Wednesday, March 16, 2011

9 Three Conditions: Scientific Evidence for Chronic Lyme

During the past year, the question of how to make the case in support of the existence and treatment of Chronic Lyme Disease (CLD) came up in The FASEB Journal.

In one critical response, the writer said that in order to support the existence and treatment of CLD, the following conditions need to be met:
  1. Develop a precise definition of what is meant by “chronic Lyme disease” so that it can be distinguished unequivocally from other medical conditions with similar symptoms.

  2. Provide direct and unequivocal evidence that a patient suspected of having chronic Lyme disease really has a persistent B. burgdorferi infection that justifies antibiotic therapy.

  3. Demonstrate, from the results of published, peer reviewed, randomized, placebo-controlled trials, that extended antibiotic therapy is beneficial and safe for the treatment of chronic Lyme disease.
Back on LN, one of the questions I posed was, "What is chronic Lyme disease?".  I posted it in all seriousness, wanting to know what people's responses were and why, in part because I was looking for consensus on the definition from the patient perspective. 

This is still an exercise I think worthy of working on - to make an effort to fulfill these three conditions in order to support or refute what is actually happening with CLD and put an end to the protracted arguments about it. 

I realize that the patient perspective and responses are only one piece that can define what is meant by CLD, and microbiologists and clinicians must confirm and define the condition - but patients' experience of their own illness and empirical evidence around it form a chunk of the data on which definitions by professionals rest.

But back to the above... How can anyone go about systematically providing the evidence required to meet these three conditions?

How many other diseases and conditions have been defined with precision, as is asked of CLD in #1? How many have not been defined with precision, but still meet the definition of a disease?

Is  #2 just about proving Koch's postulates? Yes or no? How can this be done with a xenodiagnosis study? Without a xenodiagnosis study? Remember, not all emerging diseases have had to fulfill all of Koch's postulates to be defined as they are.

Does #3 conditionally rest on the evidence of #2? This is something I always wondered and asked myself. 

Each of these three conditions to be met has its own challenges in providing evidence. How would you go about meeting these conditions, if money were no object and you had time to set it up yourself?

9 comments:

  1. The three conditions are nothing more than good science and the foundation of evidence-based medicine, as opposed to "internet chatter" and gossip. The CDC has developed case definitions for all reportable diseases including Lyme disease. However, there is no case definition for "chronic Lyme disease" that will permit one to distinguish it from other non-infectious conditions with similar symptoms, e.g., fibromyalgia, chronic fatigue syndrome etc. So, what you have is chaos with "chronic Lyme disease" meaning different things for different people. If the serological tests are negative,then they are no good. No evidence of a persistent infection? The bacterium must be hidden in the inner recesses of some organism, even though all evidence shows that Borrelia are extra cellular and reside primarily in matrix tissue.

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  2. Doctors have for centuries treated patients according to their symptoms and response to treatment. I was given steroids for 20 months without any test or evidence based medicine diagnosis, I was also recommended by a Professor of Rheumatology to take anti depressants for what he diagnosed clinically as ME/CFS, I had no feelings or symptoms of depression.
    However my GP and specialist doctor both made a clinical diagnosis of Lyme Disease - my symptoms developed after bites, bulls eye rashes summer flu' eventually becoming chronic- call it what you will my symptoms responded for all to see on long term antibiotics, with deterioration when antibiotics were stopped.

    I have an antibiotic responsive illness and doctors need to go back to basics and treat us the patients not the test results. If that means ignoring guidelines so be it especially when those guidelines are based on low levels of evidence and more on opinions.

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  3. "Each of these three conditions to be met has its own challenges in providing evidence. How would you go about meeting these conditions, if money were no object and you had time to set it up yourself?".

