Thursday, May 24, 2012

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


23 comments:

  1. A question to readers:

    Is there any evidence that the authors have at some point associated the fact that prophylactic antibiotic use prevents the development of the EM rash with the idea that the infection has ALSO been prevented?

    If so, what evidence do the authors have that this is what has occurred?

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  2. The answer is somewhere on this site.

    Hint: Look for anything on seronegative Lyme disease.

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  3. If you are doing a rash wrap-up, do not forget Ben Luft's finding that only four of 20 strains cause disseminated disease; the other 16 are rash-only For various reasons --imo on both sides, political-- no one brings this up. It means that fewer cases of Lyme actually disseminate (reasons why activists may not mention) but it also means that of those cases that DO disseminate, much more of early Lyme is actually a treatment failure (reason IDSA types may not mention.)

    It is a fact that helps no one win their political fight, but it is so important for patients to understand this.

    Pam Weintraub, Cure Unknown

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  4. Hi Pam, and thank you for reading and commenting. I appreciate the feedback.

    You said,

    "If you are doing a rash wrap-up, do not forget Ben Luft's finding that only four of 20 strains cause disseminated disease; the other 16 are rash-only."

    Yes. I absolutely intend to include this information and think the general public needs to be informed about it.

    It may be many people clear their infections more easily because they do not have what Holly Ahern refers to as "the Other Lyme disease" - the kind of Lyme disease which leaves patients with more intense symptoms but possibly no rash.

    I also want to include the fact that other borrelioses - relapsing fever borrelioses - can lead to infections which look similar to Lyme disease in symptom presentation - yet there is rarely a rash included in the presentation.

    I wrote the following in part of a series on the Daily Kos last May, in "Lyme disease: Money & Chronic Mayhem":

    "... investigators in southern Spain identified several patients with atypical Lyme borreliosis, who were serologically reactive with Borrelia burgdorferi antigens, but who lacked classical erythema migrans skin lesions and who originated from a region of the country where the recognized tick vector of Lyme borreliosis was distributed sparsely.

    Indeed, blood cultures subsequently revealed a relapsing fever Borrelia sp., genetically distinct from B. burgdorferi and transmitted by an entirely different tick species. In this case, discovery of a novel disease agent occurred because these patients did not meet the established case definition for Lyme borreliosis (Anda, et al., 1996; Guy, 1996)."

    Since I have an international readership, I want to include that anyway.

    But whether one is discussing Lyme disease or relapsing fever borreliosis, an EM rash is not enough evidence that an infection is present.

    It can be helpful indicator if it is present - but it's important to let people know the rash is NOT the disease.

    Also, on the flipside, the disease is NOT the rash. Many people will get the EM rash and never go on to develop chronic and persisting symptoms.

    Some of us are just randomly unlucky. We happen to get the "bad" bite. The rest follows.

    "For various reasons --imo on both sides, political-- no one brings this up."

    I have no problem bringing this information to light. It's important for the public to know about the relationship between rashes and the disease.

    There may be political reasons why others are not bringing this up, and if I could avoid the issue of politics entirely, I would - but I realize that is not always possible.

    I try to just write about what is known, what isn't known, and my questions about these items - and leave others to comment on the political angles which may be imposed on the facts.

    (more)

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  5. (For Pam - continued)

    "It means that fewer cases of Lyme actually disseminate (reasons why activists may not mention) but it also means that of those cases that DO disseminate, much more of early Lyme is actually a treatment failure (reason IDSA types may not mention.)"

    Have there been any studies that you know of which provide evidence of a direct correlation between time to disseminate to other organ systems and RST of Borrelia? Of strain type? Because that would be useful for me
    to read and present here in conjunction with this information.

    I know Wormer et al wrote this paper about hematagenous spread of diffferent isolates of Bb...
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776734/
    ... but there is more information out there which is supportive evidence for which strain is more likely to cause problems. (And there are a lot of different genotypes that have been found out there.)

