Friday, November 30, 2012

0 Placeholder: ILADS 2012 Conference Remarks






Coming soon... ILADS 2012 Conference Remarks - watch this space.







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0 Late November Newsletter From Camp Other

There are a few announcements I'd like to make today...

For those of you who are here for the first time, via Twitter: Welcome to Camp Other blog. I'm glad to see you here, and I look forward to having interesting discussions with you both here and on Twitter.

Whether you are new to this blog or a returning visitor, the following announcements may help you make sense of what's been happening here at Camp Other blog:

An Effort to Change Writing Style and Reporting

Joining Twitter is a recent move I made in the past couple of weeks in order to pick up more great writing on science and links to posts from science bloggers.

In some ways, this is great because I'm learning more, and I recommend following those I follow because there are a lot of interesting articles out there. But in other ways, this is a humbling experience because there are so many good writers out there - and once I've read them, I can't help but notice there is room for improvement here.

I'm not a professional blogger and do what I do for my own education and share it with others. I never attempted to make this blog a profitable enterprise because I felt that the information was something everyone should have and I wanted to remain neutral by not being funded by anyone who could be perceived as having editorial influence over my posts. This is how it has been - and this is how I want this site to continue - even if someday I manage to become a professional writer in the future.

Open source or not, after reading more science blogs and articles, I can only see that learning from those already in the trenches longer than I have been will teach me how to be a better blogger for everyone.

One thing I am already noticing, unfortunately, is that blogs which are more accessible than mine in some way - those which reach a wider audience, or those which are high volume and have short,  focused posts - are blogs which are going to be difficult for me to emulate.

Reason being: I am suffering from a medical condition which affects my cognitive abilities and energy. My ability to either stay focused on one topic or publish a brief post is challenged due to having chronic fatigue and trouble focusing.

Ironically, having more fatigue doesn't translate into shorter posts - it comes coupled with altered executive function in my brain - so I can ramble on and write a long post yet have trouble getting to the point.

I'd like to make an effort to change this, but where to begin? I could use some advice as to how to overcome these stumbling blocks and make my blog not only more easily readable for a wider audience but also optimize and work with the cognitive abilities I do have.

REMOVED: The Poll On What Causes Persisting Symptoms of Lyme Disease

For almost a year, a blogspot poll widget was on the upper lefthand corner of this blog. It asked readers to select among a number of choices as to the cause for persisting symptoms in patients after initial treatment of Lyme disease.

In recent weeks I have been monitoring the output of this widget and decided in all fairness it needed to be removed because votes were not being recorded and displayed accurately: One week I would see a score of over 110 votes, and the following week it would dip down to 93 - only to waver between 97 and 92 in the following weeks.

Any poll should be gaining and not losing the total number of votes. So it got voted off the Camp Other island, and I won't be using that widget again. Other online sources reported similar issues with this widget as well, and had I known in advance it was a problem, I would have used a different poll widget.

Despite this setback, know that each choice and the most recent results will be discussed in a future post.

A sneak preview: A little over 90% of readers who responded to the poll thought that Lyme disease can be a chronic and persisting infection after initial treatment - while a little over 30% thought persisting symptoms that occur after initial treatment are caused by an autoimmune condition.

The Challenge Of Being Both A Patient And Researcher: Bias

I placed a request on Twitter earlier today asking followers for any information on scientists who study the disease they themselves have - and in particular, blog about it.

I'm hoping to ask them a few questions about how they handle the issue of bias, and how they sort out other research they read about their own condition in order to know which leads to follow, which leads are cold, and which leads are questionable.

One of the walls I find myself banging against as I continue to write this blog is my concern over the issue of bias: Can a patient research their own disease and its causes and treatment without bias, or is there always going to be a certain amount of bias in what one reads and writes about because one is a patient?

Not sure I can sort out all the issues around this, but I wanted to bring up the question because I think it is an important one. I'd like to explore this more.

Sick, Symptomatic, And Struggling

I mention it only in passing because I am still not posting as frequently as I hoped:

I'm not doing so well lately. I suspect the symptoms I'm having are due to a new condition and I am in the middle of getting referrals to specialists to help sort it all out. In the meantime, hopefully I can find a way to continue to do research and blog more regularly.

And there is a certain level of frustration I'm experiencing here which is difficult to put into words, but it basically boils down to, "I'm sick and tired of being sick and tired, and sick of being poked, prodded, biopsied, scanned, bled, x-rayed, ultra-sounded, and analyzed in general."

I am not a number... but I have felt like one. (I'd rather say, "I am not a number, I'm a free man" - but I'm not sure how many of you reading along would catch that ref.)

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2 A Pocket Review of Dr. Steere's NEJM Reinfection Editorial

I finally had the opportunity to sit down and read Dr. Steere's editorial which accompanied Nadelman et al's study, "Differentiation of Reinfection from Relapse in Recurrent Lyme Disease".

Before I comment on the editorial, I want to acknowledge the research which was accomplished in the study as it deserves more attention.

I think it was an interesting study on two counts:

One, it showed that in a group of 17 patients, it was highly unlikely that a patient would get reinfected with the same genotype of Borrelia burgdorferi compared to one with which they'd previously been infected. Does this suggest that patients have some form of immunity to specific genotypes - or is this a reflection of random chance of infection with specific genotypes?

Two, it provided evidence in two patients that a person can be infected with one genotype of Borrelia burgdorferi in skin - while an entirely different genotype can be found in the blood. The significance of this has yet to be determined, but it does raise some interesting questions about the nature of Borrelia burgdorferi infection. How often are patients coinfected with different types of Borrelia burgdorferi? Are these genotypes competitive in any way? Can one genotype affect a patient more profoundly than the other? If there is a delay in treatment, can one genotype be more effectively treated than another?

The findings from this study inspire curiosity and more questions about the nature of Lyme disease.

Thoughts on the editorial, "Reinfection versus Relaspe in Lyme Disease"

Now that I have acknowledged two interesting findings from the Nadelman reinfection study, I have to say that unlike the connections made by Dr. Steere, I do not see the relationship between data presented in this study and patients who have been infected with Lyme disease and continue to have persisting symptoms after initial treatment.

Any good study and its findings stand on their own and an editorial on them by the authors themselves is usually unnecessary. The work should speak for itself, and I think this study does well to demonstrate a relationship between the presence of new genotypes and reinfection in a small group of patients who were bitten by ticks in the same geographic location.

If there is an editorial accompanying research, it should in some way enhance or broaden our understanding and appreciation of the findings - and by extension, lead our curiosity to new horizons.

Unfortunately, Dr. Steere's editorial is not additive in nature. It does not add nuance to or a greater appreciation of the reinfection study - nor does it address the kind of questions raised above which directly apply to his study. Instead, his editorial seems to stretch the findings' significance in order to provoke discussion on chronic Lyme disease based on claims that a small percentage of patients' erythema migrans rashes have been thought to indicate a relapsing infection.

References
Robert B. Nadelman, M.D., Klára Hanincová, Ph.D., Priyanka Mukherjee, B.S., Dionysios Liveris, Ph.D., John Nowakowski, M.D., Donna McKenna, A.N.P., Dustin Brisson, Ph.D., Denise Cooper, B.S., Susan Bittker, M.S., Gul Madison, M.D., Diane Holmgren, R.N., Ira Schwartz, Ph.D., and Gary P. Wormser, M.D. Differentiation of Reinfection from Relapse in Recurrent Lyme Disease. N Engl J Med 2012; 367:1883-1890November 15, 2012DOI: 10.1056/NEJMoa1114362
Allen C. Steere, M.D. Reinfection versus Relapse in Lyme Disease. N Engl J Med 2012; 367:1950-1951November 15, 2012DOI: 10.1056/NEJMe1211361

ALSO, to read my detailed report on the Nadelman reinfection study, see:
http://campother.blogspot.com/2012/11/what-does-reinfection-study-have-to-do.html

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Friday, November 23, 2012

0 Lyme Research Alliance Response To Reporting On Reinfection Study

The executive director of the Lyme Research Alliance responded to the New York Times' article, “New Infection, Not Relapse, Brings Back Lyme Symptoms, Study Says” which refers to the Lyme disease reinfection study recently published in the NEJM:

http://www.nytimes.com/2012/11/23/opinion/lyme-disease-study.html

(original text removed in observance of NYT copyright policy.)

