Tuesday, May 28, 2013

9 Persistence and Politics In Chronic Lyme Disease Research

The story of the controversy over Lyme disease research and treatment guidelines seems so strange to me, I wouldn't have believed it if I hadn't gotten Lyme disease and ended up looking into it myself.

I really thought when I first got bitten by a tick, got a rash, and got sick that it was going to be easy: take 2-3 weeks of antibiotics, get better, and go back to work. I had no idea at the time that one tick bite was going to change my life forever, and lead me down the path to learning about some controversy I previously knew nothing about.

And as much as I've learned about the Lyme disease controversy in several years, I still don't understand it.

A recent set of articles published by The Poughkeepsie Journal about emails requested under the Freedom of Information (FOI) Act - emails exchanged between members of the Infectious Disease Society of America (IDSA), Centers for Disease Control (CDC), and others - inspired me to write, but these, too, do not help me make any more sense of the controversy.

A Primer On The Lyme Disease Controversy

Before I proceed, for the uninitiated, here's the controversy in Lyme disease in a nutshell:

Many patients and some doctors believe that three weeks of antibiotic treatment is not enough and some patients need longer term antibiotic treatment. They think the bacteria, Borrelia burgdorferi, which causes Lyme disease can survive the recommended amount of antibiotics advised in the IDSA's guidelines. The IDSA and other organizations think that the recommended amount of antibiotics is adequate in the vast majority of cases, and giving patients longer courses of antibiotics is generally regarded as a bad idea. They have stated that chronic Lyme disease* is most likely a post-Lyme syndrome which is autoimmune in nature. The IDSA Lyme disease panelists view these patients' doctors as acting irresponsibly and taking unfair advantage of people who are most likely sick with something other than Lyme disease. The doctors and their patients disagree vehemently with the IDSA panel's position. It has become very heated from there.

* It should be noted that the use of terms such as "chronic Lyme disease", "post-Lyme disease (syndrome)", and "post-treatment Lyme disease" are often used interchangeably and can cause confusion. "chronic Lyme disease" has been used in the past by American researchers to mean "chronic infection" and continues to be used by the NIAID in the US. In Europe, "chronic Lyme disease" is used to mean "late stage infection". In America today, "chronic Lyme disease" has been used by the Lyme disease patient community to mean a chronic infection with Lyme disease Borrelia bacteria - where the patient has received at least some antibiotic treatment yet continues to have symptoms. "Post-Lyme disease (syndrome)" has been used by the IDSA Lyme disease panel and its colleagues to denote a presumed autoimmune-like condition that patients can develop after having a bonafide case of Lyme disease. "Post-treatment Lyme disease" is used by some doctors and researchers as a form of "non-partisan" terminology that tries to side-step the infection/autoimmunty debate for causation. (Sorry for any confusion. I'm confused too sometimes.)

Now that you have the controversy in a nutshell, getting back to those articles on those emails requested under the FOI…

Journalist Publishes Lyme Disease Academic Physician Emails Released Under Freedom Of Information Act

Mary Beth Pfeiffer, journalist working for The Poughkeepsie Journal wrote that Kris Newby placed the FOI request for the emails five years ago and only recently had her request fulfilled. Ms. Newby received copies of 3,000 individual emails under the FOI Act, of which several hundred were almost or entirely whited out, and shared them without condition with Ms. Pfeiffer for use in her articles.

In the two articles I'm discussing, "Interactive: Lyme, the ties that bind" and its companion article, "Chronic Lyme disease: Is it real?" - and one editorial letter in response to them by Dr. Phil Baker, Executive Officer of the American Lyme Disease Foundation (ALDF) - different sides of the debate are touched upon.

While Ms. Pfeiffer's position in her articles is that these FOI emails provide evidence of a possible unethical relationship between the Infectious Disease Society of America (IDSA) and their colleagues, the Centers for Disease Control (CDC), and the National Institute of Health (NIH), my focus here is not going to be on speculation about those relationships but instead are going to be about the need for clinical trials, how funding for Lyme disease is prioritized, patient relations, stagnation in science research, and questionable scientific conduct.

I'm going to be taking a few excerpts from Ms. Pfeiffer's articles, the FOI emails to which they refer, and Dr. Baker's editorial letter, and making comments about them.

But even more so? I'm going to be asking questions about them. Lots of questions - because to be frank, these emails and the content within them underscore the reasons why I don't want to get in the middle of the Lyme disease controversy and would much rather read about Borrelia spp. microbiology and immunology.

To me, learning about the science directly from research makes sense. The Lyme disease controversy? It doesn't make sense. And over a number paragraphs, I'll explain why - and tie these articles, emails, and Dr. Baker's letter in with information from other sources.

ILADS Should Conduct Clinical Trials Based On Clear Patient Criteria And Their Own Treatment Approaches - But Can They?

One notable passage from Dr. Phil Baker's editorial letter in response to Ms. Pfeiffer's articles got me to thinking:

"I stated that the ILADS guidelines were deficient in that they: (a) did not provide a precise definition of “chronic Lyme disease” as a clinical entity, so that it could be distinguished from other non-infectious medical conditions (e.g., chronic fatigue syndrome, fibromyalgia, etc.) with similar symptoms; (b) failed to provide unequivocal clinical evidence to indicate that patients suspected of having “chronic Lyme disease” actually have a persistent borrelial infection that justifies antibiotic therapy; and (c) failed to demonstrate, from the results of published, peer-reviewed, randomized, placebo-controlled trials, that extended antibiotic therapy is not only beneficial but also safe for the treatment of “chronic Lyme disease”.
While I do not like the same things other patients have complained about which Dr. Baker said within the FOI released emails - including his referring to patients as "Lyme loonies" (and I think he owes patients an apology for that) - I think it's important to examine this editorial comment because it is worth further discussion. And it lead to me ask the question, "Why doesn't ILADS conduct clinical trials?"

I asked, looking at the bigger picture and realized once I did, I could see where it would lead:

If you ask the vast majority of doctors and scientists who have no ties to the IDSA, they will tell you they, too, would be more comfortable using treatments which have been shown to be effective in clinical trials - and would likely refrain from making most treatment decisions without such evidence.

