4 Commentary: Slate's Article On Romney & Lyme Disease

It seems like over the past two weeks, every time I turned around, there's a new article about Mitt Romney and chronic Lyme disease. How much mileage from one topic can the media get? You would think by now they would have moved on, but today The Day decided it was going to post yet another rehashing about this subject.

Well, if they get to rehash, then so do I. I have some things to say in response to the Slate's article, "Why Is Romney Campaigning on Medical Quackery?", even though it's not the most recent in this set of offerings.

And again, I'd like to make one request of the media at large:

Can you please investigate more deeply the issue of people with persisting symptoms after delayed or initial antibiotic treatment for Lyme disease?

And not just spout out the same tired phrase that clinical trials to date have not shown that the use of long term antibiotics has been effective for the treatment of chronic Lyme disease (or what the CDC and other organizations call "Post Lyme Disease Syndrome")?

But I digress...

On to eviscerating the Slate...

"Let’s play doctor. A patient comes to you with joint pain, difficulty concentrating, anxiety, poor attention, and mood swings. You might run a series of tests to rule out a persistent infection or other disorder. If your patient lives in a tick- and Lyme-disease-infested area, you would be wise to test for the bacterium Borrelia burgdorferi and, if detected, prescribe a course of antibiotics. But suppose the tests come back negative and there is little evidence that your patient was bitten by a tick or was infected with the Lyme disease bacterium. If you are a good doctor, and you are, you might explore a diagnosis of depression, a disease that afflicts almost 10 percent of the population at any given time."

Okay, I'm going to respond to this with, "let's NOT play doctor", because it's not within our training and expertise to give medical advice if we are blogging or writing for online magazines and we are not doctors - or even if we are doctors, and have not actually seen the patient in question before making a diagnosis.

But as we are talking about some hypothetical case here - patient X - and not a real person, then I'm going to use patient X to discuss hypotheticals.

First, joint pain, difficulty concentrating, anxiety, poor attention, and mood swings can be indicative of any of a number of disorders. The doctor is correct to consider different diagnoses, and rule out or rule in anything which may be causing these symptoms. They can be related to some rheumatoid or autoimmune disorder, exposure to certain toxic substances, stress, immunological problems, and other conditions. Patient X may even have more than one condition which is producing these symptoms and need proper diagnosis and treatment.

I would not automatically leap to the conclusion that depression is the disease that is happening - and even so, depression can be a symptom of another underlying condition such as hypothyroidism, hormonal imbalance, or serious vitamin deficiency.

Let's reexamine this portion, and part of the succeeding paragraph:

"But suppose the tests come back negative and there is little evidence that your patient was bitten by a tick or was infected with the Lyme disease bacterium. [...] If you are a doctor who believes that the CDC and NIH have misrepresented carefully vetted clinical trial data about the diagnosis and treatment of Lyme disease, however, you might diagnose your patient with chronic Lyme disease and prescribe an intensive, long-term, side-effect-laden, mega-dose of antibiotics."

First of all, is clinical trial data about the diagnosis and treatment of Lyme disease the only data on which a medical practitioner should base their diagnosis and treatment of tickborne diseases in a particular individual patient?

The problem is this soundbite doesn't even begin to offer an overview of why a medical practitioner would think that maybe - just maybe - someone with a negative test for Lyme disease might still have Lyme disease. Or how it is that diagnosing Lyme disease can be a difficult task at times for any doctor.

The words chosen that follow - "prescribe an intensive, long-term, side-effect-laden, mega-dose of antibiotics" - reflect the judgment of the writer on how people with Lyme disease are treated without the writer actually investigating which antibiotics are used at which dosage for how long, nor how long-term antibiotic treatment for Lyme disease compares with long-term antibiotic treatment for other conditions, nor even what happens to those who have Lyme disease who do not receive long-term antibiotic treatment.

The costs and benefits of antibiotic treatment in general are not weighed and shared, so all it can be is a negative description of this treatment without investigating the long term outcomes of case-by-case studies of those patients who are either receiving it or where such treatment has been withheld.

On to another part of the article...

"As a Slate story pointed out years ago, chronic Lyme disease—not the persistent effects of a long-term bacterial infection but a collection of mysterious symptoms—has powerful supporters. Advocates for the diagnosis tend to blame the medical establishment for not taking them seriously enough."

Here I have a problem with this description of the condition, because it's not reflecting reality.

No one seems to really understand entirely what chronic Lyme disease is and what causes it. No one.

The CDC and IDSA have said that Lyme disease cannot become a chronic and persisting infection after a certain minimum allotment of antibiotic treatment, and offer up the hypothesis that any symptoms beyond this treatment are a (potentially autoimmune) condition known as Post Lyme Disease Syndrome (PLDS). However, this is a hypothesis, and thus far there are no treatment trials which put this hypothesis to the test.

If this hypothesis is so strongly supported, then why are federally funded treatment trials currently being conducted which are about providing evidence for Lyme disease as a persisting infection? Why is there a study currently recruiting which is entitled, "Searching For Persistence In Infection In Lyme Disease"? And why has another study been conducted in Europe, known as the "Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)"?

This doesn't sound like the issue of what causes chronic Lyme disease's persisting symptoms is settled. If so, treatment trials which address this devastating autoimmune condition would outweigh clinical trials on Lyme disease. If one searches for clinical trials for treating Post Lyme Disease Syndrome, the total sum is zero.

To add to this, why is it that the researchers who completed the most recent research on persisting Lyme disease infection in non-human primates concluded this at the end of their recent publication, "Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection"?:

"Our studies do however offer proof of the principle that intact spirochetes can persist in an incidental host comparable to humans, following antibiotic therapy. Additionally, our experiments uncover residual antigen associated with inflammatory foci. Whether persistent spirochetes or spirochetal antigen can cause PTLDS remains unanswered."

That chronic Lyme disease is a mystery is true. That one can readily come to the conclusion that it is not a persistent infection under any circumstances, in any situation, has yet to be established - just as these symptoms being caused an autoimmune condition has yet to be established.

But the content of Slate's article and that of others is very negative about the hypothesis of persisting infection without any specific evidence to strongly back an alternative explanation - or refute the evidence provided in a study such as Embers et al, above.

To continue...

"In 2008, the attorney general of Connecticut investigated the Infectious Diseases Society of America, a 50-year-old organization with more than 9,000 physician and scientist members, for misrepresenting the science of Lyme disease. Not to be outdone, Virginia Gov. Bob McDonnell assembled a governor’s task force on Lyme disease. He appointed Michael Farris as its chair. Farris is a lawyer and the chancellor of Patrick Henry College, aka God’s Harvard, whose motto is “For Christ and for Liberty” and whose “Statement of Faith” holds that the “Bible in its entirety” is “inerrant.” The school isn’t known for its biology department"

You know, we can argue this one until the cows come home. I honestly am not too keen that politicians are getting involved with medical debates - even though I as a patient want more recognition for my condition and more research for it.

What I want is more recognition from the medical profession, and for there to be programs put in place to help those of us with chronic Lyme disease. And what I really want is for someone with an understanding of the disease who has researched it extensively - and has suffered with it long term themselves - to come forward and represent me and other patients; to work from a desire to find the truth about what is causing our symptoms.

I do not need to see another advisory board, appointed chair, or politician try to defend my condition without a more intimate and thorough understanding of it. And I definitely do not need to see my condition being used in a political free-for-all from any side, from any party or special interest group, in order to try to gain more votes.

I find Slate's use of pulling out an appointed chair who is not big on science and who oversees a college with a statement of faith which holds the Bible as being infallible as being a diversion from the issue at hand: the issue of whether or not Borrelia burgdorferi can be a persistent infection.

All we see is an obvious character to take issue with if one is on the side of science and skepticism and wants an easy target to use to rail against the chronic Lyme disease issue... Of course those who are scientifically minded and skeptics are not going to take the word of an evangelical young earth creationist as being one educated about Lyme disease.

On the other hand, if we take one governor and one evangelical chair out of the picture, who do we have left that could have been interviewed instead? How about some scientists, for example? What about Dr. John Aucott of John Hopkins University, Dr. Stephen Barthold of UC Davis, Dr. Monica Embers of Tulane University, Dr. Straubinger, Dr. Brian Fallon of Columbia University, and others who have been studying Borrelia burgdorferi? They have nothing to lose by being asked for their opinion, being neither in politics, nor making money directly off treating patients, or nor working directly for the IDSA. Why doesn't Slate ask them about their scientific opinion on the cause of chronic Lyme disease?

But Slate doesn't do this. Slate goes for low-hanging fruit to support its diatribe against chronic Lyme disease - with the primary goal of denigrating Romney's attempts to appeal to voter subgroups and to support their characterization of Romney as being anti-science.

The mistake Slate makes is in conflating Romney's anti-science leanings with chronic Lyme disease as a condition which does not have enough evidence to support it. The two topics are issues which deserve independent examination.

Onward and upward...

"But the task force seems to have bought into the conspiracy theory that the infectious disease establishment is maliciously interfering with proper treatment. It states: “There is no scientific basis for concluding that 30 days or less of antibiotics is sufficient treatment for every case of Lyme disease.” Again, tell it to the Centers for Disease Control and Prevention."