Current Active Research Projects which are listed on LRA's site:
http://www.lymeresearchalliance.org/research_projects.html



For the most part, I agree with Mr. Wild's statement. I only have some questions about this sentence: "This limited study supports the theory that Lyme is effectively treated by one short course of antibiotics, yet numerous scientists vehemently disagree."

I would have phrased it differently and stated it as "This limited study supports the theory that Lyme disease is always effectively treated by one short course of antibiotics, yet numerous scientists vehemently disagree."

There is a body of research which provides evidence that Lyme disease is not always effectively treated with one short course of antibiotics - even the IDSA's 2006 Guidelines state up to 10% of early acute cases of Lyme disease result in treatment failures. Those same guidelines cite studies on late stage Lyme disease cases which are treated according to the guidelines, yet patients are recorded as having relapses and not returning to their former health pre-infection.

In addition to the guidelines, there are case studies, research studies, and individual patient reports of relapsing symptoms after initial treatment.

At the same time, not everyone who contracts Lyme disease goes on to have persisting symptoms after initial treatment. The reason why some patients develop chronic Lyme disease and some do not is not clear. A delay in receiving initial antibiotic treatment appears to play a role - and the genotype of bacteria infecting a given patient and the patient's immune profile may also play a role in development of persisting symptoms. More research is required to understand the cause of chronic Lyme disease.


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Wednesday, November 21, 2012

1 What Does The Reinfection Study Have To Do With Chronic Lyme or Post Lyme Disease?

Last week, a number of media outlets wrote articles referring to a study published in the New England Journal of Medicine (NEJM), "Differentiation of Reinfection from Relapse in Recurrent Lyme Disease".

Since I wanted to see what was actually stated in the study, I acquired a copy of the full text of this publication to see for myself why the authors might have given some journalists the impression that chronic Lyme disease - or even post Lyme disease syndrome - does not exist.

Side note: One important thing to know is that at the time I wrote this entry, I had not read the accompanying editorial by Dr. Steere which was published in NEJM. Given that the current entry was written based only on the study itself and has gotten quite lengthy, I will be writing separately about the editorial in the future.

Summing it up

After reading through the paper, if I had to give a one sentence summary of what this study accomplished, this sentence at the end of it summed it up fairly well:
"These data, in conjunction with available clinical and epidemiologic evidence, show that repeat episodes of erythema migrans in appropriately treated patients were reinfections and not relapses."

If I'm to take it at face value, what this study does is provide evidence that when patients were properly treated early for previous erythema migrans (EM) rashes in the past and they presented with new EM rashes with obvious tick bites - they almost always contained a different kind of Lyme disease than one with which the patients had previously been infected. And with early treatment of patients found with new EM, most of those patients will go on to be fine until they are reinfected again.

Seems to make sense to me.

This is what the study appears to have discovered, so at first glance I had yet to see what the findings in this paper have to do with evidence that chronic Lyme disease does not exist. Nor did I see where this study provides evidence that post Lyme disease syndrome does not exist, either.

However, after digging a little deeper, I found one statement which suggested that data found in this study implied that chronic Lyme disease does not occur:
"[...] some persons have attributed recurrent episodes of erythema migrans to relapses in patients treated with recommended courses of antibiotic therapy; they cited experiments in animals that showed persistence of B. burgdorferi despite antibiotic treatment."
This was about as close as I could get to finding a statement in the study that chronic Lyme disease does not occur, as the majority of the content of the paper focuses on the fact that new erythema migrans are associated with new infections.

But one thing which I have stated before was that when it comes to Lyme disease, the rash is not the disease. The rash is a symptom of early infection. Untreated, it will eventually disappear. It may never recur during the same episode of infection. And in the meantime, depending on the strain one has, host factors, and without proper treatment, the infection will disseminate and spread to areas of the body far removed from where the rash first appeared.

Because the patients in this study were treated either during the first sign of cutaneous infection or very early disseminated infection, they were far more likely to have been successfully treated than patients for which there was a delay in treatment or patients who were improperly treated (say with a shorter duration, or possibly a less effective or an incorrect antibiotic) earlier.

Anyway, I have a few remarks on the paper:

On the significance of EM rashes under other conditions

One of the concerns I mentioned elsewhere after reading online article after article was that journalists had not mentioned how EM rashes were relevant not only as a symptom of early infection but at other points.

To some degree - and to my satisfaction - one paragraph of the study covered other reasons EM rashes would appear outside of the first sign of infection, and mentioned that an EM rash can show up and disappear only to reappear in untreated patients and also inappropriately treated patients.

This is important to note, and I would hope that family and urgent care doctors can use the presence and timing of an EM rash relative to other symptoms to determine when more treatment is required. Dr. Jorge Benach has stated that satellite EM rashes which erupt within weeks to months after the initial EM are a sign of disseminated infection.[1] Dr. Brian Fallon of the Columbia University Lyme and Tickborne Disease Research Center has also made the same observation.[2] Combined with other clinical evidence and symptom presentation, patients with these rashes may require additional oral or intravenous antibiotic treatment.

Patients with new EM rashes have been reinfected.

In addition to the summary statment cited earlier, one should take note of this particular passage in the study:
"Patients were treated with standard courses of antibiotics at each episode of erythema migrans, with subsequent resolution of the skin lesion or lesions."
The key words to keep in mind here are: "erythema migrans" and "appropriately treated patients".

This study is about early acute Lyme disease including early disseminated infection. The patients who were followed during the course of the study were all treated for signs of early acute Lyme disease - not late stage, persisting disease.

Based on this, I suspect the authors want readers to take away from their study is that these 17 patients who have an EM rash and are treated early in their infection have successful resolution of their Lyme disease - and any new EM rashes they have are a sign of a new infection which requires more antibiotics.

In other words: Early treatment is the key to greater success in treating Lyme disease effectively.

The value of finding different OspC RST types in different EMs.

The keystone of the study is the evidence that different OspC RST types are found in each episode of EM when patients are followed over time.

What does OspC RST strain mean? Citing a definition from an earlier paper:
"Two genetically linked typing systems, one based on sequence variation of outer surface protein C (OspC) and the other on ribosomal RNA intergenic spacer type (RST), have been used to classify US B. burgdorferi strains.

OspC typing divides B. burgdorferi strains into 21 genetically distinct types, 16 of which have been identified in the northeastern United States and RST divides B. burgdorferi into three groups.

RST1 corresponds to OspC genotypes A and B; RST2 corresponds to OspC types F, H, K, and N; and RST3 corresponds to the remaining 10 OspC types, including D, E, G, and I.

In the northeastern United States, infection with OspC type A (the most common RST1 strain) or OspC type K (the most common RST2 strain) accounts for approximately 60% of Lyme disease cases; and all of the OspC types within the RST1 and RST2 groups account for approximately 80% of cases. RST3, the least common type, is the most diverse, although infection with OspC type I accounts for approximately half of the RST3 cases.

Because RST typing of isolates may miss differences within groups and because OspC typing may lead to small groups, more information for clinical correlations can be obtained from the use of both typing systems."[3]
The above description of how OspC RST typing is taken from the paper, "Borrelia burgdorferi RST1 (OspC Type A) Genotype Is Associated with Greater Inflammation and More Severe Lyme Disease".