But beyond this, if ILADS conducted their own clinical trials based on patient criteria that they clearly define and treatment approaches they use in their own clinics, then once the evidence was provided which showed their effectiveness to others, many of the grievances patients have had about how chronic Lyme disease is handled would fade away:
  • Primary care physicians across the country could treat chronic Lyme disease using ILADS' methods because they would be assured the methods are effective.
  • Patients would not have to travel long distances to see a small number of doctors who specialize in treating chronic Lyme disease.
  • Patients could see a doctor who is in-network under their insurance plan and have the cost of office visits covered or mostly covered.
  • Insurance companies would stop denying coverage for specialized antibiotic treatments because they would have new data to rely on which supported new antibiotic regimens.
The situation as it currently stands is that patient advocacy organizations have petitioned individual states to pass laws which protect ILADS doctors (actually any doctor) from losing their license to practice solely because they administer long term antibiotics to patients with chronic Lyme disease. This legislation, which has been hard won by the efforts of many advocates and activists, hasn't changed the playing field in terms of increasing patient access to long term antibiotic treatment if that was one of the advocates' goals. In those states which pass such legislation, few new doctors prescribe antibiotics longer term.

This reality means mostly only ILADS doctors continue to practice long term antibiotic treatment for chronic Lyme disease, which encourages an ongoing wave of criticism from various medical organizations, pundits in the media, and those skeptical about the existence of chronic Lyme disease as a persisting bacterial infection.

The criticism is generally two-fold, and boils down to ILADS doctors taking unfair advantage of sick, vulnerable patients by operating concierge-style clinics where insurance is not accepted and concern about the growing problem of antibiotic resistance.

Those who defend against this criticism - advocacy groups and patients - say ILADS doctors have saved their lives or at least changed them for the better.

I would be one of them, too - my obvious EM rash went misdiagnosed as an allergic reaction to a tick bite and the doctor discarded the tick which had bitten me by tossing it in the trash without sending it to a lab. This when I had been bitten in a known endemic area by the state health department. The family physician I saw was practically useless, and I ended up at an ILADS doctor's office by referral after I had gotten so ill I could barely read and write, barely walk, and had trouble tracking conversations. (I'm better now, thankfully. Not normal - but better.)

It was never my plan to end up in an ILADS doctor's office, any more than it was the plan for one woman I had talked to on Twitter to end up getting her best Lyme disease medical advice from a PhD at her local university because her own local MD had failed her. (Something is wrong when I tally up the number of times I've heard stories similar to ours. Why are family doctors missing what would be considered textbook presentations of Lyme disease?)

This experience we share may be one reason Lyme disease advocacy groups and patients are not so proactive about pushing for clinical trials by the doctors who are helping them. If they've already had their diagnoses missed by family doctors who should be well informed about the symptoms and signs of early Lyme disease - and their infection went late stage - patients could have a lack of confidence in giving family and urgent care physicians the power to make medical decisions about chronic Lyme disease.

Patients when asked will tell you they see ILADS doctors because they are already doing their best to take care of them and help them get better when nobody else would. And they support them, saying some members of ILADS have treated chronic Lyme disease since before ILADS even existed and have many years of clinical experience working with patients with tickborne diseases - diseases which other doctors have been either unable, unknowledgable about, or unwilling to treat.

If ILADS seems to have a monopoly on treating chronic Lyme disease patients, how much of it is based on how poorly other doctors respond to patients with early cases of Lyme disease - such as my own case? How much of it is based on ILADS doctors developing a reputation for their treatment based on seeing patients who mostly have suffered from tickborne diseases - therefore having specialization in their practices? How much of it - critics have inquired - is because ILADS wants to hoard the care of such patients all to themselves in order to make a tidy profit?

One of ILADS' more vocal doctors, Dr. Daniel Cameron, indicated he isn't interested in ILADS having a monopoly in treating chronic Lyme disease. He made this remark on a Morning Call chat debate back in 2011 [12:38 mark], when he and Dr. Lawrence Zemel of the IDSA (a guidelines co-author) took questions from the audience:
"We need many more physicians to diagnose and treat chronic Lyme disease. We will have less chronic LD if they are recognized early. Finally, more physicians will offer more options for patient within HMO's."
Dr. Cameron's desire seems to closely reflect those of what many chronic Lyme disease patients would like to see: access to more doctors who know how to diagnose and treat their condition, earlier diagnosis, and access to treatment options within the HMO system.

This hardly sounds like a doctor who wants to monopolize the treatment of patients so he can make a buck. But those who spend any amount of time watching the Lyme wars scroll across their screen know that soon enough, someone will say he only made such a statement because politically it sounded good - not because he meant it with sincerity.

And this is one strong example of why, by the way, I've gotten tired of reading and talking about Lyme disease when it comes to its sociopolitical aspect: Everything anyone says, no matter which side of the Lyme disease treatment debate you are on isn't to be trusted. This is, after all, a Lyme war and there are whisper campaigns, there are rumors; there are truths and half-truths - and good luck sorting them all out along with who really said what from your armchair at home.

But I digress.

I think that if Dr. Cameron and his colleagues want to see more doctors diagnose and treat chronic Lyme disease the way he does, he is going to have to find a way to conduct clinical trials in order to provide HMOs with an incentive to change their approach on how they diagnose and treat chronic Lyme disease.

An important issue, of course, is whether or not Dr. Cameron and his colleagues at ILADS would be in any position to conduct the kind of clinical trials they would like to have based on their own treatments.

Over the years, I've heard a few Lyme disease researchers complain that certain kinds of Lyme disease projects get selected for grants, again and again, and few projects are novel and bring in new talent.

This issue was briefly touched upon by Ms. Pfeiffer in her articles as well:

Ms. Pfeiffer reported that one Lyme disease researcher said to her:
"How many studies have we got on coronary disease and cholesterol in the last 30 years? Thousands. We’ve got five with Lyme disease.” (Editor's note: The "five" refers to antibiotic treatment trials only - there is a lot of Lyme disease related research.)
The scientist did not “want to be identified with either side of the controversy,” and, like others, said it was difficult to obtain government research funding for scientists with alternate theories.

