyme Policy Wonk blog. Mostly, he seemed to reiterate his concern about these two issues and focused on the single mention of ceftiofur in the paper repeatedly.

About the most positive response I heard from Dr. Baker on that blog thus far was about his view of how Lyme disease research should be conducted:

"...I favor a multi-disciplinary approach that moves the field in a different direction, rather than solutions based on the assumed yet to be proved existence of a persistent infection that can only be cured by antibiotics. I don’t really discount such a view; rather, I feel we are neglecting other possibilities that may provide the answers we all are looking for. A case in point, would be the recent work of good friend, Armin Alaedini — who I helped support when I was at the NIH– using specimens collected by Mark Klempner as part of his clinical trial. These valuable specimens are being maintained by Mark in a specimen repository for use in just such cutting-edge research. They are available free of charge on request."

Like Pamela Weintraub, I agree that a multi-disciplinary approach to research on Lyme disease is important. And while Dr. Baker also supports a multi-disciplinary approach to research on Lyme disease and he states he doesn't discount the view of persistent infection in the above paragraph - his direct responses to patients suffering with CLD/PTLDS state that most patients are suffering from some other non-Lyme disease related condition - something I find particularly unhelpful to my situation. That and a lack of sufficient research on other treatment approaches has been an issue for ages.

In my opinion, Dr. Baker's response to the Embers Rhesus macaque study was more negative than it warranted. I wouldn't have viewed it negatively at all - I see it as a stepping stone in getting a better understanding about Lyme disease.  And just because it leaves unanswered questions does not mean it was inherently flawed - which was what Dr. Baker seemed to suggest.

To quote someone else on that blog:

"My question to Dr. Baker is why don’t you and your colleagues offer some expert advice, according to your best opinions and hunches if science really has proven inadequate for your epistemic standards of validity, without having to officially disclose any sensitive data that might get you in trouble with your career, that could actually HELP these affected people lessen their pain and disability? Just disparaging some controversial or technically flawed research as being invalid does not seem helpful enough to me."

Yes. This.

Regardless of anyone's opinion - Dr. Baker, or LLMDs, or my friends and family - researchers will be expected to provide evidence to the world that these remaining spirochetes are pathogenic. They will need to provide evidence that that they can cause infection and reproduce - even if they are already proven to be alive.

Researchers who are trying to work without bias will want to cover all the bases and check their postulates twice to be 100% certain that Borrelia burgdorferi either causes a chronic infection or it does not after standard antibiotic treatment.

This may be so - but I'm impatient about it.


References:

The Absence of Linear Plasmid 25 or 28-1 of Borrelia burgdorferi Dramatically Alters the Kinetics of Experimental Infection via Distinct Mechanisms. Maria Labandeira-Rey, J. Seshu, and Jonathan T. Skare. Infect Immun. 2003 August; 71(8): 4608–4613. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC166013/

Correlation between plasmid content and infectivity in Borrelia burgdorferi. Purser JE, Norris SJ. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13865-70. http://www.ncbi.nlm.nih.gov/pubmed/11106398

High- and low-infectivity phenotypes of clonal populations of in vitro-cultured Borrelia burgdorferi. Norris, SJ, Howell, JK, Garza, SA, Ferdows, MS, and Barbour, AG. Infect. Immun. 63:2206-2212.

Plasmid Stability during In Vitro Propagation of Borrelia burgdorferi Assessed at a Clonal Level. Dorothee Grimm, Abdallah F. Elias, Kit Tilly and Patricia A. Rosa. Infect. Immun. June 2003 vol. 71 no. 6 3138-3145 http://iai.asm.org/content/71/6/3138.full

Experimental assessment of the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Grimm D, Eggers CH, Caimano MJ, Tilly K, Stewart PE, Elias AF, Radolf JD, Rosa PA. Infect Immun. 2004 Oct;72(10):5938-46. http://www.ncbi.nlm.nih.gov/pubmed/15385497

The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi. Mollie W Jewett, Kevin Lawrence, Aaron C Bestor, Kit Tilly, Dorothee Grimm, Pamela Shaw, Mark VanRaden, Frank Gherardini, and Patricia A Rosa. Mol Microbiol. 2007 June 1; 64(5): 1358–1374. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1974800/?tool=pubmed

Basic Epidemiology. Beaglehole R, Bonita R, Kjellstrom T. World Health Organization, Geneva, Switzerland, 1993

* Factors which concern others but I did not originally think of are included in comments below.

[Edited March 9, 2012 - Removed item above about brain tissue after reviewing Embers paper again - multiple brain samples were taken; one treated animal was positive for B. burgdorferi RNA in both heart and brain.]

This work by Camp Other is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 3.0 Unported License.

