Altered immune response to exercise in patients with CFS/ME: a systematic literature review

[Bob]

I think this is new. Expect some translation peculiarities.

Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review.
Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J.
Exerc Immunol Rev. 2014;20:94-116.

Abstract:
http://www.ncbi.nlm.nih.gov/pubmed/24974723

Full PDF:
http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2014/94/article.pdf

Abstract
An increasing number of studies have examined how the immune system of patients with Chronic Fatigue Syndrome (CFS), or myalgic encephalomyelitis, responds to exercise. The objective of the present study was to systematically review the scientific literature addressing exercise-induced immunological changes in CFS patients compared to healthy control subjects. A systematic literature search was conducted in the PubMed and Web of science databases using different keyword combinations. We included 23 case control studies that examined whether CFS patients, compared to healthy sedentary controls, have a different immune response to exercise. The included articles were evaluated on their methodological quality. Compared to the normal response of the immune system to exercise as seen in healthy subjects, patients with CFS have a more pronounced response in the complement system (i.e. C4a split product levels), oxidative stress system (i.e. enhanced oxidative stress combined with a delayed and reduced anti-oxidant response), and an alteration in the immune cells' gene expression profile (increases in post-exercise interleukin-10 and toll-like receptor 4 gene expression), but not in circulating pro- or anti-inflammatory cytokines. Many of these immune changes relate to post-exertional malaise in CFS, a major characteristic of the illness. The literature review provides level B evidence for an altered immune response to exercise in patients with CFS.

 

[daisybell]

I like the table showing the research that is needed in this area, and the suggestion that the effect of GET on immune function should be investigated.

 

[A.B.]

This should be cited on Wikipedia. It will look funny among all the psychobabble that tries to insinuate that CFS isn't an illness and can be cured with CBT/GET.

 

[Firestormm]

Interesting - lesson to learn I guess:

...The most frequent cause of penalization was pooling of gender data. The EBRO-classification assigns a B score for individual studies which use a casecontrol study design. Because all the included studies were comparative studies without randomization of the study subjects, an evidence level B was applicable for all studies....

 

[Firestormm]

All included studies applied a case-control design, comparing CFS patients with healthy controls. In each of the included studies, immune variables were measured at rest (pre-exercise) and following one bout of exercise, with post-exercise measurements performed immediately and/or up to days following exercise. All studies examined the acute effects of exercise on the immune system (i.e. the effects of one exercise bout on the immune system). None of the studied applied a true experimental design, or studied the effects of exercise therapy on the immune system in CFS patients.

 

[Firestormm]

To summarize the findings addressing the cytokine response of CFS patients to exercise, from the available literature data there is moderate evidence that CFS patients have a normal circulating cytokine (e.g. interleukin-1β, interleukin-6, interleukin-10, tumour necrosis factor-α) response to exercise. Exercise does not result in abnormally higher levels of pro- or anti-inflammatory cytokines in patients with CFS.

 

[Firestormm]

Taken together, moderate evidence suggests that CFS patients, compared to healthy controls, respond to strenuous exercise with a slow (not earlier than 6 hours post-exercise) but stronger increase in blood complement C4a split product levels. Importantly, these alterations appear of clinical importance as two independent studies have confirmed the relationship between altered complement response and post-exertional malaise in patients with CFS. Findings such as altered eosinophilic cationic protein response to exercise in CFS require replication.

Complement response? Does that mean symptom exacerbation? Anyone? Thanks.

 

[Firestormm]

Summarizing the findings in relation to oxidative stress, cumulating evidence indicates that oxidative stress following exercise occurs earlier and lasts longer in CFS patients, and also that the anti-oxidant response post-exercise is delayed and reduced. However, nearly all studies come from the same laboratory and hence require replication.

 

[Firestormm]

Summarizing the findings of gene expression profiling of CFS patients in response to exercise, there is moderate evidence that CFS patients showed larger post-exercise interleukin-10 and Toll-like receptor 4 gene expression increases, which accounts in part for post-exertional malaise. Although compelling, these findings have been confirmed solely by the same laboratory and hence require replication by independent researchers.

 

[Firestormm]

I like the table showing the research that is needed in this area, and the suggestion that the effect of GET on immune function should be investigated.

I did as well (attached) and...

RESEARCH AGENDA
In addition to the above outlined need for replicating findings in independent laboratories, several other recommendations for further research can be formulated based on the study of the scientific literature in this area (table 3 summarizes these recommendations).

I thought this is also important and would have implications for prescribed therapy or management practices:

First, it is important to make a distinction between the effects from therapeutic interventions using exercise therapy in CFS (e.g. reference (55)) and findings from studies examining the exercise immunology/physiology of people with CFS (e.g. references (37, 47)).

The latter often use one bout of exercise to examine the acute response to (often very strenuous) exercise. Such exercise physiology studies provide us with valuable information on the biology of post-exertional malaise of CFS, but the exercise response may be very different in longer-term low-intensity exercise programs. These are two distinct issues.

Studies examining the effects of exercise therapy on immune function in CFS patients are essentially lacking.

Given the compelling findings addressing acute responses of the immune system to exercise in CFS patients as reviewed here, this is an important avenue for future research in this area.

All studies examined here, used standardized exercise protocols. Physical activities like walking long distances or cycling are not applicable, or possible, for all CFS patients. In addition, such studies were often conducted in laboratory settings.

Hence, such studies have limited ecological validity. Therefore, there is a need to study exercise immunology using physically demanding functional tasks for CFS patients, like stair climbing and ironing, rather than graded bicycle or treadmill tests. Stair climbing has been used for studying CFS patients (14, 34), but not from an exercise immunology perspective.

