An overactive immune response appears to be a trigger for persistent fatigue, say researchers in a study that could shed light on the causes of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a debilitating long-term condition in which individuals experience exhaustion that is not helped by rest, as well as pain, mental fogginess and trouble with memory and sleep. It is also known as myalgic encephalomyelitis (ME).

Some studies into the condition have suggested the immune system could be involved, with viral infections one potential trigger for CFS.

“The evidence is largely inconclusive – there are studies which have shown elevated levels of the inflammatory markers, but such abnormalities are quite inconsistent across studies,” said Alice Russell, first author of the research from King’s College London.

Because it is not possible to predict who will get a virus, it is impossible to look at levels of biological molecules before, during and after a potential CFS “trigger” infection.

Experts say they have used a group of people with a different condition as a model to explore how immune response might be linked to persistent fatigue.

Writing in the journal Psychoneuroendocrinology, Russell and colleagues describe how they recruited 55 patients with a chronic hepatitis C infection. To treat the condition, all were given a six- to 12-month course of injections of interferon alpha, a protein that is produced naturally by the body and stimulates the white blood cells to provoke an immune response. The treatment has previously been linked to a side effect of ongoing fatigue in some patients.

While most patients recovered from hepatitis C, there was also an increase in fatigue during treatment, which reduced when the injections ended.

However, six months after treatment finished, 18 participants remained more fatigued than before treatment began. These patients had slightly higher levels of a protein linked to inflammation, called IL10, in their blood before treatment began, but, after four weeks of treatment, their levels of IL10 and another inflammatory protein called IL6 were twice as high as for those who recovered without persistent fatigue.

However, six months after the injections of interferon alpha stopped, there were no differences in the levels of the inflammation proteins between those with and without persistent fatigue. There was also no difference in history of depression, experience of a recent stressful life event or early life trauma.

For comparison, the team took one-off measurements of the same inflammation markers among 54 individuals who have had CFS for years and 57 healthy participants, but they found no difference in their levels.

Prof Carmine Pariante, a co-author of the study from King’s College London, said this showed that by the time ongoing fatigue was established, the immune activation was no longer present.

“It helps explain why we cannot find clear evidence of immune activation in patients with chronic fatigue syndrome,” he said. Pariante added the heightened immune response might trigger changes in the brain, muscles or metabolism that resulted in ongoing fatigue – although this is not yet clear – while genetics or repeated childhood infections might explain why only some people had a heightened immune response.

However, the study had a number of limitations: it is small, the hepatitis C patients were largely men and, by default, all had a serious condition which itself is more common in individuals with particular risk factors. In addition, the levels of interferon alpha given to participants was much higher than would naturally be produced in the body – and those with persistent fatigue were not diagnosed with CFS.

Michael Sharpe, professor of psychological medicine at the University of Oxford, said the study added another piece to the puzzle about what might kick off CFS. “It does seem that something to do with the immune system may be a triggering event, [but] it doesn’t actually tell us why, when that trigger seems to have gone away, the person stays fatigued,” he said.

Sharpe acknowledged the study did not shed light on how to treat established cases of CFS. “it may give us some clue down the line,” he said. “If the thing is triggered by an abnormal or excessive immune response, if we could find a way to reduce that immune response, we might stop incident cases.”

Dr Charles Shepherd, medical advisor at the ME Association, welcomed the study. “It adds to the growing weight of scientific evidence which indicates that the body’s immune system is playing an important role in the causation of CFS.”