Dr. Stephen Barthold, a Lyme disease researcher from UC Davis stated at a House subcommittee hearing last July:
"Because of firmly entrenched opinion within the medical scientific community, evidence of persisting viable but non-cultivable spirochetes is slow to be accepted and research proposals submitted to NIH that feature persistence following treatment are likely to receive prejudicial peer review in the contentious environment of Lyme disease*. Negative comments by peer reviewers of grant applications in the current financially austere NIH climate result in unfundable scores, if they are scored at all (triaged). I have no personal stake in this issue any more, as I am retiring within a year. 
In my opinion, for such important and controversial studies to go forward, NIH will need to publish a specific call for applications, known as a “Request for Applications” (RFA), that requests research on the biological significance of persisting spirochetes following antibiotic treatment.
________________________________________
* a major weakness cited by a peer reviewer in a recent unfunded R01 application:
“The lay public that has so far denied the validity of scientific data will misunderstand the significance of…[persisting non-cultivable Borrelia burgdorferi]…and use it as additional evidence to support the idea of treatment-resistant Lyme disease.
My thoughts on that footnote on Dr. Barthold's submitted testimony is that if the lay public has a misunderstanding of the significance of persisting non-cultivable Borrelia burgdorferi and how it does or does not support the idea of treatment-resistant Lyme disease, then researchers and science journalists who report the significance of such findings need to improve how they communicate with the public about them.

Another goal I think they should have is to communicate the science clearly while also giving the patient community reasonable hope and evidence that projects are in the pipeline which will help them based on such findings.

Right now, neither seems to appear to be happening as often as it should - and further educational outreach and positive patient engagement is in order.

Separately, Dr. Baker has exchanged comments with me on the issue of more antibiotic treatment trials last February on lymedisease.org, and informed me that the NIH-NIAID will most likely never do any long-term antibiotic treatment studies for chronic Lyme disease again:

"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” [sic] 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."
He thought chronic Lyme disease studies should be conducted working from different perspectives (which I agree with in principle) but I have yet to witness any of such studies actually occurring which apply to treatment - nor are any listed on clinicaltrials.gov - and I check periodically.

Given that the NIH-NIAID is now suffering under the burden of sequestration, cuts have been made to research - including in areas which were already struggling for funding. I have a difficult time seeing how anyone doing research on Lyme disease is going to meet their projected goals for the future - whether their research is about long term antibiotic treatment or immunological factors involved in chronic Lyme/post treatment Lyme disease.

With this current state of affairs it's the patients who are going to suffer the most.

What Does The IDSA Lyme Disease Guidelines Panel Think Chronic Lyme Disease Is, Anyway?

Here are a few quotes from the IDSA Lyme disease guidelines panel members/colleagues' FOI emails from 2007 Ms. Pfeiffer published, stating they don't really know what chronic Lyme disease is:
"I believe that it (CLD) is primarily psychological (but there must be biochemical correlates) and I think it is a bit like post-traumatic stress disorder…One other post infectious syndrome that might be comparable is PANDAS." - Dr. Eugene Shapiro 
"The functional somatic syndromes is an excellent reference. I don't think I would mention PANDAS." - Dr. Henry Feder 
"I doubt very much that autoimmunity or molecular mimicry has anything to do with post-Lyme disease syndrome. It is most like chronic [fatigue syndrome]." - Dr. Allen Steere
None of them think chronic Lyme disease is caused by a persisting bacterial infection that survives 2-3 weeks of antibiotic treatment - at least not in these specific emails which Ms. Pfeiffer has made public.
But neither are they in agreement about what exactly chronic Lyme disease is, either. One additional statement which has been made publicly by IDSA Lyme disease guidelines members was the possibility that post-Lyme disease syndrome is an autoimmune-like disorder.

Six years have passed since the emails' authors shared their ideas of what chronic Lyme disease is or isn't. Has anything changed since then that we can find on record? For that matter - has anything changed since 1982?

Lyme disease's causative agent, Borrelia burgdorferi, was discovered in 1982 and it wasn't long after that that doctors began noticing patients didn't always get better after having one course of antibiotics. Or even two courses. Unlike other conditions which have been labeled by others as "being invented by the internet", the same cannot be said about chronic Lyme disease. Patients who continue to have symptoms after early or delayed antibiotic treatment have been around for a long time, and over 100 Lyme disease support groups were already in existence by 1992.

One major advocacy group had an electronic newsletter distributed from Lehigh University and no web sites; only 6,000 people knew this list existed - far fewer than the number of people who have heard of Lyme disease and chronic Lyme disease today. This was before Lyme disease cases greatly escalated in number (and by extension, more patients with persisting symptoms as well).

If Lyme disease has been easy to diagnose and treat, why did we have over 100 Lyme disease support groups back in 1992? Good question. And it's a good question to ask what has happened since then, and why there are even more support groups today, multiple advocacy organizations, protests, rallies, pushes for legislation, and controversial films like Under Our Skin being produced.

When I read a transcript of a Senate subcommittee hearing on Lyme disease held back in 1993 - that's twenty years ago - it's apparent the same sort of issues doctors, patients, and researchers had back then are the same ones they have today (Copies of original hearing transcripts with commentary here: part one and part two ).

And when I see Ms. Pfeiffer write about the amount of NIH grant money that has been going to the same small group of researchers over and over, year after year, and they happen to be the same people (or their colleagues) who make statements about what chronic Lyme disease is or isn't, I have to wonder why they didn't put more money towards researching this chronic condition years ago?

And if they did put some money towards it - why it has been so non-productive an enterprise from the patients' perspective?

Why are we still stuck?

One reason why I am invested in answering these questions is apparent and biased: I'm a patient. But the other reason I am invested is that I'm genuinely curious why there has been no obvious progress on my condition and the development of more treatment studies.

The entire scene seems particularly illogical when you realize the one point of agreement IDSA Lyme disease guidelines panelists' share with most doctors in practice now - including even ILADS doctors:
Lyme disease which is treated with antibiotics early leads to a positive outcome. In terms of helping people with this disease, those who get an erythema migrans rash (the bull's-eye) and flu-like illness are treated early and go on to feel better, return to work, and go back to school. They don't NEED any further help from a doctor. They're fine.
It seems to me the sticking point - and the issue which needs more attention - are those patients who are NOT fine, and do NOT go on to be fine. Shouldn't they be the ones who should be getting the lion's share of research, to try to understand why they are not doing well and their symptoms persist?

