Taking blood

Unravelling the nature of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: The role of elastase, complement C4a and interleukin-1β


Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Fremont M, Paul L


Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels; and Division of Musculoskeletal Physiotherapy, Department of Health Sciences, University College Antwerp, Antwerp, Belgium


Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1b and complement C4a levels.


Comparative experimental design.




Twenty-two women with ME/CFS and 22 healthy sedentary controls.


Participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status.


Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1b or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.


Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1b, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.


Journal of Internal Medicine, 2010 Apr; 267(4): 418–35

Funding Acknowledgements

The study was funded by ME Research UK, a national charity funding biomedical research into ME/CFS. Jessica Van Oosterwijck was financially supported by grant no. OZR1596 from the research council of the Vrije Universiteit Brussel, Brussels, Belgium. Mira Meeus is financially supported by the Research Foundation Flanders, Belgium.

Comment by ME Research UK

The cardinal symptom of ME from the traditional literature was profound, post-exertional loss of muscle power (fatigability) associated with muscle pain, tenderness and swelling. And still today, “post-exertional” symptoms are key; the NICE Clinical Guideline of 2007 informs GPs that, for a diagnosis of ME/CFS to be made, fatigue characterised by post-exertional malaise “typically delayed, for example by at least 24 hours, with slow recovery over several days” has to be present. It is worth emphasising that post-exercise symptoms are not present in other fatigue-related disorders, and that their very presence greatly helps to distinguish ME/CFS from, say, major depressive disorder.

Given this, it is surprising that so little is known about muscle physiology, the role of exercise, or indeed about patients’ responses to exercise in a laboratory setting. One research group, however, has a long-standing interest in this aspect: Prof. Jo Nijs and his colleagues at Vrije Universiteit Brussel, and University College Antwerp in Belgium. With funding from ME Research UK, these researchers have been investigating immunological responses to exercise, and the effect of exercise on these responses, and their latest scientific report has just been published in the Journal of Internal Medicine (April 2010).

Prof. Nijs and his team were looking at whether different exercise regimes trigger increases in elastase activity, IL-1b and complement C4a levels, and whether changes in these parameters might be associated with exacerbations of symptoms following exercise in people with ME/CFS. The experimental group consisted of women with ME/CFS plus ACR-defined chronic widespread pain (a group the researchers believed would more closely represent ME/CFS patients in the community in whom pain is a major symptom), and 22 non-athletic female controls. Participants completed the two exercise tests, one week apart. At each visit they were required to fill out a range of outcome measure questionnaires, and had blood samples taken for determination of the immune variables, such as elastase activity and G-actin cleavage. One hour after exercise testing, patients again provided samples and outcome information, and 24 hours later again reported their symptoms.

The first exercise test involved a well-studied “submaximal exercise protocol” using a bicycle. The second exercise was a “self-paced and physiologically limited bicycle exercise” with three “safety breaks”; the exercise duration was determined using the principles of pacing self-management as commonly used in people with ME/CFS, and the activity duration estimated by the participants was then further reduced to account for typical overestimations.

The results were interesting on a range of levels. As regards post-exercise symptoms, the submaximal exercise and the self-paced, physiologically limited exercise both triggered symptoms, such as pain, after 1 and 24 hours, highlighting that exercise needs to be employed with caution in ME/CFS patients. Looking at the immunology, however, neither type of exercise altered circulating levels of IL-1b, complement C4a split product or elastase activity — a most unexpected result. Most fascinatingly, the complement C4a level, measured after exercise, was identified as a possible biomarker for the development of post-exertional symptoms in people with ME/CFS.

Looking at the larger picture, much of the current thinking about the role of exercise in CFS and ME is driven by models of “deconditioning”, and the notion that regular exercise will be beneficial. And overall that is true; regular exercise is good for us all. But we already know that too vigorous exercise or activity can triggers post-exertional symptoms in most people with ME/CFS. And there is some evidence that these patients respond to an exercise challenge with an enhanced complement activation, increased oxidative stress, and an exaggeration of resting differences in gene expression profile in peripheral blood mononuclear cells. So, it is entirely possible, perhaps even likely, that over-exercising causes harm, simply because something is organically wrong with muscle metabolism. What value exercise programmes in these circumstances?

In fact, the characteristic delay in muscle recovery after exercise (with pain and fatigue days afterwards) in ME/CFS is a phenomenon which few have studied, and which the deconditioning hypothesis does not address. Many questions remain. For instance, a few studies have reported abnormal mitochondrial structure and enzyme function and/or evidence of viral activity in skeletal muscle tissue in some patients with ME/CFS — are viral particles interfering with the muscles’ ability to carry out specialised functions? Again, post-exercise muscle pain is a widespread symptom — but why is there muscle pain, and could a state of energy depletion during exercise and the development of noxious free radicals be responsible? And, most pertinently, how many ME/CFS patients have ever had a proper clinical examination of their painful and tender muscles by a healthcare professional?

This essay is an extract from our article (pdf 906 KB) in the Spring 2010 issue of Breakthrough.

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