Researchers from Newcastle University in the UK investigated how white blood cells taken from healthy patients differed to those taken from individuals with a history of CFS.
For one of the scientists involved, it was more than just an academic question. Biomedical researcher and PhD student Cara Tomas knows from personal experience what the condition is capable of, and how often it is seen as poor mental health.
"A lot of people dismiss it as a psychological disease, which is a big frustration," Tomas told Andy Coghlan at New Scientist.
Derisively referred to as "Yuppy Flu" just a few short decades ago, CFS has been dismissed as a fashionable condition that reflects a lazy, unmotivated generation of layabouts.
For half a century researchers have debated underlying mechanisms of the syndrome, leading many to speculate whether it has a psychological basis.
To some, this sounds awfully like CFS is 'all in the mind', making it feel like weak willpower rather than something rooted in biology. Poorly conducted studies have made a mess of recommended treatments in recent years, continuing to leave those suffering from CFS with a stigma and few options.
Thankfully the trend is slowly changing as scientists have begun to identify stark distinctions in immune cells, gut bacteria, and blood biomarkers among those diagnosed with the disease.
Now it seems as if there is a clear metabolic difference between the peripheral blood mononuclear cells (PBMCs) in individuals with CFS and healthy controls.
Researchers looked specifically at the metabolic processes of oxidative phosphorylation and glycolysis – two ways cells break apart chemical fuel to transfer energy in respiration.
White blood cells taken from 52 patients with CFS and 35 controls were put through their paces under optimal and stressful conditions, testing their capacity to deal with low oxygen levels.
There appeared to be a number of key differences in their metabolic processes. But none were as dramatic as the contrast in maximum levels of respiration.
By forcing the cells to boost their energy production, the researchers found those with CFS could only squeeze about another 50 percent from their cells – unlike the controls, who nearly doubled their output.
"The CFS cells couldn't produce as much energy as the control cells," says Tomas.
"At baseline, they didn't perform as well, but the maximum they could reach under any conditions was so much lower than the controls."
While the research focussed on just one type of cell, it is an important step towards establishing a link between the symptoms of muscle pain, lethargy, and impeded cognitive functions and a biochemical process.
There is still an incredible amount of work to be done in teasing apart the details on this disease, which tends to affect women more than men, and could strike up to 2.6 percent of the world's population.
There remains ongoing debate over whether CFS should include myalgic encephalomyelitis, or if they represent completely different conditions.
Two years ago a panel of experts from the US Institute of Medicine recommended a list of diagnostic markers for 'systemic exertion intolerance disease' (SEID), a term that has yet to take hold.
CFS is as complex as it is debilitating, whatever name it happens to go by. Having evidence-based ways to diagnose and treat the condition are well overdue.