When it came to patients enrolled in the Klempner clinical trial (a long term antibiotic clinical trial for chronic Lyme disease patients conducted over 10 years ago), researchers said the condition could be equally disabling as congestive heart failure and osteoarthritis.

Knowing this, you would think the IDSA Lyme disease guidelines panelists would make it a priority to help such patients get better - or at the minimum, write guidelines which acknowledged the range of severity of their condition based on hard data and made actionable suggestions as to how to improve patients' quality of life. Instead, the 2006 guidelines state that the percentage of patients with this condition that suffer from pain is no higher than that found in the population at large and there is no suggested treatment advice.

When the Klempner trial was discontinued in 2001, Dr. Phil Baker said:
"The antibiotic treatment component is only one piece of NIAID's comprehensive clinical studies on chronic Lyme disease. These studies have yielded a considerable amount of new information. We intend to characterize the patients enrolled in the study as thoroughly as possible to learn more about the mechanisms involved in chronic Lyme disease," Dr. Baker adds. "The knowledge obtained from such studies should be of immense value in developing new, more promising approaches for treating this disease."
It's been twelve years since Dr. Baker made that statement. Twelve. Where are the "new, more promising approaches for treating this disease"?

Where Are The Immune-Mediated Treatment Studies For Patients Who Cannot Take More Antibiotics?

While some patients have given ILADS high accolades for saving their lives and changing them for the better due to longer term antibiotic treatment, other patients have not been as successful following the same plan. Those who support the outcomes of clinical trials done to date on long term antibiotic use for chronic Lyme disease would say hearing this is not surprising - though many patients would argue that the outcomes of those trials are not the full picture.

Regardless of whichever side of the debate you are on when it comes to long term antibiotic use, the truth is there are patients who either have not experienced much improvement on long term antibiotics or they could no longer take them due to side effects, allergies, or contracting C. difficile. These patients continue to experience symptoms of varying severity, and for them there must be other treatment options. So far, antimicrobial herbal tinctures are their first remedy to try, followed by increasingly ineffective and unproven treatments including amongst other things, Rife machines.

Is this the best that can be done for them? What about more evidence-based treatments?

If the IDSA Lyme disease guidelines panel and their colleagues think they have more evidence to support patients' persisting symptoms being caused by an autoimmune-like condition rather than a chronic infection, then where has their involvement and dedication been when it comes to the patient subgroup mentioned above?

Why hasn't the IDSA Lyme disease guidelines panel or their colleagues applied for grant money to do research on treatments which involve immune mediation or addressing autoimmune disease caused by Lyme disease?

The irony in Lyme disease research now is that a Lyme disease advocacy group - the kind of group which is typically reported about by many in the media as pushing for legislation to protect ILADS doctors and force insurers to cover long term antibiotics - has invested grant money in the development of the first novel immunological treatment for chronic Lyme disease, VGV-L.  VGV-L is a targeted peptide therapy developed by VG Life Sciences, Inc. which has already met pre-IND requirements of the FDA and is expected to enter clinical trial stage later this year.

The development of VGV-L has been funded by the Lyme Research Alliance, a patient advocacy group - and not Dr. Baker and his colleagues at the IDSA. And yet, VGV-L addresses immune dysregulation in Lyme disease - research he should be able to support as someone who does not think chronic Lyme disease is caused by ongoing infection.

Yet there has been not a peep, not a press release, not one scientific article or review from Dr. Baker and his colleagues at the ALDF or the IDSA about VGV-L and how based on the scientific understanding of chronic Lyme disease to date, it might or might not work.

And if Dr. Baker and his colleagues think that chronic Lyme disease is similar to fibromyalgia and chronic fatigue syndrome then why haven't they conducted clinical trials for chronic Lyme disease on low dose naltrexone - similar to the successful Stanford University studies using low dose naltrexone for fibromyalgia? Even now, some chronic Lyme disease patients are being prescribed low dose naltrexone off-label to help with managing pain - and some are reporting improvement.

There has been no positive engagement between the IDSA Lyme disease guidelines panel and Lyme disease patients for years - even with just this subgroup of chronic Lyme disease patients who either cannot handle additional antibiotic treatment or for whom there is evidence their symptoms may actually be more immune-mediated.

If I as a patient want to know more about post-treatment Lyme disease and how to treat it, and my doctor and I actually think my remaining symptoms are due to post-infection damage instead of persisting infection, there is no obvious resource for us to turn to.

There simply isn't enough research being done by anyone that addresses this condition. We are driving blind, and making it up as we go based on trial and error and models of other neuroimmune and neurological conditions, and by talking to other doctors and patients who are navigating the same issues.

Why ILADS And The IDSA Lyme Disease Guidelines Panel Can't - Or Won't - Meet In The Middle?

While I have wondered why the IDSA Lyme disease treatment panel dismisses the idea of persistent infection when it comes to Lyme disease - I've also wondered why a number of ILADS doctors and patients dismiss there being an element of immune dysregulation and autoimmune response where Lyme disease is concerned?

And it seems no one has considered the possibility except for a few researchers - or it's at least not discussed online much - that infection and immune dysregulation in Lyme disease could occur concurrently.

One possible combination treatment which could address both infection and immune regulation which could be used in clinical trials that both ILADS and the IDSA Lyme disease guidelines panel may want to consider is the use of IV ceftriaxone and filgrastim to treat Lyme disease patients who have persisting symptoms past initial treatment.

Dr. Isabel Diterich has used both filgrastim and ceftriaxone to treat a stubborn case of late stage Lyme disease, and the patient completely recovered and reported no relapsing symptoms in the following eight years. Additional studies were completed in animal models which showed some promise.

Such studies would involve a shorter total antibiotic treatment than any of the clinical trials for chronic Lyme disease conducted to date at the NIAID. Yet no one that I know of outside of Dr. Diterich and Dr. Albrecht Wendel has commented on this potential treatment - and neither ILADS nor the IDSA Lyme disease panel has mentioned it to my knowledge.

It's not as if getting more testing of this combination hasn't been tried before, either. Like those in the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) community, with patients and doctors who lobbied hard to conduct clinical trials on rituximab for CFS/ME patients, Dr. Wendel tried to encourage Amgen to get involved in clinical trials to treat chronic Lyme disease patients using filgrastim alongside ceftriaxone. Amgen responded that they were not interested because the market for the drug was too small.