    I am pretty sure I have come across at least one chart online in a paper which outlined the difference in virulence between different strain types and information which indicated how much they disseminated... I have to see if I saved it in any of my files. But basically, there are different virulence levels of, say, subtypes of N40 and 297 and other strains. It's not just a matter of looking at the general genotype. For example, it's not just a matter of looking at N40, knowing it's more neurotropic - it's a matter of which N40 isolate, too. It is more complicated than I first suspected. (For some info on this, see Chan et al's recent paper on this: http://iai.asm.org/content/early/2012/01/23/IAI.06326-11.short. And Brisson et al's paper as well: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022926.)

    (more)

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  6. (For Pam - continued)

    The IDSA has said in their own 2006 Lyme disease guidelines that up to 10% of patients experience treatment failure in early acute Lyme disease... but I don't know if that data has ever been made into actionable information for most practicing physicians. I don't know entirely where the IDSA's claim of "almost 10%" came from, either.

    Did they ever look into genotype of infection and this 10% when they made this statement? Or is it just a treatment response statement based on an average from different studies? In other words, is this old, carryover data from before all the genomic studies have been made? Because I think this 10% was mentioned many years ago, too.

    Reports back from patients seem to indicate they have not only a difficult time getting initial diagnosis and treatment for obvious symptoms - but they also report that doctors are reluctant if not entirely unwilling to retreat with just one additional antibiotic course even when their infection is in the acute stage.

    Further physician education, in my opinion, should include this information about how different strains (as well as bite location, if found) can affect treatment outcome and consideration of an additional course of antibiotic therapy in acute infection could be beneficial if it prevents further complications. How to manage this consideration in light of the fact that people will point out it may be overtreating some patients is going to be brought up, though, as it has before.

    Given this information, how do you offer reassurance for people who get a rash and freak out, out of worry that they may be facing a future of chronic problems? How do you know they're getting adequate treatment early on? While chronic Lyme disease doesn't happen to everyone that gets Lyme disease, nobody wants to be the one to get it. Everyone would rather approach it with an attitude of, "better safe than sorry" and do what they can to prevent it.

    I sometimes wonder if a very early PCR test on blood like the Russians have been using would be helpful. If we used the test protocols they are running, they use PCR on blood samples and then use a second step to determine genotype of the infecting strain. So they know which strains/subtypes people are infected with from the people in Russian acute cases and not just in ticks they collect for surveillance.

    if antibody tests suck anyway, may as well collect what data one can early in the process and learn something...

    "It is a fact that helps no one win their political fight, but it is so important for patients to understand this."

    I agree, Pam.

    Thank you for your comments and suggestions. You brought up very good points. I will make sure to include this in part two of my installment of "Let's Not Be Rash About Erythema Migrans".

    Best wishes for your continued good health,

    CO

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  7. CO, You can check yourself --I have yet to do this-- but I believe it is Aucott of Johns Hopkins who is showing that 5-10 percent of the early rash patients fail treatment. His work is well-regarded across the spectrum from Lyme right to Lyme Left.

    The Luft work mentioned above is critical here --contextually-- because so many of these rash patients in the Aucott study and the world writ large will never disseminate.... they would be cured with water, so the treatment is irrelevant for them.

    On the other hand, and most disturbing, the 10% or so early treatment failure that Aucott is finding is therefore, in actuality, a much larger amount of dissemination-capable Lyme than just 10%.

    I find this all extremely troubling. it suggests, as I said before, that we are treating many who need no treatment and of those who do need treatment, the early IDSA-based guidelines may be more inadequate than anyone --even the LLMDs-- assume. i

    And this is I derive from research that is not particularly controversial. For the life of me, I don't know why this hasn't raised more red flags about practice on all sides.

    Any thoughts here?

    Pam

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  8. Excuse me, looking this over I realize I wrote unclearly,let me restate so my meaning is clear:


    CO, You can check yourself --I have yet to do this-- but I believe it is Aucott of Johns Hopkins who is showing that 5-10 percent of the early rash patients fail treatment. His work is well-regarded across the spectrum from Lyme right to Lyme Left.

