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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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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1 The Phenomenon Of ‘Chronic Lyme’; An Observational Study

Recently, the results of an observational study on chronic Lyme disease in Norway were published in the European Journal of Neurology. (The full text of the study is behind a pay wall on Wiley - but otherwise you can read the abstract online.) According to the National Institute of Health (NIH) clinical trials database, the purpose of the study was:

"... to chart clinical and laboratory findings in Norwegian patients with symptoms attributed by themselves or their doctor to ongoing chronic Bb infection. Objectives are to assess laboratory findings in relation to established diagnostic criteria and to form a picture of the burden of symptoms and illness perception in this group of patients. The study is essentially exploratory, and is supposed to raise rather than to test hypotheses."

Based on this, it sounds like the authors' original expectations for this study were that the researchers would find out in a given population that among those who either suspect they have chronic Lyme disease and have it - and those who suspect they have chronic Lyme disease and don't have it - that it would be discovered what clinical differences and diagnostic markers would set them apart.

But the abstract doesn't indicate what the criteria are for a case definition of chronic Lyme disease if the researchers had one in mind. Rather, it indicates that of the patients enrolled in the study, there was no evidence that any patient had an existing infection with Borrelia burgdorferi.

The following comments are strictly preliminary and based on the content of the abstract only - a more detailed review is in order once the full text has been read:

First, I was disappointed to find out that the total enrollment expected for this study was a mere 30 participants - and in the actual study, there were only 29 enrollees. This is a very small pool of applicants, and I don't think the data can be extrapolated to fit a large group of people - or even more so, a large group of people from an area which is highly endemic for Lyme disease.

Second, this study in no way set out to solve the problem of whether or not chronic Lyme disease is a real condition - I don't think that was the researchers' goal. Their goal was to characterize those people who either self-reported that they thought they had chronic Lyme disease based on their symptoms or their doctors suspected they had chronic Lyme disease based on their symptoms. Nothing less, nothing more.

It would have been more productive for patients had the researchers taken additional steps to determine what exactly the cause of these symptoms were. But the study was not designed to take those additional steps and just left us with these basic data points:

• Twenty patients (72%) had symptoms of an unknown cause; of them six met the criteria for Post Lyme disease syndrome (PLDS).

• Fourteen patients (48%) had the presence of anti-Borrelia burgdorferi antibodies.

• Eight patients (28%) had other well-defined illnesses.

The researchers stated, "None had evidences of persistent Bb infection, but whether current diagnostic criteria are functional in patients with longstanding complaints is controversial."

Looking at all of this, I'm not sure how to even interpret the initial data shared in the abstract... When those 72% are discussed - of which six patients met the criteria for Post Lyme disease syndrome - are those six patients exclusive of the fourteen patients with anti-Borrelia burgdorferi antibodies or are they inclusive?

If it's exclusive, then twenty of the twenty nine patients have evidence of some relationship to a Borrelia burgdorferi infection. If it's inclusive, then it's only fourteen patients who have evidence of this relationship.

But let's assume they are inclusive, and only fourteen had evidence of anti-Borrelia burgdoferi antibodies. Even if only 48% of the patients studied already have a history of exposure to Borrelia burgdorferi and continue to have persisting symptoms, I think that counts as evidence towards a relationship between Lyme disease and persisting symptoms. Either as a trigger or present causative agent. The researchers themselves state that this is at least partly the case, by reporting that, "sequelae from earlier Lyme disease were probable as main explanatory factor in some cases."

That said, a whopping 72% of patients had symptoms of an unknown cause. So what did they have? It is unknown to me if the issue of seronegativity was considered in patients' reports, whether or not patients with positive antibodies were tested for other conditions with cross reactive antibodies, or whether or not patients were studied for evidence of other tick-borne illnesses.

What is known, however, without having access to the full text is that patients had their blood tested and their CSF studied for any abnormalities and the presence of intrathecal antibodies, as shown in Table 1 of the Supporting Information section. And what is found there leaves me questioning the results - at least in part.

For example, the first patient mentioned in the "unknown causes" category is a 43 year old male who is both IgM and IgG positive for Borrelia burgdorferi antibodies, had 78 weeks of IV antibiotic treatment, and yet is not considered by their definition to have Post Lyme disease syndrome because there was "no documented episode of Lyme disease". This is puzzling - if someone has serological evidence of Lyme disease and they continue to have symptoms - wouldn't this indicate by the most conservative view that the patient at least has Post Lyme disease syndrome (regardless of the controversy over persistent infection)?

