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Treatment of 741 italian patients with chronic fatigue syndrome

Discussion in 'Latest ME/CFS Research' started by heapsreal, Nov 15, 2013.

  1. A.B.

    A.B. Senior Member

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    While there is no control group, they looked at long term outcomes over 100 months. This is illustrated in table 1, showing the disease free survival time. The antiviral/immunoglobulin group does significantly better than the other groups, but seems to be small if I'm reading the tables right. I'm wondering if the group is small because few people respond (with the ones responding doing best in the long term) or if it's because few people are given antivirals/immunoglobulin?

    By the way, one of the authors is my current CFS doctor. I have my second appointment in April. From what I've seen, doctors in this clinic do not waste time on psychobabble.
    Last edited: Mar 18, 2014
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  2. Firestormm

    Firestormm Senior Member

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    Yes. But 'disease-free' relates to CFS. Not to any biological measure. So we can't tell from this study if, for example, those being treated with (I forget right now), antivirals, actually had a demonstrably positive result from a lowering of an immune activation, etc. etc. Do you see what I mean?

    And I am not suggesting they are 'wasting time on psychobabble'. Read the paper. There is no mention of any actual testing of a biological nature. The assumption is that those on medications did better because the medications must have been treating some infection or immune response: but there is no proof of that - other than patient reported outcomes.

    And that may be great for the patients. If I was one it would be for me - so long as I felt well enough to get on with my life and return to paid employment i.e. that the improvements I felt were significant. But it doesn't link the effect to any definite cause or the treatment used to any definite mechanism for CFS.
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  3. A.B.

    A.B. Senior Member

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    What I really wanted to express in my previous post is that it's hard to attribute the subjective improvement to the placebo effect (ie. temporary illusion of improvement) when said improvement persists for many years. A portion of patients in the antiviral/immunoglubolin group seems to have been effectively cured.
    Last edited: Mar 18, 2014
  4. Bob

    Bob

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    Edit: I may have misinterpreted the study in this post, as I just can't make sense of it. Perhaps it would make more sense if I read it again, in careful detail, but I'm not inclined to.


    I think this study is very poor, for many reasons. And some of its meaning/context has apparently being lost in translation, and much of the methodology has been omitted.

    It is a retrospective study, so its results must be considered exploratory/indicative, rather than an exact science.

    There doesn't seem to have been a protocol for the study, and if there was, then the methodology was changed anyway.

    The methodology isn't clear, either for the statistical analysis or for prescribing of treatments (e.g. what were they? why were they prescribed? what dosages? etc.) or for how/why the patients were selected.

    Their most basic stats don't actually make sense. In Table III, the percentages in the 'overall response' box, don't make any sense to me. I think they've made a major error with their percentages, unless I'm missing something. e.g. For the 15.3% positive outcome for antiviral/immunoglobulin treatment, what does the percentage refer to? If 93 participants received antiviral/immunoglobulin treatment, and 69 had a positive outcome, then that's a 74% positive outcome. If 69 had a positive outcome out of a total of 741 participants, then that's 9.3%. And why are there more participants included in Table III than there were supposed to be for the study? Actually, the percentages in Table III seem to be worked out in terms of the percentage of the overall 'no' response, and the percentage or the overall 'yes' response. This is utter nonsense. It's basic infant-level stats that they've got utterly wrong. (Unless I'm missing something, which is possible.)

    It doesn't give much hope for the rest of the study, especially as they've mis-interpreted their own mistakes in the body of the text.

    It's not clear if the supplements were given to every participant. It seems that they might have given in combination with the other treatments. If they were given in combination, then the supplement group would have worked as a comparison group. (i.e. not quite a control group, but a useful comparison.) But it's not explicitly stated that every patient received supplements.

    Translation issue: In Table III, it's not clear what 'no' for an overall response refers to: The wider text seem to hint that it's a negative response, but Table III suggests that it refers to a non-response or a negative response.

    I'm unable to interpret the details in Table III re 'univariate analysis' and p-values etc. But there doesn't seem much point, considering the mistakes in the basis stats. In theory, they would tell us if the patients who experienced improvement after antiviral/immunoglobulin, experienced particularly useful or significant effects.

    If we look at the numbers rather than the percentages, in Table III, then it does perhaps suggest that both antiviral/immunoglobulin treatment and Corticosteroids steroids are worthy of further investigation. (Whichever meds they used.)