    The answer is rather obvious. If one believes that the 4 NIH-supported clinical trials were flawed or not designed properly, then design and conduct your own placebo-controlled study to obtain evidence to the contrary and submit the results to rigorous peer review -- as was the case for the 4 clinical studies mentioned. No one disputes the fact that these people are suffering from something. The issue is whether it is due to a persistent infection or other causes. As long as the focus is solely on extended antibiotic therapy to treat an unproven persistent infection, these patients are never going to get the proper treatment that they need and deserve. So, who's looking out for the best interests of the patient here? If there were clear evidence that extended antibiotic therapy is beneficial, there would be no controversy.

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  4. Anonymous #1,

    What do you see as being the difference between CLD and third or late stage Lyme disease? When I've read the definition found on the IDSA's web site, what they called CLD included objective measurements of late or third stage Lyme disease - which muddies the water further in discussion of it.

    Also, what do you see as the difference between late stage Lyme disease and the latent and third stages of Syphilis?

    To me a big problem is detecting the presence of disease. People can have Syphilis in their brains for a long time and be seronegative. It can be latent.

    Question for you: How do you know that the Syphilis is there under those conditions?

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  5. Joanne,

    I agree with you, that the doctor has to make their own best clinical judgment and treat the patient. I'm sorry you were on useless treatment plans for so long and that they set you back from recovery. I think as is often the case, primary care physicians aren't thinking Lyme disease when they first see a patient - they think other candidates are more likely instead.

    Saying you have "an antibiotic responsive illness" might actually be a good part of a new definition, in its own way - and it may not even be what one would call Lyme disease. That's the trouble with defining things, yes? When Dr. Luft said many patients have a "Lyme Borreliosis Complex" because they are coinfected, that made more sense to me than Lyme disease alone.

    Tests are meant to be supportive evidence for treatment - the CDC surveillance case definition notes even say that their definition should not be used for the diagnosis of Lyme disease in patients.

    On their end they should make it really quick and easy to report confirmed and probable cases - and if I were the CDC, I'd publish both with an eye to following up on the probable cases. Just giving those early probables a test later and returning positives *would* reflect something closer to the true number of cases of Lyme disease.

    Either way, I think patients shouldn't be labeled as depressed or as having conditions for which there is no treatment until a lot more investigation is done.

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  6. Anonymous #2,

    Your idea could go towards addressing condition #3, but how would you address the other two conditions?

    On #3:

    In a general sense - aren't the safety profiles, benefits, and risks of long-term antibiotic treatment already something that is well known - and the medical profession applies their use, keeping all that in mind?
    Long term antibiotic treatment is used for people with TB, and ongoing in certain patients who are immunocompromised such as HIV patients, those with immune deficiencies, and those with organ transplants. Some people are on minocycline for a long time to treat acne.

    There is already a general track record for treatment with long term antibiotic treatment for these conditions and patients are not denied access because there are risks - they're given them because the benefits *outweigh* the risks. That's the kind of decision a doctor and their patient must discuss all the time.

    You said,

    "If one believes that the 4 NIH-supported clinical trials were flawed or not designed properly, then design and conduct your own placebo-controlled study to obtain evidence to the contrary and submit the results to rigorous peer review -- as was the case for the 4 clinical studies mentioned."

    That's a good point. Large group placebo-controlled studies are useful, and if the complaint is that the originals were flawed or not designed properly, then some independent group should redesign them, remove the flaws, and repeat them with larger groups of participants.

    But I can see both patients playing devil's advocate and researchers alike asking these questions around such studies:

    - How do you know the antibiotic is killing Lyme disease as a result of these studies? Symptom improvement may be due to other causes.
    - How do you know that any antibiotic is reducing bacterial load if there is a prolonged positive antibody response post-treatment?
    - How do you know which genotypes/strains patients have and won't that affect responsiveness to treatment and outcome?
    - If PCR and culture are not reliable indicators for presence of infection, how do you know participants are or are not infected?
    - How do you know if presence of coinfections affect the outcome? ( I think you can test participants for coinfections to eliminate them, and that works to some degree with coinfections for which there are tests.)

    Questions like that. They came up around the original trials, and I expect they'd come up in another repeat of them.

    As an aside, I think this is one of the reasons the NIH is now recruiting patients for a Lyme disease xenodiagnosis study (something that I am both curious about as well as realize makes many nervous - it would be good if they made information on their methods more available). They're trying to approach the CLD issue based on condition #2.