It remains to be established whether the observed exercise immunology abnormalities (e.g. increased oxidative stress response, enhanced complement activation) are specific for (sub)maximal exercise, or can be extrapolated to activities of daily living.

 

[Marco]

@Bob

Thanks for posting this. A very useful review.

 

[Valentijn]

It looks like a fairly honest review, though I'm not sure I agree with (or understand) some of their criticisms. For example, what sort of randomization are they complaining about a lack of? It's not like there were multiple groups to divide the patients into.

 

[Firestormm]

Where they were talking above about perhaps future experiments looking at the effects of 'daily living exercise' (if I might use that term of my own creation), might fit with what Julia Newton is talking about in the latest video (below) - around 4 minutes in - where she says that further experiments are needed to see how certain types of exercise appear to help and other types do not: in relation to muscle abnormalities:

 

[Sasha]

I've been thinking for some time that we desperately need literature reviews for specific research topics, especially this one. We can't expect most doctors to locate and read a ton of literature and attempt to synthesise it - we need these systematic reviews so that we've got evidence that we can easily point to and that people can easily read.

 

[lansbergen]

Complement response? Does that mean symptom exacerbation? Anyone? Thanks.

Possible

http://en.wikipedia.org/wiki/Complement_system

The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated.

Decades ago I tried to understand the complement system but it is so complicated I gave up

 

[Simon]

Complement response? Does that mean symptom exacerbation? Anyone? Thanks.

OK, this is a bit weird as all forms of complement response (there are three different types) target "foreign" molecules, eg bacterial cell wall sugars or antibodies bound to pathogens. It's not at al obvious to me how this ties in with exercise, though I can see how activation of the powerful complement system would make you feel lousy.

In this exercise immunology study, neither type of exercise altered blood levels of
elastase activity, interleukin-1, or complement C4a split product levels in people
with CFS or healthy sedentary control subjects. However, the change in complement
C4a level was strongly related to the increase in pain and fatigue 24 hours
following the self-paced, physiologically limited exercise (37). Post-exercise
elastase activity level and the change in elastase activity level were inversely
related to the fatigue increase one hour following the self-paced, physiologically
limited exercise (37). These findings suggest that subtle alterations in blood elastase
activity level and complement C4a split product levels account in part of
post-exertional malaise in people with CFS.

C4a is a key of the complement proteins (complement is a protein cascade, much like that involved in blood clotting), and generation of C4a is a key step in activating the complement system.

Activation of complement leads to:

• direct destruction of cells through lysis (via the Membrane Attack Complex, which basically stabs holes in target cells)
• 'opsonisation', which is making target cells 'tastier' to Neutrophils and other phagocytosing cells
• Attracting immune cells players to the target cells/infected area
• Clumping together of pathogens, which takes them out of play and makes them easier prey for the immune system.

Anyway, a surprising but interesting finding.

 

[Bob]

OK, this is a bit weird as all forms of complement response (there are three different types) target "foreign" molecules, eg bacterial cell wall sugars or antibodies bound to pathogens. It's not at al obvious to me how this ties in with exercise, though I can see how activation of the powerful complement system would make you feel lousy.

It could perhaps potentially be explained in a number of ways? e.g. If exercise activates a latent virus, or if exercise precipitates an auto-immune response involving the complement response system.


These are the two references in the paper in relation to the "complement C4a split" (I haven't looked at them yet):

37. NijsJ, Van Oosterwijck J, Meeus M,LambrechtL, Metzger K, Fremont M, and Paul L.
Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta.
Journal of internal medicine 267: 418-435, 2010
http://www.ncbi.nlm.nih.gov/pubmed/20433584

47. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, and Jones JF.
Complement activation in a model of chronic fatigue syndrome.
The Journal of allergy and clinical immunology 112: 397-403, 2003.
http://www.ncbi.nlm.nih.gov/pubmed/12897748

 

[Dolphin]

Interesting - lesson to learn I guess:

...The most frequent cause of penalization was pooling of gender data. The EBRO-classification assigns a B score for individual studies which use a casecontrol study design. Because all the included studies were comparative studies without randomization of the study subjects, an evidence level B was applicable for all studies....

What would randomization mean in this case? That they'd have some CFS patients who were measured at various times having not done the exercise? Seems like taking a measurement at baseline would do this just as well (indeed, in some ways better as one sees intra-individual variation). Perhaps optimally would be to take a few measurements in the subject before exercising to get a better baseline score than a single measurement where there may be some variability over time in the test.

 

[Dolphin]

They didn't search the Journal of Chronic Fatigue Syndrome so this study was missed:

White PD, Nye KE, Pinching AJ, Yap TM, Power N, Vleck V, et al. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. J Chronic Fatigue Syndrome 2004; 12: 51–66.

I wouldn't be surprised if Peter White published this paper in the JoCFS so it would not be seen by that many people.
He even once jointly signed a letter that said:

Five studies have examined the effect of acute exercise (not GET) on immune measures in CFS, but these have measured a number of different markers and shown inconsistent findings (9–13).
http://www.medicaljournals.se/jrm/content/?doi=10.2340/16501977-0261

The list didn't contain his own paper (mentioned above)!

 

[Dolphin]

Minor point:

The 3rd item controls for exclusion of selection bias (C3), which implied that studied groups needed to be representative of the general population. This item was scored negative when the included age range was not representative for the general adult population or when only male CFS patients were recruited. A negative assessment was given in case the patient sample was recruited solely from one sort of setting such as a specific hospital department or only through a patient support group, as combining a variety of recruitment procedures is recommended to prevent recruitment bias(33).

This meant a study was considered at risk of bias if it only used men, but not if it only used only women, which seems questionable to me.

I am left wondering whether the fact that Jo Nijs CFS studies tend to use just female cases may have influenced it.