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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1 Multicenter Clinical Study To Test For Babesia In Blood Supply

This just released in the press by the Red Cross: The American Red Cross is participating in a multi-center clinical study sponsored by IMUGEN, Inc. to help improve the safety of the nation’s blood supply.

This study will test the blood supply for evidence of a tick-borne organism, Babesia microti, by investigational test methods developed by IMUGEN. It will be conducted under Imugen’s Food and Drug Administration (FDA) approved Investigational New Drug Application (IND) and will include the testing of more than 26,000 blood donor specimens from Babesia endemic and non-endemic areas to define the performance characteristics, sensitivity, and specificity of the investigational test methods for blood donor testing. Susan Stramer, Ph.D., executive scientific officer for the American Red Cross, will act as a principal investigator for the Red Cross arm of the study.

No mention has been made of whether or not test methods will also supply evidence of Babesia duncani or WA-1, which is becoming a more common strain of the organism which causes the malaria-like illness.

Read more here, at the link:

American Red Cross Participating in an Investigational Study to Test the Blood Supply for a Tick-Borne Parasite in Donated Blood

With any luck, these test methods will perform well and be made available internationally.

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2 Wormser et al Criticism Launched at Embers' Rhesus Macaque Study

Wormser et al have recently published a critique of Embers' study, "Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection".

Vector Borne Zoonotic Dis. 2012 May 23. [Epub ahead of print]

Critical Analysis of Treatment Trials of Rhesus Macaques Infected with Borrelia burgdorferi Reveals Important Flaws in Experimental Design.
Wormser GP, Baker PJ, O'Connell S, Pachner AR, Schwartz I, Shapiro ED.

Abstract

A critical analysis of two treatment trials of Chinese rhesus macaques infected with Borrelia burgdorferi indicates that insufficient attention was placed on documenting the blood levels, pharmacokinetics, and pharmacodynamic parameters of the antibiotics used in this host. Consequently, it is impossible to conclude that the findings have validity in judging the efficacy of doxycycline or ceftriaxone for the treatment of Borrelia burgdorferi in this animal model.

PMID: 22620495 [PubMed - as supplied by publisher]

Full text of this critique is available here:
http://online.liebertpub.com/doi/full/10.1089/vbz.2012.1012

The full text of the original study which is the focus of this critique is here:
http://www.plosone.org/article/fetchArticle?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.0029914


Related material on Camp Other blog:

• Paper: Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection
• Debate About Embers Non-Human Primate Chronic Lyme Disease Study Continues
• Embers et al Rhesus Macaque Study Correction Issued
• Embers et al Issues Statement On PLoSONE
• Why Aren't Persisting Spirochetes Enough Evidence Of Infection?

Comments:

For now I am sharing the news that the free full text this critique is available online. Further comments to be made at another time. Comments by readers are welcome.

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23 Let's Not Be Rash About Erythema Migrans

On May 21, Skidmore College in New York conducted the Lyme Next Forum in which various doctors, researchers, patient advocates, and Lyme disease organization leaders gave presentations on various topics related to Lyme disease and its coinfections. (All presentations in four parts can be viewed as streaming videos on Joanne's Looking at Lyme blog.)

While different presentations may have grabbed the attention of other patients, one presentation which stood out for me early on was Holly Ahern's presentation.

Holly is an associate professor at SUNY Adirondack who teaches microbiology and was recipient of a 2008-2009 Research Residency award from the American Society for Microbiology (ASM). So she knows a little something about Lyme disease from a microbiological perspective. But she also has more direct experience of what it is like because her daughter developed a chronic form of the disease.

Holly's presentation was about the potential impact of Lyme disease in New York State in terms of projected undiagnosed cases and unreported cases. But what grabbed my attention in particular was the portion of her presentation focused on research related to the well-known "bull's eye" rash - also known as erythema migrans (EM).

Prior to this, I've read different reports of how many patients who are diagnosed with Lyme disease initially present with an EM rash and how to identify one, so some of this information was not new to me.