I am not one of those people who will sit here and spout conspiracy theories. Refer to my page, What To Expect Here, if you have any questions. But there is the issue of oversimplifying and dumbing down the issues involved with properly treating Lyme disease - which is exactly what this article is doing.

It is not true that every case of Lyme disease is sufficiently treated with 30 days or less of antibiotics. Most acute cases are sufficiently treated with 30 days or less, but even when looking at the IDSA's guidelines themselves, they state that up to 10% of all acute Lyme disease patients experience treatment failures. These patients must be retreated and investigated for presence of tickborne coinfections. Also, a certain percentage of patients will have Lyme arthritis, which even Allen Steere treats with two months of oral antibiotics - and if symptoms are still present, a third month of IV antibiotics as well.

I can offer a number of cases where IDSA infectious disease doctors themselves have given individual patients with Lyme disease more than 30 days of antibiotics without thinking too hard, but cannot do so in detail because it would violate HIPAA practices. But these patients are out there, and have been helped by more than 30 days of antibiotics by patients treated by the IDSA's own specialists.

To add to this, there are those outliers with late stage Lyme disease and chronic Lyme disease who do not respond as well to treatment as early acute cases do. These patients have not been studied anywhere nearly enough, in part because fewer cases in these categories are diagnosed - but also because these patients' conditions are not as well understood or always as easily diagnosed to begin with because the obvious, early acute symptoms like a bull's eye rash are missing.

The Slate article continues...

"Another treatment point is telling: “We received substantial testimony from lay witnesses that they had been successfully treated with long-term antibiotics.” Pro tip: the plural of anecdote is not data. Just because someone signed up to address a public portion of the task force meeting does not mean their understanding or explanation of their own medical care is accurate or relevant."

I've said before that I know that the plural of anecdote is not data. And I understand that someone's own experience of their own medical care is not admissible as treatment for everyone.

But then, I've never made the claim that it was, anywhere... I've only made the statement that I think it is possible some people might need longer courses of antibiotics than the guidelines suggest are needed. How long, I think depends on the patient and their condition (genetics, underlying conditions, coinfections, etc).

But that is not for me to judge. I'm not a doctor, and we're talking about individual cases here... If IDSA doctors have the clinical leeway to make decisions to treat individual patients with more than 30 days worth of antibiotics and have it be covered by insurance, well, so then do other doctors - including my own primary care physician and someone who calls themselves an LLMD. The keyword in the document they published, after all, is guidelines.

If that's not happening and insurers are not covering additional treatment for patients when doctors authorize it, then that's an issue that Slate and other publications should be investigating.

To continue...

"I don’t mean to make fun of people who are suffering from what they think is chronic Lyme disease. Their symptoms are real, and they deserve help. But giving them a phantom diagnosis and making them part of a crusade to bring truth to medicine just perpetuates the idea that the symptoms they describe must be part of a complex, classic disease."

Look, this is all fine and good to hold this opinion. However, consider that I don't see enough evidence supporting an alternative diagnosis. The CDC, as you've cited, mentions Post Lyme Disease Syndrome. And yet, this is just a hypothesis and it has yet to graduate to being theory.

Just because the outcome of three clinical trials for long term antibiotic treatment on some patients with chronic Lyme disease showed that continued treatment did not permanently alleviate symptoms once treatment stopped does not mean that there isn't a persistent infection present.

And if Post Lyme Disease Syndrome is a genuine condition, with what may very well be its own genuine biomarkers for it - then as its own separate disease complex, it requires its own research arm and treatment for it.

Now Slate, are you saying PLDS doesn't exist, either, and you're going to flake on this illness which has scientific evidence to back its existence and call it depression?

Of course - because the next thing out of Slate's mouth is this:

"It’s much more likely to be depression, and depression is treatable."

Here we go with the depression, again.

Funny you should say this. Because I have had episodic depression. And I will tell you: Episodic depression was a fucking walk in the park compared to Lyme disease.

There simply is no comparison between the two, other than, well, having Lyme disease has made me feel depressed because it totally changed my life and not for the better.

Why would someone who could work full time at a high paying salary who had lots of friends and opportunity to travel the world a lot give that up to stay at home on the sofa with constant headaches and fatigue and hardly see anyone or go anywhere? To be seriously broke and give up on one's dream of owning a home?

The Lyme disease made me depressed. I don't have depression here as a separate clinical entity all on its own.

And depression, in my experience, never gave me a tick bite, an EM rash, high fevers, swollen lymph nodes, visible joint swelling, paresthesias, and a stocking and glove pattern of neuropathy on my feet.

I challenge you to ask any therapist if they think these symptoms are signs of depression. They'll tell you what they told me: "Your illness is not in your head; you have a genuine physical illness. See a doctor, but see me to deal with the depression that being ill can bring on if you need it."

And seriously... While taking antidepressants can help people with depression, if there is an organic cause for one's depression, such as infection, that needs to be treated first. One only needs to look at cases of psychiatric presentations of Lyme disease - however controversial they are - to at least ask if it isn't a possibility based on the patient's clinical history and limited response to common antidepressants.

Ask those chronic Lyme disease patients who have already taken antidepressants and have seen therapists just how well they have done. Ask. Quite a number of us have already tried exactly what some doctors suggested we do, when they thought we had depression and that is why we felt as crappy as we have. Either they're wrong, or partly wrong, or the drugs they prescribe us just aren't doing the trick.

Depression. Ha. If it is depression, well, then where are the clinical trials where antidepressants and long term antibiotics are used to treat chronic Lyme disease, so we can see the outcome? How about a third treatment arm with therapy alone? At least you'll give us patients a space of our own to swear at and curse modern medicine for not doing more for us.

There's more...

"As the CDC gently points out, mentioning other diagnoses that have been favorite catch-alls, “Your doctor may want to treat you in ways similar to patients who have fibromyalgia or chronic fatigue syndrome. This does not mean that your doctor is dismissing your pain or saying that you have these conditions. It simply means that the doctor is trying to help you cope with your symptoms using the best tools available."

And no one knows what exactly causes fibromyalgia or chronic fatigue syndrome. Obviously XMRV has been taken off the table as a cause for chronic fatigue syndrome - but some other virus or another agent may be the cause of this condition.

In any case, neither of these conditions have clear etiology, so you could be trading one mystery for another. None of which are well understood. And all of which are treated symptomatically, and all of which the drugs prescribed (with the exception drugs such as Lyrica, which is the first drug specifcally prescribed to treat fibromyalgia - which also has the unfortunate side effect of potentially causing suicidal behavior) are being offered based on an educated guess that they might work and, well, patient anecdote. They're prescribed off-label for these mysterious conditions of unknown etiology.

So how is treating chronic Lyme disease with antibiotics any different in this respect, until more research comes in on how to better treat it? Until we better understand the cause?

It may be that while long term antibiotic use for everyone with persisting symptoms may not hold up in small scale clinical trials that it may hold up in individual situations for particular patients with specific backgrounds - backgrounds which may not have been widely represented in the trials which have been held to date. Often it takes years for a wider population using a given drug or treatment regimen to expose its side effects and benefits - the outcomes are not always obvious at first.

And the last bit from the Slate:

"Disregarding my own advice about not taking an anecdote as data, I have my own story about chronic Lyme disease. A friend of one of my brothers had been suffering for years from headaches, fatigue, a sense of despair, a belief that she wasn’t worthy of her job or her boyfriend. She was diagnosed with chronic Lyme disease and was treated with antibiotics, which were ineffective. What she wasn’t treated for, and could have been, was severe depression. She killed herself."

I am very sorry for your loss, no matter what the cause. This is the tragic loss of one woman's life, and it may have been prevented.

I don't know, though, and I don't know the full story either way. I only have your anecdote.

She could have had undiagnosed Lyme disease. She could have had depression. She could have had something else entirely. She could have had more than one problem which included depression.

If depression is a concern, I recommend anyone with any illness see a therapist because in many cases therapy is equally as effective as antidepressants. And if that doesn't help, cautiously try out an antidepressant that is neuroprotective if no other biological or organic cause can be found for the depression. But certainly, if one continues to have the same symptoms while on antidepressants and begins an empiric course of antibiotics later and finds those symptoms begin to lift, well, then go with what works and maybe science does not immediately have all the answers. Sometimes symptoms which appear psychiatric in nature can have an infection as their cause.

So, anyway...

Whether or not persistent bacteria is the cause of all or some patients' symptoms, in my opinion, is still up for grabs. And at this point, many patients have either made the decision to ignore the results of the three small clinical trials which have been completed, or beg for more research on treatment to help us, or both.

I am a pro-science, pro-research person with a history of skepticism. I am skeptical about my own damn disease. And yet, no one has given me any particular advice in mainstream medicine or science as to what to do about it.

You might want to send your money directly to UC Davis or Tulane University for private research instead. But don't come kvetching to me that I'm running off to an LLMD because my primary care provider referred me to one.*

That's just more complaining - rather than addressing the root of the problem in the first place. Those of us in pain can only wait so long and do nothing for so long...

* True story.

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2 Anonymous Comments On Chronic Lyme Disease

Last year someone who identified only as "anonx" wrote some interesting comments on last January's blog post on quorum sensing, "How bacteria "talk" and how to make them shut up". (There is a fascinating video there by researcher Bonnie Bassler. I highly recommend checking it out.)

