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Intermittent and GET effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8+CD38+ in ME/CFS

Discussion in 'Latest ME/CFS Research' started by hixxy, Mar 10, 2017.

  1. hixxy

    hixxy Senior Member

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    Physiol Rep. 2017 Mar;5(5). pii: e13091. doi: 10.14814/phy2.13091.

    Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8+CD38+ in chronic fatigue syndrome/myalgic encephalomyelitis.

    Broadbent S, Coutts R.

    Abstract
    There is substantial evidence of immune system dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) but little is understood of exercise training effects on lymphocyte function in this illness. This study investigated whether graded and intermittent exercise improved CD8+ lymphocyte activation and natural killer cell degranulation markers compared to no exercise. Twenty-four chronic fatigue syndrome (CFS) patients (50.2 ± 10 year) were randomized to graded exercise (GE), intermittent exercise (IE) or usual care (UC) groups; a control group (CTL) of 18 matched sedentary non-CFS/ME participants were included for immunological variable comparisons. Main outcome measures were pre- and postintervention expression of CD3+CD8+CD38+ and CD3-CD16+56+CD107a+ (LAMP-1) CD107b+ (LAMP-2) and aerobic exercise capacity. The postintervention percentage of NK cells expressing LAMP-1 and -2 was significantly higher in IE compared to UC, and higher in GE compared to UC and CTL LAMP-1 and LAMP-2 expression (absolute numbers and percent positive) increased significantly pre-to-postintervention for both GE and IE Preintervention, the absolute number of CD8+CD38+cells was significantly lower in CTL compared to UC and IE There were no significant pre- to postintervention changes in CD8+CD38+ expression for any group. Aerobic exercise capacity was significantly improved by GE and IE Twelve weeks of GE and IE increased the expression of NK cell activation and degranulation markers, suggesting enhanced immunosurveillance. Low-intensity exercise may also reduce CD8+CD38+ expression, a marker of inflammation. Both GE and IE improved exercise capacity without worsening CFS/ME symptoms, and more robust trials of these exercise modalities are warranted.

    © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

    KEYWORDS:
    Chronic fatigue; graded exercise therapy; intermittent training; natural killer cells; t‐cytotoxic lymphocytes


    https://www.ncbi.nlm.nih.gov/pubmed/28275109
    http://physreports.physiology.org/content/5/5/e13091
     
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  2. Mohawk1995

    Mohawk1995 Senior Member

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    So I put my Physical Therapist hat on to read this and have these preliminary thoughts:
    • At least this study did not appear to be completely biased from the outset
    • The use of "IE" and the fact that it "produced" similar results to GE is significant
    • That the aerobic capacity was improved basically equally between the two programs
    • That there was clearly a biochemical difference between the groups (although not being a trained physiologist I cannot tell you what that truly means at a functional level)
    • The ME/CFS groups were not by definition severe cases as they would not be able to perform the required exercise tasks. So this does not speak to that population whatsoever unless there is a treatment that can get these people to the moderate or mild level first.
    So my bias as a Physical Therapist is to always go to the place of valuing movement, mobility, increased blood flow and function above much else. The conundrum with ME/CFS is that tolerance to these activities is often quite limited making them impractical. To gain value from a "training response" the dosage of "stress" applied has to be enough to create a response, but not so much that it overwhelms the systems. In the case of most ME/CFS patients, that is an extremely narrow window if a window at all.

    The issue I have with applying GET to ME/CFS patients is not that there is not a place for it, it is in the way that it has been applied with a total lack of respect for the response to it (ultimately a lack of respect for the patient and really the person). So when I mention good clinical science or empirical science in discussions, I am saying that at all times and in all ways any treatment applied must be continually assessed as to its effectiveness (response). In the case of ME/CFS patients, it is warranted at to an even greater extent and needs to be considered over a longer period of time.