What is known not only from this paper but from many other papers is that different genotypes of Borrelia burgdorferi exist and may affect the clinical presentation of Lyme disease over time.[4-11]

And as time goes on, new genotypes are also found to spread hematogenously. However, it is important to keep in mind that just because a genotype can disseminate easily does not mean it is going to cause as much inflammation or have a particular tissue tropism.

For example:
"[...] However, when mice were infected by tick bite, as in the natural infection, RST 1 isolates displayed higher densities in blood, but the number of spirochetes in the heart or bladder was similar with either RST 1 or RST 3 strains (14). This suggests that in the natural infection, smaller numbers of RST 3 organisms, which may not be detectable in blood, are still able to spread to the joints and cause infection there. Consistent with this observation, the frequencies of B. burgdorferi genotypes in human patients in the current study were similar in EM skin lesions and in joints. Thus, it seems that all 3 RSTs have a similar predilection for dissemination, but larger numbers of RST 1 organisms are more often detectable in blood."[12 ]
According to research to date, the B. burgdorferi RST1 (OspC type A) genotype - followed by the RST3 (OspC type I) genotype - cause greater inflammation and more severe disease than other genotypes, establishing a link between spirochetal virulence and host inflammation.[ 3]

It gets more complicated from here. Researchers are still learning how these different genotypes and subtypes interact with their hosts and host immunity.

According to research (as is stated above) OspC type A RST1 and OspC type K RST2 account for approximately 60% of Lyme disease cases in the northeastern United States.

Judging from other publications, northeastern US OspC genotypes more or less break down into this list:

- Osp type K RST2 accounts for about 40% of that 60%.
- OspC type A RST1 accounts for 20% of that 60%.
- 20% of northeastern United States genotypes are mostly other RST1 and RST2 types.
- The remaining 20% are a mix of RST3 which is dominated by OspC I RST3.

That these different genotypes exist and have different pathogenicity is a fairly recent discovery and it is only just beginning to be understood.

More is understood about more common OspC types than less common RST3 strains which are highly variable and found less frequently in animal and human hosts. Additional research on these genotypes is needed.

So what kind of OspC RST types did patients have in this study on reinfection? It's a good question to ask, because if patients have genotypes of Borrelia burgdorferi which are more likely to lead to dissemination, then they (potentially) have a greater chance of invading more immune-privileged spots, such as joints, tissues, organs, and the central nervous system.

Based on a review of the overall breakdown of different OspC RST types in this study, they did align somewhat with previous research on northeastern United States genotypes.

OspC K RST2 was the dominant genotype found in skin, followed by a mix of OspC RST3 types then OspC RST1. That OspC RST3 types were more common than OspC RST1 differed from earlier research. Blood samples were somewhat different than those found in skin, with a combination of RST1 and RST3 types collectively outnumbering OspC RST2.

There are some data sets which were not collected during this study which I would have wanted to see. For one thing, Borrelia burgdorferi samples were not taken from synovial fluid or cerebrospinal fluid (CSF) for OspC RST typing. We would also be missing any data from tissue biopsies as these are not routinely done, and are rather invasive for the patient. On the immunological side, the genetic backgrounds of patients with specific HLA-DRs were not revealed.

How this study does (or doesn't) relate to Chronic Lyme disease or post Lyme disease syndrome

Patients with early disseminated infection were said to have had fever, arthralgias, headache, or fatigue which were present during the first episode of EM. The authors expanded on this point over time, demonstrating that in these 17 patients, early disseminated infection and more invasive genotypes (such as ospC A RST1 or ospC I RST3) were handily cured with a prompt course of antibiotics and that any future symptoms would be related to a new infection and not a relapse.

Based on the OspC type data, the only way I can see that this study might be trying to disprove the existence of chronic Lyme disease is the authors' position that the evidence demonstrates that the same virulent strains found during the first episode EM rash that were treated were not present during the second episode in any patient. Therefore, by their deduction, the Borrelia bacteria did not persist in the time between EM rash episodes.

In their opinion, evidence of a relapse would have been shown if the patient's samples demonstrated that the same Borrelia burgdorferi genotype would be present during both episodes of EM.

However, is this the only conclusion one can draw from such a study? I have unanswered questions about it.

Can the genetic background and varying immune system responses affect the course of Lyme disease in host mammals? (I already know the answer is yes here, but what I know is mostly about animal models. Is enough known about this as it relates to people?)

How likely it is that an existing genotype of Borrelia burgdorferi found in tissues and CNS will migrate to the blood and EM rashes during ticks feeding on humans?

In the study, given that in two patients the genotype of Borrelia burgdorferi from one skin sample did not match the genotype of that found in blood during the same episode, is there a possibility that in a handful of cases, antibiotics could successfully treat the EM rash produced by one genotype while not successfully treating a more virulent and invasive genotype if the infection had advanced for some time without treatment - say to more remote tissues such as organs or the CNS?

Could a previous infection with a Borrelia burgdorferi genotype with specific tissue tropism coexist with the onset of an EM rash containing a new genotype?

What happens if a patient has previous infection in which no EM rash was present or seen and it goes untreated - then that patient acquires a new infection with an EM rash on top of the first infection?

I don't know the answer to these questions or how likely these scenarios are, but I suspect the last one I mention above is not entirely uncommon.

Either way, based on the patient background which is supplied in this study we cannot know because patients are reported as being treated successfully during the early stages of infection.

I also don't know how often it occurs that a patient has persisting symptoms after initial treatment for Lyme disease and a new erthyema migrans is never seen during the course of their persisting symptoms.

Given my experience as a patient, I can only make the observation that other patients in my situation seldom report seeing new rashes during the course of their condition. I think researchers should take a close look at the subset of those patients who are most severely ill and are housebound - they are an important subgroup to study because their odds of reinfection are very low.

Related to this, there is one immediate key difference I also see between the patient group studied and chronic Lyme disease patients:

The patient population in this group received a course of antibiotics each time an EM rash presented itself. Because they were treated early, presumably they had a good chance at recovering completely from their infection.

Chronic Lyme disease patients and their doctors alike report that many chronic Lyme disease patients' conditions are discovered late, and symptoms and serology often reflect those of late stage Lyme disease patients - not early acute or early disseminated patients.

It is this difference which makes me wonder about the applicability of such a study to a condition such as chronic Lyme disease or post Lyme disease syndrome.

Patients with late stage Lyme disease are less effectively treated with antibiotics and can be refractory to treatment; studies cited in the 2006 IDSA Lyme disease treatment guidelines indicate that a fair percentage of late stage Lyme disease patients do not fully recover after antibiotic treatment - though the reason why is not entirely clear.[13]

Development of an autoimmune-like condition has been hypothesized by the IDSA and various researchers as being the cause for persisting symptoms after initial infection, while other researchers suspect persisting infection might occur in some patients.

In the end...

The study provides evidence that in 17 patients who are properly treated with antibiotics shortly after EM rashes appear, their infections resolve and they get new infections.

If one supports a model of chronic Lyme disease and thinks that Borrelia burgdorferi can persist in the human host past initial treatment, then this study won't provide evidence either way as to whether or not this is the case:

Part of the definition of chronic Lyme disease hinges on patients having been treated late in infection and/or treated improperly early in infection only to go on to develop later stage Lyme disease in the future.

If one applies this definition, it is important to note that none of the patients in this study had a delay in treatment and proceeded to late stage symptoms before receiving antibiotic treatment. None of the patients were reported as showing signs or symptoms of Lyme disease between episodes of EM rashes; patients experienced only acute Lyme disease which was promptly treated. None of the patients were remarked as being part of the 10% of patients with acute Lyme disease who experience early antibiotic failure, either.[13]

The study participants fit the characterization of the majority of Lyme disease patients who successfully recover from Lyme disease with early treatment - but it does not characterize those patients who do not.

