PTLDS Issues

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
duncan
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PTLDS Issues

Post by duncan » Tue 8 Jul 2014 14:12

I wanted to open a thread dedicated to discussing the many issues surrounding the concept of Post-Treatment Lyme Disease Syndrome. These issues will include definitional problems, research efforts, political forces at play, etc. I hope anyone who has something on their mind relative to PTLDS will contribute.

I want to begin by taking a look at what research efforts are currently underway specific to PTLDS. I figured a good place to start might be with the NIH in the US. Supposedly there is interest among mainstream Lyme groups, e.g. IDSA followers, to characterize PTLDS, and help develop treatments (recently Wormser and Bockenstedt went on record suggesting a CFS-protocol might be a way to go). I want to see how valid that stated goal of characterizing PTLDS, and securing effective treatments for it, are - how invested what I see as IDSA-influenced organizations, like the NIH and CDC, really are in that goal.

First, as most of you know, there are zero treatment studies currently underway under the NIH umbrella for PTLDS. At least, I couldn't find any.

I was somewhat surprised to discover there really is only one current study dedicated to PTLDS/chronic Lyme: "Evaluation of Lyme Disease: Clinical, Microbiological and Immunological Characteristics." (I am having trouble remembering cut and paste. I have instructions, but am having difficulty at the moment following. If anyone wants to cut and paste that study off of clinicaltrials.gov. I would appreciate it.) This is principally a diagnostic effort.

This should be an important study, and not just because it is meant to qualify PTLDS, and follow sufferers over a period of years, but also because here, at least, it equates PTLDS with Chronic Lyme, and that is potentially very important since it is the NIH - a govt agency - equating the two in a very public manner.

So if this is the only meaningful current study of PTLDS, seeing how it progresses, and how it defines categories, and what tests it employs, would all be meaningful, at least I think they would.

Looking over the study description, the item that pops out at me immediately is the study launch date, and the objective in terms of number of participants. Launch date was 1996. Two decades ago. Number of participants the NIH was hoping to recruit - and this includes healthy controls, individuals with PTLDS, recovered patients, etc,, for a total of seven groups - was 600. So, even if there were only six categories of patients sought, that would average out to about 100 per. At seven, I would imagine the number per category would be even less.

This study is supposedly a very important effort to characterize a disease/syndrome. The IDSA camp publicly proclaims its sincere wishes to better understand and treat PTLDS. If I accept those proclamations at face value, I am left wondering why only one study is currently active. (I don't consider Marques's pet Xenodiagnostic efforts exclusive to PTLDS, but that could just be me).

More importantly, I am left wondering, if the interest is genuine, how it could be that after 18 years the NIH is still recruiting subjects? Why after 18 years is the NIH still struggling to come up with what should be easy to find: 100 patients with PTLDS?

phyfe
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Re: PTLDS Issues

Post by phyfe » Tue 8 Jul 2014 15:13

http://clinicaltrials.gov/ct2/show/NCT0 ... yme&rank=6

Hope this is the right one Duncan.
Evaluation of Lyme Disease: Clinical, Microbiological and Immunological Characteristics

This study is currently recruiting participants. (see Contacts and Locations)

Verified October 2013 by National Institutes of Health Clinical Center (CC)

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by: National Institutes of Health Clinical Center (CC)

ClinicalTrials.gov Identifier: NCT00001539

First received: November 3, 1999

Last updated: March 14, 2014

Last verified: October 2013

Purpose: This study will determine whether patients who have been infected with the Lyme bacteria, Borrelia burgdorferi, and treated with antibiotics still have the bacteria alive inside them and whether it is causing their symptoms. The information from this study may serve as a basis for developing stringent diagnostic criteria for Lyme disease and the establishment of future treatment trials.

Individuals in the following categories may be eligible for this study: chronic Lyme disease; chronic Lyme arthritis; seropositive control (are infected with the bacteria that causes Lyme disease but do not have disease symptoms); recovered control (have been sick with Lyme disease but were treated successfully and are currently well); control with multiple sclerosis (patients with multiple sclerosis); and healthy volunteers. Patients in the chronic Lyme disease category must be age 13 and above; all others must be age18 and above. Candidates will be screened with blood and urine tests.