    Here are the percentages, as I think they should have been reported:

    Supplements alone
    positive response 134 (56%)
    No response or negative response 107 (44%)

    Corticosteroids
    positive response 203 (62%)
    No response or negative response 126 (38%)

    Antidepressant/sedative
    positive response 45 (58%)
    No response or negative response 33 (42%)

    Antiviral/immunoglobulin
    positive response 69 (74%)
    No response or negative response 24 (26%)


    In terms of positive responders, for antiviral/immunoglobulin treatment, there is an 18% percentage point increase when compared to supplements alone.
    In terms of no response and negative responders, for antiviral/immunoglobulin treatment, there is also an 18 percentage point improvement when compared to supplements alone.

    These seem like good results, but the weaknesses of the study, and the methodological omissions, need to taken into account. I'm not sure if these are legitimate comparisons, because I don't understand the methodology.

    I'm not sure if the patients selected were a subset of CFS patients (i.e. patients with viral onset, or viral issues.) If so, then the results cannot be extrapolated to the wider community, but are useful for whatever cohort they used.


    At the most, this study could be used as guide to future proper trials of these treatments. The suggestion is that antivirals/immunoglobulin (whichever specific drugs they used) maybe slightly protective and perhaps increase rates of improvement when compared to supplements alone.

    Corticosteroids were perhaps better than supplements alone, but perhaps not significantly.
    Last edited: Mar 18, 2014
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  5. Rrrr

    Rrrr Senior Member

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    @A.B. could you please ask yr doc if they are still finding that antivirals and immunoglobulin work best for this illness? can you also ask WHICH antivirals they use and WHICH immunoglobulin they use, and doses?

    THAT WOULD BE WONDERFUL!
  6. A.B.

    A.B. Senior Member

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    I will try to gather as much information as possible.
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  7. Firestormm

    Firestormm Senior Member

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    @Bob Thanks for taking a look :)
  8. Rrrr

    Rrrr Senior Member

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    @Bob thank you for this helpful analysis.

    so given the lack of more concrete info, i will be a clinical trial of one, as i'm on both famvir and gamma globulin

    (just started shots (subQ) of gamma globulin -- see my thread about my gamma globlin treatment on this forum here: http://forums.phoenixrising.me/index.php?threads/gammaglobulin.28338/)

    i did have a viral onset, over 2 decades ago. and i do currently have Parvo (the virus) as well as high titers of EBV, mycoplasma, and others.

    IS ANYONE ELSE BESIDES ME ON BOTH ANTIVIRALS AND GAMMA GLOBULIN? (oh, i just recalled that i know someone who is. she is much more active than me, less sick. but i think she always was. i'm pretty sick. i'm homebound most of the time and bedridden a lot!)
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  9. Rrrr

    Rrrr Senior Member

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    @A.B. thank you! maybe you can ask yr doc to do a follow up study! :) we do need more info, like which cohorts it helped, etc (i.e. only viral onset cases or what?)
  10. Firestormm

    Firestormm Senior Member

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    But that was not my point. You can't look at this as a significant study. For individuals it is undoubtedly significant to see and experience improvements - and I am sure those individuals had been tested and examined and monitored and seen that as their 'viral loads' or whatever reduced with treatment, their symptoms improved. But so did symptoms for others taking other treatments. And without radomisation, and better control subjects in place, it is very hard to conclude anything of significance from this study.

    It could have been so much better. How often does the chance to monitor so many patients over such a period happen, and all of them following different treatment strategies? Never I would say. It is therefore a great shame it wasn't made more of: not because it might have clearly linked a treatment to a causal mechanism for CFS necessarily, but with more details and more control we might have been any to conclude what some people clearly have.

    As it is I do not think placebo effect can be removed from the equation: those being treated all knew they were being treated and what with. All this study has done it marked down in general what the treatment was and how patients were feeling at the end compared to the beginning.

    Doesn't take anything away from what your doctor might be using to treat you or how you feel the treatment is proceeding, which is very well I hope. What your doctor might like to do - is raise funds for a controlled trial of whatever it is he is treating you with. That way when the results are published we might all learn something and stand a better chance of benefiting from your treatment as well.
  11. Rrrr

    Rrrr Senior Member

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    the cohort seems vital, too. i.e. *who* were these patients? were they "just" depressed (and that is why an antidepressant worked on them)? by the way, i don't mean to downgrade depression; i have seen what depression looks like in others i know, and it is no picnic. but neither is it me/cfs. different conditions for sure.
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  12. A.B.

