After decades of searching, researchers have finally discovered distinct immune changes that occur during chronic fatigue syndrome, proving once and for all that it’s more than just “exhaustion” or a psychological condition.

This is the first robust evidence that the illness, which can leave people bed-ridden for months at a time, is a biological disorder with distinct stages - and it means we'll also be able to diagnose it earlier than ever before.

Just last month, the US took a big step forwards by classifying chronic fatigue as a disease, and renaming it ’system exertion intolerance disease’, or SEID.

Along with the name change, it also was given a strict set of symptoms that doctors could use to diagnose the disease. In other countries such as Australian and the UK, the condition is known medically as myalgic encephalomyelitis (ME). But despite these clinical labels, scientists have struggled to find any signature biological changes associated with the disease that they could test for.

So researchers from Columbia University’s Mailman School of Public Health decided to investigate. They analysed blood plasma of 298 patients with chronic fatigue, and compared it to 348 healthy controls. After adjusting for stress levels and known immune system influences, such as age and sex, the team found specific patterns in 51 immune biomarkers that are associated with the disease. Their results are published in Science Advances.

"We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn't psychological," the lead author of the study, Mady Hornig, said in a press release. "Our results should accelerate the process of establishing the diagnosis after individuals first fall ill as well as discovery of new treatment strategies focusing on these early blood markers."

Interestingly, they also found that there were unique patterns in patients who had had the condition for three years or less, which provides some insight into what causes the disease. These early patients had increased amounts of immune molecules called cytokines, in particular, cytokines called interferon gammas, which spike after many viral infections, including Epstein-Barr.

These results support the hypothesis that chronic fatigue is the result of a “hit-and-run” infection that has interrupted the immune system’s ability to balance itself. Essentially, it seems that the immune system gets stuck in "high gear".

"It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop," said Hornig in the release. "Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness."

In fact, there are already drugs that are known to dampen cytokine behaviour on the market, which could potentially be trialled against chronic fatigue in the future. The team is now hoping to publish the results of a second study they've been running, which is looking not just at the biological changes that occur alongside chronic fatigue, but also at the agents that cause these changes.

"This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease," the lead researcher on the second project, W. Ian Lipkin, said in the release. "The question we are trying to address in a parallel microbiome project is what triggers this dysfunction."