    I also have an issue with thinking that anything as complex as ME/CFS can be treated by a single modality such as GET or CBT. The complexity of the disease and the complexity of the physiological impacts of the disease on the body demand a multi-modal and interdisciplinary approach. In today's medical world, that just does not happen very often.

    Lastly, there is a difference between applying therapeutic interventions based on "normal" physiologic responses and basing that on physiologic responses that are unique to the disorder you are treating. For instance, in patients with chronic pain they may and often are strong enough musculoskeletally to perform exercise at a level that is beyond what their pain pathways can tolerate. In addition, they may not have the after effects impact them until a day later. So they can easily and commonly do have Post Exercise Pain Wind Up similar to PEM that ME/CFS suffers have.

    At least in this case, they were looking at key biomarkers that are related to ME/CFS and assessing their response to the exercise (not just aerobic capacity, BP, Heart Rate, Respiration, VO2 Max, etc that can be best applied to "normal" physiology). This is a necessary step in moving forward with effective treatment.

    The reason I am so excited about the work that is being done at places like Stanford is because it is giving us tools to use to truly assess the unique aspects of this disease and to determine how different interventions with different onsets and presentations impact those patients. The end result I believe will be a more specific and individualized treatment approach that takes into account those variables in each patient that could truly make a difference. We are not there, but heading in a better direction for sure!
     
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  3. duncan

    duncan Senior Member

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    You could no more exercise your way out of this disease than you could cure leprosy by trying to get a sun tan.
     
    Last edited: Mar 10, 2017
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  4. RogerBlack

    RogerBlack Senior Member

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    Of course not.
    Lack of exercise can however mean the difference between getting to the toilet or doing essential tasks with the remaining control you have over your muscles, and having to struggle to do so perhaps triggering further PEM.
    When the muscles are weak to begin with, adding further weakness through fatigue can mean that you are barely able physically to complete a task. This often means the mental effort needed to control the wobbling muscles with a foggy brain skyrockets, as well as risking accidents.

    That, and it can give a sense of accomplishment to do even minimal exercise.
    I am not talking here of aerobic exercise.
     
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  5. user9876

    user9876 Senior Member

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    Too much exercise can mean a relapse making people unable to even do the basics.

    One issue with research like this is that it is around general fitness and exercise rather than particular exercises that would help keep muscle strength.

    With GET it is about pushing past limits which is where the damage seems to be done - although it is unclear what the limits are.
     
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  6. user9876

    user9876 Senior Member

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    Having a quick scan of this paper I notice a lot of comparisons are made and they don't seem to be doing a correction in their significance testing.

    It is not clear how they measured compliance to GET - for example did patients increase exercise or did they just substitute activities. Did patients push past their limits. Also it is not clear what the control groups did in terms of activity. It would be more interesting to try to correlate any changes to changes in fitness, compliance, measured amount of exercise/activity change etc.

    I wonder if the small numbers and high variances mean that the data is not greatly meaningful. For example on one measure there was a big increase in the sedentary control group but big decreases in the exercise group. Does this just represent natural variation or does it represent an effect - without more measurements it is hard to tell. Does it represent a natural variations of something else. I also worry about the use of mean values with numbers of 8 - outliers can significantly skew the data and hide what is happening. It would be better just to plot all the data points and quote the median.
     
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  7. Marco

    Marco Grrrrrrr!

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    It's all fine and well finding these improvements in various objective measures of immune function and exercise capacity but did they actually feel any better at the end - you know subjectively? ;)
     
  8. user9876

    user9876 Senior Member

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    Or even objectively in terms of activities done.

    What they didn't do was look at how the measures relate to fitness as their control group didn't seem to have an intervention or how the measures relate to feeling better either using subjective measures or objective ones. So it is hard to conclude anything.
     
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  9. Marco

    Marco Grrrrrrr!

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    I was being a little mischievous in respect of criticisms of PACE relying on subjective measures but there's a serious point too.