That there was no earlier documented acute case of Lyme disease seems to be at the heart of determining whether or not a patient is at least meeting the criteria for Post Lyme disease syndrome. According to this study, it seems that if there was no earlier record of an EM rash and evidence of a tick bite by a doctor, then the patient is disqualified from a Post Lyme disease syndrome diagnosis. Why this is the case when there is evidence patients do not always recall a tick bite, a rash is not always present (and this is even more likely in Europe based on some research), and there are documented cases of patients who are asymptomatic in the early stage - only to be profoundly disabled by symptoms later - is unknown. It doesn't make sense to me.

It would have been interesting had the researchers ran epitope and proteomic analysis of patients' CSF and confirmed earlier research completed by Chandra/Alaedini and Schutzer - so far, I see no evidence this was done; I would expect such an analysis would be included in the abstract. I would also like to know what - if any - immunological factors were examined in each of these patients.

After reading this abstract, what one is left with is are more questions about the nature of chronic Lyme disease than answers.

What is a good starting point for more research of this nature?

What is the relationship between persisting symptoms and infection with Borrelia burgdorferi?

The abstract for this study and its supporting information do not answer these questions. All this study does is begin to examine what relationship there is between Borrelia burgdorferi and persisting symptoms in a small group of people.

References:
http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2012.03691.x/abstract
http://clinicaltrials.gov/ct2/show/NCT01151150
http://www.sciencedirect.com/science/article/pii/S1521661611001914
http://www.plosone.org/article/metrics/info%3Adoi%2F10.1371%2Fjournal.pone.0017287

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64 Embers et al Issues Statement On PLoSONE

Embers et al has issued the following author statement on PLoSONE:

Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection

Author statement
Posted by membersla on 02 Mar 2012 at 15:19 GMT

We recently published this article entitled “Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection.” The subject and content of this work may be viewed very divergently, given the controversy surrounding Lyme disease treatment. Specifically, the phenomenon of post-treatment Lyme disease syndrome and its cause (s) have been viewed with much contention.

Our work, which was funded by several grants from the National Institutes of Health, is composed of two major experiments. Experiment 1 entailed a very comprehensive and time-consuming study that indicated the possibility that spirochetes could persist after antibiotic treatment, but only nucleic acid or antigen of these bacteria were detected, leaving open the question of persistence by intact organisms. Experiment 2 was intended to answer that question. The authors elected to publish these 2 studies together, as they mutually enhance the validity and scientific merit of the work.

In our study, we provide evidence demonstrating the post-treatment persistence of the B. burgdorferi spirochete that has been reported previously in a mouse model. We further demonstrate through multiple detection methods that intact spirochetes can survive antibiotic treatment in a nonhuman primate host. It is not our intent to present data in opposition of current antibiotic treatment regimens for humans, but rather to report what we believe to be objective, well-performed experiments on antibiotic efficacy in a nonhuman primate model.

These data are by no means a referendum on long-term antibiotic therapy, nor should they serve to oppose current IDSA guidelines for the treatment of Lyme disease. From the medical standpoint, these results may or may not warrant testing of additional treatments or regimens. This depends heavily on the results of further inquiry as to the duration of persistence, the viability and phenotype of persistent organisms, and the answer to the key question of whether persisters are pathogenic. Current practices could only be challenged by solid proof of better treatment options; these are currently not available.

For several decades, basic scientists and medical doctors have collaborated to understand and improve Lyme disease treatment, diagnosis and prevention. As we proceed with further inquiry into the phenomenon of PTLDS, these collaborations are essential. The continued discussion, commentary and debate will additionally be of benefit when conducted without bias.

Source Link: http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607&root=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607

Bolded emphasis mine.

My comments? I could have predicted that such a statement would be issued. The researchers in question are making a string of inquiries where they must be certain of the outcome and not make a statement about the nature of Lyme disease prematurely - even if the chronic infection model of Lyme disease makes sense to many people and is the experience which a number of patients report having.

It comes as a disappointment to many patients that there is a specific statement here against long term antibiotic treatment, with the explicit statement that the results of this study are not intended to oppose current IDSA treatment guidelines. However, it is also stated that "these results may or may not warrant testing of additional treatments or regimens". The future regarding changes in antibiotic usage is uncertain.

Statements above and within the original study reflect a certain amount of uncertainty.

And in order for this team to avoid becoming cargo cult scientists, they must be willing to look at all the possible causes for persisting symptoms. They must be willing to challenge themselves and question the strength of their suspicions and poke holes at their assumptions. This must be done not only to assure them they are on the right track - but to be prepared to answer questions coming from any critics.

They may repeat their experiments to confirm their findings and conduct another study where tick inoculation is used and not needle inoculation. A study is needed that examines what would happen in an actual case of infection under conditions found in nature - not in a lab. This experiment would not only involve the use of ceftriaxone and doxcycline - but use infected ticks on hosts and involve the complex immune interactions that take place after a tick infection which do not occur the same way as they would after injection with a bacteria-laiden needle.