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5 Debate About Embers Non-Human Primate Chronic Lyme Disease Study Continues

UPDATE - Feb. 27:  I did receive a response from Dr. Baker. See comments below this post.

There is some heated discussion going on at CALDA's web site regarding Embers et al study, "Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection (2012)".

I wrote about this study last month and commented on some of the findings and the need for further research and confirmation of the findings in this study. (I recommend reviewing that post and comments made on it.)

CALDA's Lorraine Johnson has questioned Dr. Phillip Baker, who was Program Officer for the NIH's Lyme disease research division at the time the Embers study began (then known as Mario Phillip's study; Baker retired from NIH in 2007 and is now in charge at the ALDF), over the 12 year delay of Embers et al publishing the results of this study.

Dr. Baker himself decided to respond to Lorraine's questions and respond to a number of the comments and questions patients and advocates shared on CALDA's Lyme Policy Wonk blog.

Interestingly, a number of people have discussed this study on Lymenet Europe - with one member, Henry, questioning the use of ceftiofur when Embers study was supposed to emulate Klempner's chronic Lyme study. This issue happens to be one of of main issues Dr. Baker also raises on the Wonk blog about the Embers study. (Warning: There are seven pages of spirited discussion on this topic at LNE thus far - some of which may raise blood pressure in readers.)

To follow the discussion and see an example of different points of view over the issue of chronic Lyme disease, read here: http://lymedisease.org/news/lymepolicywonk/lymepolicywonk-was-this-important-lyme-study-hidden-for-12-years.html

In the meantime, I have submitted my own questions and comments to CALDA's web site for Dr. Baker. As of this writing, my post has just cleared moderation and I await a response from Dr. Baker.

I want some answers. Not just about oversight for how the study was designed but about the lack of treatment studies for chronic Lyme disease patients.

Even if your position is that chronic Lyme disease is not caused by a persisting Borrelia infection, there is no reason why more research cannot be completed to provide evidence that this is or is not the case in some circumstances. And even if your position is that chronic Lyme disease's persisting symptoms may be caused by other factors, there is no reason why more treatment research cannot be completed to provide evidence either for or against these factors playing a role...

---

Dr. Baker,

First of all, I want to thank you for being here and presenting your view in the presence of Lyme disease patients who have different points of view than your own and who are at a minimum questioning your opinion about Lyme disease and at a maximum - quite angry.

This isn't an easy thing to do. I recognize that. But this is a necessary thing to do, and I wish that more dialog occurred between people with differing views even at the risk of it becoming contentious. It is often the only way opinions get aired and heard and questions get answered - even if we don't like the answers we hear.

I have a few questions for you, and hope I did not miss the boat on getting a response from you at this late hour:

1) Just so the storyline is clear: Who determined that ceftiofur should have been used in Embers et al study on NHP and is this decision something that NIH would have had to give approval - or is this a decision that would have been made at the individual level of the PI/researcher and not require any approval from the NIH? Would any independent governing scientific board outside the NIH been expected to approve of the study design including methods and materials? It seems that in order to emulate the Klempner study, the antibiotic chosen should either be the same as used in the original study or have, as you've stated, PK and PD that are pretty much indistinguishable from ceftriaxone.

2) In your opinion - and in the opinion of others at the ALDF - would you have to see studies separately completed on ceftiofur that provide you with evidence that its PK and PD in NHP are functionally equivalent to the use of ceftriaxone in humans? If these studies are conducted and they are found to be equivalent, then would you say that the results of the Embers et al study are valid? (Even if - according to your position - they don't yet prove a persistent infection/persister cells are the cause of patients' symptoms.)

3) The central point on which a lot of this debate hinges is whether or not spirochetes which remain after antibiotic treatment are viable and infectious. I've never gotten the impression that the majority of researchers out there have debated the existence of spirochetes after abx treatment - the impression I've had is that they either didn't think they were the cause of persisting symptoms in patients or did not know one way or the other if they were the case of persisting symptoms.

Parallel to demonstrated survival of some spirochetes after abx treatment, some research has indicated that a combination of Borrelial strain, host genetics, immune system response, and in some cases, molecular mimicry - may be causative factors for persisting symptoms. I myself think that based on evidence I've read to date, both persisting spirochetes and immune system changes can lead to persisting symptoms. I am particularly intrigued by HLA-DRs and variable immune response in this regard (see "HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens" by Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.).

My questions are:

When is the NIH-NIAID going to conduct more studies aimed towards this end? And also, if you and others are convinced that chronic Lyme disease patients are not suffering from persisting infections - why hasn't more treatment research been conducted that supports your point of view of what is or what are the causative factors for such symptoms?