As time goes on, I wonder with each passing year that Lyme disease cases rise if this will continue to be the case. I don't know.

Both the IDSA Lyme disease guidelines panel and ILADS could have investigated this treatment approach, combining both antibiotics and immune mediation to see if it improved treatment outcomes for a higher percentage of patients. Instead, we're left with this ongoing debate between the ILADS promotion of long term antibiotic treatment because chronic Lyme disease is caused by infection versus the IDSA guidelines which have no advice for how to treat chronic Lyme/Post Lyme disease at all (and lots of verbiage on how NOT to treat it).

But even if this were a treatment trial which both ILADS and members of the IDSA Lyme disease guidelines panel could theoretically agree to, due to the history between members of both and contentious accusations shared in personal communications and in the media between advocacy organizations and anyone from the IDSA Lyme disease panel, this possibility looks slim. There is too much water under the bridge there.

The most recent accusation against members of the IDSA Lyme disease guidelines panel comes from ILADS member Dr. Ken Liegner, one of the most experienced Lyme disease specialists who has been dealing with the controversy pretty much since it began. Dr. Liegner spoke to a crowd of chronic Lyme disease patients at a rally in New York City recently, accusing Dr. Dattwyler of scientific misconduct and withholding scientific information that could prevent chronic disease and save lives:

"In the year 2000, due to fortuitous circumstances, and unbeknownst to Dr. Dattwyler, I gained access to CDC-funded experimental methods in his research laboratory for more than 140 specimens of frozen cerebrospinal fluid on my patients.

Whereas only 2% of specimens tested positive on standard spinal fluid tests, some 62 % of specimens tested positive on one or more of the four experimental assays used.  Ironically, Vicki Logan’s CSF tested more than 7 times higher than the positive cut-off for detection of Outer surface protein C antigen, in the very laboratory of Empire Blue Cross & Blue Shield’s own expert consultant. 
I asked Laboratory Supervisor, Priscilla Munoz, how they knew these methods were valid.  She replied that the three collaborating research laboratories shared aliquots of samples and found excellent reproducibility between the three labs.The results of these CDC-funded studies on direct detection of OspA and OspC antigen and IgG and IgM borrelia-specific immune complexes in spinal fluid have never been published. 
Why not? Did someone at CDC “deep six” the results of this research project?  If so, who made this decision, and why? 
I demand the “raw data” from these CDC-funded research studies, which have never seen the light of day, be made public immediately. 
Thomas Frieden, as Director of CDC can ‘set the tone’ for the agency.  I call on him, to ‘step up to the plate’ and fix the mess created by CDC.  Dr. Frieden can ‘redeem’ the reputation of  CDC, which is composed of fine physicians and scientists.  Dissociate CDC from the disgraced IDSA Lyme disease guidelines.  Otherwise, step down!"
In the Lyme wars, ILADS' critics would say Dr. Liegner is only making up stories in order to smear the reputations of those who challenge his livelihood as a Lyme doctor and stir up patients' ire toward activism.

On the other hand - if he's correct, this is a very serious accusation which cannot go ignored and his anger is understandable. I think even if I were a casual outside observer and not a patient, with an accusation of this nature a full investigation is in order.

Dr. Liegner's accusations are only one of many coming from ILADS and its advocates side towards those involved with the IDSA Lyme disease guidelines panel and the CDC. On both sides of the fence, accusations of conflicts of interest and scientific misconduct fly when it comes to the Lyme wars, with the most recent volley from the IDSA and its colleagues being a highly critical editorial against ILADS and patient advocacy groups which was published in The Lancet.

The Crazy Mixed-Up World Of Persisting Spirochetes

The IDSA Lyme disease guidelines panel and its colleagues at the American Lyme Disease Foundation (ALDF) state that chronic Lyme disease is not caused by persisting spirochetes - but like most patients, we have yet to hear the reason why they think persisting spirochetes are not causing patients' symptoms - at least in some subset of patients who are most likely to respond positively to additional antibiotics.

Dr. Phil Baker (mentioned earlier as the author of the editorial letter to Ms. Pfeiffer of The Poughkeepsie Journal in this post) is executive director of the ALDF, and has strong ties to the IDSA Lyme disease guidelines panel and also to the NIAID since he was a program officer for the Lyme disease research division there in the past.

While he doesn't support additional long-term antibiotic studies for chronic Lyme disease patients, he does support additional research on persister cells related to the research one member of the ALDF's scientific advisory board, Dr. Stephen Barthold, has been conducting. He also promotes similar research to that which was completed by Dr. Bockenstedt, who has stated in her own research published last year that spirochetal antigens may get trapped in patients' joints and that may be what causes their persisting symptoms.

What has Dr. Stephen Barthold said specifically about the nature of these persistent spirochetes in the past?

From an article published at the University of California at Davis in 2008, where Dr. Barthold does his work:
In the case of Lyme disease, the research findings do not suggest that continued use of antibiotics would succeed in getting rid of the lingering bacteria. 
"I suspect that if the initial round of antibiotics hasn't eliminated them, it's not likely that a longer regimen of antibiotics would be any more successful," Barthold said. "It's more likely that a completely different class of antibiotics would be needed to accomplish that. This laboratory mouse model will allow us to address those possibilities."
If Dr. Barthold's suspicion is correct, the reason why clinical trials using long term antibiotics to treat chronic Lyme disease haven't been entirely effective may be because the antibiotics which were used were inappropriate for treating the Borrelia burgdorferi infection patients had in the first place. They may have had some positive effect for some subset of patients - but clearly they did not improve all patients' symptoms.

In other words: Patients with chronic Lyme disease could have chronic infections, but treating them with the kind of antibiotics we have now won't help much. (They might, however, help some patients who have unidentified confections.)

Dr. Barthold has confused many patients with another hypothesis: It isn't infection with the spirochetes which is the primary problem, given their low numbers - rather that it's their ongoing presence which causes patients' persisting symptoms [11:21:11 mark].