    The Luft work mentioned above is critical here --contextually-- because so many of these rash patients in the Aucott study and the world writ large will never disseminate.... they would be cured with water, so the treatment is irrelevant for them.

    On the other hand, and most disturbing, the 10% or so early treatment failure that Aucott is finding is therefore, in actuality, a much larger than just 10%. THAT IS, if only 4 of 20 strains are disseminating, then treatment failure from IDSA treatment of the remaining four strains must, de facto, be a lot larger than 10%.

    With all the sturm und drang about late Lyme, I do not know if people are getting the clear implications of this research in early Lyme and the potential for slipping through the cracks.

    I find this all extremely troubling. it suggests, as I said before, that we are treating many who need no treatment and of those who do need treatment, the early IDSA-based guidelines may be more inadequate than anyone --even the LLMDs-- assume.

    I've already discussed some of this with Ben Luft and he says my thinking here is right. I don't know why this hasn't raised more red flags about practice on all sides.

    Any thoughts here?

    ReplyDelete
  9. CO,

    Please check this thread on LymeNet Europe. I left a (long) comment for you there:

    http://www.lymeneteurope.org/forum/viewtopic.php?f=6&t=3856

    ReplyDelete
  10. Notes to share:

    From the 2006 IDSA treatment guidelines for Lyme disease:

    "Two of the largest studies of the treatment of erythema migrans in adults compared cefuroxime axetil with doxycycline [138, 139]. The first was a multicenter study in which 123 patients with erythema migrans were randomized to receive cefuroxime axetil (500 mg twice per day for 20 days) or doxycycline (100 mg 3 times per day for 20 days). This study demonstrated comparable efficacy, with satisfactory outcomes in ∼90% of patients observed for 1 year after treatment [138]. Although 10% of subjects were considered to have experienced treatment failure on the basis of the presence of continuing symptoms, most of these patients did not have any objective clinical finding. Similar results were observed in a second multicenter study of 232 patients with erythema migrans who were also randomized to receive 20 days of either cefuroxime or doxycycline [139]."

    and

    "Several conclusions can be drawn from these trials. Doxycycline, amoxicillin, and cefuroxime axetil are effective for the treatment of early Lyme disease. Most patients respond promptly and completely. Some individuals have persistent subjective complaints, despite receiving therapy that otherwise appears curative. Less than 10% of individuals do not respond to antibiotic therapy, as evidenced by the presence of objective clinical manifestations, and rarely is re-treatment required. In general, patients who are more systemically ill (e.g., febrile with significant constitutional complaints) at the time of diagnosis take longer to have a complete response to therapy. Inadequately recognized CNS infection at the time of institution of antibiotic therapy may be the explanation for antibiotic failures in some circumstances."

    Citation 139:
    Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents Chemother 1995;39:661-7.

    Link: http://aac.asm.org/content/39/3/661.abstract (free full text)


    Apparently, 10 is a magic number when you read the guidelines?

    10-15% - number of patients who develop early disseminated neuroborreliosis if left untreated.
    4-10% - number of patients who develop Lyme carditis if untreated.
    10% - percentage of patients with Lyme arthritis who do not respond to single course of antibiotic therapy

    ReplyDelete
  11. Interesting to read the study above.

    Apparently patients were given 300 mg of doxycycline a day rather than 200 mg (100 mg twice a day) in order to meet comparatively with cefuroxime's activity. Yet the current guidelines (2006) say to treat early acute Lyme disease with only 100 mg twice a day.

    The ASM paper linked above states the following:

    "The efficacy of antimicrobial treatment for early Lyme disease was evaluated on the basis of the clinical response at 1 month posttreatment. The clinical signs and symptoms evaluated and ranked as to severity (mild, moderate, severe) at all patient visits included splenomegaly, radiculopathy, regional and generalized lymphadenopathy, malaise, irritability, fatigue, jaw pain, headache, chills, stiff neck, paresthesia, myalgia, arthralgia, arthritis, pleuritis, backache, nausea, vomiting, diarrhea, sore throat, and fever.