Why are patients, advocates, and Lyme disease advocacy organizations having to donate money to Dr. Karen Newell Rogers and Viral Genetics to find alternative treatments to long-term antibiotics - why isn't the NIH-NIAID pursuing these alternative approaches now, if the argument is that long term antibiotics do not work and you consider them unsafe (Which in my opinion debatable in my eyes - I have personally benefited from more than the guidelines recommend - and I do not think the use for or against more abx is applicable to everyone because this is a heterogenous patient population. The patients need to be characterized into subgroups first rather than boxed into meeting CDC specific requirements before designing new trials.)?

I have been offended with the letter to the Lancet about Lyme disease patients and advocates supporting pseudoscience when so many of us have wanted to fund more research and get answers. When a number of our friends and families have donated their money to research even when they have already paid so much for treatment.

Some of the answers are already there. If more than one hypothesis is solid enough for testing, I'm for it. Test different combinations of antibiotics. Create drugs which have the anti-inflammatory properties of these antibiotics and use them as a control against combinations of antibiotics. Use higher doses of orals, if the fear of line sepsis freaks you out (it does me, and I have not had a PICC line by choice). Try testing thymus peptides and altering the distribution of B cells to see if that helps patients.

What I see as an observer is that Lyme disease treatment research has been shut down unless it's for acute Lyme disease. We need more late stage untreated Lyme disease research, and I'm with Fallon on this one - more specific neuroborreliosis research. His suggestions for those trials seem worthwhile.

But for God's sake, something has to be done. Some people are seriously impaired. I am doing somewhat better now and have my mind back to a large degree and don't need a wheelchair. But I am not yet well enough to work due to pain and fatigue with normal amounts of exertion. Something is broken there.

---

Dr. Baker's response to me:

Hi Campother,

Even though I feel that some have their minds made up and will not believe anything that I have to say, I will try to answer your questions:

1. Dr. Philipp received a small grant (AI042352) to conduct an experiment in NHPs to replicate the Klempner clinical trial, except of course for the manner in which the NHPs were infected. Because the grant was a small one (about $250K as I recall), Dr. Klempner was able — with support from the drug company– to provide him with the ceftriaxone and doxycycline to be used; these antibiotics were from the same lots used in the human study. Fair enough? That made working on a small grant a bit easier. 

Since NHPs are rather expensive to use and maintain, not too many could be used in the Philipp study because of limited funding. Furthermore, NHPs were in short supply at that time because of increase competition for use in studies on AIDS. The grant was funded for a 4 year period of time, during which time Dr. Philipp reported to me that he was having technical problems, especially with the strain of Borrelia that he had been using in past experiments; it appeared to have “lost its punch” and was no longer eliciting an infection of the same magnitude and character as noted in previous studies. This meant that he would have to re-drive the strain and test it in other NHPs to confirm that it was suitable for use in the definitive studies planned for the grant; that of course would take a great deal of time — and additional NHPs–to do. 

Although situations like this are unfortunate, they do happen and are part and parcel of the realities of doing scientific research — if you want to do it right. 

So, as far as Dr. Philipp’s original grant is concerned, it expired — after the 4 year period– with no data that he felt was was ready and complete for publication at that time. Obviously he continued with his NHP studies and apparently received funding from other sources; note that research Resources grants like RR00164 are designed for the purchase materials, equipment, and supplies, in this case, more NHPs I assume. But, I was “out of the picture” at that point — as far as Dr. Philipp’s research on NHPs was concerned. Keep in mind that as Program Officer, I was not the czar of NIH’s entire research program on Lyme disease, even though so people have the mistaken notion that I had such “power”.

So, you ask who made the decision to use ceftiofur instead of ceftriaxone? I honestly don’t know. 

You will have to ask Dr. Philipp, whose e-mail address is provided in the Embers paper. During the time that Dr. Philipp was doing his work under AI042352, it was being done in accordance with the terms of that grant indicated above. Whatever else he did — or may have done– must have been accomplished afterwards and with other support that did not involve me or NIAID. I must say that I find it strange that the term ceftriaxone is used throughout the Embers et al. paper, and it is only in the first paragraph on page 9 that it is first mentioned that ceftiofur was actually used. I find that very strange indeed.

As stated before and in other postings on this site, I have two major — and legitimate– concerns with the work reported by Embers et al. . First, since so little is known about the PK, PD, and MIC of ceftriofur, was the treatment adequate to eliminate the massive infection induced by needle inoculation? Since the author did not provide such assurances, that is a major and significant unknown. Second, if the therapy was adequate, there is no evidence to indicate that the “persistors” are able to infect other animals and produce disease. They might just be sitting there, for all we know, doing nothing harmful to the host. In view of these considerations, the PCR, RT-PCR, and xenodiagnosis data are not informative. In fact, there are no real differences between the antibiotic treated and sham-treated groups in terms of the objective signs of infection (pathology) noted ; that makes me wonder if the therapeutic regimen was truly effective. So, if I were reviewing this paper for publication in a journal, I would have to reject it publication for these and other deficiencies that I will not elaborate on at this time.

