Friday, March 9, 2012

10 Dr. Barthold Discusses Persistence On Diane Rehm Show

Several days ago,  Dr. Barthold was interviewed on the Diane Rehm Show on NPR. A full transcript to that show can be found on the WAMU radio/NPR web site, if you are interested in seeing what Dr. Auwaerter, Dr. Fallon, and Dr. Shor had to say about chronic Lyme disease.

I find what Dr. Barthold had to say about persistence to be very interesting.

(EDIT: Unfortunately, the strict terms about republishing any portion of the transcript were pointed out to me and I had to remove Barthold's quotes from this page - please refer to the transcript above in following what I say below.)

Did anyone else listen to the show or read the transcript and catch what he said about this:

The remaining organisms - potentially these persister cells - are in connective tissue and not eliciting inflammatory change. He sees very little inflammation in the animals he has tested and in which he found persistent spirochetes.

Yet when he removes the bacteria from a mouse and puts it in a new mouse, the spirochetes cause inflammation all over again.

What's up with that? Pretty strange, isn't it?

Can one form a hypothesis about why this is happening or at least take a shot at it?

I have a few ideas about this and will be putting them in comments in this post over the next few days, providing readers with the disclaimer that they are hypothetical and not to be taken as confirmed fact. Someone else will need to do the research on this issue.

Does anyone else here reading along have their own hypothesis about why this is happening - why after antibiotic treatment, he found persistent bacteria in these animals - yet they are not causing inflammation?

10 comments:

  1. Hi Yes it was a very significant interview. I was going to post on my blog but there was something on the website about copyright that put me off. Anyway one of the things in my experience with Lyme is that most if not all my symptoms seem to be related to inflammation and yet the usual markers of inflammation are not raised as would normally be expected. My SED rate went up to 27 which I was told was normal for my age 56 at that time- for PMR which I had been diagnosed with at the time it was meant to be in excess of about 75. Now interestingly as I started to get so much better my SED rate came down to 8.
    So for me perhaps an increase to 27 from a normal of 8 was significant.

    Perhaps the problem is more in our testing methods for inflammation after all there were in my case other markers of inflammation- Bursitis and x rays of hands showing inflammation of interfalangial? joints.

    Example if we get a tiny splinter in our finger inflammation can cause pain swelling and discomfort way in excess of what you would think for such a tiny splinter. If we have similar tiny organisms in many areas of our body then the resultant whole body inflammatory reactions could be debilitating and painful but still not necessarily registered as high inflammation such that we would have in an acute infection from some other illness.
    Lyme can be an insidious chronic illness as we all know in it's chronic stage perhaps we become a little more tolerant to the organism however if it is injected into the mouse in it's acute phase of illness then perhaps the inflammatory markers are higher.

    Certainly in my early stages of illness when I had the summer flu' it would have been interesting to have known what my inflammatory markers were then.

    ReplyDelete
  2. Joanne,

    Just going to respond to this part, first:

    " I was going to post on my blog but there was something on the website about copyright that put me off."

    I just went back to the link and only now noticed that statement about republishing on the bottom of their page. That is surprisingly restrictive for a site which is I believe supposed to be tax payer funded - NPR is national public radio here and is funded by donations and I think in small part by the federal government.

    Nonetheless, I will now have to edit this post down to the link and respond to the rest of your comment later.

    ReplyDelete
  3. Joanne,

    You said,

    " Anyway one of the things in my experience with Lyme is that most if not all my symptoms seem to be related to inflammation and yet the usual markers of inflammation are not raised as would normally be expected. My SED rate went up to 27 which I was told was normal for my age 56 at that time- for PMR which I had been diagnosed with at the time it was meant to be in excess of about 75. Now interestingly as I started to get so much better my SED rate came down to 8. So for me perhaps an increase to 27 from a normal of 8 was significant."

    That's interesting. You had a SED rate of 27, it was supposed to be over 75 for PMR - yet they still diagnosed you with PMR? I imagine you must have had (to them) other clinical indicators of PMR if that SED rate was that low. I wonder how many other patients get their SED rate regularly tested during antibiotic treatment, and if they have a pre-treatment test done? Have you been able to compare your SED with anyone else?