To my knowledge, comments on Blogger do not get syndicated on post rss feeds - though one can request rss comments separately. I think that anonx's comments are worth taking another look, so I have decided to repost select excerpts of them here. (Refer back to the original comment thread for the CO side of the dialog, if needed.)

Anonymous January 21, 2011 5:06:00 PM HST
persister cells
quorum sensing
round bodies
blebs
biofilms made of borrelia
biofilms made of a mix of pathogens
symbiosis in all its forms and iterations
intracellularity
the cascade of genospecies and strains
quiescence and dormancy
transfections
borrelia stuck in B cells with CLIP attached
the role of toll-like receptors&inflammation
the growing list of possible co-infections
xmrv
new view of PANDAS that goes way beyond strep...
molecular mimicry

guess I'll stop here but I could go on --you just need a little proof: not just proof it is happening but proof that treating it will end the illness. that's the problem.

Anonymous January 21, 2011 11:03:00 PM HST

Don't you think that looking at persistence in isolation could be futile, given the large number of people treated for years without cure? Persistence could be the imperceptible spark that incites an immune tsunami. What if it is easier to treat the tsunami --by its nature outsized and blatant and in your face-- than the spark which, though present and incendiary, we cannot find? Is it possible that the yin and yang nature of the fight has prevented a view of the system overall? What if a tiny amount of infection has caused a huge inflammatory response? What if that infection is hiding in B cells because a glitch in the system has prevented T cells from recognizing the foreign invader, and thus, from finishing the job? What IF to get rid of the persistent infection, you must treat immune dysfunction first? So no ...I don't think it is as simple as you say, or that by conceiving the issue along the old paradigms of the fight, raging fruitlessly for 30 years, you will get what you want ... unless of course, it is really as simple as you suggest. I mean, what if you prove persistence, but it still won't bring a cure?

Anonymous January 22, 2011 11:57:00 AM HST

regarding the four trials cited, they do in fact show benefit to retreatment for fatigue and pain --and thus, in fact do not match with the wording of the conclusions rendered or (in the case of two of three authors) forced down those authors throats by the powers that be. There is actually ample evidence in these trials to suggest a benefit to retreatment and longer treatment --and in the case of the Klempner trial, serious issues with methodology. But as you say, the outcome of these trials must be detached from pathophysiology --what is the mechanism of the benefit? That question the trials do not address.

Still, to detach infection from immune response is just plain wrong-headed. We are 10% by weight bacteria, and most of those organisms are beneficial. The question is --which are the pathogens, and how do those pathogens do us in? In every case, inflammation and cellular immunity are going to play a role.

Anonymous January 22, 2011 11:15:00 PM HST

It is a very complicated problem, as you say.

It is TRUE that if you suppress inflammation infection would spiral out of control: The murine studies on borrelia and toll-like receptors show that to be right.

But here's the thing: Most researchers, even most of the IDSA researchers, don't actually deny that organisms can persist. They just deny that those quiescent remaining organisms are driving the continued symptoms --they say these persisting borrelia are too few, and too dormant. And they would cite the research on quorum sensing to support their case.

As I see it, it is not really persistence you need to prove, but rather, the mechanism by which persistence at the low level research suggests drives the disease. Inflammation is not the only immune mechanism --cellular immunity or dysfunction thereof can play havoc, too, and persistent infection could drive it in an endless loop.

Also: Treatment studies without knowing more about pathophysiology can work against you, because --hell-- they are just empiricism on top of empiricism, more wandering in the dark.

I contend you need more basic biology to target such studies, strategically. If you were to move forward without that, you would need an elaborate methodology with many variables and large enough numbers of patients to test for many possibilities and separate the data from the noise. And with Lyme patients still so ill-defined, with no test extant for active infection ...

Makes my head spin. A hundred million dollars would help.

Anonymous January 23, 2011 1:34:00 PM HST

Other,

My comments refer specifically to the Barthold work, with which I am extremely familiar. Barthold's findings of small numbers of dormant, quiescent spirochetes within collagen across the range of mammalian species following treatment have been well-known inside the mainstream (though published only recently) for decades. There is no great rush to debunk Barthold, whose research really is beyond dispute --Barthold himself being an especially meticulous and careful scientist. What his critics say, however, is that these spirochetes are not active enough and not numerous enough to cause disease. (to wit: issue of quorum sensing.) Barthold theorizes otherwise, contending that the small numbers of chetes may provoke an outsized --but heretofore undetected-- cytokine cascade that causes the disease. Barthold would classify this cascade under the heading of INFLAMMATORY response. This is his theory --and a powerful one that should be explored.

You may have noticed that NIH has begun to test the Barthold work with a study of xenodiagnosis, but patients are protesting that study for fear that the ticks used might not be as naive as claimed: And really, given the confusion over pathogens involved, who knows?

Other theories of persistence to pursue include the impact of round bodies AND the work of Newell, who finds Borrelia stuck inside B cells because of a dysfunction in MHC.

In the case of Newell, especially, the notion is that persistent infection can never be cured without correcting the recognition dysfunction of MHC. In other words, even though the disease is driven by persistence, Newell says you have to correct the immune problem first.

And by the way, both she and Barthold insist you can never entirely clear borrelia infection with antibiotics alone --you need the immune system to do the final kill, and so you must have an immune correct FIRST, even if the driver is persistence.

Or it could be the round bodies... but whatever it is, it is complicated --and simply fueling the fight of persistence versus immunity isn't helpful.

There is a difference between what patients use to get well right now --the ax in the form of huge quantities of endless suppressive antibiotics-- and what they should want for the future --the chisel, which could well be an immune correction that allows infection finally to be resolved. There should be a divide between the effort to protect a Lyme doc in the here and now and the direction of research for the future --but it is hard for a lot of people to understand this.

I agree with you that if we knew the mechanism we would have a target --and that is why I am so equivocal if not outright squeamish about the continued treatment trials some patients are calling for.

What are they treating? --and if they don't really know, there is a big risk that study could bury them deeper and darker than ever before.

anonx

Anonymous  January 23, 2011 7:27:00 PM HST

Given current state of knowledge immune treatments could backfire, big time --as the literature shows. If you look at the work on toll-like receptors you find a genetic curve for inflammatory response to borrelia ranging from almost nothing to off-the-charts and everything in between. That is just one immune parameter, and there are many others. These parameters could vary for every infection or strain and every person. Therefore it is possible with current state of knowledge that suppressive abx are really the best we have... there needs to be a crunching of data to understand what we are looking at --otherwise, it is just stumbling in the dark. The amazing thing is that the IDSA crew has gotten away with such a grotesquely oversimplified story of this disease for so long --and that to explain it, they perpetuate the explanation that it is a psychosis instead of a complex spectrum of infection and immune response. But by giving an oversimplified rejoinder, patients have hurt their cause, too.

In a gross way one could do a study treating infection, treating immune issues or treating both: but this would be very crude without more data up front.

anonx


Comments:

So I do have a few comments on this, now that it's nearly a year and half since these comments were posted. My thoughts on the matter have shifted over time, and after exposure to more research.

• I'd like to see evidence that Borrelia burgdorferi is hiding in B cells in vivo. That would be informative. There has been some mention of Bb being intracellular in a few in vitro studies and one in  vivo study; we need more.
  
• This anonymous author may be on to something, and it may be that the host immune response may need to be addressed in order to manage the remaining infection if it is still present. Not enough is known, but when I read about filgrastim and rixtuximab and how they have some positive effect on a patients with persisting symptoms of Lyme disease or CFS/ME,  I think that adjusting the host immune response is an avenue worth exploring. It should have been explored more years ago.
• I still think the trials must be detached from pathophysiology. My position on this has not changed. Treatment trials have done nothing to provide evidence of persistence of Borrelia burgdorferi one way or the other.

• I strongly agree we need more basic biology research. The anonymous author's comments on the role the immune system plays in infection are noteworthy. But we also need to know what is going on if the infection does persist in some form. Is there a persister phenotype? Ongoing research into persister phenotypes should not be neglected. But I wouldn't leave all research at that, because there are other hypotheses to consider.

• One thing I wonder about is the issue of quorum sensing and efficiency sensing, and if blebs or vesicles play any role in the dissemination and pathogenesis of Borrelia burgdorferi. Blebs as a form of communication are observed in other bacterial species, and perhaps Bb uses blebs and vesicles in a different manner and they are not part of cells undergoing apoptosis. Plasmid DNA and outer surface lipoproteins have been found within blebs; there is some suggestion of blebs containing adhesins... I think there's more to blebs than meets the eye.

• Anonymous said, "There is a difference between what patients use to get well right now --the ax in the form of huge quantities of endless suppressive antibiotics-- and what they should want for the future --the chisel, which could well be an immune correction that allows infection finally to be resolved. There should be a divide between the effort to protect a Lyme doc in the here and now and the direction of research for the future --but it is hard for a lot of people to understand this." I keep reflecting on what they wrote, and its implications. Is there a more targeted approach which could be designed to help treat patients?" I think they are right - there is no reason why patients cannot ask for protection for the treatment they are receiving now while promoting research on new and different treatments. I think VGV-L is one effort in this direction, but I am not sure it will work. There is a lot of complexity involved.

