Authors Jonathan C.W. Edwards, Simon McGrath, Adrian Baldwin, Mark Livingstone & Andrew Kewley
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The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is comparable to multiple sclerosis, diabetes or rheumatoid arthritis in prevalence (∼0.2% to 1%), long-term disabil- ity, and quality of life,[1–5] yet the scale of biomedical research and funding has been piti- fully limited, as the recent National Institutes of Health (NIH) and Institute of Medicine reports highlight.[6,7] Recently in the USA, NIH Director Francis Collins has stated that the NIH will be ramping up its efforts and levels of funding for ME/CFS, which we hope will greatly increase the interest in, and resources for researching this illness. Despite scant funding to date, researchers in the field have generated promising leads that throw light on this previously baffling illness. We suggest the key elements of a con- certed research programme and call on the wider biomedical research community to actively target this condition.
For many with ME/CFS life has effectively stopped – so immediate therapeutic studies are attractive. However, although serendipity can help, as in the observation that some patients may benefit from B-cell depletion, lack of biomarkers or an understanding of the illness has held back development of targeted treatments. Study of mechanism there- fore remains a key priority.
Drawing on the experience of one of us (JE) in elucidation of pathogenesis in rheu- matoid arthritis, and its application to therapy,[10,11] we favour starting with broad systems analysis of natural history. Following Stastny, we see such an analysis as including the evaluation of internal stochastic factors (e.g. chance immunoglobulin gene rearrangements encoding auto-antibodies capable of evading deletion) as well as genetic and environmental factors. Stochastic factors, although of major importance in cancer (as cumulative random mutations), have often been overlooked in mechanistic explanations of disease and are likely to be relevant in acquired, largely sporadic con- ditions such as ME/CFS. Additionally, epidemiology provides several clues, most notably the strikingly high proportion of female patients – typically 75% [1,2] – and the apparent bimodal age distribution  suggesting an age-dependent susceptibility to initiating events.
There is some family clustering, and sometimes a common history of initial viral or other (chiefly intracellular) infection, occasionally as during an epidemic: examples include Epstein-Barr virus (EBV), Ross River virus and the bacterium Coxiella burnetii (which causes Q fever). Either prolonged exposure to a pathogen or adverse environmental factors, in combination with stochastic factors, could lead biological signalling networks to shift from a healthy steady state into a dysfunctional steady state that perpetuates the illness.[15–17] The occurrence of remission, either spontaneous or following treatment,  supports this dysregulatory model rather than one of irreversible damage.
Clues to ongoing mechanism include:
These findings have not been replicated sufficiently to provide firm anchor points for further research, but this may reflect lack of opportunities with scant resources and perhaps cohort heterogeneity. In this context a recent report suggests that plasma cyto- kine levels may be abnormal (including IL-8 and gamma interferon, which have been noticed before), but specifically in illness of under three years’ duration.
- . unconfirmed hints of genetic linkage, including to cytokine [18,19] and human leucocyte antigen genes ;
- . repeated but variable observations of defective natural killer cell populations [21,22];
- . variable changes in B and T cell control of EBV reactivation in patients whose illness began with infectious mononucleosis ;
- . reduced physiological performance on the second of a two-day cardiopulmonary exercise test, despite respiratory exchange ratios indicating maximal effort on both days ;
- . substantial changes in leucocyte gene expression of metabolite-sensing adrener- gic receptors following physical exertion ;
- . autonomic dysfunction, including orthostatic intolerance and syncope ;
- . altered brain imaging, indicating both microglial activation  and structural