Conversely, if one supports a model of post Lyme disease syndrome, this study won't provide evidence either way as to whether or not this is the case:

None of the patients in this study were reported on followup after a six month interval after any EM rash and subsequent treatment as having developed symptoms indicative of post Lyme disease syndrome. None of the patients were remarked upon as having any particular HLA-DR associated with the development of antibiotic refractory Lyme arthritis - or any potential marker for post Lyme disease syndrome.

If patients have been symptom-free between episodes, this suggests that early treatment aborted the possibility of more serious infection, that patients had a genetic background which made it less likely they would develop antibiotic refractory Lyme arthritis, and/or perhaps early treatment in this small group led to avoidance of post Lyme disease syndrome as well.

Things I Ponder:

  • The good news: If the results of this study can be extrapolated to a larger patient base, early treatment of Lyme disease as soon as one sees a new EM rash is more likely to lead to a positive outcome for the patient.
  • The bad news: This study says nothing about patients who either neither see a tick bite nor get a rash yet begin show other clinical signs of Lyme disease. Doctors have no easy way of diagnosing these patients and current IDSA guidelines do not cover management of such patients.
  • Patients were treated during early to early disseminated infection, when they were most likely to have a positive outcome from antibiotic treatment regardless of the genotype found in their samples.
  • There is no information provided about the health and quality of life of enrolled patients. Do they have any preexisting conditions? Have they ever been diagnosed with any condition with symptoms which overlap with those of Lyme disease? How does one make the distinction between these conditions and any symptoms associated with any stage of Lyme disease outside of an EM rash?
  • The timing, method, and duration of antibiotic treatment for each patient for each episode was not disclosed. Did all patients receive a course of oral doxycycline, or did some with more disseminated infections receive IV Ceftriaxone? This could have an impact on having a positive post-treatment outcome.
  • Regardless of which treatment patients received, how can family and urgent care doctors apply the data from this study to their practice? Hopefully they will see an EM rash and treat patients immediately, but unfortunately this does not always happen in clinical practice as not all EM rashes are properly diagnosed. (e.g. ringworm, eczema, etc.)
  • If infections had advanced past the early stage, I wonder which genotypes would have been found in other sample types had they been taken (synovial, CSF, other tissues). Would they have matched earlier research in previous papers or would they have been different?
  • Over time, is there a change in the kind of genotypes which infect human hosts? Do these genotypes have a "competitive" nature? How much lateral gene transfer occurs?
  • This study applies to the northeastern United States and to infections from Ixodes scapularis ticks. It does not apply to tick bites from Lone Star ticks, which are beginning to outnumber Ixodes scapularis ticks in some areas of the northeast and may carry different infections.
  • The public needs to be reminded that different ticks can carry different infections and look for other symptoms of those which may not be EM rashes.
  • Babesiosis and Rocky Mountain Spotted Fever are two other infection which come to mind where prompt treatment is necessary.
Well, this is what came to mind after reading this study.

Any questions? Comments?

Next up: Reviewing Dr. Steere's accompanying editorial...

Citations:
1) Dr. Jorge Benach. Presenting at SB Southampton Dean's Lecture Series. Video posted Apr. 20, 2010. http://www.youtube.com/watch?v=TR-aY_S8q2E Approximate Timestamp: 40:20. "Multiple EM rash is sign of disseminated Lyme disease and requires IV or parenteral antibiotics."
2) Columbia University Lyme and Tick-borne Diseases Research Center, http://columbia-lyme.org/patients/ld_lyme_symptoms.html Downloaded November 21, 2012.
3) Strle K, Jones KL, Drouin EE, Li X, Steere AC. Borrelia burgdorferi RST1 (OspC Type A) Genotype Is Associated with Greater Inflammation and More Severe Lyme Disease. Am J Pathol. 2011 Jun;178(6):2726-39.
4)Wormser GP, Brisson D, Liveris D, et al. Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. J Infect Dis 2008;198:1358-1364
5) Wormser GP, Liveris D, Nowakowski J, et al. Association of specific subtypes of Borrelia burgdorferi with hematogenous dissemination in early Lyme disease. J Infect Dis 1999;180:720-725
6) Seinost G, Golde WT, Berger BW, et al. Infection with multiple strains of Borrelia burgdorferi sensu stricto in patients with Lyme disease. Arch Dermatol 1999;135:1329-1333
7) Liveris D, Varde S, Iyer R, et al. Genetic diversity of Borrelia burgdorferi in Lyme disease patients as determined by culture versus direct PCR with clinical specimens. J Clin Microbiol 1999;37:565-569
8) Jones KL, Glickstein LJ, Damle N, Sikand VK, McHugh G, Steere AC. Borrelia burgdorferi genetic markers and disseminated disease in patients with early Lyme disease. J Clin Microbiol 2006;44:4407-4413
9) Wang IN, Dykhuizen DE, Qiu W, Dunn JJ, Bosler EM, Luft BJ. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto. Genetics 1999;151:15-30
10) Dykhuizen DE, Brisson D, Sandigursky S, et al. The propensity of different Borrelia burgdorferi sensu stricto genotypes to cause disseminated infections in humans. Am J Trop Med Hyg 2008;78:806-810
11) Wei-Gang Qiu, John F. Bruno, William D. McCaig, Yun Xu, Ian Livey, Martin E. Schriefer, and Benjamin J. Luft. Wide Distribution of a High-Virulence Borrelia burgdorferi Clone in Europe and North America. Emerg Infect Dis. 2008 July; 14(7): 1097–1104.
12) Strle K, Jones KL, Drouin EE, Li X, Steere AC. Analysis of Borrelia burgdorferi Genotypes in Patients with Lyme Arthritis: High Frequency of RST 1 Strains in Antibiotic-Refractory Arthritis. Am J Pathol. 2011 Jun;178(6):2726-39.
13) Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134

Additional Resources:
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Monday, November 19, 2012

0 CO Comments on "The Pseudoscience of Chronic Lyme"

During the weekend, Ed Yong, who writes for Discover magazine's Not Exactly Rocket Science blog, of alerted me on Twitter to Cassandra Willyard's blog post on The Last Word on Nothing blog - "The Pseudoscience of Chronic Lyme". Not wanting to pass up the opportunity to comment on some journalists' bungling of how to interpret the significance of the New England Journal of Medicine (NEJM) published study, Differentiation of Reinfection from Relapse in Recurrent Lyme Disease, I decided to stop by and read what Cassandra and others had to say and leave a few comments.

So far, commenters are asking good questions and pointing out some logical oversights in what we have read, which is constructive.

I don't know that I recommend it for casual reading for a number of chronic Lyme disease patients, though - particularly if you are in a headspace where you are currently very angry about your condition being treated dismissively and can't hold up to reading anything which is skeptical about the existence of chronic Lyme disease. But I will say that if you can handle it, it might be worth it to stop by and periodically read the comments.

So far, I've left two comments on Cassandra's blog in response to her original post and another commenter:

"I’ve been following the issue of chronic Lyme disease closely for a number of reasons, and anecdote aside, think that the situation surrounding the diagnosis and treatment of Lyme disease and other tickborne diseases is more complex than most of the media has led the public to believe.

I hear that Lantos – like Dr. Lawrence Zemel of the Infectious Disease Society of America – has more or less stated that half of those patients who claim they have chronic Lyme disease have no evidence of having prior or active Lyme disease. Lantos stated, “Only 7–31% had active Lyme disease and 5–20% had previous Lyme disease,” he writes. “Among the remainder, 50–88% had no evidence of ever having had Lyme disease. Most of these patients had either an alternative medical diagnosis or a functional somatic syndrome such as chronic fatigue syndrome or fibromyalgia.”

If this is in fact the case, then we are still looking at up to 51% of the patient population in this group as either having had Lyme disease or currently having it – meaning that up to little more than half of patients’ persisting symptoms do correlate with evidence of having Lyme disease.