    The clinical response of each patient at 1 month posttreatment was categorized as follows: (i) success (resolution of erythema migrans rash and other clinical signs and symptoms by the posttreatment visit on days 1 to 5, with a continued asymptomatic state through the 1-month
    posttreatment follow-up period), (ii) improvement (resolution of erythema rash but incomplete resolution of any other clinical signs and symptoms of early Lyme disease by the posttreatment visit on days 1 to 5, with further improvement or complete resolution by the 1-month posttreatment follow-up visit), (iii) failure (no improvement in erythema migrans rash or other clinical signs and symptoms of early Lyme disease by the posttreatment visit on days 1 to 5), or (iv) recurrence (success or improvement but with recurrence of erythema migrans rash or other signs and symptoms of early Lyme disease by the 1-month posttreatment follow-up visit)."

    Also notable:

    "Patients who had satisfactory clinical responses (success or improvement) at 1 month posttreatment were followed until 1 year posttreatment to determine whether they subsequently developed signs and symptoms of late Lyme disease.

    The clinical response of each patient at this time was categorized as follows: (i) success (no signs or symptoms of late Lyme disease [for example, arthralgia, fatigue, arthritis, carditis, neurologic disease] throughout the 1-year follow-up period), (ii) improvement (some signs or symptoms consistent with late Lyme disease but no objective evidence of active disease during the 1-year follow-up period), or (iii) failure (signs or symptoms of late Lyme disease, including seropositivity for antibodies to B. burgdorferi at the time of assessment during or at the completion of the 1-year follow-up period).

    In the case of equivocal clinical findings of late Lyme disease, the distinction between the assessment of a patient as an improvement or failure during the 1-year follow-up period reflected, in addition to the serologic evidence, the investigator’s evaluation of the patient’s overall clinical condition.

    Patients were considered to be clinically unevaluable if they were lost to follow-up or if they developed evidence of early Lyme disease (for example, erythema migrans) because of recurrence or reinfection during the 1-year follow-up period."

    (more)

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  12. (continued)

    The above statements are all found in the materials and methods section.

    Questions for our viewer audience at home (or wherever you are on your mobile device at this time):

    1) Why is the "improvement" group lumped in with the "success" group?

    2) What is objective evidence of active disease, when to this day the IDSA and others have claimed there is no way to determine past from current infection using serology? Is it just Lyme arthritis that meets the definition for objectivity evidence? CFS culture?

    3) Note the failure definition. Why was it during the time this study was made that the presence of positive serology for Bb antibody response was counted as a treatment failure one year after treatment- when today, it is not?

    (See this passage: "The three cefuroxime axetil-treated patients assessed as clinical failures during the 1-year follow-up period showed a variety of Lyme disease-related symptoms, including arthritis, arthralgia, cognitive dysfunction, and headache; these symptoms
    were moderate to severe in intensity (Table 5). All of these
    patients were serologically reactive for anti-B. burgdorferi IgG
    antibodies at the time that they were assessed as clinical failures." )

    4) Why is a patient considered "clinically unevaluable if they were lost to follow-up or if they developed evidence of early Lyme disease (for example, erythema migrans) because of recurrence"? Wouldn't that patient be considered part of the failure group?

    Anyone reading have an answer for these?

    ReplyDelete
  13. Edits: Above, "objectivity" should read "objective". "CFS" should be "CSF".

    In response to you, Pam:

    Here is the link to the Aucott study I think you wanted:

    Diagnostic challenges of early Lyme disease: Lessons from a community case series - John Aucott, Candis Morrison, Beatriz Munoz, Peter C Rowe, Alison Schwarzwalder, and Sheila K West
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698836/

    It has a pretty good writeup on the different appearances of EM rashes and how they can be misdiagnosed. I guess the important passage relevant to discussion here in comments would be this one:

    "The common misconception that a bull's eye EM is the only diagnostic manifestation of Lyme disease continues to mislead both patients and practitioners. The absence of EM for 13% of our early Lyme cases highlights this discrepancy, with the majority of these seropositive patients (54%) developing only non-specific, viral-like illnesses without objective manifestations.

    Little attention has been afforded this presentation, despite the recognition that it may account for up to 9–16% of all early cases [15,29,30].