Participants will have a physical examination and the following tests:

Blood tests Includes HLA-typing, a genetic test of immune system markers;

Leukapheresis Collection of large numbers of white blood cells Whole blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body, either through the same needle used to draw the blood or through another needle in the other arm. (Alternatively, patients will 100 cc (about 7 tablespoons) of blood drawn.);

Lumbar puncture (spinal tap) Collection of cerebrospinal fluid (CSF, fluid that bathes the brain and spinal cord). A local anesthetic is administered and a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle;

Magnetic resonance imaging (MRI) of the brain Imaging of the brain using a strong magnetic field and radio waves instead of X-rays. During the scan, the patient lies on a table in a narrow cylinder containing a magnetic field. He or she can speak with a staff member via an intercom at all times during the procedure;

Neuropsychologic testing;

Some participants may also have a hearing test and urine collection.

Participants whose test results are positive for Borrelia burgdorferi will be followed at NIH at intervals of 3 to 6 months until it is determined whether there is infection. Those who are infected will be offered treatment with the antibiotic ceftriaxone. Following treatment, patients will return to the NIH Clinical Center for follow-up visits 1 week after treatment and again at 3, 6 and 12 months. The lumbar puncture, hearing examination, blood and urine tests will be repeated at these visits to evaluate the response to treatment, and the leukapheresis will be repeated for research purposes. Patients whose MRI was abnormal during therapy will have a repeat MRI at the 3-month, 6-month and 1-year visits.

All participants with chronic Lyme disease, chronic Lyme arthritis, seropositive controls and recovered controls may be reevaluated at intervals of 6 to 12 months.

duncan
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Re: PTLDS Issues

Post by duncan » Tue 8 Jul 2014 15:16

That's it alright. Thanks, Phyfe. :)

duncan
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Re: PTLDS Issues

Post by duncan » Sun 13 Jul 2014 18:48

"All participants with chronic Lyme disease, chronic Lyme arthritis, sero-positive controls and recovered controls will be re-evaluated at intervals of 6 to 12 months."

Re-evaluated for what? What metrics are being employed to measure or monitor which factors? IgG levels? IgM? C6 levels? Cytokines and chemokines? Scores on neuropsych evaluations (I wonder whether they will emphasize cognitive factors vs. emotional. Bets?) MRI results?

Are they looking at symptoms? Symptom variance and intensity? Are they seeking correlations between symptom clusters and lab findings? Are certain Cytokine flairs or storms associated with relapsing symptoms? Can the C6 Peptide be employed as a predictor of symptom intensity? As far as I can tell, the IDSA and CDC folk seem to think PTLDS seems more a function of lingering symptoms rather than persistent biological abnormalities such as elevated Lyme titers. What is being done in this NIH effort to identify concrete lab findings and try to align them with specific self-reported symptoms? Is this even a goal? Is it being pursued?

Since sero-positivity appears to be a requirement for participation in the study, how do they determine who has an infection, and who does not? C6 Peptide? DNA? What guidance distinguishes a false positive from an old resolved infection from one that is active? Does that science even exist without the intrusion of dumb luck (e.g., a positive PCR hit)? And who makes that call?

Does anyone know if any preliminary data has been released? In light of Marques's recent apparent reference to a 24 month cap to PTLDS symptoms, does that jive with data gathered from this effort? It's been 18 years. I would imagine they must be able to generate some useful insight.

Can they compare any of the data captured through CSF exams with the data garnered from the Coyle, Shuster, Natelson et al CSF study comparing Lyme with CFS patients?

What is it Marques and company think will be changing? What are they mapping? Have they actually nailed down a goal?

If this were a class room project, even college level, I would ask where is the merit of the exercise? After 18 years, isn't it time for a review of the results?

duncan
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Re: PTLDS Issues

Post by duncan » Tue 22 Jul 2014 13:09

Given the discussion under General about LymePolicyWonk, I thought I might drop a line or two here about the NIH ChronicLyme/PTLDS study.