While everyone thinks about a Lyme disease rash as being a bull's eye with central clearing (it looks like a target) a 2007 paper published in the Journal of Emergency Medicine, 'An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark"', states the following in its abstract:

"To confidently diagnose and treat Lyme disease, the clinician must first understand the natural history of this disease, especially its protean early manifestations. Emergency physicians, primary care physicians, and other providers need to be vigilant in terms of the timely recognition of erythema migrans (EM), the unique marker of early localized stage 1 disease. The classic EM, originally described as a slowly expanding bull's eye lesion, is now recognized to be present in only the minority of cases (9%); the dominant morphologic lesion of EM is now recognized to be the diffusely homogenous red plaque or patch, which occurs in over 50% of cases. This update will define the current morphologic features of early Lyme disease, the indication for serologic studies, and the most recent treatment guidelines, including therapeutic pitfalls."

Based on this, a more evenly colored rash is typical with Lyme disease - whereas a target-like presentation is actually in the minority.

And there are other reports of just how wide the variety of rashes and skin manifestations of EM there can be.

In his testimony to the FDA in preparation for discussion of the approval of the Lymerix vaccine, Dr. Vijay Sikand shared his experience with rashes related to Lyme disease:

"In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection. In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to. Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.

Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection. Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember."

Based on Dr. Sikand's reports and laboratory testing, it would appear that a typical red rash is not the only manifestation of Lyme disease rashes and there can be much variation.

Having these kinds of reports - and that of the Journal of Emergency Medicine - leads to questions about the reliability of having a uniform description of a rash that doctors would need to look for as part of the definition of the disease. It also raises questions about the utility of using a uniformly described rash in the CDC surveillance case definition for determining where confirmed and probable cases of Lyme disease are reported.

When is a rash an EM rash and when isn't it an EM rash - if one is found at all?

It's clear that if a patient with Lyme disease has a rash which does not match the description of the bull's eye rash that they may be diagnosed with some condition other than Lyme disease.

One way to confirm the diagnosis in this situation would be to look at a patient's history of exposure to ticks, overall symptom presentation for symptoms which suggest Lyme disease, and to get a culture from an odd looking rash and test it for Borrelia burgdorferi even if it takes weeks to receive results.

But what if the patient does not present with an EM rash at all? Perhaps the rash is small and in the hairline where it is not easily seen. And taking it a step further: What if it never even happened?

Ahern pointed to a paper that I had cited on the blog before: "Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite". (You may be more familiar with this paper in reference to a recent discussion on prophylactic treatment of tick bites on this blog.)

Ahern made two statements during her presentation which I hadn't recalled reading in this publication:

1. Only tick bites from nymphal ticks produced an EM rash in the host.
   
   
2. When an adult tick (assessed by entomologist in lab for age) had bitten the host, there was NO EM rash.

In addition to these two bits of data, the authors also mentioned that a prophylactic dose of antibiotics prevented the development of an EM rash.

While I had read about antibiotics preventing the development of an EM rash before, the other two pieces of data were new to me. 

So I immediately called up the paper for review to see what had been written about these two statements, and found this information:

"In untreated subjects, bites from nymphal ticks were significantly more likely than bites from adult ticks to be associated with erythema migrans (8 of 142 [5.6 percent] vs. 0 of 97 [0 percent], P=0.02)." 

"In the two groups combined, nymphal ticks were nearly twice as likely as adult ticks to be partially engorged (159 of 266 ticks [59.8 percent] vs. 64 of 197 ticks [32.5 percent], P < 0.001)."

"Untreated bites from nymphal ticks that had been attached to subjects for an estimated 72 hours or longer were more likely to result in erythema migrans than were untreated bites from nymphal ticks that had been feeding for less than 72 hours (3 of 12 bites [25 percent; 95 percent confidence interval, 7 to 57 percent] vs. 0 of 48, P=0.006)." 

"... In addition, our findings support those of previous epidemiologic studies that have shown a temporal association between the development of erythema migrans and exposure to nymphal rather than adult ticks.13 One possible explanation for this is that adult ticks (which are considerably larger than nymphal ticks) are detected and removed earlier in the feeding process than nymphal ticks [...]"

So it seems that at this point, it was already well established that nymphal ticks were already far more likely to cause an EM rash than adult ticks - and because of their small size, nymphal ticks would be less likely to be removed by someone due to not being noticed. They could more easily transmit infection due to the duration of their feeding and missed detection. That sounds logical.