I'm looking forward to more research from Embers et al. That they close their statement with the phrase, "The continued discussion, commentary and debate will additionally be of benefit when conducted without bias," means a lot to me. It indicates to me that they are seeking the truth - which is something I can get behind. I only hope they find it soon.

Image credit: Morphology of Borrelia burgdorferi by Jeffrey Nelson, Microbe Library. Use under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

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5 Debate About Embers Non-Human Primate Chronic Lyme Disease Study Continues

UPDATE - Feb. 27:  I did receive a response from Dr. Baker. See comments below this post.

There is some heated discussion going on at CALDA's web site regarding Embers et al study, "Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection (2012)".

I wrote about this study last month and commented on some of the findings and the need for further research and confirmation of the findings in this study. (I recommend reviewing that post and comments made on it.)

CALDA's Lorraine Johnson has questioned Dr. Phillip Baker, who was Program Officer for the NIH's Lyme disease research division at the time the Embers study began (then known as Mario Phillip's study; Baker retired from NIH in 2007 and is now in charge at the ALDF), over the 12 year delay of Embers et al publishing the results of this study.

Dr. Baker himself decided to respond to Lorraine's questions and respond to a number of the comments and questions patients and advocates shared on CALDA's Lyme Policy Wonk blog.

Interestingly, a number of people have discussed this study on Lymenet Europe - with one member, Henry, questioning the use of ceftiofur when Embers study was supposed to emulate Klempner's chronic Lyme study. This issue happens to be one of of main issues Dr. Baker also raises on the Wonk blog about the Embers study. (Warning: There are seven pages of spirited discussion on this topic at LNE thus far - some of which may raise blood pressure in readers.)

To follow the discussion and see an example of different points of view over the issue of chronic Lyme disease, read here: http://lymedisease.org/news/lymepolicywonk/lymepolicywonk-was-this-important-lyme-study-hidden-for-12-years.html

In the meantime, I have submitted my own questions and comments to CALDA's web site for Dr. Baker. As of this writing, my post has just cleared moderation and I await a response from Dr. Baker.

I want some answers. Not just about oversight for how the study was designed but about the lack of treatment studies for chronic Lyme disease patients.

Even if your position is that chronic Lyme disease is not caused by a persisting Borrelia infection, there is no reason why more research cannot be completed to provide evidence that this is or is not the case in some circumstances. And even if your position is that chronic Lyme disease's persisting symptoms may be caused by other factors, there is no reason why more treatment research cannot be completed to provide evidence either for or against these factors playing a role...

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Dr. Baker,

First of all, I want to thank you for being here and presenting your view in the presence of Lyme disease patients who have different points of view than your own and who are at a minimum questioning your opinion about Lyme disease and at a maximum - quite angry.

This isn't an easy thing to do. I recognize that. But this is a necessary thing to do, and I wish that more dialog occurred between people with differing views even at the risk of it becoming contentious. It is often the only way opinions get aired and heard and questions get answered - even if we don't like the answers we hear.

I have a few questions for you, and hope I did not miss the boat on getting a response from you at this late hour:

1) Just so the storyline is clear: Who determined that ceftiofur should have been used in Embers et al study on NHP and is this decision something that NIH would have had to give approval - or is this a decision that would have been made at the individual level of the PI/researcher and not require any approval from the NIH? Would any independent governing scientific board outside the NIH been expected to approve of the study design including methods and materials? It seems that in order to emulate the Klempner study, the antibiotic chosen should either be the same as used in the original study or have, as you've stated, PK and PD that are pretty much indistinguishable from ceftriaxone.

2) In your opinion - and in the opinion of others at the ALDF - would you have to see studies separately completed on ceftiofur that provide you with evidence that its PK and PD in NHP are functionally equivalent to the use of ceftriaxone in humans? If these studies are conducted and they are found to be equivalent, then would you say that the results of the Embers et al study are valid? (Even if - according to your position - they don't yet prove a persistent infection/persister cells are the cause of patients' symptoms.)

3) The central point on which a lot of this debate hinges is whether or not spirochetes which remain after antibiotic treatment are viable and infectious. I've never gotten the impression that the majority of researchers out there have debated the existence of spirochetes after abx treatment - the impression I've had is that they either didn't think they were the cause of persisting symptoms in patients or did not know one way or the other if they were the case of persisting symptoms.

Parallel to demonstrated survival of some spirochetes after abx treatment, some research has indicated that a combination of Borrelial strain, host genetics, immune system response, and in some cases, molecular mimicry - may be causative factors for persisting symptoms. I myself think that based on evidence I've read to date, both persisting spirochetes and immune system changes can lead to persisting symptoms. I am particularly intrigued by HLA-DRs and variable immune response in this regard (see "HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens" by Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.).