Later on, in 2012, in his testimony at a federal House subcommittee hearing, Dr. Barthold stated:
"Because persistence of non-cultivable spirochetes has been shown to occur following treatment with several different classes of antibiotics, the phenomenon is likely explained by antimicrobial tolerance (in contrast to antibiotic resistance or inadequate antibiotic treatment), in which all classes of antibiotics fail to completely eliminate non-dividing or slowly-dividing subpopulations of a broad array of bacteria and fungi [44,45].

A possible explanation for these attenuated antibiotic-tolerant spirochetes may be because of plasmid loss, in which spirochetes have lost critical genetic material that favors robust growth. It has been known for decades that during in vitro passage, B. burgdorferi is highly prone to plasmid loss [46,47,48], and therefore plasmid loss is likely to also occur during the course of infection and increase over time. This may explain why treatment success in humans [3,8] and laboratory mice [2,38] appears to be most effective during early infection.

Treatment success is inversely correlated with spirochete populations, since spirochete burdens in mouse (and human) tissues are highest during early infection [49], when antibiotics work best. The biological (in contrast to medical) significance of attenuated spirochetes is probably insignificant, in that robustly dividing-, genetically-intact spirochetes would be selectively favored upon tick acquisition, transmission, and survival in reservoir hosts. The medical significance of attenuated persisting spirochetes is another matter, and compels further investigation."
For direct reference to the above citations, see full text here:
http://archives.republicans.foreignaffairs.house.gov/112/HHRG-112-FA16-WState-BartholdS-20120717.pdf

(As an aside, it is interesting to note that Dr. Isabel Diterich also published research in 2003 about antibiotic tolerance and immunosuppression involving Borrelia burgdorferi.)

Dr. Bockenstedt doesn't discuss lingering spirochetes in her most recent research which applies here - she discusses lingering antigens which might contribute to patients' persisting symptoms - rather than persister cells.

Dr. Barthold's and Dr. Monica Embers' research involving persistent spirochetes have intrigued the Lyme disease community, and it has called upon a world expert on persister cells, Dr. Kim Lewis, to help.

Dr. Lewis, Distinguished Professor and Director, Antimicrobial Discovery Center, Northeastern University, Boston, Massachusetts. Dr. Lewis, in collaboration with Brian Fallon, MD, MPH, Director of the Lyme and Tick-Borne Diseases Research Center at Columbia University, has recently been awarded a grant from the Lyme Research Alliance to do research which will focus on persisters and introduce a new, rapid method for determining antibiotic sensitivity. A particular variant of persisters will be studied to better understand chronic infection and several experimental compounds will be tested in an effort to eradicate persister populations.

Only further research can determine exactly what is happening with the pathology of chronic Lyme disease, but this research demonstrates that chronic Lyme disease is not easily dismissed with a vague diagnosis of something "a bit like post-traumatic stress disorder".

Something else is going on which is affecting patients and science help can determine what's behind patients' symptoms even if it takes longer to fully understand the process.

I applaud Dr. Barthold, Dr. Embers, Dr. Lewis, and Dr. Bockenstedt for further investigating the cause of chronic Lyme disease even amid dissent and scientific uncertainty. This is the only way to get real answers and stop the decades-long argument about who is right - and who is wrong.

End point?

What is the future of chronic Lyme disease (or post treatment Lyme disease, if that's your preferred term)? I don't know. My current hope is that research which is done with integrity by scientists who have no conflicts of interest and care about patients will be the focus of the next decade and not the kind of petty, low-minded handling my condition has received both in the media and behind the scenes.

If it is confirmed patients have an infection with persister cells, this will spur a whole new generation of treatment development to address persisters. If it is confirmed that retained antigens are a problem, then perhaps a different treatment will be designed for that. But as it stands, no one gets anywhere if we keep fighting. And it seems that patients, their families, and advocates have to hope that Lyme disease advocacy organizations can get together enough of the funding they need to offer grants for research to look into the problem rather than hope and pray that one of a handful of projects patients see as important gets funded by an NIH-NIAID under sequestration.



And people wonder why I want some more scotch...


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[Minor edit August 17, 2013 - Changed "fourteen years" to "twelve years" due to basic miscalculation error.]

9 comments:

  1. Have you seen the paper published in the April International Journal of General Medicine "Review of evidence for immune evasion and persistent infection in Lyme disease"? You can find it at:

    http://www.dovepress.com/review-of-evidence-for-immune-evasion-and-persistent-infection-in-lyme-peer-reviewed-article

    It is a very interesting read which seems to layout a well reasoned case that Borrelia bacteria have more then enough mechanisms which it can use to evade both an immune response and prolonged antibiotic treatment. I found it particularly fascinating that the bacteria will actually grab a protein out of the ticks saliva which the Borrelia then uses to hide from the initial immune response of the newly infected host. If I read the article correctly in studies where the ability of the bacteria to grab the protein was inhibited the bacteria had almost no ability to infect a host. I wonder if this is what can explain why Lyme disease is not transmitted by other insects like mosquitoes or through blood transfusions.

    ReplyDelete
  2. Given all the energy expended on the "chronic-Lyme" controversy, it is a shame that fear seems to be dominating the progress of science. I've reached out to a number of prominent researchers offering to fund research and have been ignored. There appears to be a fear of "reputation" and/or "career" damage by simply exploring certain questions.

    For example: I offered to fund a study utilizing the new ALS culture and the latest DNA sequencing tools to test the culture's validity, investigate persistence in humans, the reliability of the CDC 2T antibody testing and the impact of genotype on both. I was blown off by all but one researcher. Would Camp Other like to utilize this Blog to help promote some research I would fund that would actually help resolve the controversy or move the science forward?

    ReplyDelete
  3. Anonymous,

    I received your comment late - hope you are seeing my response now.

    I think that your research goals sound laudable and are valid work to pursue. Why you are receiving a cold reception is something I don't understand, and last I checked two universities were planning on evaluating ALS' culture test themselves (are you familiar with this validation and verification?).

    I would very much like to promote research that may help resolve the controversy, move science forward, and help patients. I have already promoted researchers working on Lyme disease studies who have run #SciFund rocketfund crowdfunding campaigns online (For example, http://tickproject.blogspot.com/). I would, of course, like to have as much information as possible as to who is conducting proposed research, their credentials, and any potential conflicts of interest before I would offer any form of endorsement for their crowdfunding campaign.