However, what about the adult ticks?

Has there been verification beyond this publication that those who are bitten by adult ticks do not develop an EM rash? Does the lack of an EM rash - not even in the hairline - indicate one is not infected with Borrelia burgdorferi? Or can a host still be infected by an adult tick without the presence of an EM rash?


Further discussion of these questions and this phenomenon will be found in the next installment of "Let's Not Be Rash About Erythema Migrans"...

Image Credit:
"Bulls-eye" Lyme Disease rash by Mangojuice's father

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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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3 "Time For Lyme" Becomes "Lyme Research Alliance"

Just recently, the Lyme disease advocacy group, Time For Lyme - which is credited with creating a partnership with Columbia University Medical Center and the national Lyme Disease Association to establish and endow a Lyme and Tick-borne Disease Research Center in New York City at Columbia - changed its name to the "Lyme Research Alliance".

The name change came about as an effort to reflect the organization's growing emphasis on supporting more research into chronic Lyme disease and how to improve serological testing and treatment.

See this page to view a list of their currently funded research projects:

http://www.lymeresearchalliance.org/research_projects.html

Camp Other blog has written about a few Lyme Research Alliance funded projects such as:

Dr. Karen Newell Rogers' proposed chronic Lyme disease
treatment, VGV-L:
Viral Genetics' VGV-L Candidate For Treating Chronic Lyme Disease
Notes Posted On VGV-L 

Dr. Armin Alaedini's research on antibody response in chronic Lyme disease/PLDS patients:
Antibodies linked to long-term Lyme symptoms 

Dr. Steven Schutzer's research on biomarkers for late stage Lyme disease/PLDS:
Spinal Fluid Proteins Distinguish Lyme Disease From Chronic Fatigue Syndrome

I've checked out the Lyme Disease Alliance's new web site, and I approve of their overall mission and think it was fantastic they gave $3 million to fund the Columbia Lyme and Tick-borne Disease Research Center.

One thing I'm hoping to see with the change in name and greater commitment to research is a shift in the kind of accomplishments they had in the past, where videos, education packets, and legislation has been a focus - to a focus in assessing what kind of research projects would settle the Lyme disease controversy as well as focus on backing research on more novel treatment methods, such as they have done with VGV-L.

It is my dream that someday all the different Lyme disease organizations will unite for a single effort and come up with one large scale, fully funded Lyme disease research project that will help thousands of patients. I'd like to see focus on that project alone for a solid two or three years and see how far we can get in our understanding of Lyme disease.

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10 Commentary On Chronic Lyme Disease and Skepticism

When I began writing this blog, I originally wrote it to give a point-by-point analysis of how one article in the Chicago Tribune, "Chronic Lyme: A dubious diagnosis", did not address the issue of whether or not Lyme disease could be a chronic and persistent infection after initial or delayed antibiotic treatment. I wrote the analysis using Carl Sagan's Baloney Detection Kit, because I thought it was a good framework for deconstruction of the article.

I thought this analysis would attract the attention of a number of skeptics, and from there, we'd engage in a lively discussion about how the article skirted the issue of whether or not chronic Lyme disease is possible and dive into the evidence for and against chronic Lyme disease being a persistent - if only subclinical - infection.

It never happened. 

Over a year later, and it still didn't happen.

And, to this day, only one person has ever left me a comment which directly challenged what I was writing about and judged the content of this blog - at least as far as the idea of persistent infection is involved.

That comment was this:

You error in giving any credit to the "chronic lyme disease" movement.

I recommend this paper in the current issue of The Lancet (Sep 2011;11:713-719) :

Antiscience and ethical concerns associated with advocacy of Lyme disease

Abstract: Advocacy for Lyme disease has become an increasingly important part of an antiscience movement that denies both the viral cause of AIDS and the benefits of vaccines and that supports unproven (sometimes dangerous) alternative medical treatments. Some activists portray Lyme disease, a geographically limited tick-borne infection, as a disease that is insidious, ubiquitous, difficult to diagnose, and almost incurable; they also propose that the disease causes mainly non-specific symptoms that can be treated only with long-term antibiotics and other unorthodox and unvalidated treatments. Similar to other antiscience groups, these advocates have created a pseudoscientific and alternative selection of practitioners, research, and publications and have coordinated public protests, accused opponents of both corruption and conspiracy, and spurred legislative efforts to subvert evidence-based medicine and peer-reviewed science. The relations and actions of some activists, medical practitioners, and commercial bodies involved in Lyme disease advocacy pose a threat to public health.