It is this population of which I am a part of, having had a textbook case of Lyme disease – known tickbite in endemic area, an EM rash, flu-like illness, severe joint pain and swollen lymph nodes – the whole nine yards – only to be followed by years of ongoing symptoms I did not have pre-infection.

So, when someone brings up the pseudoscience of “chronic Lyme disease”, understand that I might get a little testy because it seems almost inevitably, the cases which are highlighted in skeptical discussions are those Lantos states do not have evidence of Lyme disease. Whether that is accurate or not, what about the rest of us? (Side note: chronic fatigue syndrome and fibromyalgia are problematic diagnoses in their own way, too, as they are of unknown etiology.)

I want to know as much as the next person exactly what has led to persisting symptoms. After doing the research on my condition to the extent I have, I’m coming to the conclusion that more research is necessary. I am skeptical about their being “sides” to this debate in the first place and also think science has not come to a full understanding about the process behind why we have persisting symptoms.

Embers et al’s recent study on persistence of Borrelia burgdorferi after antibiotic treatment in Rhesus macaques brings up the question of persistent infection after antibiotic treatment. More research is required on this, and persistence studies such as an NIH-NIAID xenodiagnosis study where patients with chronic Lyme disease are bitten by lab-raised ticks in order to see if they pick up the infection are underway. On the autoimmune angle for finding cause, Bockenstedt recently published a paper showing gfp concentration of Borrelial antigens in tendon* tissue in mice, and the hypothesis is spirochetal antigens cause persisting symptoms long term. See this Research Blogging blog post for more info: http://spirochetesunwound.blogspot.com/2012/11/inflammatory-spirochete-debris-left.html

So one cannot avoid that persisting symptoms after initial infection and treatment or delayed treatment is an issue; the research is there and being conducted on it.

But in the meantime, people are suffering, and voting with their feet: The vast majority of patients in my situation think there is something to the persisting infection hypothesis, and treat with long term antibiotics. A number of them recover and report improvement in symptoms while on treatment.

Yes, it is anecdotal – true. And it doesn’t support the outcomes of some of those small clinical trials which were conducted. But perhaps instead of dismissing them, someone could step in and collect the data on these patients (with their consent, of course) based on how they are currently being treated, what the patient base is and common factors of different subpopulations, and so on – and see if any commonalities float to the top? This could be informative, to study patients who have made the decision to accept this treatment and see how they fare."

And the second comment:

While I have not read the full text of the study yet, I agree that your logic path is one I traveled as well. An EM or “bull’s eye” rash is a key part of the case definition for acute Lyme disease – however, it’s not always present with infection, nor do all EM rashes signal the presence of infection.

Much of the media’s write-up on this study has conflated the existence of reinfection with the nonexistence of a chronic condition connected with Lyme disease – but it has also left out a huge chunk of the story about the significance of EM rashes in Lyme disease infection.

Dr. Jorge Benach of Stonybrook University has stated that if multiple “satellite” rashes show up weeks to months after initial infection, that the bacteria has disseminated. This may mean the patient needs a different course of treatment at this stage, so new rashes in this situation are important to separate from new EMs from a new infection.

Dr. Benjamin Luft has been doing extensive mapping of the genetics of different strains of Borrelia burgdorferi and has discovered some strains create a rash but no infection, some create a rash and infection, and some create no rash and infection. These strains can have varying targets within the body; varying levels of virulence.

And not long ago, Horizon Press published a book, “Borrelia: Molecular Biology, Host Infection, and Pathogenesis”, and it mentions big gaps in patient management around EM rashes: Some people who were screened to be subjects in studies were seropositive for Lyme but have never had ANY symptoms – whereas others went on to develop a case of late stage Lyme disease. (See pp. 501-502)

This is problematic for patients and doctors alike, who may have difficulty diagnosing the cause for the patients’ symptoms with no prior history/evidence of Lyme disease.
(Serology might help – but you have to suspect Lyme disease first.)

(As an aside, you might want to check out this discussion on Lymenet Europe: http://www.lymeneteurope.org/forum/viewtopic.php?f=6&t=3856 – if only because of the references offered.)

So, I am concerned about the emphasis on rashes and think either one has to suspect Lyme disease based on other symptoms and potential exposure to ticks – or we need better testing… Solid direct detection tests would be great, but we don’t have one yet. I’m waiting to see what GMU does with its nanotrapping test development… It’s antigen based; hopefully superior to existing serological tests. But again: First one must suspect Lyme, and if there is no EM rash present, where do you begin?

* That should have been "joint" tissue, not "tendon".

When I wrote these comments for their intended audience, my goal was to focus on what by their standards would currently count as evidence they relied on in order to focus on the relevance of erythema rashes in infection. I avoided discussion of other issues I could have gotten into - such as the accuracy of early serological testing and differences in antibody response during infection - because my focused comment was already long and thought these topics were not as closely related.

One thing that has changed between the time I posted these comments and now: I now have a copy of the full text of the NEJM reinfection paper. So I am in the process of reading it, examining the data, and seeing how the authors correlate their findings with chronic Lyme disease. More later...

Edited to Add: When I talk about being skeptical about there being "sides" to the debate, what I am really meaning to say is that while two sides have developed over time, the only side that really matters is the truth.

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Thursday, November 15, 2012

4 Do Not Conflate Reinfection With Absence Of A Chronic Condition


It's been a busy day for Lyme disease in the media today. And for me, too, as I have been trying to do some education (translation: damage control) regarding the inaccuracies which were reported concerning the findings from small study on Lyme disease that was recently published in the New England Journal of Medicine (summary only; full text behind pay wall).

With a sample size of 17 participants, the study advanced the idea that most patients who have new erythema migrans (also called "bull's eye") rashes have been reinfected and do not have a previous relapsing infection. Bacteria sampled from the new rashes and run through PCR do not match bacteria from old rashes from a previous infection - therefore, patients have been reinfected.

In and of itself, these findings are not problematic. And they make sense, knowing what is known about EM rashes and immune responses to Borrelia burgdorferi. It is only one small study, and I don't see it as earth shattering nor does it tell anyone everything there is to know about Lyme disease.

But what follows is problematic: A number of online news articles stated that this outcome provides evidence that Chronic Lyme Disease and (unwittingly, in some cases either implied or by extension) Post Lyme Disease Syndrome do not exist.

Now, while most Lyme disease patients with persisting symptoms support a chronic infection model, there may be some people who develop an autoimmune condition such as Post Lyme Disease Syndrome due to having had Lyme disease. I simply don't know, and think more research is required on this subject. But either way, the conflation of this small study's findings with the nonexistence of a chronic condition is erroneous.

Even by the IDSA's standards, some interpretations of Dr. Allen Steere's editorial which accompanied the study (briefly blogged about here on the NEJM) seemed to get it wrong. On one hand, Dr. Steere acknowledges persisting symptoms and he states that "infection-induced autoimmunity, retained spirochetal antigens, or both may play a role in this outcome." And on another, a number of journalists seemed to gloss over this statement and not mention it - alongside stating or implying that a new, acute infection is the only reason patients get ongoing or new symptoms.(Um, late stage untreated neuroborreliosis, anyone? Coinfections? These things can happen on occasion...)

This is incorrect, and so I've tried to correct this inaccuracy in reporting by responding to media outlets online. I've spent a good part of today looking online for articles which I could respond to about this issue, and noted that several news outlets and online magazines either do not allow comments on posts related to this topic or require one to post comments using Facebook and other services which not everyone uses. But I posted to as many places as I could, and wrote more or less the following comment in most locations:

"This is one of several articles I have seen which conflates this study on new rashes and new infection with the issue of chronic Lyme disease or persisting post-treatment symptoms - when the two issues are distinctly separate ones.