• Last but not least, my anonymous commenter said this: "The amazing thing is that the IDSA crew has gotten away with such a grotesquely oversimplified story of this disease for so long --and that to explain it, they perpetuate the explanation that it is a psychosis instead of a complex spectrum of infection and immune response. But by giving an oversimplified rejoinder, patients have hurt their cause, too." 

I think there's a lot of truth in that last statement. Now, what does one do about it?

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0 Commentary: 20/20 And Needing A New Focus For Lyme Disease

This past Friday, the ABC program, 20/20, aired a show on medical mysteries. Included in this show were segments on people who fly into a rage at certain sounds (misophonia), eat rocks or other unusual non-food items (pica), and one on a girl with Lyme disease who is speculated by doctors to have developed a condition known as foreign accent syndrome (FAS) due to being coinfected with Bartonella.

While I have sympathy for everyone dealing with such conditions and hope everyone who was interviewed for the show gets better, what I'm about to write isn't about their personal interest stories.

Instead, I want to discuss how the media portrays the strange and unusual case to get higher ratings while other stories and information about tickborne infections are either downplayed or avoided.

On Dr. Phil's show several weeks ago, a young model was interviewed - a photogenic young woman who was having partial seizures and self-medicating to treat her pain. While there is evidence that people with Lyme disease can experience seizures, these cases are considered to be in the minority. In Friday night's 20/20 show, a teenager in high school who contracted Lyme disease and Bartonella was speculated to have developed a condition known as foreign accent syndrome (FAS). This is a documented condition, and while I think more evidence is needed to provide a link between Bartonella as its cause in this instance - FAS is even rarer than seizures are.

These stories are getting aired because the media tends to want to focus on the strange and unusual in order to grab viewers' interest and get ratings. The delivery must generate buzz and be sensational in approach in order to get traffic and fixed stares. And this is exactly what the promos for Dr. Phil's show on the young model, Stephanie, tried to achieve - as well as promos by 20/20's on Elaina, the teenager with FAS.

Most viewers at home seeing these shows are watching it because of the weird factor. They see the promo and want to know more, perhaps with their own internal dialogue of, "Wow, that's weird, I wonder how that happens - and does this really happen or is it just made up?" or, "Gee, that's messed up - glad it's not me. But I'm curious, so I'll watch." Some people just have a thing for watching other people's problems in general, and segments like these appeal to their nature.

For those of us who suffer from a disease that is portrayed on television, the first thing that happens is praise. The initial comments from the Lyme disease patient community are congratulatory. They contain the good cheer of finally getting more recognition for what ails us, those of us who have been suffering with chronic Lyme disease and/or coinfections.

And then, the next round of responses trickle in from other patients - a second wave which is not as cheery as the first and criticizes the shows for picking out one narrow and possibly rare symptom and putting it in the spotlight while the rest remain in the darkness.

Then the real, serious criticism gets rolling in the third wave, which is about how these shows will question the afflicted about the true nature of their condition and whether or not they are "faking it". From the perspective of a number of Lyme disease patients, this criticism could be heard regarding the exchanges about Dr. Phil asking the model if she was faking her condition, and in his not arguing against Dr. Auerwater's position that chronic Lyme disease is not a verifiable condition.

Indignant responses fly. Suddenly, what began as a great show for spreading awareness has become a show where a number of people see the value of airing it - yet admit it fell short of their hopes for letting people know what Lyme disease and coinfections are really like and what impact persisting symptoms have had on people's lives.

People just like them. People just like the guy next door, who was mowing the lawn one week and playing soccer afterwards - and now can't make the walk to his mailbox, let alone get to work.

As I see it, there has to be more of an effort in the media to offer education about what Lyme disease and coinfections are from a scientific perspective, and educate people on the most common symptoms which people will experience. From a personal interest perspective, more people need to see how these conditions affect middle class working adults with children of their own.

With this education, more people would be able to relate to the people on the screen and be willing to look into the possibility that they might have a tickborne infection and seek medical advice and testing. They would at least be alerted to the possibility.

With the edutainment of the strange and unusual offered, there isn't enough there for the viewer to grasp the possibility that they, too, may be suffering from this disease - or to know what signs to look for in the future if they do come down ill with tickborne infections.

If someone sees the story of a patient with partial seizures or FAS, they may shrug off the story and not apply it to their own experience of having joint aches, muscle pain, headaches, and blurred vision, and say to themselves, "Thank god I have fibromyalgia and eye problems and not Lyme disease or Bartonella - this stuff is weird". And maybe their current diagnosis is correct. However, there's a chance it's not. In which case, they are better off having the knowledge so they can decide to investigate another diagnosis.

The strange and unusual won't help viewers relate what they see on the screen to their own situation. Truly spreading awareness means educating people on the symptoms for conditions one is most likely to see. It doesn't mean that there aren't exceptions or that unusual symptoms can't occur. It just means that what most people with a given condition experience what one expects to see and to get based on the majority of cases which have occurred.

One more point about the media's focus and where I think it should be - then I'll go:

Why is it that we can easily find these sensationalized stories about unusual symptoms about Lyme disease - but there's seemingly little television coverage of what seems to be the most costly case of Lyme disease in the country - the Lyme disease contracted by senior banker Ina Drew, who worked at JP Morgan Chase, whose absence from work due to Lyme disease led to those remaining in the office making decisions leading to a $3 billion trading loss?

Yes, you did not misread that. $3 BILLION.

You would think this story would be pretty sensational and the media would put this on 20/20 and other shows right away.

There is the personal cost of Lyme disease to the individual. This the media does well to portray to a certain degree. But then there is the cost to their family, their job, and society as a whole. This has not been portrayed that well. It needs to be.

 Image Credit: Peter Wolber

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0 Female Pheromones and Infection May Affect Tick Behavior

Image: Researcher drags white
flannel to collect questing ticks. 

Recently I came across an abstract for the paper, "The correlation between tick (Ixodes persulcatus Sch.) questing behaviour and synganglion neuronal responses to odours".

I'm looking forward to reading the full text, as the abstract demonstrates two findings on tick behavior which may reveal who is more likely to be bitten by ticks.

In this experiment, the taiga tick or Ixodes persulcatus is used - a tick common in parts of Russia. It is unknown if other Ixodes ticks would respond to the same odors the same way, and I think the same experiment should be conducted in Western Europe and North America with local Ixodes ticks to see if there would be a similar outcome.

The researchers experimented with seeing which odors would attract and repel ticks, focusing on seeing how ticks respond to synthetic hormones and insecticides/acaricides. Osmopherone®, Osmopherine®, DEET®, ethanol, and water were placed in a simple maze, and changes in their synganglia - basically their entire central nervous system, as ticks do not have a brain as we think of one - were measured to reflect whether they were attracted, repelled, or neutral to the specific odor tested.

Also, researchers tested which odors were most likely to encourage the maximum height ticks could reach during questing behavior by placing ticks on glass rods which were held at a 75 degree angle.

Two notable findings came from these experiments:

1. Ticks were, as expected, repelled by DEET® and ethanol. It's good to have further confirmation that DEET® works as a repellent. But what was interesting is that ticks were totally neutral to Osmopherone® and water - and attracted to Osmopherine® .
   
   
2. Questing ticks were studied not only for their attraction to certain odors but were tested for whether or not they were infected with Borrelia burgdorferi sensu lato and tickborne encephalitis virus. It was found that not only did those ticks which were most attracted to Osmopherine® reach the highest questing height - but also those ticks which were infected with Borrelia burgdorferi sensu lato were more likely to reach the highest questing height.
   

What is the difference between Osmopherone® and Osmopherine®? Osmopherone® is a synthetic sex pheromone that is meant to mirror the scent human males give off. Osmopherine® is a synthetic sex pheromone that is meant to mirror the scent human females give off. Each of these pheromones are found in their natural form on people and are not an obvious smell people give off - they are registered on a subconscious level and may act as an attractant to the opposite sex.

In these experiments, it appears the female sex pheromone, Osmopherine®, attracts ticks, and ticks infected with Borrelia burgdorferi sensu lato are more likely to have the highest questing height in a laboratory.

What is not known is whether or not the same behavior occurs in the wild, outside a lab - and how much other factors may play into ticks' behavior when questing. Different ticks have different behavior in the wild to begin with, such as Amblyomma americanum tends to be more aggressive in searching out a blood meal and Ixodes scapularis is a more passive questing tick.

Ticks are already attracted to the source of their blood meal through detecting heat and carbon dioxide (CO₂) given off by exhalation. One thing I would hope the full text of this article would explain is how the presence of warm blooded, CO₂ exhaling researchers was shielded so they did not have any influence on these ticks. It may be that these indicators of the next potential dinner may play a bigger role than the gender of the potential host in front of them and whether or not the tick is currently infected with Borrelia burgdorferi s.l. 

Certainly more research is needed to determine what the case is in the wild, but in the meantime these findings provide one with more food for thought as to how a tick host's gender and the tick's state of infection might play a role in tick behavior.

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0 Commentary: Antibiotics Are Only One Tool - I Want Others.

A few weeks ago, I commented on a Wall Street Journal blog post about chronic Lyme disease. Since then, I have been reflecting on this response to my comments there:

"Camp Other – The cure for chronic Lyme is known. If you want a sustainable, long term cure, you can gamble on long term antibiotics, or can you take an alternative approach, which consists of doing between 20 and 50 different things, including Low Dose Naltrexone. Yes, they get you to a cure, at which point a good alkaline diet, oxygenation, vitamin D, etc etc etc should maintain health.