    However, the IDSA guidelines for the management of Lyme disease do not specifically address nor provide treatment options for this subset of patients [12] and they are not included in treatment trials or long term outcome studies [31,32].

    Our data suggests that 7% (95% CI: 2%–12%) of all acute cases may present with a viral-like illness and positive serology. Further, our identification of a subset of seronegative patients presenting with similar, non-specific viral-like illnesses of unknown etiology is notable.

    It is unclear whether a proportion of these patients represent probable
    cases who simply failed to meet current serological criteria. Until more effective antigen detection, PCR or culture become available, diagnosis of non-specific, viral-like illnesses in Lyme endemic areas will remain problematic."

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  14. Pam, to clarify the above passage related to my original post about the misdiagnosis of EM rashes based on their appearance, and the fact that a viral-like illness could present without an EM rash. I have to wonder if this early viral-like illness occurs without more obvious objective signs of Lyme disease if it is likely these illnesses will later become late stage Lyme disease.

    The following passage may be more pertinent to your comment:

    "Among previously misdiagnosed early Lyme patients, 41% received ineffective antibiotics which have been associated with treatment failures and higher relapse rates [11,12,38]. For misdiagnosed patients or those presenting with a viral-like illness, administration of ineffective antibiotics may produce unintended consequences. In studies showing suboptimal results with azithromycin, patients were often seronegative after treatment [16], raising the potential impact of sub-optimal therapy on seroconversion and further complicating reliance on a serology-based diagnosis [39]."

    You stated, "I believe it is Aucott of Johns Hopkins who is showing that 5-10 percent of the early rash patients fail treatment". Here Aucott is pointing at very specific subgroups of patients early cases which were misdiagnosed and incorrectly treated, and became treatment failures. More than 10%, indeed.

    You said, "I find this all extremely troubling. it suggests, as I said before, that we are treating many who need no treatment and of those who do need treatment, the early IDSA-based guidelines may be more inadequate than anyone --even the LLMDs-- assume."

    It's not clear to me from this particular study from Aucott that it applies. to this situation where many patients need no treatment. Maybe you mean this study? Or was it something by another author?

    Borrelia burgdorferi ospC Heterogeneity among Human and Murine Isolates from a Defined Region of Northern Maryland and Southern Pennsylvania: Lack of Correlation with Invasive and Noninvasive Genotypes
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1081366

    I'm not sure, as the most relevant excerpt from that paper would be this one:

    "B. burgdorferi ospC groups G, H, J, N, and T are usually associated only with erythema migrans and not invasion in humans (25). However, in this study, their invasiveness in both animals and humans was demonstrated by identification in disseminated sites. Although not well investigated, animal invasiveness in groups G and T suggests the potential for invasion in humans."

    Based on Aucott's first study I cited, it sounds like a number of early acute Lyme cases belong to patients with "unusual" EM rashes which were misdiagnosed and patients without EM rashes and viral-like presentations whose diagnosis would've been missed without any obvious objective Lyme disease signs.

    And that is problematic. How many are there? Can one extrapolate based on the data of one study? I think more studies could give us an idea, but in the meantime, the goal is to close the gap and have more people properly diagnosed and treated early on to head off trouble.

    (more)

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  15. (For Pam - continued)

    You said, "I've already discussed some of this with Ben Luft and he says my thinking here is right. I don't know why this hasn't raised more red flags about practice on all sides."

    How common are Bb isolates which lead to an EM rash only and do not lead to disease? Has Ben Luft said anything about this?

    Strle and Steere and their buddies published this one last year, even: "Borrelia burgdorferi RST1 (OspC Type A) Genotype Is Associated with Greater Inflammation and More Severe Lyme Disease."

    And I have notes on another paper, "Bb genotype predicts the capacity for hematogenous dissemination during early Lyme disease" (Journal Infectious Diseases) which mentions there is an association between RST genotype and presence of disseminated infection. It states RST1 was overrepresented in blood and RST3 was underrepresented, that no association was found between mulitple EMs and RST type, but of 3 RST genotypes there were 16 OspC types, of which four were associated with dissemination in over 50% of patients infected with the same genotype: I, A, H, and B - with RST1 being highly invasive.