It seems to me that since this is already up and running, perhaps Marques and company could broaden the testing. If they have kept a repository of blood samples of patients over the last 20 years, that would be helpful, because maybe they could tap into that and retest old samples going forward. i'm not counting on that, though. In fact, personally, I'm not counting on much of anything, because I really don't see meaningful effort to uncover data in this project, to push into new terrain. That reservation aside, the point is the NIH Lyme Team COULD incorporate new tests and try to capture new data. After all, this is a home-grown effort, requiring no outside academic involvement.

For instance, Henry and Velvetmagnetta spoke of cytokines, and I too have, as has Camp Other and many from this Forum. More importantly, researchers like Steere have suggested looking for specific Cytokine/Chemokine signatures (e.g.CXCL13). Is such an effort underway for this Study? I was told it would be, but I have seen no evidence to date to suggest it actually is. And LHCTom and Margherita have spoken to the microbiome and the role it may play. Here is a study that may be able to incorporate that objective, instead of imo laboring forward so slowly and aimlessly as to gather dust instead of insight.

So this may be a good vehicle - already approved, already set into motion - to scrutinize PTLDS patients using the latest methods. Of course, the effort would have to be genuine. It would have to be sans posturing. They would have to be actually looking for something other than a way to toss PTLDS into the CFS dustbin, which is what I personally believe the current goal to be (especially in light of the Bockenstedt/Wormser recommendation). They would have to be looking in earnest through a Science prism (Hello, Henry) to find meaningful data, rather than half-heartedly going through the motions to substantiate that "See, no Bb here, people, move along" attitude that pervades just about every paper that manages to crawl out from under the weight of 35 years of accrued dogma.

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LHCTom
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Re: PTLDS Issues

Post by LHCTom » Tue 22 Jul 2014 20:00

Duncan,

I'm involved in a Metabolomics based study of CFS/ME. I believe Metabolomics is among the best approaches to understanding the underlying mechanism of any chronic illness. Most other strategies are forced to make simplifying assumptions and looking at a small subset of possibilities because of cost. Metabolomics only makes the broad assumption that the chronic illness will effect the metabolism such that it can be detected by abnormal metabolites and their patterns.

In the case of the study I'm involved in, a gas chromatography-mass spectrometry system (GC-MS) is able to identify about 700 small to medium molecules in blood. That's equivalent to a blood test for 700 chosen molecules that show the intermediate and end product metabolites of a large number of cellular processes at once. That means it takes into account everything from diet, genetics, gene expression, gut microbiome etc., all in one test. It goes well beyond studies like the CSF Proteomic Study which only looked at proteins but doesn't say anything about why there are differences. So its a biomarker but not diagnostic of cause. Immune system signaling molecules like the cytokines would be a small subset of the 700.

The metabolic pathways are reasonably well understood. So abnormal metabolites and their patterns can be traced upstream. When your doctor tests for liver enzymes, its a marker that can be traced to the liver processes. But this has the potential to trace through thousands of cellular processes looking for the origin of the abnormality. That means it may be possible to both identify abnormalities and trace their source to the metabolic process causing it. So the metabolite patterns can be used as a biomarker while the upstream pathway trace can be used to try and find what is wrong.

Even though this study is for CFS/ME, many of us with PTLDS have symptoms very similar to CFS/ME and have been diagnosed with both. Metabolomics is evolving and the technology is improving quickly. Of all the diagnostic strategies, I suspect Metabolomics has the best chance of identifying the cause of chronic diseases in general. That is because a chronic condition with ongoing symptoms almost certainly will show up as an abnormality in the metabolic system and its metabolites. The CDC and NYU recently did a study using Metabolomics as a Lyme Disease test but were only looking at signatures/patterns for diagnosis.

The next step is using Metabolomics capable of identifying the metabolites to study PTLDS in hope of finding where the problem(s) originate. Once the origin is identified, looking for treatments to correct the abnormality becomes possible.
Metabolomics of Lyme Disease: A Novel Diagnostic Approach
John T. Belisle, PhD

The currently recommended method for diagnosing Lyme disease is a two-tiered serology-based test that is limited in its ability to differentiate active from previous infection, diagnose early LD, and is not standardized among laboratories. Moreover, the interpretation of test results is open to subjectivity. Thus, a fresh approach for improved diagnostic development is critical to the field. Studies applying the global evaluation of small molecule biomarkers, "metabolomics", for the discovery of biosignatures and biomarkers for monitoring cancers and metabolic diseases have shown tremendous promise. Although this technology has not been widely applied for infectious diseases, it is recognized that infectious diseases are manifested based on alterations in the biochemistry of a biological system.