    I am also okay with informing my readers about the existence of any Lyme disease research crowdfunding efforts without my endorsement, and would add a disclaimer stating that due to a lack of further information on my part (or other reasons such as known conflicts of interest) I could not heartily endorse the campaign.

    I don't know why it seems Lyme disease/Borreliosis research has been stuck in the same place for years, and have written this post to point out the nagging, sticking problem that even if those who have dominated the treatment guidelines do not support a model of persistent infection in patients, they have either failed to accomplish the research necessary to help patients who suffer from their described "Post Lyme disease syndrome" or they have accomplished some, and failed to communicate their setbacks and reasons for them in coming closer to an understanding about the disease process. There is - as others in the health management field would say - a distinct lack of education and outreach, no patient management, and a seeming lack of compassion for patients (which was demonstrated in the released Freedom of Information Act letters which the Poughkeepsie journal published).

    I realize the letters which were shared are a mere fraction of the total Ms. Newby received long after her request, and so I do not know what they all say - so I may not be doing this story complete justice. However, just reading the small fraction of what was published leaves me with more questions about the state of affairs in patient-centered Lyme disease/Borreliosis research than it does answers.

    In the fourteen years since Dr. Baker said more research outside of antibiotic trials would be completed that would help patients, what was it and how has it helped patients? We don't need the 50th EM rash study; we need studies which help patients who suffer for many months - if not many years - after initial infection.

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  4. It seems to me that there is something like a logjam in scientific progress and some fairly simple studies could break it. I suspect its caused by a lack of funding by the NIH to explore the right questions combined with a general fear by researchers to tackle them due to professional risk. The Embers study is a perfect example where it was delayed, got hung up in peer review, Dr Barthold was attacked for his views and finally it was criticized in a journal paper.

    I would like to propose and fund a study specifically aimed at exploring persistence, antibody test reliability in late Lyme and whether treatment failed similar to the Embers study but using humans that appear to have persistence.

    If a significant number of cases of "real" persistence where the CDC 2T test failed and treatment failed could be identified and studied, it could provide evidence that the NIH and CDC could not ignore.

    Adrianna Marques of the NIH is currently using xenodiagnosis to explore this question. Her selection of patients though will bias the study. The use of xenodiagnosis in humans will probably yield poor results since the quantity of spirochetes in human blood is very low and even using 20 ticks may not be enough.

    Dr Eshoo developed very reliable high sensitivity technique to perform PCR by using larger volumes of blood.

    http://www.ncbi.nlm.nih.gov/pubmed/22590620

    Eva Sapi developed the ALS culture by increasing the blood volume as Dr Wormser had done plus adding a 2 stage growth medium.

    Dr Eshoo's technique when combined with the Eva Sapi culture should provide a very reliable detection of persistence beyond reproach when combined with the latest DNA sequencing.

    Selecting CDC 2T seronegative people who are highly suspected of Lyme after treatment and have either a positive C6 or suspicious antibody profiles (2/5 - 4/5 specific antibodies) would be the ideal study population.

    They could be CDC 2T, C6 and ALS cultured and PCR tested using the Eshoo approach. The results of both could be partially sequenced by an independent outside DNA lab such as Eurofins Operon http://www.operon.com . The sequences could then be compared against one another and against the NCBI Borrelia database.

    If you would like to help formulate a study plan to promote, let me know how I can contact you. You seem like a competent Lyme sufferer who believes the right science could break down the political and emotional barriers.

    Your blog is very good and might be a good platform for trying to find a research group open to doing the study if I fund it. They don't respond to emails. The key would be recruiting researchers that are respected or the results would be ignored. The other problem is recruiting patients that fit the best profile.

    ReplyDelete
  5. Hi Anonymous,

    Apologies for the delay in responding to your comment - have been having internet access issues and computer problems lately. Hopefully things are on the mend.

    All of what you say about there being a logjam in Lyme disease/Borreliosis research is correct - there isn't enough novel research or research directed towards patients suffering from long term symptoms, long after the initial tick bite and initial treatment. With repeated searches of the vast body of research available, more research tends to focus on vaccine development and early Lyme disease, with some research on immunological factors involved with Lyme disease/ Borreliosis - but not much focuses on resolving the persistence issue once and for all.

    Some researchers believe it has been settled already - I do not think it is, given both Barthold's and Bockenstedt's recent studies. Is it the antigens or is it persister cells? Can we know, and how can a xenodiagnosis study accurately determine which of these possibilities occurs (one, the other, or perhaps as I've postulated: both) - animal xenodiagnosis studies have failed to consistently provide evidence that is required by many scientists, and do not resolve the problem of there being PCR-positive samples which are culture negative in animal studies; do not resolve the issues around what the nature is of persisting spirochetes found after initial antibiotic treatment (even though many patients and advocates will testify that additional antibiotics have helped them).

    One highly critical (and criticized) paper, "Antibiotic Treatment of Animals Infected with Borrelia burgdorferi" (2009) asks questions which need to be answered yet I don't know how much research funding is available towards them (NIH sequester cuts being a huge problem at the moment):

    The following are outstanding questions regarding the phenomenon of PCR positivity without culture positivity after antibiotic treatment of experimental animals with B. burgdorferi infection.

    (i) Does the duration of treatment affect the development of
    PCR positivity in the absence of culture positivity? What is the
    shortest duration of treatment possible?

    (ii) Do pharmacodynamic considerations such as total daily
    antibiotic exposure affect the development of PCR positivity in
    the absence of culture positivity?

    (iii) What are causes of the attenuation of the spirochetes
    that persist posttreatment? Are they in the process of dying?
    Are they producing mRNA, and if so, which mRNA? Are they
    motile? Can they replicate? Are they genetically altered? Can
    they regain pathogenicity?

    (iv) Does development of PCR positivity in the absence of
    culture positivity occur in SCID mice that are treated with
    antibiotic therapy; i.e., does the process occur independently of
    an adaptive immune response?

    (v) Is PCR positivity reduced over time in SCID mice; i.e.,
    does PCR positivity resolve spontaneously due to the death of
    damaged spirochetes?