 Easier said than done though. Even when you cure your Lyme, you need to maintain the healthy diet, and some of the supplements that got you there. You also want to do genetic testing for things like methylation, as part of treament and post-cure maintenance. I’m certainly not banking on the Viral Genetics research. It could be many years before that turns into a drug we could take. I already know people who are fully cured and back to their old lives, so it is curable with current knowledge."

And I also sadly know people who are not fully cured with current knowledge.

Reflecting on this, it's not an easy statement for me to make - but I don't think the cure for chronic Lyme disease is entirely known.

If it were known, then all the patients I know would have had the treatment they needed and would be better now. But some of them are not. And I don't think it's some personal failing that they aren't or that they haven't done the right things - it's that their individual condition is different and may require different treatment - including treatments which haven't even been developed yet.

I can see that long term antibiotics, some alternative medicine, or some combination of the two have helped a number of people improve their condition and alleviate symptoms. Many have gotten their old life back. But it's never been guaranteed that any of these treatments will work for everyone.

 Even the Lyme disease patient support groups have often repeated the statement, "Every patient is different," and Polly Murray herself stated in her book, The Widening Circle:

"I am struck by how Lyme disease never seems to act exactly the way it is supposed to, how each individual seems to respond differently to the spirochete."

I'm a fairly pragmatic person, so my basic position on using antibiotics to treat persisting symptoms related to Lyme disease has been that if they might offer relief and improve your quality of life, if nothing else has helped, and a doctor has agreed to this treatment - then try them. Use them, while being aware that there are risks in taking them longer term - and note that perhaps there are even unforeseen consequences of which scientists are not yet aware.

But while I've been an advocate for the use of longer than standard courses of antibiotics in the subset of patients with Lyme disease who have persisting symptoms and I feel they saved my life, I have never wanted that to be the end of the story. Because it seems to me that even if they do help, if they don't cure everyone then more research is needed for effective treatment which helps all patients.

If there is evidence that comes out of Embers' Rhesus Macaque study - along with others - that Borrelia burgdorferi s.l. does have a persister cell phenotype as part of its pathogenesis, then more antibiotics may only be a maintenance treatment at best. What would really be needed is a treatment which reactivates the dormant persisters and kills them - something which antibiotics alone cannot do.

Persister cells are tolerant to antibiotics. So in theory, it may be that antibiotics of some kind plus a metabolite would be needed to eradicate any remaining spirochetes.

In the long run, I'd like to see more effective, less expensive treatments of shorter duration for my condition.

I'd like to avoid taking antibiotics out of concern for my poor digestive system and my palate, which is disgusted with bitter tasting substances rolled into barely swallowable pills in general.

I'd like to avoid the strange side effects which I have experienced which, thankfully, in most cases abated after the first week or two of treatment - yet they inexplicably seemed to be those which are less common to experience and more difficult to cope with.

Antibiotics are great tool and have helped a great number of people - and they have helped me, too. But I think it's time to look past long term antibiotics alone and push for research on other avenues of treatment.

Researching them doesn't mean abandoning antibiotic use entirely - they are scientifically proven effective against Lyme disease and its coinfections. Researching other avenues means investigating what else can be done to help patients improve their quality of life and to find something that could cure them in less time. It means exploring more options, not fewer. It means more patient freedom, not less.

 If at one point I seemed to strongly advocate Viral Genetics' VGV-L candidate for the treatment of chronic Lyme disease, it isn't because I am certain it will work. I don't know for sure that it will. I am hoping, though, that it will help at least some portion of those of us suffering and will not have serious side effects.

And I'm hoping it marks the beginning of more research into different ways to treat patients who are suffering with persistent symptoms. The antibiotics will still be there if you need them - and after how much of them I've already consumed, I'd rather not need them. I'd like to try something else if I can. A round of Buhner's herbs, perhaps - or perhaps something entirely new.

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3 Abstract: Population Dynamics Of Borrelia burgdorferi In Lyme Disease.

Credit goes to Joanne, of the Looking at Lyme blog, for mentioning this abstract: It describes a response to Borrelia burgdorferi infection in mice where the first immune response almost clears the infection - but approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase.

Front Microbiol. 2012;3:104. Epub 2012 Mar 22.
Population Dynamics of Borrelia burgdorferi in Lyme Disease.
Binder SC, Telschow A, Meyer-Hermann M.

Source
Department of Systems Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany.

Abstract

Many chronic inflammatory diseases are known to be caused by persistent bacterial or viral infections. A well-studied example is the tick-borne infection by the gram-negative spirochaetes of the genus Borrelia in humans and other mammals, causing severe symptoms of chronic inflammation and subsequent tissue damage (Lyme Disease), particularly in large joints and the central nervous system, but also in the heart and other tissues of untreated patients.

Although killed efficiently by human phagocytic cells in vitro, Borrelia exhibits a remarkably high infectivity in mice and men. In experimentally infected mice, the first immune response almost clears the infection. However, approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase.

We developed a mathematical model describing the bacterial growth and the immune response against Borrelia burgdorferi in the C3H mouse strain that has been established as an experimental model for Lyme disease.

The peculiar dynamics of the infection exclude two possible mechanistic explanations for the regrowth of the almost cleared bacteria.

Neither the hypothesis of bacterial dissemination to different tissues nor a limitation of phagocytic capacity were compatible with experiment.

The mathematical model predicts that Borrelia recovers from the strong initial immune response by the regrowth of an immune-resistant sub-population of the bacteria. The chronic phase appears as an equilibration of bacterial growth and adaptive immunity.

This result has major implications for the development of the chronic phase of Borrelia infections as well as on potential protective clinical interventions.

(Special thanks to Frontiers in Microbiology journal for having what appears to be a solid peer review process and Creative Commons license.)

Comments:


I can't wait to read the full text of this paper. This is an intriguing abstract and it leads to more questions.

How did these researchers come up with their mathematical model? Have other researchers previously observed this second wave of bacteria during infection? What about evidence of peaks in immune response in Borrelia burgdorferi infected animal models which have been documented?

In which way, precisely, is the regrowing immune-resistant sub-population actually immune-resistant? What is happening to B cells and T cells in relationship to this second phase of Borrelia?

From Fig. 3 of Tunev et al., 2011.  Day 8 of infection.  The arrows point to intact extracellular B. burgdorferi in the subcapsular sinus of the lymph node, which was culture positive beginning on day 1 of infection.   Source

Do these phases respond with plasma B cells containing low quality antibodies in germinal centers?

Is there typical somatic hypermutation and antigen affinity or not? What is happening to the T-cell independent response?

And does this model have any implication for antibiotic treatment? As in: Does this second immune-resistant sub-population also have a different response to antibiotics than the initial wave? This model is about infection without treatment, and it is not discussed what the implications could be.

Lots of questions here...


UPDATE: Joanne has informed me the free full text is available online. See: http://www.frontiersin.org/Microbial_Immunology/10.3389/fmicb.2012.00104/full

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4 Viral Genetics VGV-L Candidate For Treating Chronic Lyme Disease

On Friday I posted about the use of Filgrastim and Ceftriaxone for treating persisting symptoms in a Lyme disease case study as well as the use of Rituximab for treating CFS/ME. I also touched upon Viral Genetics' VGV-L or targeted peptide therapy for treating chronic Lyme disease, and wanted to write an entry about this treatment on its own.

What I can tell you is to some degree limited by the fact that VGV-L's exact design and mechanism is proprietary in nature, so I can only report based on what the researchers and Viral Genetics choose to disclose. But hopefully, what I post here and future publications by Dr. Karen Newell Rogers will shed some light on the matter.

Dr. Karen Newell Rogers from Texas A & M is in the middle of contributing to the following three papers which seem to have a relationship between VGV-L and chronic Lyme disease:

• S. Harris, E. W. Newell, R. P. Tobin, C. P. Harvey, N. Kurzman, E. M. Hechinger, P. Cipriani, and M. K. Newell. 2010. Comparative Analysis of Peptide Binding, MHC alleles, and B cell activation in patients meeting CDC criterion for Chronic Lyme Disease. (manuscript in preparation).
• E. Connick, R. Schlichtemeier, J. Folkvord, R. Tobin, C. P. Harvey, and M. K. Newell. 2010. TLR activation of human peripheral blood B cells can be reversed by peptide treatment. 2010. Manuscript in preparation.
• Cabrera, J. and M. K. Newell. 2010. Polyclonal TLR-induced B cell activation is controlled by Peptide-dependent B cell death (manuscript in preparation). 

All three in preparation, but I think they are tightly related to the same research and stem from this previous publication:

 M. K. Newell, R. P. Tobin, J. H. Cabrera, M. B. Sorensen, A. Huckstep, E. M. VillalobosMenuey, M. Burnett, E. McCrea, C. P. Harvey, A. Buddiga, A. Bar-Or, M. S. Freedman, J. Nalbantoglu, N. Arbour, S. S. Zamvil, and J. P. Antel. 2010. TLR-Mediated B Cell Activation Results in Ectopic CLIP Expression that Promotes B Cell-Dependent Inflammation. Journal of Leukocyte Biology.
Online e-Pub. July 14, 2010.