My questions are:

When is the NIH-NIAID going to conduct more studies aimed towards this end? And also, if you and others are convinced that chronic Lyme disease patients are not suffering from persisting infections - why hasn't more treatment research been conducted that supports your point of view of what is or what are the causative factors for such symptoms?

Why are patients, advocates, and Lyme disease advocacy organizations having to donate money to Dr. Karen Newell Rogers and Viral Genetics to find alternative treatments to long-term antibiotics - why isn't the NIH-NIAID pursuing these alternative approaches now, if the argument is that long term antibiotics do not work and you consider them unsafe (Which in my opinion debatable in my eyes - I have personally benefited from more than the guidelines recommend - and I do not think the use for or against more abx is applicable to everyone because this is a heterogenous patient population. The patients need to be characterized into subgroups first rather than boxed into meeting CDC specific requirements before designing new trials.)?

I have been offended with the letter to the Lancet about Lyme disease patients and advocates supporting pseudoscience when so many of us have wanted to fund more research and get answers. When a number of our friends and families have donated their money to research even when they have already paid so much for treatment.

Some of the answers are already there. If more than one hypothesis is solid enough for testing, I'm for it. Test different combinations of antibiotics. Create drugs which have the anti-inflammatory properties of these antibiotics and use them as a control against combinations of antibiotics. Use higher doses of orals, if the fear of line sepsis freaks you out (it does me, and I have not had a PICC line by choice). Try testing thymus peptides and altering the distribution of B cells to see if that helps patients.

What I see as an observer is that Lyme disease treatment research has been shut down unless it's for acute Lyme disease. We need more late stage untreated Lyme disease research, and I'm with Fallon on this one - more specific neuroborreliosis research. His suggestions for those trials seem worthwhile.

But for God's sake, something has to be done. Some people are seriously impaired. I am doing somewhat better now and have my mind back to a large degree and don't need a wheelchair. But I am not yet well enough to work due to pain and fatigue with normal amounts of exertion. Something is broken there.

---

Dr. Baker's response to me:

Hi Campother,

Even though I feel that some have their minds made up and will not believe anything that I have to say, I will try to answer your questions:

1. Dr. Philipp received a small grant (AI042352) to conduct an experiment in NHPs to replicate the Klempner clinical trial, except of course for the manner in which the NHPs were infected. Because the grant was a small one (about $250K as I recall), Dr. Klempner was able — with support from the drug company– to provide him with the ceftriaxone and doxycycline to be used; these antibiotics were from the same lots used in the human study. Fair enough? That made working on a small grant a bit easier. 

Since NHPs are rather expensive to use and maintain, not too many could be used in the Philipp study because of limited funding. Furthermore, NHPs were in short supply at that time because of increase competition for use in studies on AIDS. The grant was funded for a 4 year period of time, during which time Dr. Philipp reported to me that he was having technical problems, especially with the strain of Borrelia that he had been using in past experiments; it appeared to have “lost its punch” and was no longer eliciting an infection of the same magnitude and character as noted in previous studies. This meant that he would have to re-drive the strain and test it in other NHPs to confirm that it was suitable for use in the definitive studies planned for the grant; that of course would take a great deal of time — and additional NHPs–to do. 

Although situations like this are unfortunate, they do happen and are part and parcel of the realities of doing scientific research — if you want to do it right. 

So, as far as Dr. Philipp’s original grant is concerned, it expired — after the 4 year period– with no data that he felt was was ready and complete for publication at that time. Obviously he continued with his NHP studies and apparently received funding from other sources; note that research Resources grants like RR00164 are designed for the purchase materials, equipment, and supplies, in this case, more NHPs I assume. But, I was “out of the picture” at that point — as far as Dr. Philipp’s research on NHPs was concerned. Keep in mind that as Program Officer, I was not the czar of NIH’s entire research program on Lyme disease, even though so people have the mistaken notion that I had such “power”.

So, you ask who made the decision to use ceftiofur instead of ceftriaxone? I honestly don’t know. 

You will have to ask Dr. Philipp, whose e-mail address is provided in the Embers paper. During the time that Dr. Philipp was doing his work under AI042352, it was being done in accordance with the terms of that grant indicated above. Whatever else he did — or may have done– must have been accomplished afterwards and with other support that did not involve me or NIAID. I must say that I find it strange that the term ceftriaxone is used throughout the Embers et al. paper, and it is only in the first paragraph on page 9 that it is first mentioned that ceftiofur was actually used. I find that very strange indeed.