    (more)

    ReplyDelete
  6. Barthold, Hodzic, and Embers have been working more on answering these questions with which Wormser and Schwartz challenge them. But not many researchers are doing this kind of work, and I don't completely understand why as answering these questions would help the entire Lyme disease patient community which is suffering with late Lyme disease; suffering with persisting symptoms after initial treatment.

    I often look at all this and ask the question of whether or not murine models of study of persisting Lyme disease are the wrong models, because while one can use specially bred mice to look at some aspects of human immunological pathways, Borreliosis in humans can be different in important ways. Mice are also regarded by Barthold as being poor models of neuroborreliosis, so other models need to be examined especially since CNS manifestations are often the most life disabling if not life threatening to patients.

    Regarding your comments:

    "I would like to propose and fund a study specifically aimed at exploring persistence, antibody test reliability in late Lyme and whether treatment failed similar to the Embers study but using humans that appear to have persistence. "

    Sounds great. Is it your intent to systematically map antibody patterns over the course of infection in humans? How do you intend to collect this data (find patient population, get proper consent, verify their histories)? I say this because it can be an expensive undertaking, and involves a number of ethical considerations.

    Also, what kind of validated test results will you look at - one test? multiple tests which cross correlate the serological results? Which labs will you be using and how can you independently verify outcomes if tests differ?

    "Dr Eshoo's technique when combined with the Eva Sapi culture should provide a very reliable detection of persistence beyond reproach when combined with the latest DNA sequencing."

    Ah, so is this the design: Use Dr. Eshoo's technique with Dr. Sapi's culture to detect persistence along with DNA sequencing? Do you think this will well answer the challenging questions put to Lyme researchers at large? A positive culture test would be good given PCR positive, culture negative outcomes in the past, agreed. But I think the nature of the acquired spirochetes also needs to be nailed down without a doubt.

    (more)

    ReplyDelete
  7. (cont'd)

    "Selecting CDC 2T seronegative people who are highly suspected of Lyme after treatment and have either a positive C6 or suspicious antibody profiles (2/5 - 4/5 specific antibodies) would be the ideal study population. "

    Sounds like a reasonable patient population to pursue, but how will you distinguish late stage treated patients with suspicious antibody profiles from those who have been reinfected and from those who are potentially simultaneously infected with an older Borrelia infection plus a newly acquired infection? (This is harder than it sounds, especially given since some patients have an undulating antibody response, and this response has been studied more closely in Europe than in the US - makes me wonder if more antibody response differences over time studies need to be completed in US as well.)

    "If you would like to help formulate a study plan to promote, let me know how I can contact you. You seem like a competent Lyme sufferer who believes the right science could break down the political and emotional barriers."

    Yes, I am interested in what you're doing - I would like to know more about your study design and how you best think to approach these issues. You can email me at CampOther at gmail dot com.

    "Your blog is very good and might be a good platform for trying to find a research group open to doing the study if I fund it. They don't respond to emails. The key would be recruiting researchers that are respected or the results would be ignored. The other problem is recruiting patients that fit the best profile."

    Thank you. One of my main hopes in writing this blog has been to bring up the issues in Lyme disease/Borreliosis research, uncertainties, and unanswered questions. Both the key concerns you mention - researchers who are respected and finding the best patient study groups are really valuable to discuss and address.

    ReplyDelete
  8. Anonymous and CampOther,

    There was mention of the Steven Schutzer study of the CSF (cerebro-spinal fluid) proteome of CLD and CFS, here, in this blog. Camp Other, you mentioned that the study could be augmented by testing acute LD patients, as well as those that responded well to treatment. Other classes of patients could include strictly neuroborreliosis patients, those that have been heavily treated with IV abx and are still suffering, and also those that were bitten by infected ticks, asymptomatic and never took antibiotics. We cannot forget we are dealing with lots of coinfections, too.

    So for Anonymous, I believe it would be fruitful to consider these extended proteomic studies that include the CSF as well as blood. Chronic Lyme patients need vindication these days rather than being kicked to the curb all the time.

    This research is going to get done, anyway. It may throw gasoline on the whole controversy, notwithstanding, of the putative link between Lyme disease and Alzheimer's, ALS, Parkinsons, MS, Lupus, FM, CFS, etc.

    Throw in studies of the microbiome, too, as there has been a groundswell of recent research tying in the gut bugs to various diseases.

    I'd like to be able to help in this endeavor, too, continuing to extricate myself from the train wreck since getting Lyme.

    ReplyDelete
  9. Sounds like a reasonable patient population to pursue, but how will you distinguish late stage treated patients with suspicious antibody profiles from those who have been reinfected and from those who are potentially simultaneously infected with an older Borrelia infection plus a newly acquired infection? (This is harder than it sounds, especially given since some patients have an undulating antibody response, and this response has been studied more closely in Europe than in the US - makes me wonder if more antibody response differences over time studies need to be completed in US as well.)


    If a new infection is due to the exact same strain, it would be difficult to distinguish even with complete sequencing. The Borrelia individual spirochetes that arrive in a single bite could not be distinguished from those in 2 subsequent bites especially if it happened in the same backyard with closely related spirochetes.

    If one were looking for the ideal patient population, one might consider choosing people that do not have Borrelia endemic in their neighborhood. I live in CA and the Lyme infection rate is lower than in the Northeast even though the tick infection rate can be similarly high. The likely reason is most people in CA live in track-like island neighborhoods where ticks rarely invade their yards. Most of the people who get infected in CA either live in the country or acquire the infection while visiting the country such as hiking in parks. By excluding people with endemic yards/homes, the probability of a reinfection with a closely related strain is greatly reduced.

    I'm looking for a study design optimized with the greatest probability of providing results showing evidence that some of the current assumptions are not as absolute as suggested. Its purpose is not to prove anything but provide sufficient doubt to encourage more focused studies.

    Mainstream medicine currently believes that the sensitivity of the CDC 2T test is virtually 100% in the later stages. It also believes that persistence after treatment is virtually 0%. Dues to these beliefs, they are not looking at these issues since they are "settled". The purpose is to add enough doubt that they are no longer considered "settled".

    The reinfection question is certainly one that would be proposed by mainstream researchers. If the patient population was selected with care to minimize the likelihood, then sequencing could show its probable that some post treatment infections were not reinfections since the Borrelia population was so closely related.

    ReplyDelete

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