Even if one does not believe that Lyme disease can be a chronic infection (which in the scientific world it continues to be a matter of debate if a study like Dr. Embers' Persistence of Borrelia Burgdorferi after antibiotic treatment in Rhesus Macaques has been published recently and the NIH-NIAID is funding a xenodiagnosis study to see if human hosts with chronic Lyme disease can pass their infection onto lab-raised ticks - hardly a sign the debate has been resolved), the IDSA itself recognizes that a percentage of patients who were treated for Lyme disease go on to have persisting symptoms for months to even years after initial infection. Their organization thinks it is possibly autoimmune and call it Post-Lyme disease syndrome; there are now proteomics studies that have been done which provide markers for this condition.

Whichever model of persisting symptoms you support, it is incorrect to associate this one study with disproving the existence of either a chronic infection or post-infection autoimmune condition in patients with ongoing disease and disability since contracting Lyme disease.

I think that one also has to be careful about the utility of the EM or bulls' eye rash in proper diagnosis of Lyme disease in general: According to Dr. Jorge Benach of Stonybrook University, if more satellite rashes erupt after the initial rash (usually within weeks to months) the infection has disseminated. Also, not all cases of Lyme disease present with an EM rash, and research by Dr. Benjamin Luft has shown that some strains of Borrelia which disseminate with a rash do not cause disease and some without rashes do cause disease.

One study like this is not enough to set the course for Lyme disease, which is an emerging infectious disease which requires more research."

In other words, as it bears repeating: The rash is not the disease.

I really don't know what else I can say in response to these articles. I've made my point where I can, short of writing letters to the editor.

Other than this, of course, I recommend responding in your own way to these articles online and cite research that has been published or is currently in progress on Chronic Lyme Disease, Post Lyme Disease Syndrome, or both. And if you're a patient, inform people about the science that is out there and let them know you are in the 10-20% of patients who has persisting symptoms after initial infection with Lyme disease. You exist. Your condition is real.

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Friday, November 9, 2012

2 New Lyme Disease Detection Test For All Stages Of Infection

For all those observing today: Happy Carl Sagan Day! For everyone else: Happy New Lyme Test Day! I say this because today a new blood test for the detection of all stages of Lyme disease has been launched.

In a press release, Boulder Diagnostics reported the European market launch of the CE marked SpiroFind in vitro diagnostic test for the detection of active Lyme Borreliosis. The makers of the novel SpiroFind test claim it can detect active Lyme Borreliosis through all stages of disease from early disease to late and persistent manifestation.

The test is based on measuring the cellular immune response to a specific challenge with the Borrelia organism. The effectiveness of the SpiroFind test was confirmed in a clinical study at the Radboud University* Nijmegen Medical Centre, which is submitted for peer-reviewed publication and for presentation at the ECCMID conference in Berlin, Germany in April, 2013.

“We are proud to offer this important new tool for the correct diagnosis of Lyme disease”, comments Dr. Wolfgang Pieken, CEO of Boulder Diagnostics Inc., and adds “the SpiroFind test is the first method to query the trained immunity to Borrelia infection as a signal for active disease”.

“At our clinical laboratory in Mellrichstadt, Germany, we now accept whole blood samples for testing by the SpiroFind method,” states Dr. Anton Waldherr, laboratory physician of Boulder Diagnostics Europe GmbH.

Professor Leo Joosten of Raboud University has been collaborating with Boulder Diagnostics and has worked on a project by Oosten et al which may have shaped the design of this test, "The interaction between NOD2-autophagy pathway and inflammasome activation determines the chronicity of Lyme arthritis" - see this paper's full text on Pubmed. The reason why some patients may develop persisting symptoms is because of a defect in their immune system.

Looking at Dr. Joosten's long list of publications on immune factors involved in infection, one can see that he has accomplished a lot of research on cytokines, Toll-like receptors (TLRs), and biomarkers of infection and inflammation.

It also should be noted here that Raboud University has also been involved in clinical studies on the use of long term antibiotic treatment for chronic Lyme disease as the sponsor of the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) - perhaps subjects of this study were also used to help assess this new test?


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Wednesday, November 7, 2012

0 Rant: Can The IDSA Meet Lyme Disease Patients Halfway?

A background story for this rant is in order: The following is a rant from Lymenet Europe in response to one member's comment that I blame the IDSA for dysfunction when it comes to the quality of communications between the IDSA and patients and advocates, and don't place enough responsibility for that dysfunction on patients and advocates instead.

I disagree with this assertion. I'm not looking at blame. I'm looking at accountability. And I think both "sides" of this conflict are responsible for letting things get to the point where they are now.

All I know as a patient is that I'm looking at over twenty years of the conflict over causation for my persisting symptoms and even if that's not resolved to the degree that everyone would like - I want greater acknowledgement of my condition by the IDSA and medical community as a whole.

I'm not looking for a sign that the IDSA will change everything they do to fulfill all chronic Lyme disease patients' wishes. That isn't what this is about and I don't think it's something that is realistically achievable at this point in time.

This is about moving beyond awareness to acknowledgement that people with persisting symptoms can have a range of severity in their symptoms and be affected by them anywhere from minimally to profoundly.

This is about being taken seriously, regardless of what causes my persisting symptoms after having contracted Lyme disease. This is about having the medical community as a whole not write off symptoms as being psychosomatic in nature. This is, in a nutshell, about respect...



Camp Other wrote:

"My issue is with the quality of interactions they have had with advocacy groups and patients, and their inability to provide education, outreach, support,and research that helps those of us with persisting symptoms."


Bagge wrote:

"It seems you are blaming them for the dysfunction, and not placing adequate responsibility onto the activists. I'll leave it at that. It would be an inappropriate use of this forum for me to comment further as to my opinion on activist antics and the degree to which their specific actions are directly endangering and exploiting patients. If I had the means, I'd write a Lancet article about it so as to warn the public about the dangers."

Camp Other wrote:

Bagge, I'm not blaming anyone. I am venting my frustration to some degree, and it is not about any one "side". It's about the situation and how this conflict over causation has gone on for a long time now.

When I hear you discuss chronic Lyme disease, your focus is very much on pseudoscience. And doctors who you want to condemn for their actions, whether its unfounded treatments or egregious behavior. But I hear very little from you on how best to serve the needs of patients suffering with persisting symptoms after contracting Lyme disease. So after you have warned the public to the degree that you find necessary and make the parties accountable that you think should be accountable, what's next?

I don't know who, ultimately, could be responsible for creating what I'd call détente, but it would be refreshing to see. I think one sign of it was when patients protested the IDSA conference in San Diego and instead of getting called hypochondriacs and crazy, some conference participants came up to them and asked them questions about why they were there. Polite exchanges, and no one got their head ripped off from what I've heard.

Not all activists and patients are frothing at the mouth and posting conspiracy theories daily and harassing the IDSA and its doctors. We might be angry, but we have reasons to be and I think it's reasonable to request that those reasons be addressed and that there be a dialog between Lyme disease patients and the medical community, including the IDSA.

It used to be that Lyme disease patients were welcome at conferences where different infectious disease specialists would discuss their research on Lyme disease and patients could ask them questions - but that changed. I had read somewhere at some point that this practice stopped some time in the 1990's when some researchers wanted to discuss the issue of persistent infection and their papers were rejected for presentation - but later were accepted after some amount of pressure on the IDSA from patients and support groups. The full story on what happened is not clear to me, though, and I think the only online accounting of it I read has been removed (The old LDF site? Not certain.).

I think some essential rift in the social fabric may have been torn there, if that's what happened. I would like to hear someone else's story on how the "sides" unfolded. I don't know how many people know what happened and which key events took place that led to the development of "sides". I don't know the whole story myself.

