Some more speculation on ME/CFS

• Efforts to finger the family of Enteroviruses as the causative agent in a large sub-group seem to have gone nowhere (e.g. Chia, or the British in the Eighties)
• Efforts to finger the family of Herpesviruses as the causative agent in a large sub-group seem to have gone nowhere (e.g. Montoya)
• Efforts to finger Retroviruses as the causative agent in a large sub-group turned out to be a large fraud
• Cytokine studies seem to have gone nowhere to identify large sub-groups
• Lot's of things can be misdiagnosed as ME/CFS (e.g. Newton et. al 2010)
• Many pathogens can cause Post-Viral-Fatigue, that may or may not be the same thing as ME/CFS (among others Hickie et. al 2006)

At the moment I would say:

• The ME/CFS patients are not suffering all from the same disease. 
• ME/CFS is an umbrella term for many different diseases. 
• Localized outbreaks (localized both in time and in space) are most likely caused by one distinct causative agent.
• The agent in one outbreak is most likely different from the agent in another outbreak.
• There is not one single causative agent that is shared by a majority of people with ME/CFS.
• The ME/CFS patient population is heterogenous. 

Therefore I would say:

Any research that works under the assumption of a homogenous ME/CFS patient population will fail.

Symptoms alone are probably not specific enough to delineate sub-groups*, objective measurable data (e.g. exercise challenge ala Snell, gene expression ala Light, RNA deep sequencing ala Lipkin, orthostatic measurements, and so on) is needed to delineate sub-group.

The question that remains: How do patients divided up into sub-groups? Are there a few disease entities that make up a majority of ME/CFS cases? (Of which I am no so sure any more) Or are there many many sub-groups, with a highly fractioned "landscape" with many many diseases hiding under the label ME/CFS?

[Addendum]
I think certain properties (non-refreshing sleep, VO2max exercise intolerance) can be shared by different disease entities. And even the neurological symptoms may be a (common) result of different pathological processes.

* Possibly with the exception of the POTS/Ad2A sub-group, which has the potential to be a single disease entity in its own right.