Monday, August 1, 2011

16 Abstract: Chronic Tick Associated Poly-organic Syndrome

Diagnosis and treatment challenges in patients with chronic Tick Associated Poly-organic
Syndrome (TAPOS) - Case series
A. Radulescu, M. Flonta, D. Tatulescu
University of Medicine and Pharmacy, Cluj, Romania,
The Teaching Hospital of Infectious Diseases, Cluj, Romania
Int J Infect Dis 2010;14

Background: Chronic Lyme disease is often considered in case of long lasting miscellaneous symptoms after tick bites. Despite new codified diagnosis algorithm and treatment persistent signs and symptoms frequently occur. The aim of the study was to assess the diagnosis of Tick Associated Poly-organic Syndrome (TAPOS) and to evaluate the treatment’s efficacy.

Methods: A consecutive case series of patients referred to the Cluj-Napoca Teaching Hospital of Infectious Diseases (January 2006 -October 2009) revealed 52 patients with TAPOS. Inclusion criteria were: more than 18 years of age, chronic symptomatology, positive Borrelia burgdorferi serology and/or tick-bite. Data was collected through chart review and medical observation. We used two clinical scores classifying the diagnosis of TAPOS. All patients were seropositive for IgM and/or IgG antibodies to Borrelia burgdorferi (EIA and western blotting). Treatment regimen was established according to the literature data. They received intravenous ceftriaxone, 2 g daily for 21-28 days and doxycyline 200 mg daily for 21 days. Patients with persistent symptoms were retreated with the same regimen.

Results: The baseline assessment documented that the most frequently reported symptoms were neuropsychological (90%), systemic (98%) and articular (23%). The sex ratio was 0.26 (41 women, 11 men), the average age was 43.2 ±12.6 years. Only 7 patients experienced erythema migrans, 57% had tick exposures and Borrelia burgdorferi serology was 92% positive [44 (84%) IgM positive, 19 (36%) IgM and IgG positive]. According to both clinical scores all patients were classified as “very probable” or “probable”. All patients were evaluated at 3 months showing a decrease in the number and intensity of signs and symptoms and the same serologic pattern. Ten patients were 2-3 times retreated due to persistent clinical picture, all presenting mood disorders or depression. No case of clinical aggravation or serious adverse events was reported and Jarish-Herxheimer syndrome was observed just in two cases. Most of the patients remained with at least one neuropsychological complaint.

Conclusion: Diagnosis of miscellaneous Borrelia burgdorferi chronic infection is challenging but should be always considered if prolonged symptomatology or tick related. Treatment regimens are not standardized, we appreciate as reasonable shorter 6 week regimens.



Comments: 

First of all, "Tick Associated Poly-organic Syndrome" or TAPOS - is this a new name Romanian doctors have come up with for what Dr. Benjamin Luft was referring to as a "Lyme Borrelia Complex" at the IOM workshop in October 2010 - or instead of Chronic Lyme disease? It's an interesting name, and I'm wondering where the "Poly-organic" part comes in.

The statements "Ten patients were 2-3 times retreated due to persistent clinical picture" and "All patients were evaluated at 3 months showing a decrease in the number and intensity of signs and symptoms and the same serologic pattern", caught my eye. Presumably, those ten patients also experienced a decrease in the number and intensity of symptoms as well as in their serologic pattern - so retreatment was a benefit for them.

So, let's look at the treatment: "They received intravenous ceftriaxone, 2 g daily for 21-28 days and doxycycline 200 mg daily for 21 days." Should one assume based on their report that those ten patients were treated with up to 4 months of  IV ceftriaxone plus 84 days of doxycycline - or is that off? Two to three times the baseline treatment seems to put the upper range in that ballpark.

"No case of clinical aggravation or serious adverse events was reported and Jarish-Herxheimer syndrome was observed just in two cases."

Boy, does that sound very different from the other reports from the American clinical trials on extended antibiotic treatment for chronic Lyme disease. One of the reasons extended treatment with IV antibiotics was recommended against was because of serious adverse events such as line infections. On a large scale, how often do line infections occur in thousands of patients worldwide? It's a risk, but is it that difficult to prevent with proper care?