2. Since ceftiofur and cetriaxone differ significantly in chemical structure, I would not be at all surprised if they had different PD/PK properties; those who do drug design research find that the addition of a single chloride atom is enough to alter the properties of some drugs. What is certain is that ceftiofur is not approved for use in humans and there is no published evidence on its efficacy for treating borreliosis in animal models. Obviously, the use of ceftiofur is a big unknown. My best advice, if someone wanted to replicate the Klempner studies in an animal model would be to use ceftriaxone and doxycycline in the same manner that he did and not introduce another variable like ceftiofur– unless you plan to get the FDA to approve the use of ceftiofur in human studies. That may take a long time to do….

3. Since I have retired from the NIH, I don’t know what their plans are for future research on Lyme disease. But, I can tell you that about 90% of the research that NIH supports is driven by proposals submitted as investigator initiated grant applications — the RO1 grants. 

So, if anyone has any good ideas, they are always welcome to submit a grant application, although competition for grants is very keen and only about 25% of all applications submitted are funded. One has to be persistent as most of my colleagues are to make it in science. 

Although I am not opposed to conducting another clinical trial, the odds for such a proposal getting funded are rather slim, especially since NIH has already supported 4 trials indicating that extended antibiotic therapy is not beneficial. 

Obviously, I would like to see more work done on whether the “persistors” Bockenstedt and Barthold noted in mice are infective and can cause disease, as well as whether they can stimulate a local inflammatory response. But, I think we would be making a big mistake by not considering other possibilities as I’ve mentioned in a recent article (http://www.fasebj.org/content/26/1/11.long). 

There are MANY people who believe that they have “chronic Lyme disease” with no evidence that they ever had Lyme disease in the first place. Some have been misdiagnosed and are being subjected to all sort of unproven therapy. Also, there are individuals who go from one doctor to another seeking a “cure” and who often are victims of “quack” remedies. 

One reason we had so much difficulty enrolling patients into the Klempner study was that only about 5-8% of those who presented themselves for enrollment had unequivocal evidence in their medical record of having been diagnosed correctly for Lyme disease in the first place. Obviously, one can not have a chronic infection without first having an active and correctly diagnosed infection in the first place. That was made a criterion for enrollment to ensure that we would have a cohort of patients with a reasonably high — though still not absolutely certain– probability of having a persistent infection — if one were present. I assure you, and you can ask Brian Fallon and Lauren Krupp, such people are NOT easy to find.

But, I have said enough. The biggest obstacle to making any progress is the lack of trust and the tendency to condemn anyone in the scientific community who disagrees with the unproven concept of others. Some simply have no understanding of evidence-based research and how it works, let alone things like the placebo effect. There is just too much misinformation being spread on the internet — and too many people gobbling it up as though it were fact. It’s an ideal environment for all the “quacks” to thrive — and they surely do. And that is what disturbs me the most………

---

So, there you have it - that's his response, and while I posted a response to the Wonk blog, because my response was too lengthy it has not been posted there. So I posted it to comments below, after an explanation of why my response was not posted there.

The moderator emailed me personally and said that I could post another 150 word comment of my choosing, but I have declined for now because I don't think what I can say in response to Dr. Baker is adequately summed up in 150 words.

There was a second comment with other content which I submitted that I later decided needed a serious rewrite before posting - I won't be posting that here now and am okay with the moderators not publishing it (good job, mods - thanks).

I just want to take a moment here to acknowledge those who left intelligent and insightful questions and comments on the Wonk blog - even when addressing someone with whom they vehemently disagree. I would like to see more dialog such as this, but even more so I would like to see more thorough education and outreach going on which deconstructs all the hypotheses behind why chronic Lyme disease patients have persisting symptoms and what research is required to resolve the debate over cause.

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21 Rant: Why Dealing With Lyme Disease Drives Me Crazy. (Part 2)

Note: The content that follows is part two of a personal rant and is atypical of most content as well as context covered by this blog.

This is part two of a two part rant. Part one can be found here: http://campother.blogspot.com/2012/01/rant-why-dealing-with-lyme-disease.html

To continue where I left off, and to share other reasons as to why dealing with Lyme Disease drives me crazy from a patient's perspective:

7) Because the organizations and institutions which have the most influence on treatment and research for my condition are engaged in a political battle of the wills where if "you ain't with us, you're against us". It's a position where being in the middle is difficult at best.