    "If we have similar tiny organisms in many areas of our body then the resultant whole body inflammatory reactions could be debilitating and painful but still not necessarily registered as high inflammation such that we would have in an acute infection from some other illness."

    Maybe. It's something to think about, certainly.

    When I think of your analogy with the splinter in the finger, I think of this picture that is part of Embers' study. Here you see a lot of inflamed tissue with monocytic and lymphocytic infiltrate in it - but the spirochete density in the same tissue is very small. There can be a lot of localized inflammation relative to the low number of spirochetes present in tissue.

    But Barthold is saying he sees very little inflammation. I wish he could quantify that, and come up with his own analogy so we can easily visualize what he's talking about.

    "Lyme can be an insidious chronic illness as we all know in it's chronic stage perhaps we become a little more tolerant to the organism however if it is injected into the mouse in it's acute phase of illness then perhaps the inflammatory markers are higher."

    Don't know. I can speculate about this, though I'd have to think about it more and read more?

    Do we become more tolerant, or immune suppressed, or it is possible that if there are a few of these persister cells, that they aren't generating that much inflammation when they're in a low metabolic state?

    I know that persisters in general are protected from the immune response by the extracellular matrix - maybe after a round of antibiotics, they're left there, and those spirochetes which are not persisters get killed off and there's an immune response and inflammation generated by that - but the persisters just kind of sit there, oblivious to it all. If they aren't growing or only slowly growing, they might not trigger an immune response - followed by inflammation - until conditions are right.

    And maybe when they are in a new mouse, inflammation is triggered by a new immune response to presence of the spirochetes?

    ReplyDelete
  4. Perhaps there is something to do with the undulatory immune response http://www.isrn.com/journals/immunology/2012/719821/ and perhaps something to do with Borrelia going to the lymph nodes and although producing inflammation not being able to clear the infection.
    http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002066

    Whatever, it is all far too complex for me to understand or explain but inflammation was the most obvious sign in my symptoms and 20 months of steroids for wrong diagnosis only managed to suppress the symptoms a little whereas antibiotics taken long term has restored my health. Although a year without antibiotics and inflammation is creeping back in some areas again.

    I liked your analogy with the picture in the Embers study.

    Aside from this Prof Luc Montagnier Nobel prize winner has been taking quite an interest in Lyme disease recently and was interviewed again on French TV saying it as is - well by our experience rather than IDSA opinion. As soon as I get the U tube copy with English subtitles I will pass it along.

    ReplyDelete
  5. http://www.youtube.com/watch?feature=player_embedded&v=LRQ-NhEkLXU#!
    Prof Luc Montagnier talking about Lyme Disease in France - I am trying to get a copy of translation so that I can post on my blog with this U tube as it runs rather quickly to read.

    ReplyDelete
  6. Joanne,

    You said,

    "Perhaps there is something to do with the undulatory immune response http://www.isrn.com/journals/immunology/2012/719821/ and perhaps something to do with Borrelia going to the lymph nodes and although producing inflammation not being able to clear the infection.
    http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002066 "


    Very interesting, Joanne. The undulatory immune response you cited above was also present in one of the two untreated groups of Rhesus macaques.

    Look: Figure C from Embers et al

    If you look at the third group of animals' C6 responses there, you can see that their immune response seems to start out the same as the treated and other untreated groups of macaques. But as time goes on, the other groups - both treated and untreated - have immune responses which return to close to baseline. This one group maintains an elevated response that oscillates well after the other animals' response declines.

    In Group C - the oscillating response which remains elevated - there does seem to be a peak at week 5 and another around week 11.

    To quote from your cited paper:

    "The immune response (IR) started in week 1 after tick bite and peaked in week 5, when 5 of the 7 tested sera (71%) reacted positively (Figure 1). In the following weeks there was a wavelike decrease of seropositive reactions. Furthermore, from week 8 there was a second increase in seropositivity peaking at week 9. "

    This is good to take note of:

    "Both the IgM and IgG IR showed an undulatory distribution with antibodies coming and going in untreated patients over weeks. A similar periodicity is known in other bacterial infections, like relapsing fever with recurrent bacteraemias."

