People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have long struggled to have their symptoms taken seriously. Now, the largest molecular analysis of the disease to date has identified blood-based biomarkers linked directly to ME/CFS itself, not just to the reduced activity it causes.
“ME/CFS is an extraordinarily underserved disease,” said Chris Ponting, a bioinformatician at the University of Edinburgh and coauthor of the new study published in EMBO Molecular Medicine.
ME/CFS has no recognized biomarkers or diagnostic tests, and research into the condition has been dogged by enduring debates regarding the efficacy of existing treatments. One of these, graded exercise therapy (GET), supposed that gradually restoring the activity levels of people with ME/CFS would relieve their symptoms. GET trials have since been heavily criticized, and health bodies have discredited the treatment.
Growing evidence suggests the disease’s origin is not psychological, but underpowered and inconsistent prior research has impeded progress towards a biological explanation, said Ponting.
The new analysis examined data on 1,455 ME/CFS cases and 131,303 healthy volunteers from the vast UK Biobank biological data resource. The authors found 511 blood-based biomarkers that differed significantly between people with ME/CFS and healthy controls.
The associations identified were weak, which Ponting’s team predicted. “We did not expect to see clear blue water between cases and controls,” he said. “Rather, we wanted to see whether it might yet in the future be possible to make such a diagnostic panel.” The study identified changes indicating enhanced inflammation, insulin resistance, and liver damage in ME/CFS. Keith Geraghty, a health psychologist at the University of Manchester, said that this evidence paints a picture of ill health among patients. “It's a whole array of biological markers to show biological dysfunction in most systems in the body,” said Geraghty.
One of the study’s aims was to ascertain how exercise altered patients’ biomarkers. One defining trait of ME/CFS is a worsening of symptoms after exercise called post-exertional malaise (PEM). When the Biobank first collected data, PEM wasn’t recognized as a key ME/CFS symptom, meaning that roughly 45 percent of the patients in the study didn’t report PEM at the time their data was recorded. Ponting says this could reflect the “ebb and flow” of ME/CFS symptoms. Those who were currently experiencing PEM when their data were recorded showed the strongest alterations in their blood markers.
The Biobank cohort all answered questions about their activity level, which allowed the team to determine how exercise level mediated biomarkers. Some researchers, especially those in favor of GET, would predict that exercise is the key factor in patients’ altered blood. This isn’t what Ponting’s team found. “Essentially all of the traits were influenced from ME CFS status directly and not at all by activity,” he said.
The team found that 116 traits were altered in both male and female groups. This is an important finding, as women are more likely to be diagnosed with the condition in a ratio of at least three to one.
Even though the findings cannot explain this difference, Ponting said the results could have significant ramifications for future work. “If in the future there were to be a blood-based biomarker panel, at the moment we might expect it to work equally for females as for males,” he said.
While the study leaves many questions about this complex disease unanswered, Ponting is working on a much larger study involving 20,000 people with ME/CFS with a PEM diagnosis. Geraghty said that these projects are filling in the gaps in our understanding of ME/CFS, one by one. “We see a sort of picture developing, taking shape, but we don't have all the pieces,” said Geraghty. “But with some more pieces, and attaching more pieces to another, the picture will become clearer and clearer.”