I wonder why Chronic Lyme Disease is different, because when it comes to other illnesses including rare and hard to treat ones, in a number of cases patients have closer relationships to those researchers and clinical doctors who are working on their disease. In Lyme, we don't have that relationship in a number of ways - though we do have researchers like Dr. Luft and Dr. Norris who will attend Columbia Lyme disease conferences and present their research which is very much appreciated by me. But it's not a broader scope conference such as the IOM workshop held in 2010. That was a rare, one time event.

But getting back to this part of what I said: "inability to provide education, outreach, support, and research that helps those of us with persisting symptoms."

I guess my thoughts on that when I wrote it is that I don't have the kind of relationship as a patient with different scientific institutions that, say, some patients for other conditions have with researchers at the NIH-NIAID for theirs. And I see that, while as a patient I can be affiliated with Lyme disease advocacy organizations and groups such as the Lyme Research Alliance or a member of my local Lyme disease patient support group where we share tips and discuss the major impact being ill has had on our lives - there isn't really this sense of being a person with my condition which is integrated into the mainstream medical model somehow...

Basically, either I get my support and have a voice with Lyme disease advocacy groups and other patients - or I don't get it. And this is true for a lot of patients. We have each other, but we don't have the back of the mainstream medical community the way that someone with, say, cancer has or someone with Chagas disease. These are recognized conditions which are complicated and not well understood, have a major impact on people, and family doctors try to work with patients with these conditions.

But say you have chronic Lyme disease, and because there is no acceptance of this condition from much of the mainstream, you get looked at oddly because doctors have read from the IDSA and other institutions that it doesn't exist... Yet, just the same, I am not well, and not at my pre-infection baseline for health, and if there IS permanent damage due to having been infected, then that needs to be taken into consideration and worked with as a doctor.

Problem is, it isn't by most doctors. I'm probably lucky I have one doctor who is willing to consider that having a history of Lyme disease infection may have affected my health in a number of ways. Not everyone is that lucky.

Because patients in my situation do not have the back of much of the mainstream medical community, we are isolated and turn to our support groups, advocacy orgs, and LLMDs for support and validation. And why go somewhere else where people don't take you seriously? You don't. You stay as far away from it as you can.

As a patient, the only other choice that you have is to totally back away from support groups, advocacy orgs, and LLMDs and avoid all doctors and basically try to manage life on your own the best you can. And either choice is isolating, in its own way.

And let's look what is happening from the perspective of a patient:

On the one hand, the IDSA guidelines which are supposed to be used by doctors to guide them in treatment state that there is no entity called chronic Lyme disease but that some patients have post treatment symptoms which are described as "the aches and pains of daily living" (which is considered minor, one-can-live-with-it pain) when, on the other hand, the Klempner study discusses patients enrolled who at their most severe are as disabled as someone with congestive heart failure.

When looking at that description, those who are the most disabled after contracting Lyme disease and have persisting symptoms after initial treatment are going to be upset, because that statement in the guidelines minimizes their pain. It doesn't even begin to describe the degree of dysfunction some of them are experiencing. It sure as hell would not have described my symptoms in the two years after infection began, and at times, it would not describe my symptoms now.

So to patients, it's minimizing, and gives all doctors relying on those guidelines the idea that our problems can be shrugged off and we can function with them. A lot of us can't function (or at least do not function very well), though, so I think that if the IDSA and other medical organizations would state in a professional manner in the next guidelines review that there is a range of symptom severity after initial treatment in those patients who do not completely recover that would at least reduce some of the anger.

"The aches and pains of daily living" phrase has to go, regardless of whatever problems were found in the population at large over time. That kind of comparison is like saying "let's compare one sick person to another sick person". It's not useful, and from a scientific perspective, it is more accurate to describe the patients' symptoms in terms of how they are limiting mobility and functionality and quality of life measures, so why not do that instead? That would more accurately characterize our problems without being dismissive.

I am aware that the IDSA is, in all likelihood not going to change their guidelines to designate longer term antibiotic treatment courses as Lyme disease patients and advocacy groups would like to see them do. That is unlikely to happen unless certain postulates of Koch's are met regarding Borrelia burgdorferi. But in the meantime, can't something be done to at least acknowledge the range of severity of symptoms and QOL issues patients have? Can any kind of suggested safe and effective treatment be included (one reason I wished something like Low Dose Naltrexone could be studied would be to include it here) that helps patients? There is, at present, NOTHING.

And then there's the issue of family doctors and urgent care doctors not even knowing how to treat EARLY ACUTE Lyme disease. Before we even get to the issue of whether or not Lyme disease can be a persistent infection, it seems so many patients have had an encounter with a doctor who didn't even know how to properly apply existing IDSA guidelines to patients.

Patients go to family doctors and urgent care doctors FIRST, not an infectious disease doctor, and not usually an LLMD, either. Some patients see a doctor for a tickbite and have no insurance, and could not afford to see either an infectious disease specialist or an LLMD, when it comes down to it.

And there are many, many stories of patients seeing family doctors or urgent care doctors where they either they misdiagnose the rash, or they test too early so the patient's test is predictably negative,or they see a rash but wait for test results weeks later to go ahead with treatment, or they do not consider coinfections in the percentage who do get them. That's just a few examples. And then they get disseminated infection later - if not late stage - when it's more difficult to effectively treat the infection.

Based on experiences like these, from the patients' perspective, a certain percentage of us have lost some faith in a lot of doctors and would rather turn our health care over to LLMDs and alternative practitioners. We feel the system failed us, and if our symptoms are serious, then the system seriously failed us. That's how it is.

If the IDSA wanted to make life better for everyone, is there anything they could do to ensure doctors had more training to make early clinical diagnoses of Lyme disease and other tickborne infections? Maybe they are already doing this training, but a refresher is needed from time to time. From what I know about med school, tickborne illnesses are covered very quickly and not in great depth. There is a LOT to learn and remember.

I can't help but think that there has to be some way to avoid becoming another member of the controversial disease club I'm in and to avoid paying its horrible annual dues. I keep thinking my situation could have been prevented if more family doctors and urgent care doctors were better trained to handle acute cases of tickborne diseases. So if the IDSA did more such training, put educational posters on clinic walls as reminders, and let patients know that they were working on improving diagnosis and treatment in the typical clinical scenario and not one where you have more specialized tests and tools to use as an academic physician, then some patients might be less angry at the IDSA and say, "Thank you for doing this". They might also add, "Why didn't you do it sooner?", but that's how it goes.

By and large, the IDSA could do more to at least explain where they are coming from by creating an informative web site explaining what research they are doing, how they have come to the conclusion that even if they do not have enough evidence to support that patients have a persisting infection after initial treatment - they do have some evidence that supports an autoimmune hypothesis, and allow some method of allowing patients to ask questions online about this hypothesis. Put it all in one place. And also: educate medical professionals and society about the range of severity of symptoms in patients with persisting symptoms. Take the condition seriously, even if patient advocates and the IDSA disagree as to the cause of those symptoms.

It is probably not going to be a site that all Lyme patients will use, but it would make it clear what the IDSA's viewpoint is without anyone else misinterpreting their view. The IDSA could expect to see some very vocal detractors because of the controversy. At the same time, it could be informative if patients were given a chance to air their complaints and also ask questions so the IDSA knows what is on their minds. Just like this board - as contentious as it can get - there can be rules about threats and harassment in response to articles posted and those who violate them can be removed.

I get the impression, though, that part of the problem is that when it comes to the "sides", no one wants to change anything because it would be viewed as a concession, and would become a slippery slope.

I don't think it has to be that way, though, because in my opinion, there is a reasonable middle ground which could be found which offers patients more acknowledgment for the serious nature of their condition and support without labeling based on its cause on one side - and on the other, opens the floor to some dialog from patients who are not going to be hostile to the IDSA on the other.

But when you're looking at over twenty years of Lyme disease patient history, from the perspective of many patients and advocacy groups, they have lost trust and faith in IDSA. These changes would help, I think, in lowering the volume of anger that is out there - but it would not remove it.