 Link to free full text this publication: http://www.ncbi.nlm.nih.gov/pubmed/20631258

Originally, I found one patent for this technology online:

http://www.faqs.org/patents/app/20100166789

In this patent, the portion attributed to Lyme disease states:

 "[0116] It is believed according to the invention that Borrelia burgdorferi also produces a Toll ligand for TLR2. Replacement of the CLIP on the surface of the B cell by treatment with a thymus derived peptide with high affinity for the MHC fingerprint of a particular individual, would result in activation of the important Tregs that can in turn cause reduction in antigen-non-specific B cells. Thus treatment with thymus derived peptides could reactivate specific Tregs and dampen the pathological inflammation that is required for the chronic inflammatory condition characteristic of Lyme Disease. With the appropriate MHC analysis of the subject, a specific thymus derived peptide can be synthesized to treat that subject. Thus individuals with all different types of MHC fingerprints could effectively be treated for Lyme disease."

However, I just found out that there are additional patents on this technology of which I was previously unaware. These patents contain a great deal of detail about what these targeted peptides can do and their effect on polyclonal B cells:

http://www.faqs.org/patents/app/20090258027
http://www.faqs.org/patents/app/20100034839
http://www.faqs.org/patents/app/20100166782
http://www.faqs.org/patents/app/20110118175

In addition to the above published paper on CLIP expression, Viral Genetics published the following excerpt in its research newsletter which explains what VGV-L does for HIV in easy-to-understand terms - substitute "Lyme disease" for "HIV" here:

"The conventional approach to HIV vaccines, for example, is to develop therapeutic vaccines to stimulate immune system response. The problem with the conventional approach is that the infected cells are camouflaged and not visible to the body’s immune system. The body’s powerful T-cells are unable to seek out and destroy the infected camouflaged cells because they cannot recognize that the cell is infected.

To understand the issue, think of the Klingon space ship on Star Trek that has its cloaking device activated. The U.S.S. Enterprise has no way of knowing where the enemy is in space. The only hope it has in winning the battle is for the Klingon vessel to be de-cloaked and, once revealed, use their ammunition to destroy it. What’s worse in the case of HIV is that while the infected cell is cloaked, it is also effectively setting off an alarm that triggers the immune system to create inflammation. Why is this important? It turns out that this inflammation is critical for allowing the HIV virus to spread to even more cells.

Many other viruses and bacteria also trigger inflammation but, unlike HIV, the inflammation does not necessarily allow or facilitate the spread of the virus or bacteria itself. * However, in these cases, the inflammation itself is harmful because it creates a hostile and inflamed environment that provides the necessary components for a potential autoimmune reaction that can cause the immune system to attack and damage one’s own body. Viral believes that diseases such as Lyme Disease, Multiple Sclerosis and others involve this inflammatory mechanism.

To use the Star Trek metaphor, what Dr. Newell Rogers has developed with TPT is a de-cloaking device for the body’s immune system to use in its pursuit of invaders. Through the development and use of computational biology programs and databases, Dr. Newell Rogers and her team have created a way to remove the camouflage that is cloaking the infected cells, flagging them with custom peptides that allow the body’s immune system to seek out and destroy them.

The key discovery of the TPT platform is that a self-peptide (in other words, one that is naturally produced and a healthy part of one’s normally functioning immune system) called ―CLIP2 that was until now thought only to exist primarily inside certain immune system cells, is sometimes displayed on the outside of cells, thus leading to harmful inflammation. Dr. Newell Rogers discovered that the products of some pathogen invaders such as viruses and bacteria, when picked up on the surface of certain immune system cells, sometimes incorrectly cause those cells to display CLIP externally (i.e. ―ectopically).

Normally, when an invader strikes, this process may promote needed inflammation early in infection, but it is quickly controlled when a more specific, immune response takes over, allowing a highly-targeted immune response to be marshaled against the pathogen. However, when CLIP is improperly displayed, displayed for too long or displayed chronically, the immune system is marshaled to promote a broad and unspecified inflammation without the specific targeting, leaving open the possibility that this inflammation actually turns against one’s own cells. Replacing CLIP is the focus of Viral’s Targeted Peptides because it turns off the harmful alarm."

Read more from the source - including about individual MHC genetic profiles here:
http://www.viralgenetics.com/investors/press-releases/Research_2.0_Report_Feb1_2011.pdf

One thing which I have thought of (and heard a few patients mention in passing) is that this candidate drug is only for treating inflammation and would only address an autoimmune angle relating to chronic Lyme disease.

However, this is not the case:

If you read the full patents, VGV-L's technology works not only to reduce inflammation, it also works to rebalance the immune system so that it is focused on fighting infection in a targeted manner. And in terms of treatment with VGV-L, patients may not just receive VGV-L alone - but also receive a bacterial antigen and antibacterial (possibly also antiparasitic and/or antiviral)  therapy concurrently to treat their condition.

Refer to this patent: http://www.faqs.org/patents/app/20110118175.

Here is the excerpt from the patent concerning the treatment of infections using this technology - including Lyme disease:

[0169] Bacterial diseases that can be treated or prevented by the methods of the present invention are caused by bacteria including, but not limited to, mycobacteria, rickettsia, mycoplasma, neisseria, Borrelia and legionella.

[0170] Although Applicant is not bound by a specific mechanism of action it is believed that the CLIP inhibitors of the invention displace CLIP from MHC class I and cause down regulation of Treg activity and/or activation of effector T cells such as γδT cells. Downregulation of regulatory function of Treg activity prevents suppression of the immune response and enables the subject to mount an effective or enhanced immune response against the bacteria. At the same time the Treg cell may shift to an effector function, producing an antigen specific immune response. Thus, replacement of CLIP with a peptide of the invention results in the promotion of an antigen specific CD8+ response against the bacteria, particularly when the peptide is administered in conjunction with a tumor specific antigen. Activation of effector T cells also enhances the immune response against the bacteria, leading to a more effective treatment.

[0171] One component of the invention involves promoting an enhanced immune response against the bacteria by administering the compounds of the invention. The compounds may be administered in conjunction with an antigen to further promote a bacterial specific immune response. A "bacterial antigen" as used herein is a compound, such as a peptide or carbohydrate, associated with a bacteria surface and which is capable of provoking an immune response when expressed on the surface of an antigen presenting cell in the context of an MHC molecule. Preferably, the antigen is expressed at the cell surface of the bacteria.

[0172] The compounds of the invention may be used in combination with anti-bacterial agents. Examples of such agents to treat bacterial infections include, but are not limited to, folate antagonists (e.g., mafenide, silver sulfadiazine, succinylsulfathiazole, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, pyrimethoamine, trimethoprim, co-trimoxazole), inhibitors of cell wall synthesis (e.g., penicillins, cephalosporins, carbapenems, monobactams, vacomycin, bacitracin, clavulanic acid, sulbactam, tazobactam), protein synthesis inhibitors (e.g., tetracyclines, aminoglycosides, macrolides, chloramphenicol, clindamycin), fluoroquinolones (e.g., ciproloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin), nalidixic acid, methenamine, nitrofurantoin, aminosalicylic acid, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampin, clofazimine, and dapsone.

I don't know entirely what the researchers intend to use as a bacterial antigen... An Osp? They are suggesting a peptide or carbohydrate, though, and not a highly immunogenic lipoprotein from the cell's outer membrane - even though that's what I think they would have to use if they were to use an antigen. Reading ahead, though, there is the potential that any of a number of Borrelia burgdorferi antigenic products may be used.

Both items #0171 and #0172 have wording which implies that they are optional treatments, as they use the word, "may be administered"  or "may be used" rather than "will be administered" or "will be used", respectively. I would assume that whether or not these individual treatments are applied depends entirely on the individual patient and their needs and clinical diagnosis.

So, it seems that whether there is current infection or not, VGV-L may be one way to effectively treat chronic Lyme disease and lower inflammation due to runaway immune dysregulation. And if infection is currently present, then it looks like VGV-L will trigger a more targeted immune response towards bacteria rather than the overload that polyclonally expanded B cells can be.

One of the more fascinating sections of the patent is towards the end. The researchers give a number of examples of how their technology was applied and what the results were. Example 13 of this patent appears relevant to demonstrating how Borrelia burgdorferi activators affect tissue and about eliminating excessive B cells which cause inflammation in tissues. They did an in vitro post-mortem study of these actions in mice:

Example 13 - TLR Activators Promote CLIP-MHC HLA Association and CLIP Inhibitor Peptides Reduce an TLR Activator Promoted CLIP-MHC HLA Association

[0480] Methods

[0481] Preparation of Cells: Mice were Sacrificed by Cervical Dislocation. Spleens and lymph nodes were removed; the tissues were minced through cell strainers to create single cell suspensions; red cells were lysed using buffered ammonium chloride followed by addition of phosphate buffered saline and centrifugation to wash out the ammonium chloride; and the cells were counted using trypan blue exclusion to determine live versus dead cell discrimination and to determine the number of cells per tissue.

