Definition of late-stage Lyme disease

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
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Henry
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Definition of late-stage Lyme disease

Post by Henry » Sun 7 Dec 2014 18:00

Lorima: Before I forget, sometime you will have to explain to me what you mean by late-stage Lyme disease, as well as when --or if-- it ever become chronic Lyme disease.

You still don't understand that the only way to show how effective/efficient a medium like BSK is in supporting the growth of Borrelia is to do a limiting dilution assay. Just reporting that a medium is able to culture positive 48% or 90% of the time using clinical specimens -- be they blood or whatever -- doesn't provide that kind of information and doesn't indicate that the Sapi modification is superior to BSK. Such an approach is very much dependent upon bacterial cell density and when specimens were collected for culture; more important, since the same specimens were not cultured by Wormser et al and Sapi et al. to give the percentages noted, one can not say that one medium is superior to the other.

Since several collections clinical isolates are available, it should be rather easy to do a limiting dilution assay using such specimens -- if it hasn't been done already. Even though Barbour reported doing a limiting dilution assay using Borrelia derived form the midgut of infected ticks, aren't these the very same type of ticks and Borrelia that cause Lyme disease in humans? I would say that the ability to culture on BSK from a single bacterial cell -- from wherever it was derived -- is quite relevant, don't you think?

Lorima
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by Lorima » Sun 7 Dec 2014 18:38

Henry,
That's a reasonable post. Thanks. I'll answer it this evening, when I get back from my family outing.
"I have to understand the world, you see."
Richard Feynman

duncan
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by duncan » Sun 7 Dec 2014 18:56

Sorry, don't mean to butt in here, but just out of curiosity: Henry, are you asking how one (Lorima) defines late stage Lyme, or manifestations of late stage Lyme?

It's an important distinction since I think the IDSA Guidelines primarily explore the latter - which is a curiosity in and of itself. For instance, directly from those Guidelines under the heading Late Lyme Disease, "Late manifestations include arthritis, encephalopathy, encephalomyelitis, and peripheral neuropathy." Of course, all these manifestations also can occur in acute stages. So, how do you differentiate between stages, and where along the timeline does late stage become appropriate? For instance, does it occur when IgM's convert to IgG's? When the EM dissipates? When the patient is no longer febrile?

Do you subscribe to the belief that one can be diagnosed with late stage Lyme after treatment has been rendered?

Would you at least agree that there is such a thing as late stage Lyme?

Henry
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by Henry » Sun 7 Dec 2014 22:13

I asked Lorima in response to one of her postings. But, if you want to tell me you views about where along the spectrum these conditions lie, I'd like to hear your precise definitions. Those who speak about these things ought to be prepared to define their terms. That would be helpful to us all.

duncan
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by duncan » Sun 7 Dec 2014 23:04

Hmmm, seems to me I asked you first. But no problem. Well, not true - the problem is that most definitions of late stage invite criticism for one reason or another, but mostly for the simple fact that there really isn't a steadfast rule (at least not that I can think of off the top of my head) that is embraced by the entire Lyme community.

Personally, I think acute = early stage. That's one measure. I like it because it's simple and it sticks. Once acute Lyme morphs - assuming it goes untreated or is unsuccessfully treated - what it changes into is late stage. Both early and late are active Lyme.

Another possible threshold would be when the individual's immune system converts from early reaction (in most, IgMs)to IgG's. Problem is, not all Lyme patients have this happen. Many stay locked in IgM mode, so early stage transforms to late via symptom manifestation, i.e. resolved fever and disappearing EM mark the end of early stage, but continued symptoms such as encepholapathies and peripheral neuropathies and arthritic presentations and sleep dysfunction and arthralgias and extreme fatigue and so on - in the absence of fever and EM - mark the transition to late stage.

I think we would like to gauge a lot via the immune system, but this is an imprecise and even unreliable and certainly inconsistent exercise to date.

But I absolutely support the concept of Lyme stages. I also believe you cannot make late stage Lyme disappear just by throwing some doxy at it and proclaiming it is now PTLDS. That's manipulation. It is not reflective of patients' reality, but rather political preferences.

Edited to add: I would also point to the actual dissemination of the spirochetes from concentrated sites like the EM in early stage, to more sparse and scattered presentation in the blood (early disseminated), to even more isolated incidences in privileged sites such as brains and other tissue, where it becomes increasingly difficult to find and culture in blood (late stage). This process parallels the entire transition from early to late stage. The problem with this, of course, is actually tracing this process. I like the theory, but demonstrating it is a different matter I think.
Last edited by duncan on Mon 8 Dec 2014 0:40, edited 1 time in total.

Lorima
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by Lorima » Mon 8 Dec 2014 0:36

[See Henry's post, above, for the questions I'm addressing.]

Wow, good answer, Duncan. Mine is so simple.