I find it interesting that these case studies were shown at a poster session at the 14th ICID. An international professional infectious disease conference - pretty much showing a conclusion where chronic infection treatment is mentioned as not being standardized and setting 6 week regimens as being reasonable.

Wait a minute... doesn't this case series treatment study sound very similar to one of the American clinical trials on extended antibiotic treatment for chronic Lyme disease?

[Camp Other goes to new window, googles...]

I guess it is somewhat similar to the 2001 Klempner trials, but the fact that multiple retreatments were permitted under the case studies are a noted difference among other differences. I think for me, I'm wondering what the full text stated, and not just the abstract - in order to see the authors' line of reasoning on the dosage and regimen - but also wondering why there was only a three month followup on patients after treatment? Where are these post-treatment Romanians today, and how are they doing?

I have more questions...

Patients had the following serology at the start of their studies: [44 (84%) IgM positive, 19 (36%) IgM and IgG positive. How was it IgM positive-only patients were included in the study, when other researchers have stated that a sustained IgM response to Bb with no IgG response means the test was a false positive? (I'm not pushing this idea, as I am still working on the whole "how are new and newly intense IgM bands significant" issue - just putting it out there for the overview.)

"All patients were evaluated at 3 months showing a decrease in the number and intensity of signs and symptoms and the same serologic pattern."

Two questions here: What symptoms and signs did they have to begin with, and what changed, objectively and subjectively?

What does it mean to state in the above sentence, "the same serologic patterns"? Did all patients serological results remain the same across the board despite treatment?

"Most of the patients remained with at least one neuropsychological complaint."

What is the cause or what are the causes of the neuropsychological complaints?

Also, even if the authors reported a decrease in the number of signs and symptoms of infection three months post-treatment, how close were patients to their pre-infective state of health? This is always the question for which I want an answer - especially after reading through the results of treatment trials mentioned in the IDSA 2006 Lyme disease treatment guidelines - results which did not always post a clear outcome of cure.

There are a lot of unanswered questions on this abstract - hopefully getting the full text some time will help in answering them.

16 comments:

  1. I think "TAPOS" comes from this paper:

    J. Clarissou, A. Song, C. Bernede, D. Guillemot, A. Dinh, F. Ader, C. Perronne, J. Salomon, Efficacy of a long-term antibiotic treatment in patients with a chronic Tick Associated Poly-organic Syndrome (TAPOS), Medecine et Maladies Infectieuses, Volume 39, Issue 2, February 2009, Pages 108-115, ISSN 0399-077X, DOI: 10.1016/j.medmal.2008.11.012.
    (http://www.sciencedirect.com/science/article/pii/S0399077X08004289)

    Abstract: Settings
    Despite a now codified antibiotic treatment for Lyme disease, a significant proportion of patients treated according to recommendations complain of persistent signs and symptoms. The pathophysiological mechanisms which underlie this syndrome of post-treatment chronic systemic illness remain unclear. For some physicians post-treatment symptoms indicate a persistent infection requiring prolonged antibiotic therapy. For others, there is no benefit from antimicrobial therapy. The difficulty of assessment encountered in studies is significant because many symptoms are subjective. We think that the term 'chronic Lyme disease' is not appropriate and should be replaced by chronic 'tick associated poly-organic syndrome' (TAPOS).Objective
    This open-label prospective study was made on a group of 100 patients having followed a medical treatment for a chronic TAPOS and to evaluate their evolution under prolonged antibiotic treatment.Results
    The medical management was found to be effective for symptoms, especially for patients with a high probability of chronic TAPOS (NEJM score). Patients with post tick-bite symptoms, which often worsens their quality of life, deserve particular attention.Conclusion
    This study had methodological limitations but could help in terms of feasibility, choice of inclusion criteria, and design of follow-up for a future randomized, double blind study to test for an optimal management of TAPOS.