And pertinent to this blog, the authors conclude, in part:

"This situation is not likely to end anytime soon. As with other antiscience groups, many Lyme disease activists are well funded and often connected to influential political and media sources. Treatment of Lyme disease with long-term antibiotics is profitable for LLMDs and can be falsely reassuring to patients, who believe that they have a debilitating chronic infection and thus do not seek diagnosis and treatment for other disorders. There is no deficiency of either new patients or activists. The medical anthropologist Sharon Kaufman wrote that “Information technology has transformed the way trust and knowledge are produced”.67 Most people now find medical information on the internet, and the websites of LLMDs and activists are often viewed as legitimate and reliable sources of information, which they may not be."

         - LindaRosaRN


I responded to her, asked her a few questions, and she never responded in return. A drive by. 

She obviously wanted to be heard but did not want to engage. Her comment was on a post about the Huffington Post and Under Our Skin; it wasn't even related to the antiscience letter to which she referred.

And since then, it's been crickets all around when it comes to skeptics  - even though I get visits from Spirochetes Unwound (of Research Blogging), and other web sites which are science and skeptic-oriented on a number of levels.

It's almost as if someone gets to the front door of this site and decides it's not for them just because it mentions the words, "chronic Lyme disease".

I'm guessing the skeptical person who stumbles upon this page with that first glance thinks, "Oh, well, it's another one of those chronic Lyme activists. Why are they ignoring all the evidence that after antibiotic treatment, those with persisting symptoms develop an autoimmune disorder? I'm getting out of here. I'm not wasting my time on this..."

If they're thinking that, then perhaps an overhaul is in order for this blog because I'm not trying to ignore the evidence about autoimmunity or immune dysregulation related to persisting symptoms.

I'm trying to look at a number of different hypotheses - including chronic infection - because these topics are of interest to other patients and I think they all deserve discussion. And there are other hypotheses outside of chronic infection and autoimmunity which are being researched such as chronic Lyme disease as a metabolic disorder, and I give them exposure.

Because I enjoy science, I look at research and science news related to tickborne infections and their reservoir hosts in general, without any particular goal in mind other than to say, "Hey, look at this - isn't this weird/interesting/informative?" I want to inspire the curiosity of the world I have in others.

At first glance, this blog has been primarily written for other patients with persisting symptoms related to Lyme disease infection. But it has also been written to open the floor to anyone for discussion about different causes for persisting symptoms.

This includes skeptics. They are welcome to comment here and share their perspective, as long as they aren't rude and can state their position while providing supporting evidence.

After all - I have a history of being a skeptic myself, and at times don't just want the cheering section behind me saying they support me as a fellow patient. I also want someone to occasionally shake me out of my complacency if I've been stuck in it. I occasionally want someone to present me with a different point of view or new evidence if they have it so I can consider other lines of inquiry in trying to understand my condition.

I have to wonder sometimes if I need a colorful banner or animated message on the top left corner of the homepage which states, "I am a skeptic and a patient with persisting symptoms related to Lyme disease".

Or maybe I need a paragraph at the top of one of my sidebars in order to say more about who I am.

Something like this:

Side note to all scientists and skeptics, in case you missed it: 

This blog is written from the perspective of one person who has been in the unfortunate position of being a skeptic who is suffering from persisting symptoms after receiving an infected tick bite.  

I want answers to questions such as, "What on earth does someone in my position do?" and "What kind of pragmatic approach can I have to dealing with my illness when I am a skeptic and want evidence to support my position and the decisions I make?" and "What research is out there which supports one or another position as to the cause for my condition?"

This has to be done carefully, though, for the sake of my audience.

While I want skeptics to feel welcome here,  I don't want to scare other patients away who are dealing with the same struggles. And I want everyone to feel welcome here and not like they have to constantly defend their illness to others who may not only be skeptical - but who have the potential to engage in less than civil behavior online.