As stated before and in other postings on this site, I have two major — and legitimate– concerns with the work reported by Embers et al. . First, since so little is known about the PK, PD, and MIC of ceftriofur, was the treatment adequate to eliminate the massive infection induced by needle inoculation? Since the author did not provide such assurances, that is a major and significant unknown. Second, if the therapy was adequate, there is no evidence to indicate that the “persistors” are able to infect other animals and produce disease. They might just be sitting there, for all we know, doing nothing harmful to the host. In view of these considerations, the PCR, RT-PCR, and xenodiagnosis data are not informative. In fact, there are no real differences between the antibiotic treated and sham-treated groups in terms of the objective signs of infection (pathology) noted ; that makes me wonder if the therapeutic regimen was truly effective. So, if I were reviewing this paper for publication in a journal, I would have to reject it publication for these and other deficiencies that I will not elaborate on at this time.

2. Since ceftiofur and cetriaxone differ significantly in chemical structure, I would not be at all surprised if they had different PD/PK properties; those who do drug design research find that the addition of a single chloride atom is enough to alter the properties of some drugs. What is certain is that ceftiofur is not approved for use in humans and there is no published evidence on its efficacy for treating borreliosis in animal models. Obviously, the use of ceftiofur is a big unknown. My best advice, if someone wanted to replicate the Klempner studies in an animal model would be to use ceftriaxone and doxycycline in the same manner that he did and not introduce another variable like ceftiofur– unless you plan to get the FDA to approve the use of ceftiofur in human studies. That may take a long time to do….

3. Since I have retired from the NIH, I don’t know what their plans are for future research on Lyme disease. But, I can tell you that about 90% of the research that NIH supports is driven by proposals submitted as investigator initiated grant applications — the RO1 grants. 

So, if anyone has any good ideas, they are always welcome to submit a grant application, although competition for grants is very keen and only about 25% of all applications submitted are funded. One has to be persistent as most of my colleagues are to make it in science. 

Although I am not opposed to conducting another clinical trial, the odds for such a proposal getting funded are rather slim, especially since NIH has already supported 4 trials indicating that extended antibiotic therapy is not beneficial. 

Obviously, I would like to see more work done on whether the “persistors” Bockenstedt and Barthold noted in mice are infective and can cause disease, as well as whether they can stimulate a local inflammatory response. But, I think we would be making a big mistake by not considering other possibilities as I’ve mentioned in a recent article (http://www.fasebj.org/content/26/1/11.long). 

There are MANY people who believe that they have “chronic Lyme disease” with no evidence that they ever had Lyme disease in the first place. Some have been misdiagnosed and are being subjected to all sort of unproven therapy. Also, there are individuals who go from one doctor to another seeking a “cure” and who often are victims of “quack” remedies. 

One reason we had so much difficulty enrolling patients into the Klempner study was that only about 5-8% of those who presented themselves for enrollment had unequivocal evidence in their medical record of having been diagnosed correctly for Lyme disease in the first place. Obviously, one can not have a chronic infection without first having an active and correctly diagnosed infection in the first place. That was made a criterion for enrollment to ensure that we would have a cohort of patients with a reasonably high — though still not absolutely certain– probability of having a persistent infection — if one were present. I assure you, and you can ask Brian Fallon and Lauren Krupp, such people are NOT easy to find.

But, I have said enough. The biggest obstacle to making any progress is the lack of trust and the tendency to condemn anyone in the scientific community who disagrees with the unproven concept of others. Some simply have no understanding of evidence-based research and how it works, let alone things like the placebo effect. There is just too much misinformation being spread on the internet — and too many people gobbling it up as though it were fact. It’s an ideal environment for all the “quacks” to thrive — and they surely do. And that is what disturbs me the most………

---

So, there you have it - that's his response, and while I posted a response to the Wonk blog, because my response was too lengthy it has not been posted there. So I posted it to comments below, after an explanation of why my response was not posted there.

The moderator emailed me personally and said that I could post another 150 word comment of my choosing, but I have declined for now because I don't think what I can say in response to Dr. Baker is adequately summed up in 150 words.

There was a second comment with other content which I submitted that I later decided needed a serious rewrite before posting - I won't be posting that here now and am okay with the moderators not publishing it (good job, mods - thanks).

I just want to take a moment here to acknowledge those who left intelligent and insightful questions and comments on the Wonk blog - even when addressing someone with whom they vehemently disagree. I would like to see more dialog such as this, but even more so I would like to see more thorough education and outreach going on which deconstructs all the hypotheses behind why chronic Lyme disease patients have persisting symptoms and what research is required to resolve the debate over cause.

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0 Article: The Mouse Trap: How One Rodent Rules The Lab

Slate recently posted a three part series on the use of mice in biomedical research and how that use has helped as well as hindered drug development and scientific understanding of human illness.

This three part series kicks off with "The Mouse Trap: the dangers of using one lab animal to study every disease", which examines the rise in the use of the murine (mouse) model  to test new pharmaceuticals and get a better understanding of human processes in illness. We also learn that this model - useful as it has been - has its drawbacks.