    TicksSuck

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  2. Interesting passage in that paper, related to symptoms cycles

    J Clarissou et al. Efficacy of a long-term antibiotic treatment in patients with a chronic Tick Associated Poly-organic Syndrome (TAPOS)

    The partial lack of antibiotic efficacy could also be due to the capacity of Borrelia to escape the bactericidal effect of antibiotics as cystic forms. The cyclic conversion of cystic forms in free spirochetes could release new Borrelia in tissues. The cyclic evolution was noted clinically for 28% of the patients in our study and could correspond to bacterial multiplication
    cycles.


    That makes sense to me... I could hardly explain these cycles by the autoimmune thesis. Could a study be devised to see if that's what's happening in vivo? Seems that this hypothesis have been advanced many times before. Can't it be verified?

    TicksSuck

    ReplyDelete
  3. TicksSuck,

    Thanks for sharing this. So it looks like the French came up with the term, TAPOS - not the Romanians. Good to know. It was late when I posted the abstract and my comments - I didn't look up related literature yet.

    Your comment about cystic forms is something I have been wondering about in general. Researchers have been divided on their purpose - whether or not they are survival mechanism or a degradation artifact. I've read a number of studies and if I recall correctly, these are the only two in vivo studies:

    Conversion of Borrelia garinii Cystic Forms to Motile Spirochetes In Vivo.
    (2001)
    Gruntar I; Malovrh T; Murgia R; Cinco M.
    Institute of Microbiology and Parasitology, Veterinary Faculty,
    Ljubljana, Slovenia.
    APMIS, 109(5):383-8.

    Abstract
    Cystic forms (also called spheroplasts or starvation forms) and their ability to reconvert into normal motile spirochetes have already been demonstrated in the Borrelia burgdorferi sensu lato complex. The
    aim of this study was to determine whether motile B. garinii could develop from cystic forms, not only in vitro but also in vivo, in cyst-inoculated mice. The cysts prepared in distilled water were able to reconvert into normal motile spirochetes at any time during in vitro experiments, lasting one month, even after freeze-thawing of the cysts. Motile spirochetes were successfully isolated from 2 out of 15 mice
    inoculated intraperitoneally with cystic forms, showing the infectivity of the cysts. The demonstrated capacity of the cysts to reconvert into motile spirochetes in vivo and their surprising resistance to adverse
    environmental conditions should lead to further studies on the role and function of these forms in Lyme disease.

    and

    Heterogeneity of Borrelia burgdorferi in the Skin
    (1994)
    Aberer E; Kersten A; Klade H; Poitschek C; Jurecka W.
    Department of Dermatology, University of Vienna, Austria.
    American Journal of Dermatopathology, 18(6):571-9.

    Abstract
    The reliability of various in vitro techniques to identify Borrelia burgdorferi infection is still unsatisfactory. Using a high-power resolution videomicroscope and staining with the borrelia genus-
    specific monoclonal flagellar antibody H9724, we identified borrelial structures in skin biopsies of erythema chronicum migrans (from which borrelia later was cultured), of acrodermatitis chronic atrophicans, and of morphea. In addition to typical borreliae, we noted stained structures of varying shapes identical to borreliae found in a “borrelia-injected skin” model; identical to agar-embedded borreliae; and identical to cultured borreliae following exposure to hyperimmune sera and/or antibiotics.
    We conclude that the H9724-reactive structures [atypical shapes of borreliae] represent various forms of B. burgdorferi rather than staining artifacts. These “atypical” forms of B. burgdorferi may represent in vivo morphologic variants of this bacterium.