My concern here is not unwarranted. I have read skeptic sites for a number of years, and while I can read sites where issues concerning chronic Lyme disease are debated by infectious disease specialists, researchers, doctors, and patients - such as this BMJ series of Rapid Responses - I practically choke on some of the comments on this chronic Lyme disease post on Respectful Insolence blog, because some of the exchanges are insulting and do little to advance serious discussion about Lyme disease. (Some of them are thoughtful and intelligent, too, though, so I don't avoid reading the thread entirely just because there are insults.)

And I have to remind myself that any blog on the internet has the potential for ill-informed comments, regardless of the original content.

One response on the above linked blog betrays a certain basic ignorance about Lyme disease:

"Yikes, always knew Chronic Lyme disease was complete woo. It's called an anxiety disorder, get your meds. Even acute Lyme disease is looking to be a bit far fetched, now I am far from an expert but it seems a little bit out of a sci fi novel for a tick to harbor some strange virus, who proved this and what experimental data did they have? What were the experiments that prove that some tick borned virus is the cause of a human disease in the first place?"

What the... 

Acute Lyme disease looks far fetched and it must be sci fi that a tick harbors a strange virus?

Far from expert?

Indeed. 


And some comments are thoughtful and the response is respectfully delivered even if the content is something a number of patients would find disagreeable:

"...I don't doubt your story, but given how common tick bites are, it seems likely that an association could be found regardless of whether or not the tick bite actually caused the condition. Thus, anecdotes are not that useful in understanding the disease. Anecdotes don't tell us cause and effect. They show us why we should care, and they are important for that reason, but they do not tell us what is true. It takes a lot of carefully collected data to do that. 

How do you know the antibiotics are really responsible for your improved state of health? Remember, coincidences do happen -- during the summers I take Pulmicort, but is it really making my asthma better, or is the variable course of my asthma just being kind to me right now? I have anecdotes galore, but it's the clinical trial data that convinces me the Pulmicort really is working and it's not just my own desire for it to work making it seem as though it is.

Indeed, one day the truth may come out. But it'll have a hard time coming out when the science of Lyme disease is decided by politicians, and when those most invested in chronic Lyme disease would rather spend their effort treating patients than finding out whether or not they're actually doing the right thing for their patients. Too many of the positive studies I have seen have been enterprises in proving a point rather than testing an hypothesis; science can't be fair or unbiased or *truthful* if it does not entertain equally the possibility of being wrong."

They have a valid point. I can see that.

The problem is, when is this "one day where the truth may come out"?

I have to make decisions about what to do about my health TODAY.

That's the one truth which few of these exchanges seem to address:

How does one make an informed decision as to how to approach and treat one's condition when there is a medical controversy over how to treat it where one of the two options is not to treat it at all - and doing nothing leads to more suffering?

While the author takes the time to explain that anecdotes are not data (with which I agree) and that tick bites in and of themselves are common, there is plenty of medical research and documentation which provides evidence that a subset of infected Lyme disease patients go on to have persisting symptoms after initial treatment. For some of these patients, these symptoms are severe. For a number of them, symptoms persist not for months but for years.

The IDSA and other medical institutions and researchers acknowledge this condition. It's not well understood - but this phenomenon has been documented and is not the creation of a handful of woo charlatans looking to cash in on me.

And I am, for whatever unfortunate reason, the poor bastard who has this condition. And I:
- had a documented tick bite,
- developed an EM rash,
- received a positive blood test later on,
- developed all these symptoms which were clinically diagnosed as Lyme disease.

Unlike the claim made by Ms. Rosa above, no one has tried to con me into this diagnosis. I had a textbook case of Lyme disease. The evidence was there.

If anything, when I first contracted Lyme disease, I thought I was getting it taken care of early enough and would not have to touch the "Lyme controversy" with a twenty foot pole.

Unfortunately, life had other plans for me.

I ended up not being able to work, got sicker than I'd ever been in my life for months on end, then finally got better and off antibiotics and return to work... only to relapse, have to leave my job, and try to figure out what to do next.