Most patients with persisting late stage untreated Lyme disease and those with post treatment Lyme disease have voted to stick with ILADs doctors and other non-ILADS LLMDs for treatment, and support the organizations and advocates which support ILADS and other LLMDs. They think that a chronic infection is the cause of patients' persisting symptoms.

Most chronic Lyme disease patients and advocates view the IDSA Lyme disease guidelines group as being highly restrictive in terms of treatment of their disease, and not only that - think that the IDSA Lyme disease guidelines group does not care about patients and only cares about profit. The IDSA guidelines group thinks that some autoimmune condition is the cause of patients' persisting symptoms.

One segment of the chronic Lyme disease patient population has grown a general distrust of scientific researchers and allopathic medicine in general. This growing group of patients voices its dissent against not only the IDSA - but any group which may be viewed as profiting off of those with chronic illness in some way: The FDA, pharmaceutical companies, government and non-government researchers with patent rights to their technology, grad and post doc microbiology students, and then some.

Watching all this go by and unfold,  the position I'm in is that because I am not interested in completely aligning myself with any one of these groups in this battle, that I have been viewed by some patients as not being loyal enough to the chronic Lyme cause and not loyal enough to supporting alternative medicine. And for some small portion of my readers,  I'm not loyal enough to the hypotheses about chronic Lyme disease which the IDSA espouses, either, because I have this seemingly odd idea that some people may need more than the standard amount of antibiotics set out in their guidelines.

Because of this, sometimes I have not been able to get the support and understanding I need as a patient from other patients going through the same thing - presumably because they view me as fence sitting and it makes them feel distinctly uncomfortable. Heck, last year I was even banned from participating on one Lyme patient support group - so I have a sign that at least to some people, I'm not welcome.

But I'm not here to make people feel uncomfortable. It's not what I want to do, though I acknowledge that some of what I write may bring up uncomfortable feelings. What I do want to do is figure out what the truth is in this area full of conflict and get a greater sense of it. Move past any ideological conflict and look at the science. This is why I do research and try to avoid what all the pundits are saying - whether they are pro or against something - whatever it is.

I think that what causes persisting symptoms in patients is not a one answer deal, after all the research I've read. It's not that simple. And I wish that all of those involved in the study and treatment of Lyme disease would come forward and say that, and admit that they do not know what the best treatment is for everyone.

We need a different starting point than where we've been gridlocked over the treatment for the past two generations of Lyme disease patients. Why can't more people consider that those with persisting symptoms may have them both due to persisting infection as well as changes to the immune system? Or that the cause may differ in different patients? Do more research into how different strains of Bb and genetic backgrounds (e.g. HLA-DRs) of patients influence outcomes?

Two of the most supportive and outspoken figures in the Lyme disease community see the need for middle ground as I do - Pam Weintraub and Dr. Brian Fallon. I think we need more middle ground to be covered if we're going to make any progress on understanding chronic Lyme disease and getting better treatment for it. More research is really the key. More fighting over cause is not.

8) Because parts of the mainstream media continue to sensationalize this taking of sides and fails to examine and share all the scientific evidence available (and areas where evidence is also lacking on either side) about my condition, it contributes to the growing problem of scientific illiteracy in this country. It also contributes to dismissive attitudes towards patients with my condition.

I don't know how to say it enough or loudly enough to be heard: The Chicago Tribune's article, "Chronic Lyme: A dubious diagnosis" is exactly the kind of journalism that fails to address the issue of chronic Lyme disease from a scientific perspective.

I spent a fair chunk of my time deconstructing the article and pointing out how it was about two doctors' disciplinary records and flawed alternative treatments for chronic Lyme disease - rather than about whether or not Lyme disease could actually be a chronic infection. That issue is never really discussed throughout the entire article when one would think that based on the title that would be exactly what it would have been about.

Whether one believes chronic Lyme disease/post Lyme disease syndrome is caused by a chronic infection or not should not affect the fact that patients are suffering from a condition which is not "all in their heads".  Articles like the above characterize doctors and patients in the worst light without getting the full picture or an accurate one, while simultaneously failing to examine, state, and challenge the range of research on the disease itself. Anyone reading that article would walk away not having learned more about Lyme disease in general - let alone any reason why some people may think it can be a persistent infection and other people think it cannot.

This article is not the only article or the first article to become a meal to feed the trolls. There have been others. And because so many of these sensationalist articles have been printed, they have made it more difficult for the public to take my condition seriously. A condition which - as you may recall - an academic researcher said that at its worst was equal in severity of symptoms and lack of functionality in patients with congestive heart failure.