    In clinical trials of drugs or other interventions, subjective measures of symptoms or overall measures such as quality of life are used alongside objective ones as a means of 'anchoring' the outcomes in terms of value to the patient. If a drug etc improves certain physiological parameters thought to be pertinent to the disease but has little or no impact on how the patient experiences their illness then what's the point?

    Re this study if changes in immune parameters and exercise capacity don't result in any subjective (or other objective) improvements then you have to question the value of the intervention or even whether either issue has much to do with the underlying pathophysiology.
     
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  10. user9876

    user9876 Senior Member

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    I realized that
    That's kind of the point I was trying to get to. But with a drug trial (double blinded placebo controlled) then subjective measures are more valid - although I agree they need anchoring alongside other measures.

    With GET patients know what they are receiving. It depends on quite what GET is - in the PACE case it involved telling patients that it was an effective treatment that could lead to recovery and that is due to deconditioning an hence symptoms should be ignored. Hence asking about symptoms is not a good way to judge progress. In this paper I'm not clear if they mean that by GET but still dodgy to use subjective measures.
     
  11. Marco

    Marco Grrrrrrr!

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    It looks like a similar approach sometimes used for post-concussion syndrome. You exercise within your capabilities to the point where symptoms are exacerbated and stop right there. Capabilities will differ for each individual.

    Very much not the GET one size fits all and ignore your symptoms approach.
     
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  12. user9876

    user9876 Senior Member

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    I think that could be a very important caveat to watch for when this paper gets quoted. In that case it does not support the GET being pushed with PACE.
     
  13. Marco

    Marco Grrrrrrr!

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    You can bet on that!
     
  14. M Paine

    M Paine Senior Member

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    If anyone else is looking for what their Graded Excercise and Intermitant Excercise protocol was, they mention the following in this paper:


    That paper is available here -> Graded vs Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome

    From that paper:

    I really wish they had included that information in each paper covering this type of intervention. There's too much ambiguity as it is around Graded Exercise.
     
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  15. M Paine

    M Paine Senior Member

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    From this paper:

    From that paper:


    12 weeks is a fairly short time, and they initially started by performing VO2 Max testing, which is likely going to cause a crash going into the study. I would like to see a longer study.
     
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  16. Jonathan Edwards

    Jonathan Edwards Senior Member

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    There are lots of problems with this paper. How I wish editors would help authors by requiring the most basic standards of writing.

    1. The text makes no immunological sense. 'expression of CD3+CD8+CD38+' is not something a competent immunologist would write.

    2. There are no numerical data so we have no idea whether any of this is of interest.

    3. The references to mechanisms and what findings might mean again suggests no real understanding of immunology.

    4. In a physiological experiment you do not compare an exercise programme with 'usual care'. You compare it with less exercise. This is not about 'care' or treatment. Or is it? I don;t think the authors have worked that one out. Most people would be interested in the effect of exercise in ME to see how it caused symptoms by making things worse.But the authors seem to have assumed they would be studying making people better. I really don;t think they are clear what they are doing.

    All this should have been sorted out by referees. Who the heck refereed this I wonder?
     
  17. A.B.

    A.B. Senior Member

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    Why is it that some researchers find PEM effects (in the form of increased impairment on some relevant measure), and other find more or less the opposite: exercise seemingly helping patients.
     
  18. M Paine

    M Paine Senior Member

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    Yes, I found this really annoying. I don't know what the better terminology is exactly, Cytotoxic T Cells? Not sure what the CD38 represents, but I would really prefer not to need to reference Lymphocyte phenotyping to read a damn abstract. To be honest, I decided not to look to deep into that data, as the relevance of it seems questionable. It's nice that they are trying to look at a biomarker, but I think we can do a little better than this. The subjective data just doesn't match the objective data.
     
  19. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I am not sure we can conclude anything has been found here.
     
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  20. Dolphin

    Dolphin Senior Member

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    So this is different to the exercise model that Peter White and some others use which is about breaking the link between symptoms and how much you do.
     
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