Why me? I didn't ask for this. As someone who reads Free Inquiry on occasion, worked as a researcher, lived in a dorm full of physics and chemistry geeks, and thought Carl Sagan was one of the most brilliant and compassionate minds on Earth, I really did ask "Why me?".

But you know, the answer to a pathetic "Why me?" really is "Why not me?". No one asks for this. No one asks to be hit by a car, abused as a child, diagnosed with breast cancer, or to watch a parent die. We are all subject to things which happen beyond our control. It was just the random luck of the draw that someone who happened to be a skeptic would get a condition of which others are skeptical.

Ticks don't care if you like Sagan or vote for Romney. They just want lunch.

For better or worse, here I am. Now, how can I make the best of this? What can I make of this situation now that I'm smack in the middle of it?

I've thought that all I can do is write, research, and encourage others to do research. Learn and encourage others to learn more about tickborne illnesses. Encourage those who are out there who are working in microbiology and biology to engage in education and outreach which helps patients and sidesteps the politics. Educate one doctor at a time that someone with my condition exists, and that a tickborne infection can lead to chronic symptoms. Warn others and tell them to protect themselves when they go hiking and camping so they can avoid my fate.

Mainly what I want to do is get better and get back to living life as I was before - but this time, perhaps a little humbler, a little wiser, and with more compassion for others and more gratitude for myself.

In meantime, I keep hoping I'll meet others here who came from a similar background.

So far, in terms of scientists, I have had a few other Lyme disease patients with science degrees and research positions (or friends and partners of patients with science backgrounds) comment on this blog. Outside of these patients, researchers have commented less often and anonymously.

And I keep hoping someone who is a skeptic and also struggling with chronic Lyme disease or perhaps CFS/ME will come forward and we can review research together and try to make sense of it and figure out what the best course of action is. Even better? I keep hoping to see a microbiologist who researches Borrelia burgdorferi and has had persisting symptoms from Lyme disease take up blogging on their own and publish more insights of which are but a faint glimmer in my own head.

But so far? Crickets.

Surely we can do better than this. Surely one can light more candles against the darkness?

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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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1 Abstract: Delays and Diversions Mark the Development of B Cell Responses to Bb Infection

Another insightful paper on the immune response to infection with Borrelia burgdorferi has been published. "Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection" by Hastey et al is closely related to previous research completed by Tunev et al on the immune response found in murine lymph nodes which were invaded by Borrelia burgdorferi.

A well-written blog article on Tunev et al's previous research on B cells and plasma cells and their associated (lack of) T cell response in reaction to Bb infection can be found here:

Spirochetes Unwound Blog - Does Borrelia burgdorferi cause an inadequate antibody response by altering B cell activation in the lymph node?

I recommend reading that link first before proceeding to the following abstract.

Christine J. Hastey, Rebecca A. Elsner, Stephen W. Barthold and Nicole Baumgarth. Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection. The Journal of Immunology. April 30, 2012

Abstract

B cell responses modulate disease during infection with Borrelia burgdorferi, the causative agent of Lyme disease, but are unable to clear the infection.

Previous studies have demonstrated that B. burgdorferi infection induces predominantly T-independent B cell responses, potentially explaining some of these findings. However, others have shown effects of T cells on the isotype profile and the magnitude of the B. burgdorferi-specific Abs.

This study aimed to further investigate the humoral response to B. burgdorferi and its degree of T cell dependence, with the ultimate goal of elucidating the mechanisms underlying the failure of effective immunity to this emerging infectious disease agent.

Our study identifies distinct stages in the B cell response using a mouse model, all marked by the generation of unusually strong and persistent T-dependent and T-independent IgM Abs.

The initial phase is dominated by a strong T-independent accumulation of B cells in lymph nodes and the induction of specific Abs in the absence of germinal centers.

A second phase begins around week 2.5 to 3, in which relatively short-lived germinal centers develop in lymph nodes, despite a lymph node architecture that lacks clearly demarcated T and B cell zones.

This response failed, however, to generate appreciable numbers of long-lived bone marrow plasma cells.

Finally, there is a slow accumulation of long-lived Ab-secreting plasma cells in bone marrow, reflected by a strong but ultimately ineffective serum Ab response.