[0482] Treatments: The spleen or lymph node cells were treated in vitro with various stimuli (TLR activators: CpG ODN (Alexis), LPS (Sigma), Polyl:C (BD Pharmagen), Pam3Cys (Genway); IL-4 (BD Pharmagen), anti-CD40 monoclonal antibody (BD Pharmagen), both IL-4 and anti-CD40 antibody and OspA and Osp C (Genway) and the cells were cultured for the indicated time periods. The cells were grown in RPMI 1640 medium supplemented with standard supplements, including 10% fetal calf serum, gentamycin, penicillin, streptomycin, sodium pyruvate, HEPES buffer, 1-glutamine, and 2-ME as well as (where indicated) the stimuli listed above. The cells were incubated at 37° C. in an atmosphere containing 5% CO2 and approximately 92% humidity. The cells were incubated for 3, 24, and 48 hours. At each time point, the cells from that experimental time were harvested and stained for flow cytometric analysis of cell surface expression of CLIP (MHC Class II invariant peptide/IAb, Santa Cruz) by using the commercially available anti-mouse CLIP/IAb peptide, anti-mouse B220, anti-mouse CD4, anti-mouse CD8, and anti-mouse FoxP3 (all commercially available from Becton Dickinson/Pharmingen). Harvested cells were stained using standard staining procedure that called for a 1:100 dilution of Fitc-anti-mouse CLIP/IAb or isotype control. Following staining on ice for 25 minutes, cells were washed with PBS/FCS and resuspended in 100 microliters and added to staining tubes containing 400 microliters of PBS. Samples were acquired and analyzed on a Coulter Excel Flow Cytometer. The data were analyzed using FloJo software.

[0483] Results

[0484] B cell death, including total B cell death and % CLIP positive B cell death in cells treated with a TLR activator (CpG ODN) alone or in combination with MKN3 in the presence or absence of CLIP was assessed. The results are shown in FIG. 12. FIG. 12 is a line graph having a double Y axis, on one side depicting % total B cell death (diamonds, representing CpG ODN alone and squares representing CpG ODN+MKN3) and on the other side depicting % CLIP+ B cell death (triangles, representing CpG ODN and CLIP alone and Xs representing CpG ODN+MKN3 and CLIP). The data reveal that CpG ODN cause an initial increase in B cell death which after 72 hours appears to level off. The CpG ODN+MKN3 data demonstrate that MKN3 is capable of preventing the increase in B cell death.

[0485] Changes in CLIP positive B cells in spleen versus lymph nodes were also assessed. FIG. 13 is a line graph having a double Y axis, on one side depicting % CLIP+ B cell numbers in spleen (light gray square with solid lines representing CpG ODN alone and dark gray square with solid lines representing CpG ODN+MKN3) and on the other side depicting % CLIP+ B cell numbers in lymph nodes (diamonds with dashed lines representing CpG ODN alone and light gray square with dashed lines representing CpG ODN+MKN3). In both spleen and lymph nodes the addition of the peptide to the cells with CpG ODN resulted in less CLIP positive B cells.

[0486] CLIP positive B6.129 cultured B cells (H-2b haplotype) and H2M-/- (from C3H HeJ mice) cultured B cells were also examined in the presence or absence of treatment with a number of different TLR activators. The data is shown in FIGS. 14A and 14B. As shown in the Figures, several TLR activators were able to induce levels of CLIP+ B cells.

Just so it's clear, this isn't the treatment a patient would receive - Dr. Newell Rogers and her colleagues won't be breaking your neck and removing your tissues if you sign up for a clinical trial, okay?

This is an example of an experiment they did to show that VGV-L technology is effective in reducing the number of ineffective B cells which cause inflammation. The end result measured this change, and also measured the end of the sordid relationship between TLR-promoted CLIP MHC-HLA association in the immune system.

[Edited Apr. 3, 2012: Removed mention of CLIP positive cells - these cells need to be removed not added. ]

Now time for a brief lesson in immunology, based on what normally happens in immune response:


Terminology:
MHC = major histocompatibility complex; key components of T cell immunity. Think of them as immune response genes.
HLA = human leukocyte antigen (think of earlier discussions on this blog about HLA-DR4 and HLA-DR11, and different alleles which respond to infection differently)

So the story goes, B cells express MHC class II. Once antigen has been bound on the antigen receptor on the B cell, the antigen and its receptor are sucked into an endosomal compartment inside the B cell. Then the endsomal compartment fuses with another compartment, the lysosome.

Antigens are broken down into smaller pieces inside the lysosome and then loaded onto the MHC class II component, then the MHC is transported to the B cell surface where the B cell displays the antigen to a CD4+ T cell. This T cell is also known as a helper cell, of which there are two types - Th1 and Th2.

Susceptibility or resistance to many diseases appears to be determined by the genes encoding Major Histocompatibilty Complex (MHC) molecules. Often referred to as immune response genes (or IR genes), these molecules are the key players in restricting T cell activation.

T cells, both CD8 and CD4 positive T cells, recognize antigens only when the antigen is presented to the T cell in association with MHC class I (expressed on all nucleated cells) or MHC class II molecules (expressed on cells that present antigens to CD4+ T cells), respectively.

To sum up:

1. B cells express MHC class II.
2. Different people produce different levels of allele variation in MHC locus.
3. Because of this genetic difference, some people are more or less vulnerable to certain diseases.
4. The B cell's expression of MHC class II  is noticed by CD4+ T cells.
5. These CD4+ T cells are known as helper cells - of which there are two types, Th1 and Th2.
6. CD4+ T cells are a major player in our immune systems for fighting infection.
7. These helper cells do not kill - they activate and direct other immune cells. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

Look at these handy diagrams as an overview to what happens with B cells, MHC molecules, and T-cells...

Or, if your learning style is better geared towards watching videos, watch this one (warning: might be preceded by an ad, which you can mostly skip):

A simple overview of the immune system [Time: 5:56]
 

If you've gotten this far, right about now you might be asking yourself, "So what's the big deal? Why is it an issue that there are excess B cells, and how getting rid of them going to make a difference in fighting off Lyme disease if I have a chronic infection?"

Good questions. 


Obviously, you can see so far that one reason to not have certain B cells around is that they trigger autoimmune responses. No one wants that. But there are other reasons to avoid an overzealous non-specific B cell response.

Let me unwind the answer, step by step.

Google "polyclonally expanded B cells Borrelia" and tell me what you find. Or, read on and I'll tell you what I found:

Remember that study on Borrelia burgdoferi that Tunev and Barthold did, where it was noted that there was an outsized yet seemingly inadequate immune response to Borrelia burgdorferi found in lymph nodes? One with ill-formed B cells? This one: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002066 ?

Well, the phenomenon that's happening there is somewhat different from what is happening in polyclonal B cell activation in general. In polyclonal B cell activation, there can be lots of B cells which are produced which are non-specific. In this case, in Tunev and Barthold's research, a notable percentage of the B cells were Borrelia burgdorferi antigen specific - yet the cells were of low quality and inadequate to the task.

That's different than what is generally understood to be the typical polyclonal B cell activation, which is what I think is the hypothesis behind this treatment, VGV-L. In both cases, what one observes is an overwhelming number of B cells being produced.

[Edit Apr. 3. 2012: Updated correction to describe Tunev and Barthold difference in outcome of B cell activation.]

Polyclonal b cell activation has been thought to be a useful immune defense mechanism early in acute infection. What has not been investigated as much is how it might be a damaging process in chronic infection and immune dysregulation.

And there has been some argument in the microbiological world about whether polyclonally expanded B cell generation is essentially good or evil - the pros of cons of which are discussed in detail in this paper, "Polyclonal B cell activation in infections: infectious agents’ devilry or defense mechanism of the host?"

It's important to settle this argument because dysregulated and mis-targeted B cell antibody responses could result in autoimmunity, whereas impaired antibody responses during an actual infection could result in an immune deficiency.

Either way, over time it has become clearer that the production of these B cells relates to the appearance of an IgM response, and the relevance of the presence of an IgM response - particularly a prolonged IgM response - has also become a subject of heated discussion. See: "IgM in microbial infections: Taken for granted?"

But I digress...

This early paper from 1992 which is about Borrelia's relationship to polyclonal B cell activation, "Evidence for B-Lymphocyte Mitogen Activity in Borrelia burgdorferi-Infected Mice" (full text), has this to say in its abstract:

"We have used the murine model for Lyme disease described by Barthold et al. (S. W. Barthold, D. S. Beck, G. M. Hansen, G. A. Terwilliger, and K. D. Moody, J. Infect. Dis. 162:133-138, 1990) to determine whether the B. burgdorferi B-cell mitogen is expressed during active infection.

To correlate arthritic changes with immune events, we have studied two strains of mice injected with B. burgdorferi; one of them, C3H/HeJ, developed severe disease, and the other, BALB/c, developed only mild disease. C3H/HeJ mice displayed a persistent 10-fold increase in circulating immunoglobulin G (IgG) levels, a 2-fold increase in IgM levels, and a 15-fold increase in peripheral lymph node B-cell numbers, providing evidence of mitogenic activity. Infected BALB/c mice also had evidence for mitogen activity, since the IgG level in serum increased three- to fourfold. 