9) Because having my condition has been life changing and entirely game changing for me. All the plans I had before I got ill have been completely trashed. Many opportunities I would have said "yes" to I ended up having to turn down. And as such, for a number of these plans and opportunities - there are no second chances.

This is the same story that many people could say about other conditions, I know: Car accidents leave people with injuries and disabilities that can affect them for the rest of their lives. Cancer and many chronic conditions can affect people for the rest of their lives, too. Someone with my condition shares this much in common with many other people. And we might improve; we might not. No one knows.

That said, I can not easily describe just how much I have lost to my condition and complications related to it. Lost income and the loss of my career and the ability to work, lost opportunities to travel and go hiking in the mountains, lost time spent with friends and family because of illness preventing me from participating in events, lost positive life changes such as buying my own home and filling it with the things I want... all of these things and more have happened to me and many other people.

But these are the big things. Sometimes even the small things can be a noticeable and painful loss. Not being able to wash my own back put me at an all time low when it happened.

10) Because just living with my condition and all the symptoms it causes is crazymaking, and few people really understand it.  They don't "get it". Seeing someone with a broken leg makes it clear to someone else that something is wrong and what their limitations are - seeing someone like me makes it clear as mud what is wrong and what my limitations are. And things change from day to day.

This is a more difficult thing to explain, and perhaps some of it can be better articulated by web sites about invisible illnesses. My own attempt at it is to say imagine that you have a splitting headache almost constantly, have trouble taking full breaths day and night, your muscles ache - and ache worse with any repetitive motion, even after a short period of time, and your joints ache all over your body. And no one can see the pain you are in. At most, they can see you are moving more slowly than they would be. But other than that - you appear normal to them.

And tomorrow, those symptoms might change. But still be limiting and make you dysfunctional in different ways.

This is a small snapshot of how life has been for me. Sometimes it's better, sometimes it's worse. But if it weren't for walking around with a cane or borrowing a scooter to get around, a lot of people may not see that anything is wrong with me. Someone with a broken leg has the benefit of an obvious visual sign they are messed up. I don't. And because of this, some people have either forgotten I'm not well when they next see me - or worse, don't believe I am unwell in the first place.

And if I am at home in bed? That's a truly invisible illness - out of sight, out of mind.

That is its own problem: lack of external confirmation and validation of my condition.

Another problem related to this is my not knowing what to expect from my body and to expect from myself from one day to the next - and sometimes one moment to the next.

I may be able drive to the doctor's office, the hardware store and grocery store and come back home and still have the strength and energy to do something else the same day. I may not, and have trouble getting out of bed at all. On those days - if I get back and forth to the bathroom - that's my travel for the day.

Attached to that is a host of problems around how difficult it is to make plans and keep them, and the economic, social, and other costs that come with poor follow-through.

I feel alienated about living in my own body. It doesn't cooperate with what I want and need to do. And at times, the pain, fatigue, and isolation are hard to bear. I hurt. I've lost sleep on many nights because pain kept me awake. I've had to struggle through that pain alone, and wished there was someone to keep me company through it - yet at the same time, did not want to subject anyone to my misery.

Sometimes I don't even want company - and the funny thing is, during those times I don't like my own company, either. I become a total ass. I find my own ruminations while ill to be counterproductive and leading down the path to a dark and deep sense of hopelessness, one where there is no point in making plans for the future because I'm likely not able to keep them anyway. Serious depression here.

And even when I reach a stretch of acceptance of my condition and its limitations (and there is acceptance, but it's part of an ongoing process where it is revisited and not a destination where I can park),  living with it is still so damn HARD...

When I am around other people, I feel like the ghost at the table. I am there, but mentally and physically not solid. I can affect things, but only indirectly and weakly compared to one's normal human form. I can hear people and engage in conversation with them, but from my own perspective it always seems as if there is a thick layer of atmosphere I have to communicate through where speaking requires extra force to push the words out of my mouth and listening is like trying to decipher the words of people talking underwater. All of this communication takes extra effort I never needed to make before I got sick. I never would have even imagined one could get sick in such a way that normal social interaction would be draining. This is what chronic fatigue and brain fog are like. I didn't know it until I got it.

This is hard on an extrovert, and over time I've had to become more and more introverted in order to cope and adapt to my condition. I "don't have any spoons" to be the energetic and engaging person I used to be. I don't have it in me. Only a few people close to me are lucky enough to see a glimmer of my former self for brief moments of time.

In a very real sense, my condition has robbed me of being me. Which is one of the highest insults I can imagine any condition causing to anyone. I've been forced to become someone I do not want to be because of my condition. How sucky is that? It's pretty sucky.

So this is the end of part 2 of why dealing with Lyme disease drives me crazy. Maybe there will be a part 3 sometime in the future - I don't know. For now, I'll leave it at this.