Overall, the study indicates that B. burgdorferi might evade B cell immunity by interfering with its response kinetics and quality.

This work was supported in part by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant AI073911 (to N.B. and S.W.B.) and T32 Training Grant AI060555 (to C.J.H. and R.A.E.).

Full text is available behind pay wall here: http://www.jimmunol.org/content/early/2012/04/30/jimmunol.1103735.full.pdf+html

Comments:

This is an interesting development in the ongoing process of trying to understand how Borrelia burgdorferi evades the immune system. What we know is what starts out looking like the host mounting a strong immune response to infection ends up looking like a poorly differentiated immune response where plasma cells are inadequate and not engaging in the right immune class switching to fight infection - and where T cells are not fully participating in B cell activation.

This study indicated that not only is the immune response inadequate and ill-directed in its early phase in lymph nodes (which Tunev et al studied) but that in later stages antibody response is inadequate as well.

These studies indicate that the host immune response fails to clear Borrelia burgdorferi and somehow the bacteria is able to evade it. More details on specifically how is likely available in the pay-for-view full text of the paper (until the six month NIH/NIAID publication embargo is over).

Questions remain as to how this research applies to human hosts. Does the same immune response occur in humans that occurs in mice? How does the introduction of antibiotics affect this response? Knowing how both the host immune system and antibiotics work together in combatting this infection would be useful.

One thing I would like to see Tunev, Hastey, Barthold, and others doing this work is to somehow detect which outer surface proteins are upregulated during the time they are invading the lymph nodes and generating a lot of inflammation. In particular, I am wondering if OspA is being expressed in the lymph nodes as much as it has been proposed as being expressed in the CNS in neuroborreliosis.

I leave those reading to consider this paper which was published in Nature, and the following excerpt from it:

OspA-CD40 dyad: ligand-receptor interaction in the translocation of neuroinvasive Borrelia across the blood-brain barrier

"Some authors have suggested downregulation of OspA in early phase of the infection 21, 22, while others have reported expression of OspA in the unique environment of the brain and CSF, but not in the serum 23, 24. Therefore, it was essential to determine whether OspA is expressed in borreliae that are present in the brain vasculature in vivo in infected laboratory animals. PCR analysis of the brain and brain microvasculature of Wistar rats infected with SKT-7.1, revealed not only the presence but also the augmented expression of OspA (Fig. 3). This finding is crucial to support a role of OspA as an adhesive molecule in the transient tethering of Borrelia."

"OspA is undoubtedly a multifunctional protein that is absolutely necessary in the various stages of borrelial lifecycle and pathogenesis. OspA is abundantly expressed in tick gut as an important adhesive molecule 29. To avoid an inflammatory response, expression of OspA is downregulated in the early stages of Lyme disease. However, OspA expression in vivo can be significantly induced if the spirochetes are kept in an inflammatory environment 46. OspA plays an important role in binding to neuronal cells. These data indicate that OspA must be upregulated during the CNS invasion and acts as an important adhesion factor, which is essential in the pathogenesis of Lyme neuroborreliosis 23. It is also well known that Borrelia can bind plasminogen via OspA on their surface 47. OspA also upregulates membrane urokinase-type plasminogen activator receptor (uPAR) 48. Plasminogen can be activated to plasmin 47, 48 leading to degradation of the extracellular matrix. The mammalian plasminogen-plasmin proteolytic system plays a crucial role in extracellular matrix degradation (intercellular junctions) and cell migration 49. Binding of host-derived proteinases (like plasminogen and MMPs) via OspA supports the theory that Borrelia exploits these proteinases to degrade the intercellular tight junctions. Owing to the hypervariability of OspA among several Borrelia strains, it is important to note that only expression of OspA is not sufficient, but its ability to interact with host's receptors is crucial in the invasion processes."

After reading a passage like this - plus these studies on B cell activation during Bb infection - I have to ask if OspA plays a role in in vivo infection not only inside the CNS in neuroborreliosis - but also in dissemination to other parts of the body. Would this account for the widespread pain patients experience from inflammation, since OspA is highly immunogenic? What is OspA's degradability?
See: http://en.wikipedia.org/wiki/Immunogenicity

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