 Mark Mattson, neuroscientist, finds that murine studies may not accurately represent what happens between the study and control group when the control group is often overfed, sedentary, and develops cancer, renal problems, and diabetes - unlike a wild mouse living in its normal habitat. It was later discovered that medication which worked in chubby rodents did not go on to work in rodents with a normal weight and activity level.

Furthermore, in clinical trials on humans later on, the difference between plump mice and a diverse group of humans was too great. A drug which worked in the rodents did not work in humans at all.

Cheap, efficient, and mass produced, these mice are raised in germ-free barrier rooms and sometimes pumped with antibiotics. The ease in which they can be raised, bred, and genetically modified to single out specific processes similar to those in the human body to study has made mice very popular for researchers. While they can closely model many processes in the human body, are they a close enough match for modeling and testing everything?

Mattson argues they are not, and that science needs to wake up and take a closer look at how heavily mice have been used to make decisions that affect human medicine. He's not the only one, either - Clif Barry, the nation's leading expert on tuberculosis, thinks the murine model has shortcomings too. This is no clearer than in work in his own field: The latent form of TB that humans get is not one which can be found in mice. Mice do not experience a latent stage of TB - they only get progressively weaker, age, and die.

This particular passage from the article gave me a moment to pause and reflect:

"[...] for some patients a latent case of tuberculosis can suddenly become active. The granulomas rupture and propagate, spilling thousands of organisms into the lungs, where they can be aerosolized, coughed up, and passed on to a new host. Left untreated, the infection migrates into the bloodstream and other organs; widespread inflammation leads to burst arteries or a ruptured esophagus; and in about half of all cases, the patient dies.

The layered granuloma is the defining feature of human tuberculosis: The place where the host fights the infection (successfully or not), and the necessary site of action for any drug. To cure the disease, a treatment must be able to penetrate each ball of cells, whatever its type or composition; every last bacterium must be destroyed. "It's the structure of those granulomas that makes it so difficult to treat TB," says Barry. And they simply don't exist in mice.

If you infect a mouse with TB—if you spritz a puff of infected air into its nostrils through a trumpet, as so many labs do around the world—the animal's lungs quickly fill up with bacteria and immune cells, like a nasty case of pneumonia. There are no discrete balls of tissue, no well-defined granulomas sheathed in fibrin, no array of structures that harbor the bugs at various stages of development. The mice have no special, latent form of TB, either, and no way to pass on the disease. They simply die, after a year or two, of a slow and progressive decline.

That's why we've made so little progress using mice to generate new drugs and treatments, Barry tells me."

The article continues to outline the history behind why mice have become the dominant research model to use to determine whether or not a drug or treatment plan will be tried in clinical trials on people, and also discusses the setbacks generated by this decision. In the end, the verdict is that using mice has distinct limitations and a number of studies may be invalidated and useless because of it.

It does get me to wondering, of course, as to how useful the murine model is for studying Borrelia burgdorferi. Perhaps in some ways it is useful, but in others it is less so: Dr. Stephen Barthold has said mice are a poor model for neuroborreliosis.

And this does raise the question of which details are important in a study that the layperson will miss when reading it. The average person will read about the study design, and perhaps some discussion and the conclusion - but will one question the decision to use one research animal model over another? What about primers? What about media? What about any number of small details that once changed could result in a different outcome?

Read the full Slate article, and continue with the next two articles in the series. It is a fascinating look into the world of biomedical research, tradition, and profit.

Reference: http://www.slate.com/articles/health_and_science/the_mouse_trap/2011/11/lab_mice_are_they_limiting_our_understanding_of_human_disease_.html

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0 Identification of membrane associated drug targets in Borrelia burgdorferi ZS7- subtractive genomics approach.

Identification of membrane associated drug targets in Borrelia burgdorferi ZS7- subtractive genomics approach. Shivkumar Madagi,Vijayakumari Mali Patil, Saremy Sadegh,Abhishek Kumar Singh, Bhavana Garwal, Atreyi Banerjee, Usha Talambedu,and Biplab Bhattacharjee. Bioinformation. 2011; 6(9): 356–359.

Abstract

Lyme disease is an infectious disease caused by a spirochete Borrelia burgdorferi ZS7. This spirochete is most often spread by ticks. Single antibiotic therapy is sufficient for containment of the early stage progression of the disease but combinational therapy is more preferred in later stages. Research is in progress for the development of drugs against the pathogen, but till date no vaccines have been developed to effect the late stage infections.

There is a rapid rise in the cases of antibiotic-resistant population which is more than 10% of the total infected individuals. In such condition vaccine becomes the sole alternative for prevention. Therefore effective treatment includes antibiotic combination and combination of antigenic surfaces (for vaccine preparation). Thus, a comprehensive list of drug targets unique to the microorganisms is often necessary.