    The prior mentioned questions are questions patients are uncomfortable in asking, because they reflect what the IDSA Lyme disease guidelines group have said at one point or another about long-term antibiotic treatment: that antibiotics can have anti-inflammatory effects of their own (even if they can also eliminate bacteria) or a placebo effect.

    I don't have an issue with acknowledging the possibility and reality of those effects, but... one has to separate out those points from whether or not bacteria is present and actually being wiped out by antibiotics. And also, if any bacteria remains behind post-treatment which can cause infection. This is were the heart of the controversy lies.

    (more)

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  7. (For Anonymous #2 - more)

    You said,

    "No one disputes the fact that these people are suffering from something. The issue is whether it is due to a persistent infection or other causes."

    Agreed. It's not always clear what people are suffering from - it may be late stage Lyme disease, it may be a coinfection or two, or it may be other conditions - it's not always an 'or' thing, either... it may be an 'and' situation.

    You said,

    "As long as the focus is solely on extended antibiotic therapy to treat an unproven persistent infection, these patients are never going to get the proper treatment that they need and deserve."

    That's a matter of opinion. One that sounds very much in line with the current IDSA Lyme disease guideline panel, if I'm not mistaken. I would think some patients do need extended antibiotic therapy for persistent infection - or at the very least, new and different courses for a relapsing infection. (Yes, I know one could say proof of this persistence or relapse is required - who makes this determination on an *individual case* basis, though?)

    I think one of the issues in proper treatment is that it's not always clear which infections are present right away - Babesiosis may not produce positive blood smears for weeks or many months, and that confounds the clinical picture. Other infections and conditions may complicate it, too - such as an immune disorder/deficiency.

    You said,

    "So, who's looking out for the best interests of the patient here? If there were clear evidence that extended antibiotic therapy is beneficial, there would be no controversy."

    I would hope all doctors would look out for the best interests of their patients in any case. And you're right, but I think that's only part of the picture in assessing the controversy - I think one has to prove persistence is an issue first. Fulfilling condition #2 is, in my eyes, a separate issue from fulfilling condition #3.

    Speaking for myself, longer-term antibiotic therapy *has* helped me. I regained functionality, reduced pain, and eliminated some symptoms entirely by using it. I had more gains from treating Babesia - and that wasn't found until later.

    My early onset of symptoms mirrored that of patients with coinfections profiled in research. But my LLMD was waiting for a positive test before treating. Evidence.

    I don't fully understand why long-term antibiotic use has become such a loaded issue in some ways. Resistance and secondary infections are risks I don't like, but if there is some evidence antibiotics alleviate symptoms and improve quality of life for some patients, why not let clinicians make that decision? A lot of medications out there have some pretty gnarly side effects either way, antibiotic or not - so it has to be a case by case decision. Ongoing antibiotic treatment is used in some patients with rheumatoid arthritis with little controversy and some interest - it's another area where more research is needed.

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  8. Here's a question for everyone reading along:

    Is it justifiable to use long-term antibiotic treatments for certain conditions even *if* there is no evidence those conditions are caused by a persistent infection?

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  9. Anonymous,

    I want to readdress something you said:

    "As long as the focus is solely on extended antibiotic therapy to treat an unproven persistent infection, these patients are never going to get the proper treatment that they need and deserve."

    Been thinking about how to view that statement from a different angle... What do you suggest another or an additional treatment to extended antibiotic therapy could be - if you are proposing that, say, part of the issue is an immune dysregulation problem and not just or instead of an infection?

    Have you read particular research you could point me and the readers to on these alternative treatments for CLD (where I'm going to state that the definition for CLD for the sake of this particular discussion is the condition where patients have been bit by a tick, have had positive serology for Bb, the EM rash - let's say the whole nine yards of the textbook IDSA definition of Lyme disease - and have had treatment with antibiotics for 3-4 weeks but still suffer symptoms which look like Lyme disease)?

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