    A.B. Senior Member

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    I agree that the study comes across as vague and haphazardly organized. It is probably difficult to perform a long term study (over a period 14 years) in a situation where understanding of the illness is constantly evolving. The CCC didn't even exist when they started.
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  13. Bob

    Bob

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    Ah, I may have misinterpreted Table III. The methodology section says that individual patients received various different treatments, or combinations of treatments (including supplements). So it maybe the case that all of the patients received all of the treatments, and Table III indicates positive and negative (not neutral) responders for each treatment for all 741 participants. But even if that is the case, their statistical methodology still doesn't make sense to me, and their percentages are difficult to interpret, although it may make a little more sense.

    i.e. perhaps they mean that 15.3% of the overall positive responses (for all treatments) can be attributed to Antiviral/immunoglobulin. But if this is the case, then it's very difficult to interpret, because it's a relative figure.

    If this was the case, then it would mean that 9.2% of the 741 participants had a positive response to Antiviral/immunoglobulin, and 3.2% had a negative response. But did they all received Antiviral/immunoglobulin treatment?

    And if this was the case, then fewer of the 741 patients had a positive effect from Antiviral/immunoglobulin (9.3%) than from supplements alone (18.1%). But fewer patients had a negative response from Antiviral/immunoglobulin (3.2%) than from supplements alone (14.4%). If looking at net figures (positive response minus negative response) then there's not much between them: +6% net for Antiviral/immunoglobulin and +4% net for supplements alone.


    But I can't make sense of it all, and I don't think this is a correct interpretation because I'm not sure if all of the patients received all of the treatments. (According to Table I, it's not the case.)
    I'm not going to study the paper in any more depth because I'm not particularly interested in it.


    The reason that I can't make sense of the methodology is, for example, as follows:

    "Drugs were changed according to patients' response to therapy or when there was an intolerance to the drug given." "As the patients would have received different drugs during the observation period, we assigned an overall treatment response for each patient assessing which drug maintained the longest response, and according to the drug schedule. A global assessment of efficacy of treatments for each patient was assigned on the basis of which drug was given the longest response."

    So, it's as clear as mud!

    The results are confounded because patients were taken off a treatment if there was obvious intolerance to it, and it's not clear to me how such a response was recorded.

    I'm not sure if I'd understand the methodology any better if I took a few hours to read it in careful detail. As it is, I can't make sense of it. Some of the confusion might be because they perhaps used quite a complex statistical analysis. But I also think they've miscommunicated the methodology, and some of the stats, and have omitted important details.
    Last edited: Mar 18, 2014
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  14. Firestormm

    Firestormm Senior Member

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    @Bob Thanks again. I thought it would have been easier to understand and conclude its poor quality.
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  15. Bob

    Bob

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    I wish I hadn't started to try to understand it! I don't think I've ever come across a more confusing paper! :confused:
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  16. Bob

    Bob

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    According to Table I, only 93 out of 741 patients received Antiviral/immunoglobulin. So please ignore the struck-through text in my previous post!

    I've now got a head-ache!
    Last edited: Mar 18, 2014
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  17. NK17

    NK17 Senior Member

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    @ A. B. Is your doctor Prof. Umberto Tirelli in Aviano? I'm Italian and although I don't live in Europe anymore, I'm familiar with some of the "players" there in the CFS arena.
    Last edited: Mar 19, 2014
  18. NK17

    NK17 Senior Member

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    Indeed a very confusing and confused retroactive "study".

    I personally think that there isn't much in this paper.

    The only serious biomedical research coming out of Italy regarding ME/CFS is the one of Dr. Nicoletta Carlo-Stella group from Pavia. She is an immunologist and one of the ICC cosignatories.

    She'll present at the IACFSME ;).

    By saying this I'm not ignoring or downplaying the fact that many CFS patients treated by Dr. Tirelli's group have recuperated and have been in a long remission phase.
  19. A.B.

    A.B. Senior Member

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    Unfortunately, he said that he doesn't feel comfortable giving advice to patients that he hasn't seen in person. The treatment is also personalized. What I can say is that immunoglobulin is still used when appropriate, but they prefer to start with lighter interventions first.
  20. Rrrr

    Rrrr Senior Member

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    @A.B., thanks for asking him. as i'm sure you understand, i was not asking for advice, but rather asking to hear which antivirals and immunoglobulin he tends to use with his patients. oh well. thanks for asking.

    do you know what the "lighter" interventions are that they tend to use first?
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