Availability of Borrelia burgdorferi ZS7 proteome has enabled insilico analysis of protein sequences for the identification of drug targets and vaccine targets. In this study, 272 essential proteins were identified out of which 42 proteins were unique to the microorganism.

The study identified 15 membrane localized drug targets. Amongst these 15, molecular modeling and structure validation of the five membrane localized drug target proteins could only be achieved because of the low sequence identity of the remaining proteins with RCSB structures. These 3D structures can be further characterized by invitro and invivo studies for the development of novel vaccine epitopes and novel antibiotic therapy against Borrelia burgdorferi.

Free Full Text Here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143400

Comments:

I noticed that the authors stated that combination antibiotic treatment is more effective in late stage Lyme disease. What research have they read, what experience do they have which indicates this, and which combination of antibiotics works?

"There is a rapid rise in the cases of antibiotic-resistant population which is more than 10% of the total infected individuals." Does this mean that antibiotics do not work in these patients, and the infection remains - or does it mean something else, in terms of the authors' view? It's not clear to me what they think of this population.

"till date no vaccines have been developed to effect the late stage infections." - I'm wondering if something got lost in translation, because this phrase doesn't make sense. I'm guessing it means vaccines are thought to prevent infection and by extension, late stage infection? I can't see how a vaccine can affect late stage infection.

I welcome the development of new drugs for treating Lyme disease which are disease-specific and non-toxic, and hopefully come with fewer side effects than the choices available now. What will these antibiotics and/or drugs of the future look like? How will they work? How will patients feel when they take them?

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1 Immune + Infection = HLA-DR alleles determine responsiveness to Borrelia burgdoferi

Recently I've been reviewing the relationship between specific genetic haplotypes and alleles and the development of chronic Lyme arthritis. One speculation that I had made early on was that I suspected chronic and persisting symptoms were the result of both immune dysregulation and persisting infection - and here is one paper which points out this may be the case...

HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens
Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.

Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828865

The authors of this particular paper wrote up their own informative article, Sometimes It's All In Your Genes with descriptions of their project for the layperson. I highly recommend reading it, as it is an educational and easily readable description of their research in greater detail from the perspective of the researchers themselves.

In the above study, researchers experimented with mice who have the genetic profiles of HLA-DR4 (which is related to developing arthritis) and HLA-DR11 (which is predicted to clear spirochetes quickly).They infected both groups of mice with Borrelia burgdorferi and monitored their ability to clear spirochetes and develop signs of arthritis.

According to the researchers, mice with HLA-DR4 alleles produced lots of interferon gamma and very few antibodies to the spirochete - whereas those with HLA-DR11 alleles produced lots of antibodies but no interferon gamma.

To translate:

Interferon gamma = Produces LOTS of inflammation, which hurts and sucks.
Very few antibodies = Nothing much to fight off the infection.
Lots of antibodies + No Interferon gamma = Fight off infection while having little or no inflammation.

When you look at the paper itself, this is of particular note:

"We found that DR11 tg mice mount a vigorous Ab response, but are defective in IFN-γ production. In addition, Bb-infected DR11 tg mice had decreased spirochete burden compared to DR4 tg mice, measured by qPCR of Bb DNA. This is in contrast to DR4 tg mice, which produce an inflammatory response characterized by high level of IFN-γ production, in accordance with our published results (10). Furthermore, the Ab response to Bb-antigens was significantly lower than that of DR11 tg mice, which is consistent with the higher spirochete burden observed in DR4 tg mice after Bb-infection. Thus, our data provide a possible explanation for the differential regulation of the immune response in DR4+ and DR11+ patients upon Bb-infection; namely, HLA-DR4 would predispose individuals to chronic Lyme arthritis by generating an inflammatory milieu to Bb-infection, while HLA-DR11 would exert a protective role through the production of anti-spirochetal Abs."

So, to review, in this study:

HLA-DR4 mice have a significantly lower antibody response to Bb antigens compared to HLA-DR11 mice.

HLA-DR4 mice have a significantly higher inflammatory response (measured as Interferon gamma or IFN-γ ). (It sounds as if HLA-DR11 has no real inflammatory response.)

HLA-DR4 mice have a significantly higher spirochetal load compared to HLA-DR11 mice.

If you look at figure 5b & c (if I'm to read the caption properly based on the full text) the amount  of spirochetal DNA present in an ear punch sample was twice as high in the HLA-DR4 mice compared to the HLA-DR11 mice, and the amount of spirochetal DNA present in the joints appears to be about 6 times higher in HLA-DR4 mice compared to the HLA-DR11 mice.

That's a huge difference.

To add to this, the study also immunized two groups of mice with these alleles with rOspA and found out that:

HLA-DR4 mice mount a poor response to rOspA.