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3 Pam Weintraub at 2010 IOM: on being in the middle

I realize that in my rush to write extensively about the Chicago Tribune's *clears throat* journalism... I hadn't mentioned what brought my mention of Pamela Weintraub to my blog in the first place, and why what she said is such an important part of gaining acknowledgement of Chronic Lyme Disease and beginning to understand the complexity of tickborne illnesses.

During the October 2010 Institute of Medicine (IOM) workshop, Pam gave a presentation and told of her own personal experience with Lyme Disease, an experience which has been written about in Cure Unknown and also issued as a written statement for the IOM.

This story - as usual - is gripping and hits me to the core, as it does many Lyme patients. But as much as that was gripping, what was said during the Q & A session afterward was more thought-provoking because I hadn't heard it before:


Lonnie K  (IOM mod) asked:

"Question for Pam: What do we need to do to find common ground and move forward?"

And Pam said:

"This very polarized fighting is the most destructive thing out there and #1 reason so many people are so sick out there and we’re still here. So many other journalists have capitalized on the sound bites of either side and the drama. For me that’s a distraction to the story. 

When I went out and interviewed many people of high expertise, most scientists working with this on a deep level were very intelligent, thoughtful people who had very nuanced ways of looking at this. And in the nuance I was able to see a path. But when you pull back out and read these articles about the controversy, it becomes shouting that drowns out the actual complexity and nuance... and work we need to do. 

I don’t know what can be done. Patients are very angry, I understand, look what happened to me with a classic case in my son and I had to go to doctor to doctor. There was such a political sense of staying away from Lyme or finding other diagnoses first. I don’t know how to heal this. I think there are people who can work together to heal this, but they’re not the people at the extremes... they’re the people in a center space. I wish everyone could get there together because then perhaps patients could be healed. This can’t be dumbed down, it’s not going to get us anywhere."

This.

This entire response that Pamela Weintraub said where the Lyme controversy can only be dealt with by those who are coming from the center space, or middle.

I want to know how to find that center space or middle, too, if that is what is going to get me and others out of this mess.

I know some of you absolutely love Pamela and she did a tremendous amount of work on Cure Unknown and help in getting the Chronic Lyme patient's story across. (You should know, by the way, that she does not use the term "Chronic Lyme" for herself, and I may follow suit, regardless of the familiarity it brings - read about it in comments here.) I also know that some of you who are reading this blog might find her to be an unreliable source of information because she is a science journalist and not a scientist, and many a science journalist has oversimplified the facts or missed a crucial piece of information that would change the entire message of their article had they published it. Everyone is entitled to their opinion, of course.

That said, I think Pam is right about this one: Fighting and polarizing this issue for years - and I mean years - has not gotten people very far in terms of acknowledgement and treatment. 

I'm glad a few bills got passed to protect doctors who prescribe long-term antibiotics - that certainly helps patients in some ways - but it is a case of too little, too late, for many patients. Including patients who should be getting their treatment covered by insurance and not selling their homes to finance it. 

How do I think we can work from the center or the middle? Difficult question. I'll take a stab at it, though.

I think it requires taking a step back and assessing where we are as patients, activists, advocates, and those standing alongside them. What are we doing? What are our goals? How do we spend our time?

It requires knowing who and what your detractors believe and why. What is at stake for them? Does all of the IDSA believe as the guidelines panel does, or do some of that 8,600 have doubts or never even really learned about Lyme Disease and other tickborne infections?

I think it requires uniting all the patients and their advocates and working toward a common goal, not twenty or two hundred different ones, all with their own personal bent.

The AIDS community was able to rally their efforts together for a cure. In ten years they ended up with a treatment that has extended their lives so that many are now living long lives HIV+; working and playing while managing their condition. And there is ongoing work on a cure, though they're not there yet.

Ten years.

We've been at this shit with Lyme for what? Over thirty years? Beginning with Polly Murray?

It's been said that the AIDS community could only get the attention for their disease because it was immediately clear it was sexually transmitted and transmitted through transfusions, whereas Lyme Disease is not (though I know there is speculation about both of these, let's put these issues aside for the time being - it's not really relevant to where this is going right now). And this may be true, but this is not a good reason for Lyme Disease and other tickborne infections to not get attention. 

The one thing the AIDS community had that the Lyme community currently doesn't have is enough commonality of direction. Each group has its own drives towards somewhat different goals (though there is overlap) and groups are not united enough towards one specific goal. Unfortunately, the one thing the Lyme community currently has that the AIDS community did not have is one select group of panelists setting the standard of care for Lyme Disease and other tickborne illnesses worldwide - and not even just the US, which is its intended jurisdiction.