Over the past three years our laboratory in collaboration with the Centers for Disease Control and Prevention, and New York Medical College successfully developed a serum based metabolomics approach to identify a small molecule biosignatures that can differentiate early Lyme disease (localized and disseminated) patients from healthy individuals from both endemic and non-endemic regions in the United States, and from patients with diseases that have look-alike symptoms or that are cross-reactive with existing serology-based tests for Lyme disease. This biosignature was developed with well-characterized retrospective samples and has significantly enhanced sensitivity as compared to the two-tiered serology-based testing of the same samples. These analyses provide proof-of-concept that a Lyme disease multi-analyte small molecule diagnostic can be developed. Further validation of this model; structural identification of biosignature metabolites; and additional comparisons targeting early localized versus disseminated Lyme disease, baseline versus 1-month post-treatment, and early Lyme disease versus Lyme arthritis are being performed. These efforts not only hold potential for new Lyme diagnostic and prognostic tools, but will also provide new information about the biology of Lyme disease.
The greater the ignorance, the greater the dogmatism.

Attributed to William Osler, 1902

duncan
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Re: PTLDS Issues

Post by duncan » Tue 22 Jul 2014 20:11

This sounds very cool. Can you discuss who is running the study? I am assuming it's not this Dr. Belisle since his efforts appear specific to Lyme, and I believe were done in conjunction with Wormser, among others.

Is this CFS/ME study European-based?

velvetmagnetta
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Re: PTLDS Issues

Post by velvetmagnetta » Wed 23 Jul 2014 2:18

Hi Duncan!

Thanks for opening this thread. It is a very important subject to me and, unfortunately, to many others.

In the first study:
The lumbar puncture, hearing examination, blood and urine tests will be repeated at these visits to evaluate the response to treatment, and the leukapheresis will be repeated for research purposes. Patients whose MRI was abnormal during therapy will have a repeat MRI at the 3-month, 6-month and 1-year visits.
Doesn't it seem like they and our doctors should have been doing these tests on us the WHOLE TIME? Not that I welcome a lumbar puncture, but I, and others, are just desperate enough to figure out what's wrong and how to fix it to go ahead and do it!

It seems like we all should have been getting MRIs this whole time at 3, 6, and 9-month intervals.

And the blood and urine tests? These should be a given for a suspected spreading epidemic disease! Why is this happening only in a little tiny obscure study? Shouldn't the NIH and CDC have been tracking this disease?

Ugh! Makes me wonder if I am living in a 4th-world nation.

------

Tom,

That metabolomics study does sound incredible.

Lyme and post-treatment Lyme may share some cytokines in common with CFS, but I suspect they are completely different diseases - would the metabolomics of each disease be able to tell the difference even if they express the same cytokines? I'm sorry if my question sounds elementary. I tried to read up on metabolomics before when you posted about it, but still have not quite gotten the idea. But I'm learning.

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LHCTom
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Re: PTLDS Issues

Post by LHCTom » Wed 23 Jul 2014 4:06

Duncan,

Its a US study with a colaboration between the Gordon Clinic here in Sonoma and the Dr. Robert Naviaux genetics lab gas chromatography-mass spectrometry system at UCSD. The CFS/ME patients are from the Gordon Clinic while the controls and testing and analysis will being done at UCSD. It involves 20 men and 20 women with aged matched controls for each. I'm funding the testing.

Some of the work Dr. Naviaux has been involved in:

http://www.ncbi.nlm.nih.gov/pubmed/23981537
http://www.ncbi.nlm.nih.gov/pubmed/23516405
http://www.ncbi.nlm.nih.gov/pubmed/23949796
http://www.ncbi.nlm.nih.gov/pubmed/24304883
http://www.ncbi.nlm.nih.gov/pubmed/24249002
http://www.ncbi.nlm.nih.gov/pubmed/24141271
http://www.ncbi.nlm.nih.gov/pubmed/24135141


The UCSD Lab

http://medgenetics.ucsd.edu/research/Pa ... x-lab.aspx

Gordon Clinic

http://www.gordonmedical.com/

The NIH has a metabolomics program discussed here: http://commonfund.nih.gov/metabolomics/index

More on the various UCSD metabolomics programs can be found here: http://www.metabolomicsworkbench.org/
The greater the ignorance, the greater the dogmatism.