    (more)

    ReplyDelete
  4. TicksSuck (con'td)

    One paper I wonder about is this one: Electron Microscopy of Langerhans Cells and Borrelia burgdorferi in Lyme Disease Patients from 1994... I don't have a copy of it here, but in notes I have here, a passage from it supposedly says this:

    "The observation of tightly packed vesicles attached to the surface of Bb or located freely among collagen fibrils suggested that these vesicles may play a role in the protection of Bb cells aganst detection by the immuno-cell system. Lyme disease spirochetes produce membrane vesicles, which bud from the membrane of the cell to become free-floating packages of spirochetal surface proteins. We found these vesicles also in CSF and blood samples. Garon (7) has suggested that these vesicles transfer intact DNA and thus genetic information.” (p.357)

    Everything I've read about this phenomenon suggests it's what's known as blebbing - the spirochete's outer membrane proteins are pinched off into little packets - almost like leaving a trail of breadcrumbs behind. These blebs trigger immune response in the body even though the actual spirochete has gone off somewhere else.

    Hearing that there also could be DNA from them makes me wonder what the original author means by that. My skin cells contain DNA. I wish they could have been more specific about what they think that DNA is and what it might be doing.

    See: http://en.wikipedia.org/wiki/Bleb_(cell_biology) - It becomes clear that one has to be certain of exactly what one is seeing and follow these blebs to see what happens with them and what their composition is.

    ReplyDelete
  5. The cyclic conversion of cystic forms in free spirochetes could release new Borrelia in tissues. The cyclic evolution was noted clinically for 28% of the patients in our study and could correspond to bacterial multiplication cycles.

    TicksSuck said:

    "That makes sense to me... I could hardly explain these cycles by the autoimmune thesis. Could a study be devised to see if that's what's happening in vivo? Seems that this hypothesis have been advanced many times before. Can't it be verified?"

    This is what I'd like to see as well, and I don't understand why I haven't seen longer term studies to track spirochete activity in vivo other than they do eventually get harder to find - which is a definite downside. But why not track its movement from an earlier point and continue as long as possible? And why isn't the US doing more on this - even the in vitro studies are mostly from Europe, of which the Brorsons are most well-known (and now, within the Lyme community, Sapi).

    It's not just studying morphology I don't see much mention of - lack of study in this area can be based on many looking at the cyst form as a spirochete on its way out and only a short-term survival mechanism at best.

    I'm wondering why there aren't more longer-term GFP in vivo studies, because it seems to me that would be the way to go. We have GFP studies which follow spirochetes in real time as they attach to endothelial cells, but not for a longer time frame so one can see what they do.

    ReplyDelete
  6. I was going to post a link to Prof Peronne's study TAPOS when i first read this I was not impressed with the name change but put in my place by someone far more knowledgeable than I on Lyme disease and also in what Prof Peronne was trying to do. Since I heard him at the London ILADS conference and some of his coleagues at ab earlier Lyme Disease Action conference I do not have those presentations but here is one from an earlier LDA conference http://www.lymediseaseaction.org.uk/conference/salomon_2003.htm
    Of course the IDSA refused to look at research from Europe in their review hearing despite some of it being on the same species there is in the US.
    If studying something called TAPOS helps get research done published and recognised then so be it. The sooner we leave the name Lyme Disease behind with the IDSA deniers and move on with research and treatment the better whatever we decide to call it.

    ReplyDelete
  7. Here is the whole study:
    http://scholar.googleusercontent.com/scholar?q=cache:kg3v8goSKqsJ:scholar.google.com/+lyme+author:%22A.+Radulescu%22&hl=en&as_sdt=0,5

    ChuckG

    ReplyDelete
  8. Should have posted the pdf link:
    http://scientia.zooparaz.net/2010_11_01/sp2010-pp38-43%20-%20Tatulescu.pdf

    ChuckG

    ReplyDelete
  9. ChuckG,

    Thanks for the link - been out most of the day and haven't really had a chance to write here. I'll take a look at the paper later - probably tomorrow.

    ReplyDelete
  10. Joanne,

    Thanks for the conference link. How much did you learn about the name change and what it means?

    I think that we are a global economy and also many people travel, so I think it would be beneficial for every country to strive for tests and research on all pathogenic strains of Borrelia. It's only going to help more people and help our understanding of how connected everything is on planet earth.

    The strain issue is important, and as I continue reading, I've found that serological profiles tend to progress differently based on different strains. I'm still trying to sort it out - there's a lot to read, and I have (as always) more questions. One of the goals of the C6 test was to catch more strains from what I understand - but the returns are not as great as they should be and even a recent ID conference mentioned its shortcomings.