HLA-DR11 mice mount a strong antibody response to rOspA. They have a good humoral response.

---

So upon learning this, of course there are more questions:

1. How does this study apply to humans with Lyme arthritis?
   
2. How does this study apply to humans with post-treatment chronic Lyme disease?
   
3. How does this data relate to findings in the recent Alaedini paper about those with post-treatment chronic Lyme disease having had infections for a long time (and Alaedini's speculations about different antibody responses and a possible need for more aggressive treatment)?
   
4. How does this data relate to Steere's study suggesting an additional month of antibiotic treatment is needed for some patients with Lyme arthritis?
   
   (Re:"Patients with Lyme arthritis were treated with oral antibiotics for one or two months, and in those for whom the arthritis did not resolve, IV antibiotics were administered for an additional month. If they had persistent arthritis despite three months of antibiotics, patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).")
   
5. How does the existence of more virulent and quickly disseminating RST of Bb affect hosts which are HLA-DR4 versus HLA-DR11?
   
6. What kind of mice were studied in this recent study by Barthold et al?
7. Is there a reason found here as to why some people experience relief with longer courses of antibiotics? Is it because they just don't have an immune response needed to clear the infection but antibiotics both help keep infection under control plus act as an anti-inflammatory in the presence of interferon gamma?

So much to think about here, tying these studies together.

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0 Video: Baloney Detection Kit

I found this video narrated by Michael Shermer, a skeptic, which discusses a 10 question baloney detection kit which is similar in nature to Carl Sagan's Baloney Detection Kit.

I recommend it for its straight-forward approach and good questions to ask - and though it is made by the Dawkins foundation, its focus is not about religion but on questioning evidence.

Check it out...

[Video time: 14:40]

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1 Paper: Evaluating Research Quality

This is a brilliant, well-written publication, Evaluating Research Quality, on how to assess the quality of research you are reading - written by Todd Litman at the Victoria Transport Policy Institute - which is "an independent research organization dedicated to developing innovative and practical solutions to transportation problems".

Read Evaluating Research Quality Here: http://www.vtpi.org/resqual.pdf

Todd provides a number of examples of what makes good, well-informed research and what is biased, ill-informed research, drawing from examples in the transit sector but also general examples such as the source of statements such as "Eskimos (Inuit) have 23 words they use to describe snow" and ideas such as "AIDs doesn't kill people, antiviral medication kills people".

The entire document is well worth a look from start to finish, and the "Sixty Four Methodological Potholes" table is an interesting and extensive read. It's more detailed than Carl Sagan's Baloney Detection Kit and highlights some of the same illogical fallacies and bias some have presented in their publications and arguments.

This specific portion could be applied (and I should probably more stringently apply these pointers to papers reviewed here) to Lyme disease research and all research in general, so I want to share it. Credit goes to Todd Litman and the Victoria Transport Policy Institute, who allow republication with credit. (Thanks, guys.)

Research Document Evaluation Guidelines

The guidelines below are intended to help evaluate the quality of research reports and articles.

Desirable Practices

1. Attempts to fairly present all perspectives.
2. Provides context information suitable for the intended audience. This can be done with a
   literature review that summarizes current knowledge, or by referencing relevant
   documents or websites that offer a comprehensive and balanced overview.
3. Carefully defines research questions and their links to broader issues.
4. Provides data and analysis in a format that can be accessed and replicated by others.
   Quantitative data should be presented in tables and graphs, and available in database or
   spreadsheet form on request.
5. Discusses critical assumptions made in the analysis, such as why a particular data set or
   analysis method is used or rejected. Indicates how results change with different data and
   analysis.Identifies contrary findings.
6. Presents results in ways that highlight critical findings. Graphs and examples are
   particularly helpful for this.
7. Discusses the logical links between research results, conclusions and implications.
   Discusses alternative interpretations, including those with which the researcher disagrees.
8. Describes analysis limitations and cautions. Does not exaggerate implications.
9. Is respectful to people with other perspectives.
10. Provides adequate references.
11. Indicates funding sources, particularly any that may benefit from research results.

Undesirable Practices

1. Issues are defined in ideological terms. “Straw men” reflecting exaggerated or extreme perspectives are use to characterize a debate.
2. Research questions are designed to reach a particular conclusion.
3. Alternative perspectives or contrary findings are ignored or suppressed.
4. Data and analysis methods are biased.
5. Conclusions are based on faulty logic.
6. Limitations of analysis are ignored and the implications of results are exaggerated.
7. Key data and analysis details are unavailable for review by others.
8. Researchers are unqualified and unfamiliar with specialized issues.
9. People with differing perspectives are insulted and ridiculed
10. Citations are primarily from special interest groups or or popular media, rather than from peer reviewed professional and academic organizations.

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