    But it's useful to keep in mind that ability to disseminate and virulence do not necessarily go hand in hand. One can be present without the other.

    One notable point in this paper is that it stated genotype K infections were more common than infections due to other genotypes and was most frequently associated with disseminated infection in the patients studied. But it is considered fairly rare in ticks and causes a skin infection only.

    OspC genotypes A, B, I, K = 80% of early Lyme cases in the study, but were found in only 45.7% of the strains in the lower Hudson Valley tick nymphs.

    So who is getting exactly which Lyme in New York? Elsewhere?

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  16. CO,

    Check these link/references.These refs can help you get started to see what I mean, but in summary Luft said that of 20 strains he studied, 6 did not infect humans. 10 caused only a rash. And 4caused disseminated disease. He estimated, in discussion, that the 4 amounted to about 40% of the rashes. (first ref)

    What makes the four strains different? Addressed in second ref --the four strains are involved in genetic exchange and carried an OspC molecule with an altered structure that facilitates dissemination.

    To me this is relevant to any discussion of rash.

    http://iai.asm.org/content/67/7/3518.full.pdf

    http://www.pnas.org/content/101/39/14150.full?sid=fd68bd5c-6ecf-49d2-b748-c6e3bd1d2b47

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  17. Pam,

    I reviewed the first paper. It is interesting, and seems to relate to the later research I found which I quoted earlier on this string of comments.

    Yes, I see what you say. Seinost et al - Luft - found these strains, and found 10 caused only a rash and 4 caused disseminated disease. Looking at the tables in this paper, those 4 don't even disseminate a majority of the time, either - sometimes these isolates (A, B, I, K) are only found in skin. It looked like two of those 4 isolates - A and K - were responsible for the majority of infections even if they only presented in the skin in study subjects.

    This paper was published in 1999, and the other papers upthread are more recent. The more recent papers confirm these genotypes' tendency to disseminate in human hosts - and OspC RST1 type A being worst so far for virulence and inflammation. (I have conflicting notes on OspC genotype K's ability to disseminate which need resolving.)

    In all this time, though, I don't get the impression that there has been movement towards tracking OspC genotypes in patients relative to outcome over time - or has there been? If not, there should be, if dissemination is more likely with certain OspC genotypes. I reiterate my earlier comment that earlier testing should include PCR examination of blood then a second pass at identifying Bb genotype with some sort of amplification - possibly post-culture. If this were done with a greater number of patients in early Lyme disease, that would provide more data confirming this hypothesis.

    One thing I'm wondering about right now is what the specifics are around these 4 types dissemination and being found in only part of the blood and CSF samples but not all. I wonder what other factors might play a role in that dissemination - host factors; environmental, maybe other factors.

    I'll take a look at your second link Tuesday sometime and comment some more. Right now it's getting late and I need some rest.

    ReplyDelete
  18. Ah, yes, Pam... Thanks for sharing that second paper. Hmm. It's all coming back to me now...

    Some of the content in these papers and our discussion relate to Ben Luft's and Steven Norris' IOM presentations in 2010. The same IOM workshop at which you spoke, from which I transferred your comments in the Q & A to my "middle" page.

    These are paraphrases, but I draw them from some useful notes on the IOM workshop:

    Norris said, "OspC has overall the lowest sequence identity between diff OspC’s from different organisms/strains - 69% identity 79% similarity
    VlsE system is under a high degree of evolutionary selection and pressure."

    There is a lot of recombination going on and not so much mutation. The second paper said that; the first paper indicated it as a hypothesis and in findings; both relate to their presentations.

    Luft said, "We flagged for ticks and wanted to see OspC within population of ticks. Where there were more dots in slot blot = variance of Bb that were found in the population. Different ticks had 1 variant up to 9 variants of Borrelia in each tick. This infection is a lot more complicated than Bb alone."