    As an aside, totally for your benefit/disgust: The C6 test is not exactly all it's cracked up to be in Europe: http://www.sciencedirect.com/science/article/pii/S1438422108001562.

    To quote from the above abstract: "In the serology of EM in Europe, C6 ELISA does not seem to cover all cases. An ELISA using a mixture of B. burgdorferi sensu stricto IR6 peptide and the C6 peptide could be of value in the serodiagnosis of LB in Europe. Further studies on combinations of variant IR6 peptides and the C6 peptide in other manifestations of LB are needed to address this issue."

    A lot of people were saying the C6 should be an improvement on the old ELISA and be more accurate in testing positive for European Bb. Apparently, this isn't always the case.

    I think your conjecture about the inflammatory response in the lymph nodes is also a good one, too.

    (more)

    ReplyDelete
  7. (For Joanne - cont'd)

    "Whatever, it is all far too complex for me to understand or explain but inflammation was the most obvious sign in my symptoms and 20 months of steroids for wrong diagnosis only managed to suppress the symptoms a little whereas antibiotics taken long term has restored my health. Although a year without antibiotics and inflammation is creeping back in some areas again."

    It is complex, even for the people who are doing professional research on this all the time. I think the one thing we can do, though, is have more time to see different pieces of the puzzle from afar rather than a section of the puzzle from close up. It would help to have more people get involved to collect and synthesize data from studies that are already out there.

    I'm sorry you had the experience of taking steroids for so long, and I'm glad you improved. I hope whatever inflammation you have now is temporary and minor, and won't require additional treatment.

    Thanks for the link to the Prof Luc Montagnier video. I think someone else already forwarded a link to me with the English subtitles, though, so I be watching that. If you ever find something in German about Lyme disease which is not translated, feel free to pass that on without English subtitles - not a problem on this end. (I learned about the massive TBE vaccine campaigns in Germany from a German news show clip, and also learned about a few people who reacted badly to the TBE vaccine including kids.)

    ReplyDelete
  8. Hi Camp Other.
    Thank you for the link to the radio programme. I listened to it all today. I'm an English psychiatrist and my partner has Lyme disease, but was an anomaly who tested negative for Lyme -despite a huge EM rash and antibodies to Babesia. We're OK now, obviously he's never fully recovered (because it was LD), but we have quality of life back and support.

    I've always thought that the truth would lay somewhere in the middle or 'elsewhere' so when I came across you blog I was relieved to find someone trying to open up rational thought and debate in this way. Thank you! Also thanks for the link to the radio show.

    I heard what Barthold said but wondered if he was referring to gross signs of inflammation in heart and joint tissues? Fallon appeared to draw something else from the paper and commented that there was evidence of inflammation at the site of the immunoflourescent marker used to indicate the presence of spirochaetes. Hmmmm...
    Surely inflammation could be conceptualised as a variable rather than categorical state also with a spectrum of activity depending on the nature of the host-pathogen interaction?

    Have you seen this from 'ViralGenetics'?: http://www.viralgenetics.com/investors/pr_030712.php - a new approach to LD treatment seeking FDA approval. Possible hope here?

    Also I was surprised to hear nothing more about vaccines on the radio show. The European human vaccine Phase I and II trials were registered 22/12/11 and confirmed by Baxter on 10 Jan 2012 on the WHO ICTRP Portal:
    http://apps.who.int/trialsearch/default.aspx
    http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT01504347
    http://clinicaltrials.gov/show/NCT01504347
    It's also on the ClinicalTrials.gov web-site.

    I almost wondered if the Embers/Barthold publication was delayed until after this was underway, due to the timing ?? I wonder if they'll use the C6 test in the protocol? Presumably the possibility of vaccinating a person with a few persistent borrelia on board isn't such a problem (or is it?) if it's just there and not doing anything...as seems to be the 'party line'...Maybe the needs of the many outweigh the needs of the few....or the one!

    I'm all for creating a new paradigm - it's the only way forward - out with the old in with the new.

    Live long and prosper1
    Sandra

    ReplyDelete
  9. Hi Sandra, and welcome to Camp Other blog.

    Thanks for dropping a comment - glad to hear you enjoyed the radio show, and sounds like you're another Star Trek fan.