Attributed to William Osler, 1902

duncan
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Re: PTLDS Issues

Post by duncan » Wed 23 Jul 2014 13:52

Yes, Velvetmagnetta, it is puzzling that many of the tests used for this chronic lyme/PTLDS study are not used more often, if not even routinely by clinicians in cases where symptoms map with Lyme. Part of that may be insurance issues. Certainly part of that is physician ignorance.

Mainstream Lyme researchers can't seem to agree on which term is correct - chronic Lyme vs PTLDS vs PTLD vs late stage (yes, late stage can be confused with PTLDS). It gets even stranger when you see them try to qualify the disease/disorder.

Did you know the IDSA proposes in its Guidelines that PTLDS, going forward, should EXCLUDE any ill person with any objective abnormalities? No objective abnormalities allowed. Anybody with objective abnormalities in the cognitive testing would be exempt. Anyone with continued elevated Bb titers would be exempt. Anybody with abnormal MRI results, etc.

Sound familiar? It should. It's almost identical language to a description of ME/CFS.

This Marques study is intriguing in part because it flies in the face of those IDSA recommendations. But it too falls prey to that need to equivocate in the way it plays with definitions. For instance: it appears to me post-treatment can refer to almost any variation of recommended treatment at almost any time in a patient's history. Also, you need to be sero-positive for inclusion in this Marques effort; this provides, imo, a possible platform for some serious and potentially egregious errors. For instance, the ease with which a late stage case that was not adequately treated might be "converted" to PTLDS status is frightening. Remember: antibiotics are not recommended for PTLDS, but they certainly are for late stage Lyme. Naturally, if the NIH is doing this, even savvy physicians, those who closely follow Lyme, by virtue of being familiar with this study could be inclined to make similar mistakes.

BTW, a problem with MRI's used in conjunction with Lyme is they really are pretty much non-specific. Since MRIs are usually used for suspected cases of NB, I don't know why studies dont also embrace additional imaging technologies like SPECT scans and PET scans, so that they might generate a more robust and comprehensive picture of damage. This certainly should be done in the PTLDS study since the implication here, in part, is that Lyme left in its wake residual damage, at the very least, and at its worst, may still be present inflicting harm, or may have triggered a perpetual "on" switch for our immune system that also is wreaking havoc. The point is, if the brain appears to be altered by Lyme - and this can often be identified with a basic array of cognitive tests (although these too have weaknesses) - then those assigned to characterize PTLDS need to be examining the brain as thoroughly and exhaustively as our technology permits. And the sooner the better as far as this study is concerned, because it actually proposes to FOLLOW patients over an extended period of time. So once those first set of images is captured, they can be compared with subsequent images from follow-up visits, and a more accurate impression of what damage is occurring can be realized.

The same holds true if cardiac problems are indicated. Or liver. Or, you name it.

One of my problems with this PTLDS study is that for me it seems that if you scrape the surface, you don't appear to come up with much that is substantive. So yes, Velvetmagnetta, I agree, clinicians should be performing more of these tests. But then if these tests prove positive, those clinicians need to keep digging. Only, there's no set of instructions that tells them to do that, let alone advises them about what they should be looking for.

LHCTom, I wonder if our friend Dr. Marques is aware of the Belisle/Wormser effort. :)

You know my concerns with approaching this from the ME/CFS vantage, but I am a hypocrite because I have to admit I have done it myself. Let me ask you something: How far off do you think it is before this kind of testing will be embraced by the NIH; I mean, validated by them? And just keep in mind the Shuster/Natelson/Coyle CSF study that compared ME/CFS patients with Lyme patients and demonstrated concrete differences - has yet to be replicated by an NIH-backed effort as far as I am aware.

That being said, I applaud you helping to pioneer this path.

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