    More Luft notes:

    "What is the variation of Borrelia? Different Borrelia have different capacity to cause human disease. This has important implications for this committee in thinking of size of study, geographic region of study, and more."

    "OspC is the major outer surface protein of Bb when it enters the skin. We looked at its structure. Showed invasive ones had structure identical to non-invasive ones except at the very head. Had very high electropositivity at the head (asked if this was a sign of its invasiveness... apparently hermsii has this too)."

    "Looked at Bb ss...Going out about 14 genomes, number of new genes identified were small. With each round of sequencing, 4 new genes were found, same with next... we stopped at 17 genomes or strains.

    We think we’ve found the core genetic material or core genome and know what is common to all Borrelia. Good idea of pan genome, too.

    The genome is more of an open genome type of process though. How much exchange is there between genotypes? We don’t know how fluid it is. It needs more study. It may cause problems."

    Two years since IOM 2010, and I have to wonder about some of the projects/issues Luft said he's been working on during his presentation.

    (more)

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  19. (For Pam - continued)

    From notes:

    "NY, CT, IN, CA - studied for genotypes
    Genotype prevalent in one part of country gives antibiotic response in one part of country but different response in another.
    Needs more study and to be considered when developing appropriate trials."

    So has he thought about developing trials relevant to this genotype research? How would one design a study for this (I imagine begin with doing the PCR/culture/amplification tests on early Lyme which I suggested, but there is so much more to it than that.) - especially treatment trials?

    And he made two points about needing trials during his presentation:

    "Multicentered therapeutic trials will be needed with many patients.
    we need double blinded controlled studies that show universal efficacy
    These studies need to be looked at in a circumspect way."

    "Is 200 patients an appropriate number for study design? I don’t think so. Until we have larger studies, more smaller studies with treatment breakthroughs and failures need to be appreciated."

    In saying this, has he been working on more small treatment studies, and working towards a multicenter treatment study based on his research?

    I guess this is the part that really struck me:

    "got 15 sera from the CDC from patients who had EM and many diff cultured Bb were taken from their EM.
    Only 54% of these folks were serum positive
    With the protein array, ALL of them had antibody response to Borrelia
    When you have the knowledge, the tools, the information, you don’t have seronegativity. This comes with good science."

    So, is there or isn't there seronegative Lyme disease? Perhaps Volkman and others are right - there is seronegative Lyme disease, using the tools we have been using for the past three decades. But if one can update the LD test by using this protein array, it sounds like seronegative Lyme disease would be a diagnosis of the past?

    If I knew how to do this and knew this protein array could be used on a wide scale commercially, I'd be patenting this test...

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  20. Pam, you recently said this at Skidmore:

    "If we don’t know who has the disease, for sure, we cannot document the scope of the problem, and we cannot hope to solve it. Reliable, validated 21st century diagnostics must be the linchpin of any research initiative. When we have diagnostic tools in hand, we can treat our patients earlier and find true cures for the chronic group that has never gotten well."

    It sounds like Luft has these diagnostics. What can be done to move forward on widescale studies?

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  21. CO, what you say above captures a lot of my thinking. The accepted dichotomy is that early ld is understood and chronic, not. That there is a Maginot Line separating the known world of early disease from the unknown cosmographies of late --as if there is a kind of Newtonian predictability underlying the first realm but an uncertainty principle driving the second. I'm not convinced of this anymore. Instead, I think that the early disease itself is insufficiently charted, knowable but not truly known, not deeply known through the best tools of interrogation we have today. A new interrogation of early ld along the lines you suggest could reveal valuable clues as to what unfolds later on --contrary to what is often said. As with so many other issues in Lyme, the continual fight over the second realm, only, might be obfuscating the field.

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  22. CO, As to your question on what can be done to move this forward, funding is required by an entity that admits the status quo tests are unnecessarily crude in light of the superior new technologies available today. Future initiatives have got to be based on more nuanced grasp of pathophysiology and things like strain differences, biomarkers, and variation of the host. Proprietary tests that cannot be validated are impediments to our forward progress because they ask us, yet again, to accept on faith, without proof --clearly unacceptable at this late date.

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