I wouldn't use the term "chronic Lyme disease." It doesn't retain its literal meaning any longer; it has become a sort of medical-political code word. Carina, aka X-member, who is Swedish, would disagree; perhaps in Sweden and maybe some other countries, the term can still be used by doctors without requiring a knowing grimace, or actual statement such as "There's no such thing as CLD" or "I don't believe in CLD", or "You don't believe in CLD, do you?" In the US, it's either a code word for "not really Lyme disease", or evidence of not being conversant with the terms of the controversy.

Late Lyme disease is, what it says. It's not well-defined, because it doesn't indicate how late, or what the manifestations are. It's still useful, even though it is a broad category. It indicates that we're not talking about the EM stage, but what happens way down the pike. Maybe we should call it "tertiary," like syphilis. But I use simple English whenever possible. The person could have had LD for a year, or 20 years, or longer.

On to the culture questions:
With regard to whether it matters, where a Bb cloned cell comes from, I think it might. No one disputes that Bb changes its pattern of gene expression, as it moves from the tick gut, into the salivary gland, and then into the patient. As a well-known example, OspA is downregulated, and OspC is upregulated, during this transition.

I think it's also not controversial, that later in mammalian infection, OspA can be expressed again. For example, late-stage patients often have antibodies to OspA. It seems likely to me, that in mid- and late-stage infection, Bb is present in many epigenetic (gene-expression) forms, and adapts according to the pressures it encounters, in whatever microenvironment of the body it colonizes. One would think that is part of the repertoire it would have evolved, to live persistently in the reservoir host, without getting killed off by the innate or adaptive immune system. We could search the literature for evidence suggesting this, but I don't think it would be conclusive. Let's just say, that as a biologist, it seems likely to me.

So I wouldn't scoff at LHCTom's point about changing gene expression affecting optimal culture conditions.

There is also the likelihood that some strains or species of Bb s.l. may just be easier to cultivate than others. That is the case for most cells, prokaryotic or eucaryotic, as far as I can tell. Some of them are slow, or finicky, or easily killed, and others grow well, in culture. B31 is a real workhorse strain, obviously; it is grown in large amounts for use in WCS ELISAs and Western blots. We can surmise that it was relatively inclined to grow well in culture, right out of the tick, from the very beginning; otherwise Barbour's culture of tick mid-guts would have resulted in the cloning some other, better-growing, strain, and it would be the workhorse.

Is it plausible that one can optimize culture conditions, beyond what Barbour and others have achieved, so that strains, or gene-expression variants, that wouldn't thrive in BSK, would become cultivable? Yes, I think it is plausible. For example, I like the step of providing a solid matrix-like surface for them to grow upon; that seems reasonable, considering that we know Bb is not inclined to stay in the blood, except in a few reservoir species.

You're right, Henry, experiments could be done on this. But what experiments get done, is up to your team, in the sense that they influence what seems important and necessary, by their predominance in the literature. If the IDSA guidelines authors wrote editorials calling for more detailed culture experiments and more out-of-the-box grant applications for LD diagnostics, they might get them. Conversely, if they say the current tests are fine, current treatment is fine, there are almost no late-stage patients, and anyone who says otherwise is anti-science, then no such research will occur.

What I don't know, yet, is how well and how consistently the ALS culture might perform, and for what kind of patients. Scientists make mistakes all the time; it's possible it doesn't really work at all, despite their honest efforts. Or it might work somewhat; many new techniques are published that turn out not to work very well in practice, including drugs or tests approved with much fanfare and sold to millions of patients. Or it could work really well. I need a lot more information, and I'm not embarrassed to wait for it. But I don't think the people who jumped right on it are "fools"; I'm kind of a late adopter, in general. I just got my iphone last year. It takes all kinds, as my father used to say. ;)

Actually, I doubt that culture it would work in my family patients. They don't have fevers or markers of inflammation, and their symptoms, when they recur, are in the same old body parts. They don't have the high antibody levels needed to be CDC-surveillance positive, which all of Sapi's patient-subjects did have. Maybe people with high antibody levels have more frequent episodes of spirochetes in the blood. No one knows.

Just let people do experiments, getting the funding however they can, and find out these things. (It's a pretty good bet that researchers who question the IDSA's LD model, aren't likely to get much funding from any of the conventional sources, like the NIH, or Big Pharma. ;) )

Whatever harm ALS might do to patients is minuscule, compared to the harm done by telling doctors to use the 2T test for diagnosis, and claiming that a negative test excludes the possibility of LD. The harm from that, is incalculable.
"I have to understand the world, you see."
Richard Feynman

Henry
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by Henry » Mon 8 Dec 2014 4:41

Lorima: Sorry, but I don't find your definition of late-stage Lyme disease to be very helpful or at all clear. It lacks a very important element, i.e., certainty. In the absence of an objective test of some sort or a biomarker, all one has is an array of symptoms that could be caused by several other medical conditions. No one can say that this is late-stage Lyme disease and not some other medical condition that certainly deserves appropriate treatment and care. Such uncertainty results in much confusion and makes it impossible to establish common ground and/or reach any sort of consensus. All we have is speculation, with no attempt to gather evidence to support such speculation. Lots of "free thinkers", but nothing to hang your hat on. That is not science. Since none of it is evidence-based, it is not likely to result in a solution to this or any other problem. Ideas and talk are cheap. Proving them takes a lot of hard work and few are up to that task.They are not members of ILADS for sure.

radicale
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by radicale » Mon 8 Dec 2014 7:03

I don't think it's true to say that the modification of BSK has not been undertaken before Sapi. et al. There are other countries in the world apart from the United States of America.