There is a lot of anger. A lot of frustration. I share in it, and yet, I'm not always certain where my anger is directed. It changes:

Am I angry at my ex-family doctor who misdiagnosed me and did not treat me? Yes. Am I angry that the current guidelines seem to minimize my experience and discount my condition, and don't even recognize their alternative, PLDS, as a legitimate diagnosis, for those who have developed some autoimmune disorder? Yes. Am I angry that this makes it harder for patients to file for disability with a diagnosis like chronic Lyme disease? Yes. Am I angry that IV antibiotic treatment would not be covered by insurance even when I only wanted to try it for no more than one month? Yes. Am I angry that mainstream doctors in the ER have dismissed my medical history in making medical decisions about my care? Yes. Am I angry that a few ER doctors have labeled my condition somatic when they have never seen my entire medical record? Yes. Am I angry that, while I have had a lot of antibiotics and they have helped, now they do not seem to help with my remaining symptoms? Yes. Am I angry that there isn't a new treatment that is proven to help with remaining symptoms? Yes. Am I angry I haven't been able to work in years and have lost income and more medical debt? Yes. And it goes on.

So as a patient, I have a number of things to be angry about, and my anger is probably best described at being aimed at a lack of societal support and acknowledgment for this condition, as well as lack of the same from the medical profession, and anger that more research hasn't been done that puts an end to the controversy and/or comes up with a treatment that works well enough that I can work again and can live with it.

There are a number of patients who feel as I do and are in the same situation I find myself in. We might periodically try antibiotics again or herbs and acupuncture, just to see if it makes a difference. And we know that in the future research might find an answer for us...

But in the meantime...In the meantime, what can we do to make life better?

If both "sides" of this debate could engage the medical community at large in answering that question, and have compassion for patients and recognize we do have nerve damage, musculoskeletal pain, and moderate to severe fatigue (for example) due to having had Lyme disease - rather than labeling us with some psychosomatic problem - it would be a meaningful step.

And if the controversy between the "sides" will not end, I've always thought a third party could be established. On my own site I've advocated for a middle ground, a third independent party to somehow step outside the struggle and just say, "This is how it is. This is what we know about Borrelia. This is what we don't know about Borrelia. Any questions?" and let someone who is not invested in the struggle financially or ideologically become a source of reliable information from what would be viewed as a neutral platform.

But in the meantime, the "sides" is what I have to live with.

What do you think would have to happen to better meet the needs of patients, Bagge, now that I've outlined what makes me angry?

Imagine you are a patient, living with daily pain and dysfunction, and you haven't been able to work since you became ill with persisting symptoms after contracting Lyme disease? What would you do, and what would your expectations be of the medical community and society in response to your condition?



Edited to include:

I just received information about this call to action ILADS is making for patients to comment asap on the US Health & Human Services Department Healthy People 2020 campaign.

Link here: ILADS Healthy People 2020 Campaign

It's something I can support, and I wish that this announcement had been made sooner as the deadline is today, November 7.

The overall announcement is as follows:

"ILADS has submitted four objectives addressing chronic manifestations of Lyme disease to the U.S. Department of Health and Human Services (HHS) for inclusion in their Healthy People 2020. Healthy People 2020 is an ambitious, yet achievable, 10-year agenda that could improve the Nation’s health for individuals with Lyme disease. It is important that your voice be heard.

ILADS Lyme Disease Objectives:

1. Increase the proportion of persons with acute disease who are timely and accurately diagnosed.

2. Decrease the proportion of persons with chronic manifestations of Lyme disease.

3. Increase the proportion of persons with chronic manifestations of LD who are timely and accurately diagnosed.

4. Reduce the number of persons with a history of Lyme disease with subjective symptoms severe enough to result in a substantial reduction in previous levels of occupational, educational, social, or personal activities."

These all sound like reasonable goals. Goals everyone can back, no matter what causes my symptoms.


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Friday, November 2, 2012

2 On Tick Spit, Immune Evasion, and Round Bodies

There has been much interest in the relationship between tick saliva and the immune response to Borrelia burgdorferi in their host mammals - both animal and human. Recently, the following paper, "Neutrophil Extracellular Traps Entrap and Kill Borrelia burgdorferi Sensu Stricto Spirochetes and Are Not Affected by Ixodes ricinus Tick Saliva", from the Journal of Immunology added to data on how tick saliva affects the immune response at the bite site in a murine model, and may also explain what happens in humans bitten by Ixodes ricinus ticks.

J Immunol. 2012 Oct 29. [Epub ahead of print]

Neutrophil Extracellular Traps Entrap and Kill Borrelia burgdorferi Sensu Stricto Spirochetes and Are Not Affected by Ixodes ricinus Tick Saliva.

Menten-Dedoyart C, Faccinetto C, Golovchenko M, Dupiereux I, Van Lerberghe PB, Dubois S, Desmet C, Elmoualij B, Baron F, Rudenko N, Oury C, Heinen E, Couvreur B.
Laboratory of Human Histology-Centre de Recherche sur les Protéines Prion, University of Liège, B-4000 Liège, Belgium;

Abstract

Lyme disease is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. They are transmitted mainly by Ixodes ricinus ticks. After a few hours of infestation, neutrophils massively infiltrate the bite site. They can kill Borrelia via phagocytosis, oxidative burst, and hydrolytic enzymes. However, factors in tick saliva promote propagation of the bacteria in the host even in the presence of a large number of neutrophils.

The neutrophil extracellular trap (NET) consists of the extrusion of the neutrophil's own DNA, forming traps that can retain and kill bacteria. The production of reactive oxygen species is apparently associated with the onset of NETs (NETosis).

In this article, we:
  • Describe NET formation at the tick bite site in vivo in mice.
  • Show that Borrelia burgdorferi sensu stricto spirochetes become trapped and killed by NETs in humans and that the bacteria do not seem to release significant nucleases to evade this process.
  • Show that saliva from I. ricinus did not affect NET formation by human neutrophils or its stability. However, it greatly decreased neutrophil reactive oxygen species production, suggesting that a strong decrease of hydrogen peroxide does not affect NET formation.
  • Demonstrate that round bodies trapped in NETs were observed, some of them staining as live bacteria.

This observation could help contribute to a better understanding of the early steps of Borrelia invasion and erythema migrans formation after tick bite.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23109724

Comments:

Previous research on Ixodes scapularis and Ixodes ricinus ticks has shown that these ticks' saliva proteins have a negative effect on neutrophils, such as:

Use of CFSE staining of borreliae in studies on the interaction between borreliae and human neutrophils
Inhibition of Neutrophil Function by Two Tick Salivary Proteins
Tick Saliva Reduces Adherence and Area of Human Neutrophils
Horizon Press: Vector-Host Interactions In Disease Transmission

In this new research, there is evidence that even if neutrophils do not kill Borrelia burgdorferi spirochetes from I. ricinus ticks - that NETS stand a chance of killing them instead. And that when neutrophils form NETS, spirochetes found trapped in them often form round bodies which are alive.

What are NETS?

To quote "Neutrophil extracellular traps: Is immunity the second function of chromatin?":

"Neutrophil extracellular traps (NETs) are made of processed chromatin bound to granular and selected cytoplasmic proteins. NETs are released by white blood cells called neutrophils, maybe as a last resort, to control microbial infections. This release of chromatin is the result of a unique form of cell death, dubbed “NETosis.”"

At the above link, readers may watch a video of NETS being formed from neutrophils.

It is not known from this abstract which interactions between spirochetes and human cells took place or if the interaction in humans was extrapolated from a murine model. A reading of the full text is necessary for greater understanding.

More on neutrophil extracellular traps:
http://en.wikipedia.org/wiki/Neutrophil_extracellular_traps
http://jcb.rupress.org/content/198/5/773.full


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