    Anyway, I do hope that more research is done that is useful in helping patients regardless of the name of our condition(s). That's the more important issue.

    ReplyDelete
  11. There are many different strains 100's within each species, generally I think it is accepted that there is only the one species in US although several species in Europe that is before we get into strains within each species.

    I think using a different name was intended to investigate this away from the IDSA controversy of Lyme Disease, after all we know it is not just Lyme Disease but everything else that is associated with it. The MCIDS being put forward by some of our US LLMD's is sounding even better as this incorporates many other known infections which seem to activate with immuno supression ones not necessarily from the tick but latent ones which can become more problamatic.
    MCIDS (Multiple Chronic. Infectious Disease Syndrome) - Richard I.Horowitz,

    ReplyDelete
  12. Joanne,

    Even when one just looks at Borrelia burgdorferi, there are different kinds of Bb, and they have somewhat different characteristics. If there is already research which shows that some can produce a rash but no other symptoms while others can produce numerous symptoms but no rash - it makes clinical diagnosis difficult (especially early in infection when serology is not accurate). Add to this the existence of asymptomatic infections and possibility of latency, and the picture is even more challenging.

    I understand the desire to move patients' conditions away from controversy and view them with an independent approach - something I'd like to see happen very much. I'd like to see more independent research on Lyme disease in general... I'm not sure what I think of MCIDS as a new name - I'm lukewarm on it at the moment. I probably need to read more about it to make a better informed opinion.

    ReplyDelete
  13. Just a general comment related to something I wrote upstream:

    This kind of imaging study may give us more info about Bb's pathogenesis in tissue:
    Fiber optic microendoscopy for preclinical study of bacterial infection dynamics

    I don't think it's going to stop here, by the way - I think other techniques which are in development and being tested now will be helpful in the next few years. Further ahead, possibly graphene and nanotechnology will help in R & D for new bacterial imaging equipment.

    ReplyDelete
  14. ChuckG,

    I finally got a chance to look at the paper tonight. Briefly, my preliminary impression is it is one odd paper.

    The authors cite from both the IDSA and Stricker and Johnson, and it seems they believe in persistent infection yet only advocate for 6 weeks treatment based on a combination of ceftriaxone and doxycycline. They are against the IDSA's restrictive guidelines, yet stated they did not really want to retreat and decided to retreat in 20% of cases based on patients' requests. At the same time they saw some retreatment was beneficial.

    At the end of the paper, the authors use the phrase "Lyme hysteria" to describe some patients' desire to take antibiotics to help with any remaining symptoms they have, and the authors then state:

    "We cannot appreciate the optimal duration of the treatment but since no patient experienced a severe adverse event we conclude that a 6-week regimen is reasonable and it is close to the nowadays attitude of reducing the longer treatments considered before."

    Part of this paper was hard to read possibly because it may have been written in Romanian first and then translated into English, and something may have been lost in translation. The rest I can't blame on odd sentence structure - I think there is more specific data and metrics missing that I would have wanted to see.

    Fascinating. My head hurts.

    I've been having trouble sleeping, and perhaps reading that paper wasn't the greatest help for insomnia. A hot toddy might be better at this point.

    I think I'll get some rest and take another look at it once I've had more sleep.

    ReplyDelete
  15. I only scanned it. Nothing in there that advances the areas of lyme disease science that I am interested in.

    I have "bad" nights when I can't shut the mind down. But I am retired and so can nap at will.

    ChuckG

    ReplyDelete
  16. ChuckG,

    I don't know that it's worth another look at this point... I did try to read through it again, and it both needs to be better written and show more data. Not only that - but the authors' position remains unclear.

    Which areas of Lyme disease science are you interested in?

    I'm not well and not working. I would like to nap at will, but my body decides for me whether I will sleep or not. Regardless of time of day. And sleep is not refreshing for me - I only know that if I don't do it, my symptoms worsen.

    ReplyDelete

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