1]
http://www.scielo.br/scielo.php?script= ... 7000800017
Evaluation of a modified culture medium for Borrelia burgdorferi sensu lato
Islay RodríguezI, +; Reto LienhardII; Lise GernIII; Marie Colette VeuveII; Fatima JoudaIII; Hans H SiegristII; Carmen FernándezI; José Enrique RodríguezI

2]
http://www.doiserbia.nb.rs/img/doi/0354 ... 02533V.pdf
ISOLATION, CULTIVATION, AND IN VITRO SUSCEPTIBILITY TESTING OF BORRELIA BURGDORFERI SENSU LATO: A REVIEW
GORANA VEINOVIĆ, BRANKICA FILIPIĆ and JELENA STANKOVIĆ
Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia

I would recommend people review the the second paper in full, it is filled with facts that make one stop and think.

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LHCTom
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by LHCTom » Mon 8 Dec 2014 7:27

All we have is speculation, with no attempt to gather evidence to support such speculation.
We have plenty of evidence but you and your cronies are selecting your preferred evidence, avoiding studies that might provide evidence that disagrees with your positions, and avoiding the forward progress of science and knowledge by not being unable to "free think", ask tough questions, use imagination and fear creativity.

Lots of "free thinkers", but nothing to hang your hat on. That is not science.
The only thing that comes to mind about your thought processes is: :bonk: :bonk: :bonk:

Did you fall on your head as a child?

Its called making a reasonable hypothesis based on real world observations and supporting evidence. If you don't think that is a critical step in the scientific method than its hopeless.

You and your cronies stopped using science a long time ago. You, your silly front ALDF and IDSA are control freaks and non thinkers.
Since none of it is evidence-based, it is not likely to result in a solution to this or any other problem.
There you go again. There is plenty of evidence you just don't like and avoid looking into obvious observations so you don't have to free think about any interesting hypothesis that you don't want the answer. You would lose your big salary, soap box, Pharma deals, patent royalty streams, and worse of all your egos might deflate. In the end, your legacy will be very sad. I almost feel sorry.

Ideas and talk are cheap. Proving them takes a lot of hard work and few are up to that task.
Science starts with ideas. Duh! The work is underway and just because you try and block it, in the end we will see. I've accomplished more than you could in ten lives. Look at what you do.
They are not members of ILADS for sure.
There you go again... black and white... Most of the research that will send you running with your tail between your legs is not ILADS. You just love to paint everything with one broad brush. I think most of the research being done to fill the void you block is being funded by foundations and has nothing to do with ILADS.

You and your cronies take NIH money and keep doing the same old studies over and over without ever testing your own views. That is pseudoscience. Good scientists try and disprove their beliefs not get on forums and argue with ill people. Think about that. I think its sick.

ALDF = Propaganda Front!
The greater the ignorance, the greater the dogmatism.

Attributed to William Osler, 1902

duncan
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Re: Rebuttal published to CDC vs Advanced in J Clin Microbio

Post by duncan » Mon 8 Dec 2014 12:53

Henry, you ignore the definitions I provided per your request, and you denigrate Lorima's for lacking certitude. Meanwhile, you don't provide your own definition.

This was predictable and self-serving. Worse, imo it is small.

There is no definition of late stage Lyme that doesn't present with difficulties, and most of the Lyme community knows this. That you seem to feign ignorance in an attempt to somehow debase your opponents while you weasel out of providing your platform's interpretation, may speak to character - and I doubt it's saying nice things.

This is representative of why many distrust both you and the shrinking elitist cabal people like you serve.

I don't get people like you. It would appear that you cannot even hold your own in a definitional debate. To me, your statements and awkward omissions are reflective of your insular group's fear of open discussion. Many from that group resort to talking points instead of engaging in free discussion unencumbered by outdated and flawed opinions. Some actually denigrate patients when they should be speaking for them. They promote inertia in the name of Science, all the while disengaging from meaningful discussion, and dismantling the means of progress. They cry attention to lack of evidence like it's a panacea, instead of a hurdle that needs to be overcome. Instead of speaking to patient issues, they cavalierly dally with semantics as if words were little more than parlor tricks and distractions. For many, they appear to have swapped candor for cover up, and chosen profits over progress, and that is unconscionable.

LHCTom is right when - if I might paraphrase - he suggests you and your pack appear to have abandoned the spirit of Science - the very deficit you delight in accusing your competition of.

Here's another chance: What is your definition of late stage Lyme, and how would you characterize it?

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