If what Dr. Willy Burgdorfer says is true - that 30 years of research has produced the same thing  - nothing - and the development of new serology has to be started from scratch; if he and other researchers say that Borrelia can persist and symptoms can vary based on genotype - then what is needed is more research and for the word to get out about existing research from the researchers themselves.

Science is what turned things around for AIDS patients. Science can turn things around for Lyme Disease and tickborne infection patients as well.

I don't think anyone should have to wait for a cure to continue treatment, and as long as we have LLMDs there is a shot at getting it. But I do think in order to continue to justify the need for treatment (I know, crazy isn't it? People need treatment now!) and to make it more widespread, that the first goal should be to make sure the case for persistence in humans and its significance is beyond questioning. 

Otherwise, there may always only ever be a handful of LLMDs treating this. Is this what everyone wants for their children? For their family? For their friends? 

I'm concerned about it, because watching changing epidemiological Lyme Disease (and other tickborne illnesses) data for humans and animals together is scary. It's only going to get worse as time goes on. And then we'll have what... even fewer doctors treating even more patients? Or worse - just more people who are sick and without treatment?

Instead of beating at the brick wall that is the guidelines panel, look for Volkman and others who have rejected it. How about Dr. Luft and Dr. Barthold's new research? How about more research that's already been out there for ages that needs to be brought to light?

How about pushing for clinical trials with larger patient populations - to prove persistence in human patients, and not just whether or not specific long-term treatments with antibiotics will work or not? 

Those four clinical trials with small sample sizes that get cited ad nauseum? What if they weren't about long-term antibiotic treatment, which many medical professionals are loathe to touch? Have trials that show persistence first. Incontrovertible proof.  

Then it will be much easier to get better-designed long-term antibiotic trials done and push for research for better antibiotics and other medications. Antibiotic R & D has been incredibly behind the curve in years and that alone is going to cause problems in the future.

Heck, I'm about ready to sign up and have someone take a biopsy from me from several places - those places are hurting anyway and that isn't going to change any time soon from my experience!

Instead of tearing at your neighbor there on Lyme-whatever-group who is arguing with you about the value of detoxing and bouloke or Samento, put your enmity aside and work towards the issue of persistence. You can still make whatever choices you're going to make. But I think this one is going to be a big one to not duck out of. Because once peristence and its significance is established beyond a doubt, then all the naysayers on the Tribune and the panel and science blog and god-knows-where-else can STFU and there will be support for antibiotic and antiprotozoa treatment, where and when it is needed. And insurance should cover it, and doctors will stop getting cited and disciplined for treating.

I think this is THE issue: persistence. 

Not whether or not you need to challenge someone's posting because they said something about treatment you disagreed with, or because you want to use an herbal treatment like Buhner's or Zhang's protocol instead of antibiotics because you can't afford the antibiotics, anyway. 

All those issues? They are detracting from the main one underlying it all. All those issues will still be there as you live your life day to day, but in the meantime progress will really be made if this one issue - persistence - is worked on. 

And all those issues? A lot of those issues are bound to become non-issues if everyone's access to treatment improves and more research is done to develop better antibiotics and other technologies to stop persisting Borrelia and other infections from wrecking havoc on your body. And if it turns out that there is an immune dysregulation process going on, that will probably also be confirmed in the process of looking at persistence. But it isn't going to happen unless research is encouraged in that direction.  Otherwise, it's just going to remain someone's seemingly unsupported speculation of some panelist's wet dream of what is happening in "Post Lyme Syndrome" until then.

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0 Science journalist critiques Chicago Tribune Chronic Lyme Article

Last week, The Chicago Tribune posted an article,"Chronic Lyme Disease: A dubious diagnosis" that was intended to not only dismiss the existence of Chronic Lyme Disease, but also lump it in with discussion on a number of other issues that were not solely the domain of this disease such as doctors who make errors, unproven alternative medicine practices, and conspiracy theories.

The sad question I have to ask after reading it is this: Where is the science? There is nothing educational or informative about this article which reads like a sensationalistic tabloid piece that seems out of place in a newspaper like The Chicago Tribune.

Apparently, Paul Raeburn agrees with me. Or I agree with Paul Raeburn. Either way, he took this article to task today in the Knight Science Journalism Tracker for its lack of attribution and lack of drawing opinions from experts from both sides of the debate over the existence of Chronic Lyme Disease.

So far, only a few people have responded to Raeburn's critique, and most notable to the Lyme patient advocacy community was Pamela Weintraub, author of Cure Unknown. I look forward to seeing more intelligent comments there, and if possible, on the original article in the Tribune.

I have my own thoughts about this and will write more on it tomorrow.

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