The bulk of the increase in circulating IgG levels was not directed against B. burgdorferi antigens, supporting the occurrence of polyclonal B-cell activation. Analysis of IgG isotpes pointed out a contrast between C3H/HeJ and BALB/c mice in that levels of all isotypes were elevated somewhat in both strains of infected mice but IgG2a levels were much more dramatically increased in the C3H/HeJ mice (28-fold) than in the BALB/c mice (4-fold). In this study, interleukin-6 levels were found to be persistently elevated in the serum of infected C3H/IHeJ mice. Interestingly, interieukin-6 levels in serum were much lower in the infected BALB/c mice. These findings indicate that the B. burgdorferi mitogen is active in infected animals and may contribute to the inflammatory and immune response to infection."

Right from the start, you get the idea that this paper is going to tell you that the presence of these polyclonally activated B cells have a relationship to IgM and IgG levels.

This is relevant, very relevant - because it can reflect how antibodies to Borrelia burgdorferi are present and how they are picked up in serological testing like ELISA and Western Blots.

Meaningful excerpts from this paper include:

"Immunological abnormalities, including hyperactive B cells, elevated IgM levels in serum, lymphadenopathy, impaired natural killer function, and delayed development of humoral immunity, have been documented in patients with Lyme disease (11, 16, 29, 30, 32). This has suggested a possible involvement of the specific or innate host responses in the pathogenesis associated with stage 2 and 3 disease(32)."

"Because of the persistent nature of infection and the ability of the organism to gain access to the joint and other tissues (5, 15, 29), a B-cell mitogen present during infection could play a role in the pathology of Lyme disease. To support this possibility, it was important to determine whether the mitogen functioned in vivo. This paper provides evidence that a B. burgdorferi mitogen is active in vivo in infected animals.

Three lines of evidence support the conclusion that B-cell activation in vivo is polyclonal or oligoclonal in addition to being antigen specific. 

First, the level of IgG in serum in infected mice was elevated about 10- to 15-fold, with the value ranging from 10 to 15 mg/ml (Fig. 1C). In comparison, the amount of IgG specific for B. burgdorferi antigens was approximated at 0.6 mg/ml (Fig. 2). 

Second, the number of B lymphocytes in peripheral lymph nodes of infected animals was increased 10- to 15-fold, with a 5-fold rise in the ratio of B to T cells (Fig. 4). The number of B cells also increased about twofold relative to the number of T cells in spleens from C3I/HeJinfected mice. 

Third, the IgG titer in the serum of infected animals to an unrelated antigen, ovalbumin, was increased 10- to 15-fold, which resembles the increase in the total IgG level (Fig. 3). 

These findings suggest that levels of autoreactive antibodies might be also expanded in infected animals, although anti-collagen antibodies were not identified. Because CD5+ B cells have been shown to produce autoreactive antibodies and are selectively increased in patients with rheumatoid arthritis (7), we determined whether they were expanded in B. burgdorferi-infected animals. No selective increase in the number of B cells of this lineage were found in C3H/HeJ animals at any stage of infection. Further studies are required to determine whether autoreactive antibodies are generated during infection."

So their initial experiment to see if there was an overwhelming B cell response provides us with evidence that yes, there is, and also - while there is a high IgG response, only a small percentage of IgG produced is B. burgdorferi specific. There was at the time no indication that autoreactive antibodies were involved.

(This process can be a precursor to autoimmunity developing - but that's later on.)

A later paper, from 1997, "Why is chronic Lyme Borreliosis chronic?"(full text), also brings up a host of issues related to TLRs, MHC class II, and the relationship between B and T cells in lymph nodes.

Doesn't it seem a little prescient?

"The question remains whether downregulation or even loss of MHC class II molecules on LCs might influence a patient's disease susceptibility. It is MHC class II molecules that bind antigenic peptide fragments, present them to CD4+ Th cells, and induce cytokine secretion and IgG secretion by B cells [55]. In vitro investingations have shown that MHC II class molecules are downregulated on antigen-presenting cells after coculture with Th cell clones in the presence of antigenic peptides of tetanus toxoid or staphylococcal superantigen, which elicit a strong HLA-DR-restricted T cell response.

Several hypotheses were suggested as the cause of this down-regulation. 

(1) Downregulation occurs when antigenic peptides catabolized in macrophages are recognized by CD+4 helper T cells, in order to control the size of a T cell clone and provide a homeostatic mechanism [55]. (2) Downregulation occurs for completion of T-B cell collaboration after antigen presentation, limiting excessive T cell help to the triggered B cells, or (3) it occurs for focusing the T cell repines to one or a few immunodominant peptides.

(4) LCs of patients with AIDS express decreased amounts of MHC class II molecules. Polyclonal B-cell activation, as seen in these patients and in patients with ACA, could cause the appearance of autoantibodies or immunocomplexes that interact with LCs and block their surface-staining characteristics [45]. (5) IL-10, originally identified as a product of Th2 cells, has a significant inhibitory influence on the antigen-presenting functions of macrophages and LCs by downregulation of MHC class II molecules. In fact, LCs pretreated with IL-10 were converted from specifically sensitizing to specifically tolerogenic antigen-presenting cells in vitro and in vivo [56]. In other studies treatment of LC cultures with IL-10 inhibited to upregulation of HLA-DR [57].

(6) Downregulation is initiated for establishment of self-tolerance. This downregulation can protect the antigen-presenting cell by inhibiting the presentation of self-antigens [58]. On the other hand, the downregulation of MHC class II antigens on LCs could result in inadequate presentation of antigens in lymph nodes, which in turn may reduce activation and proliferation of both B and T cells and the secretion of relevant cytokines. This may be what happens in CLB."

Dr. Karen Newell Rogers et al recent patent has this to say about TLRs (Toll Like Receptors) and B cells:

"Many bacteria and viruses produce substances, collectively called Toll ligands, that elicit an immediate response from an individual's immune system. These Toll ligands appear to promote inflammation by activating a wide variety of immune cells to bring them rapidly into battle against the invading pathogen. 

In most cases, these events correlate with a healthy and productive immune response to the pathogen. However, in some cases the Toll ligand binds to a Toll-like Receptor (TLR) on lymphocytes and non-specifically activates immune cells called B and T lymphocytes that would normally to respond to infectious pathogens with an exquisitely specific response. When Toll ligands activate B cells in a non-specific way, the non-specific activation is a pro-inflammatory event that may result in uncontrolled, or even auto-reactive, production of antibodies. When a B cell is activated non-specifically, we have discovered that the B cell expresses an important, small self-peptide called MHC class II invariant peptide, CLIP. In most individuals, a control cell, known as a T regulatory cell (Treg for short), has been shown, to kill the activated B cell.

During a viral or bacterial infection, non-antigen specific B cells in close proximity to an inflammatory or inciting lesion could manage to become activated in a bystander fashion. In those cases, CLIP would remain in the groove and get transported to the cell surface of the B cell. Its presence on the cell surface can be undesirable because if CLIP gets removed from the groove by a self antigen, the B cell would be in a position to present self antigens to self-reactive T cells, a process that could lead to autoreactivity and autoimmune disease. 

For some B cells this may result in death to the B cell by a nearby killer cell, perhaps a natural killer (NK) cell, unless the antigen receptor on the B cell has engaged antigen. Antigen recognition would thereby provide a survival signal for the B cell. However, if a killer cell doesn't remove the potentially autoreactive B cell and it encounters a CD4+ T cell that can recognize that antigen (most likely one that was not in the thymus) the B cell might receive additional help from a T cell specific for the antigen that now occupies the groove (antigen binding location in the MHC molecule). Alternatively, a nearby cell whose job it is to detect damaged self cells, may become activated by the self antigen-presenting B cell. Such a damage detecting cell is, for example, an effector T cell (Teff) such as a gamma delta T cell, also referred to as a γδT cell (γδ refers to the chains of its receptor). The γδT cell can then seek out other sites of inflammation (for example in the brain in MS, in the heart for autoimmune myocarditis, in the pancreas in the case of Type I Diabetes). Alternatively, the γδT cell might attempt to kill the CD4+ T cell that may respond to self antigens."

So based on all this, I think one has to consider that the complex interactions within the immune system related to B. burgdorferi infection have to be paid close attention to - and not just any persisting spirochetes themselves.

I am really interested in seeing what VGV-L - along with supportive and antibacterial treatment together - can do for chronic Lyme disease. It appears it not only prevents autoimmune responses to infection, but redirects the immune response so it can better target infection.

I do wonder, though,  how VGV-L would handle a situation where many B cells are being created and a good percentage of them are antigen specific but are of low quality - such as those mentioned in Tunev and Barthold's research.

* It may be that Lyme disease is more like HIV in that inflammation may allow or facilitate the spread of spirochetes as it encourages vlsE recombination. See: http://www.jimmunol.org/content/167/6/3383.long for one example.

Additional Resources:
Interview with Dr. Karen Newell Rogers: http://www.timeforlyme.org/TFL_newsletter_july_2011_q_a.htm
Marketwatch on VG Pre-IND submission to FDA: http://www.marketwatch.com/story/viral-genetics-submits-pre-ind-document-for-lyme-disease-drug-candidate-to-fda-2012-03-07

[Edit Record: This page was edited 2 times on April 3, 2012.]

If you've made it this far and still want to learn more about VGV-L, there are other posts on this subject on the site. Begin with this link: http://campother.blogspot.com/2012/04/notes-posted-on-vgv-l.html

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

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