    One of my "jokes" since contracting Lyme disease has been when I get an experience of brain fog, I'd say "Brain and brain... what is brain?" to a friend nearby and they'd automatically know what I meant. To those who have seen the episode, "Spock's Brain", it also makes sense - but everyone else just gives me a blank stare. (Oh well - it's probably not that different from the blank stare I give them right back.)

    But I digress.

    Yes, I have been trying to approach the subject of chronic Lyme disease from an exploratory point of view. I started out with the question of, "Is it a chronic persistent infection or is it an immune disorder?", because that is what the basic controversy has been all about - what chronic Lyme disease is, and whether to treat it with lots of antibiotics or not. But then as I did more research on it, it became clear there were more pieces to the Lyme puzzle as to why some people seem to fare better on early treatment compared to others, and why some people seem to get better on longer term antibiotic treatment than others, and so on. It became a more complex question to ask, and I found out as I went along that there were more variables at play.

    If these persister cells which were hypothesized about in a study which was recently published by Embers et al really are responsible for patients' chronic symptoms (including my own!) then this will be yet another factor in the puzzle. A big one, but still not the only one.

    "Surely inflammation could be conceptualised as a variable rather than categorical state also with a spectrum of activity depending on the nature of the host-pathogen interaction?

    Well, that is what I was driving at in my comments above. I wanted to know how Barthold was defining the state of inflammation he witnessed on a quantitative level. I definitely think host-pathogen interaction would be required there; the immune response being the key thing.

    "Have you seen this from 'ViralGenetics'?: http://www.viralgenetics.com/investors/pr_030712.php - a new approach to LD treatment seeking FDA approval. Possible hope here?"

    Yes. Have you seen these posts? :

    http://campother.blogspot.com/2012/02/viral-genetics-issues-latest-report-on.html
    and
    http://campother.blogspot.com/2012/02/patent-viral-genetics-chronic-lyme.html

    I've been following the Viral Genetics story for a while. A few days ago they posted they were ready to file their pre-IND.

    I'm hoping to post an entry explaining how their product is supposed to work based on what is known about it - given that they have proprietary technology I can only speculate on it on more general level, but that is what most people are interested in reading.

    (more)

    ReplyDelete
  10. (For Sandra - cont'd)

    I read the news about the European vaccines. I already knew they were underway for a couple years. I loitered at various NIH trial sites and university web sites and knew it was up and coming. There is OspC vaccine development in the works, too...

    On OspC vaccine patent, see:
    http://www.freepatentsonline.com/y2011/0070257.html
    And Dr. Earnhart did a presentation about this at the last year:
    http://columbia-lyme.org/research/scientific.html

    The short summary there says:

    "Dr. Chris Earnhart’s talk described work developing a novel next-generation Lyme disease vaccine based on outer surface protein C. Osp C is expressed by all Bb species and strains and is expressed in the human host for several weeks before being down-regulated. The first generation OspA vaccine killed Bb in the mid-gut of the tick and was only 68-76% effective, requiring very high antibody titers in the human to maintain its effect, thus requiring frequent boosters. The OspA vaccine also raised considerable fears because of the putative autoimmunogenic T cell epitope that might trigger a type of arthritis. Other groups have tried to revise the OspA vaccine by changing amino acids within this immunogenic epitope. Dr. Earnhart then went on to report progress in developing an OspC polyvalent chimeric vaccine. This work appears highly promising and may soon lead to animal trials to test its effectiveness. "

    "I almost wondered if the Embers/Barthold publication was delayed until after this was underway, due to the timing ??"

    Don't know. What are your thoughts on this?

    " I wonder if they'll use the C6 test in the protocol? Presumably the possibility of vaccinating a person with a few persistent borrelia on board isn't such a problem (or is it?) if it's just there and not doing anything...

    I would hope if they use the C6 test in the protocol that they'll be mindful of the research that I just cited for Joanne, and do additional testing.

    As for the persisting bacteria being on board during vaccination, I couldn't say that it wouldn't be a problem. It might be. It might be that vaccinating itself can be a problem under certain circumstances. There is a good summary about what has happened with OspA vaccines and the future of OspC vaccines on Medscape: http://www.medscape.com/viewarticle/710148 (you will need to sign up to read it - free registration)

    ReplyDelete

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